Headaches: Nonsurgical Management

Number: 0462

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses nonsurgical management of headaches.

  1. Medical Necessity

    Aetna considers the following nonsurgical interventions for headaches medically necessary when criteria are met:

    1. Intravenous (IV) administration of dihydroergotamine (DHE) medically necessary for the following indications:

      1. Treatment of status migrainosus (i.e., a debilitating migraine lasting more than 72 hours) in the emergency room, urgent care or hospital setting; or
      2. Treatment of other intractable severe migraine attacks that are unresponsive to analgesics and triptans (e.g., Almotriptan, Amerge, Axert, Frova, Imitrex, Imitrex nasal spray, Maxalt, Maxalt MLT, Onzetra Xsail, Relpax, Sumavel, Treximet, zolmitriptan, zolmitriptan ODT, Zomig, and Zomig ZMT) in the emergency room, hospital or urgent care setting; or
      3. Treatment of cluster headache attacks that do not respond to oxygen or triptans in the emergency room, hospital, or urgent care setting; or
      4. Treatment of medication overuse headache in the inpatient setting.
    2. Intramuscular (IM) ketorolac tromethamine (Toradol) for the short-term (less than or equal to 5 days) management of acute migraine.
    3. Eptinezumab-jjmr (Vyepti) for the preventive treatment of migraine in an adult member when the criteria are met. See CPB 0970 Eptinezumab-jjmr (Vyepti) for coverage criteria for Vyepti.
    4. Intramuscular (IM) and intravenous (IV) steroids for the treatment of acute migraines.
    5. Caffeine citrate infusion for the treatment of post lumbar puncture headache when the member is unable to take caffeine orally.

  2. Experimental and Investigational

    Aetna considers the following nonsurgical interventions for headaches experimental and investigational because the effectiveness of these approaches has not been established:

    1. Intravenous (IV) DHE for all other types of headache not included in Section I;
    2. Intravenous (IV) DHE for members with inadequately controlled intermittent migraine attacks who do not have an active, prolonged, and debilitating (i.e., lasting more than 72 hours) headache at the time of admission;
    3. Measurement of serum and/or cerebrospinal fluid (CSF) levels of tumor necrosis factor-alpha for intractable migraine or cluster headache;
    4. The following interventions for the management of members with migraines (not an all-inclusive list):

      1. Cefaly migraine headband
      2. Chemodenervation with P2G (phenol-glycerine-glucose) for migraine prophylaxis
      3. Greater occipital nerve block
      4. Intramuscular bupivacaine
      5. Intramuscular ketamine
      6. Intramuscular magnesium
      7. Intramuscular nalbuphine or other opioid agonist-antagonists
      8. Intranasal ketamine
      9. Intranasal lidocaine
      10. Intrathecal dilaudid or hydromorphone
      11. Intravenous aspirin (lysine acetylsalicylate)
      12. Intravenous ketamine
      13. Intravenous lidocaine
      14. Intravenous magnesium
      15. Intravenous nalbuphine or other opioid agonist-antagonists
      16. Intravenous propofol
      17. Intravenous valproic acid (Depacon)
      18. Lidocaine injections into the supraorbital nerve and supratrochlear nerve, supraorbital nerve and supratrochlear nerve blocks
      19. Manual trigger points treatment
      20. Melantonin (for prophylaxis of migraine)
      21. Memantine (for prophylaxis of migraine)
      22. Nerivio (remote electrical neuromodulation [REN])
      23. Occipital nerve stimulation
      24. Orally inhaled DHE
      25. Oral magnesium
      26. Spheno-palatine ganglion stimulation
      27. Supraorbital transcutaneous stimulation (for migraines and other types of headaches)
      28. Transcranial magnetic stimulation (e.g., SpringTMS)
      29. Tx360 nasal applicator (spheno-palatine ganglion blockade);

    5. The following interventions for the treatment of cluster headache (not an all-inclusive list):

      1. Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies eptinezumab, erenumab, and fremanezumab
      2. Blockade / stimulation of the sphenopalatine ganglion and its branches
      3. Greater occipital nerve block
      4. Ketamine infusion combined with magnesium
      5. Ketogenic diet
      6. Manual trigger points treatment
      7. Melatonin
      8. Onabotulinum toxin A
      9. Percutaneous bioelectric current stimulation
      10. Sodium oxybate
      11. Sphenopalatine ganglion stimulation;
    6. Photo-biomodulation, and the Reed procedure (combined occipital and supraorbital neurostimulation) for the treatment of chronic headaches (e.g., cluster, migraine, and tension headaches);
    7. Combination benztropine mesylate (Cogentin) / diphenhydramine (Benadryl) / promethazine HCl (Phenergan) cocktail with intravenous haloperidol (Haldol) or droperidol (Inapsine) infusion for the treatment of status migrainosus because the effectiveness of this combination for this indication has not been established;
    8. Epidural steroid injection, and radiofrequency ablation for the treatment of cervicogenic headache and neck pain.

  3. Related Policies

    See Commercial Pharmacy CPB on Calcitonin Gene-related Peptide (CGRP) Receptor Antagonists for selection criteria.

    See also:

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Other CPT codes related to the CPB:
96365 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

Intravenous administration of dihydroergotamine (DHE):

HCPCS codes covered if selection criteria are met:
J1110 Injection, dihydroergotamine mesylate, per 1 mg

ICD-10 codes covered if selection criteria are met:
G43.001, G43.011 - G43.019, G43.101, G43.111 - G43.119, G43.401, G43.411 - G43.419, G43.501, G43.511 - G43.519, G43.601, G43.611 - G43.619, G43.701, G43.711 - G43.719, G43.A1, G43.B1, G43.C1, G43.D1, G43.801, G43.811 - G43.819, G43.821, G43.831 - G43.839, G43.901, G43.911 - G43.919 Migraine with status migrainosus and/or intractable
G44.001 - G44.029 Cluster headaches
G44.41 Drug-induced headache, not elsewhere classified, intractable [medication overuse headache]

ICD-10 codes not covered for indications listed in the CPB:
G43.009, G43.109, G43.409, G43.509, G43.609, G43.709, G43.B0, G43.C0, G43.C1, G43.809, G43.829, G43.909 Migraine without status migrainosus and not intractable
G44.031 - G44.89 Other headache syndromes [except cluster]
R51 Headache

Intramuscular (IM) ketorolac tromethamine (Toradol):

HCPCS codes covered if selection criteria are met:
J1885 Injection, ketorolac tromethamine, per 15 mg

ICD-10 codes covered if selection criteria are met:
G43.001 - G43.619, G43.B0 - G43.B1, G43.801 - G43.919 Migraine without aura, migraine with aura, hemiplegic migraine, Persistent migraine aura without cerebral infarction, Persistent migraine aura with cerebral infarction, Ophthalmoplegic migraine, Other migraine, Menstrual migraine, or Migraine, unspecified [acute]

ICD-10 codes not covered for indications listed in the CPB:
G43.701 - G43.719 Chronic migraine

Eptinezumab-jjmr (Vyepti):

HCPCS codes covered if selection criteria are met:
J3032 Injection, eptinezumab-jjmr, 1 mg

ICD-10 codes covered if selection criteria are met:
G43.001 - G43.919 Migraine

Intramuscular (IM) and intravenous (IV) steroids:

HCPCS codes covered if selection criteria are met::
J0702 Injection, betamethasone acetate 3mg and betamethasone sodium phosphate 3mg
J1020 Injection, methylprednisolone acetate, 20 mg
J1030 Injection, methylprednisolone acetate, 40 mg
J1040 Injection, methylprednisolone acetate, 80 mg
J1094 Injection, dexamethasone acetate, 1 mg
J1100 Injection, dexamethasone sodium phosphate, 1 mg
J1700 Injection, hydrocortisone acetate, up to 25 mg
J1710 Injection, hydrocortisone sodium phosphate, up to 50 mg
J1720 Injection, hydrocortisone sodium succinate, up to 100 mg
J2650 Injection, prednisolone acetate, up to 1 ml
J2920 Injection, methylprednisolone sodium succinate, up to 40 mg
J2930 Injection, methylprednisolone sodium succinate, up to 125 mg
J3300 - J3303 Injection, triamcinolone
J3475 Injection, magnesium sulfate, per 500 mg
J7312 Injection, dexamethasone, intravitreal implant, 0.1 mg

ICD-10 codes covered if selection criteria are met:
G43.001 - G43.919 Migraine

Caffeine citrate infusion for the post lumbar puncture headache:

HCPCS codes covered if selection criteria are met:
J0706 Injection, caffeine citrate, 5 mg

ICD-10 codes covered if selection criteria are met:
G97.1 Other reaction to spinal and lumbar puncture

Interventions considered experimental and investigational for migraines and cluster headaches:

CPT codes not covered for indications listed in the CPB:
64405 Injection(s), anesthetic agent(s) and/or steroid; greater occipital nerve
83520 Immunoassay for analyte other than infectious agent antibody or infectious agent antigen, quantitative; not otherwise specified [measurement of serum and/or cerebrospinal fluid levels of tumor necrosis factor-alpha]
97140 Manual therapy techniques (eg, mobilization/ manipulation, manual lymphatic drainage, manual traction), 1 or more regions, each 15 minutes [manual trigger points treatment]

HCPCS codes not covered for indications listed in the CPB:

Melatonin - no specific code:

ICD-10 codes not covered for indications listed in the CPB:
G43.001 - G43.919 Migraine
G44.001 - G44.029 Cluster headaches

Interventions considered experimental and investigational for migraines:

CPT codes not covered for indications listed in the CPB:
64400 Injection, anesthetic agent; trigeminal nerve, any division or branch[supraorbital and supratrochlear nerves]
64505 Injection, anesthetic agent; sphenopalatine ganglion [with Tx360 nasal applicator]
90867 - 90869 Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment

HCPCS codes not covered for indications listed in the CPB:
Cefaly Migraine Headband, NAS, IV and IM ketamine, IV valproic acid (Depacon), Memantine, orally inhaled DHE, oral magnesium, Chemodenervation with P2G (phenol-glycerine-glucose)) - no specific code:
A4540 Distal transcutaneous electrical nerve stimulator, stimulates peripheral nerves of the upper arm
C9290 Injection, bupivacaine liposome, 1 mg
J1170 Injection, hydromorphone, up to 4 mg
J2001 Injection lidocaine HCL for intravenous infusion, 10 mg [intravenous or intranasal administration]
J2300 Injection, nalbuphine HCl, per 10 mg
J2704 Injection, propofol, 10 mg
J7509 Methylprednisolone, oral, per 4 mg
J7512 Prednisone, immediate release or delayed release, oral, 1 mg

ICD-10 codes not covered for indications listed in the CPB:
G43.001 - G43.919 Migraine

Interventions considered experimental and investigational for cluster headaches:

CPT codes not covered for indications listed in the CPB:
Ketogenic diet, Percutaneous bioelectric current stimulation –no specific code

HCPCS codes not covered for indications listed in the CPB:

Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (e.g., eptinezumab, erenumab, fremanezumab, and galcanezumab), ketamine infusion combined with magnesium, Sodium oxybate - no specific code :
J0585 Injection, onabotulinumtoxina, 1 unit

ICD-10 codes not covered for indications listed in the CPB:
G44.001 - G44.029 Cluster headaches

Reed procedure (combined occipital and supraorbital neurostimulation):

CPT codes not covered for indications listed in the CPB:

Reed procedure (combined occipital and supraorbital neurostimulation), Photo-biomodulation - no specific code :

ICD-10 codes not covered for indications listed in the CPB:
G43.701 - G43.719 Chronic migraine headache
G44.021 - G44.029 Chronic cluster headache
G44.221 - G44.229 Chronic tension-type headache
G44.321 - G44.329 Chronic post-traumatic headache
R51 Headache

Combination benztropine mesylate (Cogentin) / diphenhydramine (Benadryl) / promethazine HCl (Phenergan) cocktail with intravenous haloperidol (Haldol) or droperidol (Inapsine) infusion:

HCPCS codes not covered for indications listed in the CPB:
J0515 Injection, benztropine mesylate, per 1 mg
J1200 Injection, diphenhydramine hcl, up to 50 mg
J1630 Injection, haloperidol, up to 5 mg
J1631 Injection, haloperidol decanoate, per 50 mg
J1790 Injection, droperidol, up to 5 mg
J2550 Injection, promethazine hcl, up to 50 mg
J2950 Injection, promazine hcl, up to 25 mg
Q0163 Diphenhydramine hydrochloride, 50 mg, oral, fda approved prescription anti-emetic, for use as a complete therapeutic substitute for an iv anti-emetic at time of chemotherapy treatment not to exceed a 48 hour dosage regimen
Q0169 Promethazine hydrochloride, 12.5 mg, oral, fda approved prescription anti-emetic, for use as a complete therapeutic substitute for an iv anti-emetic at the time of chemotherapy treatment, not to exceed a 48 hour dosage regimen

ICD-10 codes not covered for indications listed in the CPB:
G43.001, G43.011, G43.101, G43.111, G43.401, G43.411, G43.501, G43.511, G43.601, G43.611, G43.701, G43.711, G43.801, G43.811, G43.821, G43.831, G43.901, G43.911 Status migrainosus

Epidural steroid injection and radiofrequency ablation:

CPT codes not covered for indications listed in the CPB:
Radiofrequency ablation for the treatment of cervicogenic headache and neck pain –no specific code
64479 Injection(s), anesthetic agent(s) and/or steroid; transforaminal epidural, with imaging guidance (fluoroscopy or CT), cervical or thoracic, single level
64480      transforaminal epidural, with imaging guidance (fluoroscopy or CT), cervical or thoracic, each additional level (List separately in addition to code for primary procedure
64483      transforaminal epidural, with imaging guidance (fluoroscopy or CT), lumbar or sacral, single level
64484      transforaminal epidural, with imaging guidance (fluoroscopy or CT), lumbar or sacral, each additional level (List separately in addition to code for primary procedure)

ICD-10 codes not covered for indications listed in the CPB:
G44.86 Cervicogenic headache
M54.2 Cervicalgia

Background

Migraine is a paroxysmal disorder with attacks of headache, nausea, vomiting, photo- and phonophobia and malaise.  Cluster headaches occur as a severe, sudden headache typified by constant, unilateral pain around the eye, with onset usually within 2-3 hours of falling asleep.  Pharmacologic symptomatic treatment is aimed at reversing, aborting, or reducing pain and the accompanying symptoms of an attack, and to optimize the patient's ability to function normally.

Subcutaneous, intramuscular, and intravenous dihydroergotamine (DHE) can be safely administered in the office, clinic, or emergency room setting at any time during a migraine attack, including the aura.  Intravenous administration provides rapid peak plasma levels and is the most effective form when a rapid effect is desired or for patients with intractable severe headache (status migrainosus, transformed migraine, rebound headache) and cluster headache.  One of the most appropriate indications for intravenous DHE is status migrainosus.  Another important indication of repetitive intravenous DHE administration is a transformed migraine type of chronic daily headache with or without analgesic overuse.  Intramuscular administration is effective for moderate to severe migraine with or without nausea and vomiting in the outpatient setting.  Patients can even be taught to self-administer DHE intramuscularly, thus avoiding emergency room or doctor visits.

For unresponsive patients with severe or ultra-severe attacks, intravenous (IV) prochlorperazine (5 to 10 mg) may be administered in the emergency room, followed immediately by 0.75 mg DHE IV given over 3 minutes.  If there is no relief in 30 mins, another 0.5 mg of DHE IV may be given.  Overall clinical efficacy of DHE is highly satisfactory with a reported 90 % of the attacks aborted when the drug was given intravenously.  Occasionally, intravenous fluids and repeated injections of intravenous DHE for about 24 to 72 hours may be necessary to relieve uncontrollable pain.  Hospitalization may be necessary for such prolonged multi-day administration, but only after maximal treatment in the outpatient setting fails to abort the headache.  Various protocols are available for the use of repetitive injections of DHE.  In all of them, an initial test dose of 0.33 mg of DHE plus 5 mg of metoclopramide or prochlorperazine is given, followed by 0.50 mg of DHE with either of the 2 anti-emetics every 6 hours for 48 to 72 hours.  Such therapy allows a break in the headache cycle sufficiently long enough to facilitate the patient's transition to prophylactic therapy.

According to the Food and Drug Administration (FDA)-approved product labeling, DHE-45 administration is contraindicated in any of the following patients:

  1. Nursing mothers; or
  2. Persons having conditions predisposing to vasospastic reactions such as known peripheral arterial disease, coronary artery disease (in particular, unstable or Prinzmetal's vasospastic angina), sepsis, vascular surgery, uncontrolled hypertension, and severely impaired hepatic or renal function; or
  3. Persons on vasoconstrictors because the combination may result in extreme elevation of blood pressure; or
  4. Persons with hemiplegic or basilar migraine; or
  5. Persons with previously known hypersensitivity to ergot alkaloids; or
  6. Pregnant women, as DHE possesses oxytocic properties.

Fisher et al (2007) evaluated the effectiveness and tolerability of DHE nasal spray for the treatment of headache that is refractory to triptans.  Patients who failed previous treatments with 1 or more triptan formulations were considered refractory to triptan treatment and were included in the study.  Headache severity was assessed by the patient at the center using a visual analog scale (VAS) of 1 to 10 (10 being most severe) at baseline and 4 weeks after initiating DHE.  The responses to DHE were assessed and categorized as complete response (headache symptoms resolved), partial response (greater than or equal to 50 % reduction in VAS), or unresponsive (less than 50 % reduction in VAS).  Four weeks after DHE use, any adverse event (AE) that occurred during DHE use was reported by the patient at the center.  The effectiveness of DHE was determined by headache severity reductions.  Tolerability was assessed in terms of AE frequency.  A total of 97 patients met the study criteria: 13 patients were lost to follow-up; 33 patients (34.0 %) reported a complete response to DHE treatment, 13 (13.4 %) experienced a partial response, and 38 (39.2 %) were unresponsive.  Seven of 97 patients (7.2 %) reported AEs (e.g., nasal congestion, dysphoria) while using DHE.  The authors noted that this retrospective chart review included patients who failed triptan therapy for treatment of headaches.  They reported that 47 % of patients experienced partial to complete response to DHE treatment.  Study limitations included the retrospective design, the small sample size, and the use of patient recollection to evaluate the effectiveness and tolerability of DHE.  They stated that randomized, double-blind, controlled studies are needed to ascertain the clinical value of this approach.  This is in agreement with the findings of a pilot study by Weintraub (2006) who reported that repetitive intra-nasal DHEmay be a safe and effective therapy for refractory headaches.  However, interpretation of these results is limited by the open-label, uncontrolled design and the small number of patients.  The author stated that development of a double-blind, placebo-controlled study to further evaluate this treatment regimen is warranted.

Migraine without aura is a complex genetic disease in which susceptibility and environmental factors contribute towards its development.  Several studies suggested that tumor necrosis factors (TNF) (TNF-alpha and lymphotoxin-alpha or TNF-ss) may be involved in the pathophysiology of migraine.  In a case-control study, Asuni et al (2009) evaluated the possibility of an association between TNF gene polymorphisms and migraine without aura.  These researchers examined 299 patients affected by migraine without aura (I.H.S. criteria 2004) and 278 migraine-free controls.  The polymorphisms G308A of the TNF- alpha gene, and G252A of TNF-beta gene were determined by NcoI restriction fragment length polymorphism analysis.  These investigators found a statistically significant difference in allele (p = 0.018; odds ratio [OR] = 1.46; 95 % confidence interval [CI]: 1.066 to 2.023) and genotype (trend chi2 = 5.46, df = 1, p = 0.019) frequencies of TNF-beta gene, between cases and controls.  Allele and genotype frequencies of TNF-alpha polymorphism did not differ significantly between the 2 groups.  These data suggested that subjects with the TNFB2 allele have a low-risk of developing migraine without aura and/or that the polymorphism of the TNF-beta gene is in linkage disequilibrium with other migraine responsible genes in the HLA region.

Measurement of TNF-alpha is an indicator of persistent systemic infection or inflammation.  It has been observed that new daily persistent headache (NDPH) may occur following infection and is one of the most treatment-resistant headache types.  A number of investigators have evaluated TNF-alpha levels in serum and cerebro-spinal fluid (CSF) in patients with NDPH, chronic migraine or post-traumatic headache.  These studies have found elevated CSF TNF-alpha levels in persons with these headaches.  The results from these studies suggested that elevated levels of CSF TNF-alpha may play a role in the pathogenesis of migraine and other chronic headaches.  These studies might also suggest that elevated CSF TNF-alpha may be an indicator of refractory headaches.  The studies suggested that TNF-alpha inhibitors may have a therapeutic role in treating patients with migraine and other types of headache (Perini et al, 2005; Rozen and Swidan, 2007; Bo et al, 2009).  However, there are no prospective clinical studies demonstrating the clinical utility of TNF-alpha measurement in migraine or other headache disorders.  Additional studies are needed to further investigate the relationship of CSF TNF-alpha levels in subjects with various types of chronic headache.

Schurks (2009) assessed the modes of administration, effectiveness and safety profile of DHE in the treatment of migraine.  Evidence-based data are scarce.  Parenteral DHE appears to be as effective as or less effective than triptans with regard to pain control, but more effective than other drugs used in the treatment of attacks.  The nasal spray is more effective than placebo, but less effective than triptans.  Additional reports suggest that DHE is especially beneficial in migraine patients not satisfactorily responding to analgesics, in those with long attacks or headache recurrence, and those at risk of medication-overuse headache.  The author noted that the effectiveness of the oral formulation in migraine prevention is not substantiated by clinical trials.

Management of headaches is not an FDA-approved indication for aspirin (lysine acetylsalicylate).  Weatherall et al (2010) stated that intravenous (IV) aspirin has been shown to be effective in the treatment of acute migraine attacks, but little is known about its effectiveness and safety in patients hospitalized for management of severe headache, typically arising from abrupt withdrawal of other acute attack medications.  These investigators presented an audit of their use of IV aspirin in 168 patients in a tertiary referral setting.  The findings demonstrated subjective approval of this medication by the patients and objective improvements in pain scores, a decrease of greater than or equal to 3 points on a 10-point VAS being seen on greater than 25 % occasions on which the medication was administered.  Further, side effect rates were low (5.9 %), with no serious adverse events.  The authors concluded that IV aspirin is safe, effective, and useful in the inpatient management of headache.  The drawbacks of this study were its uncontrolled, retrospective nature and the results were confounded by the fact that many subjects received more than 1 medication.  The findings of this small study need to be validated by well-designed studies. 

In a randomized, double-blind, placebo-controlled cross-over study, Alstadhaug et al (2010) examined the effects of melantonin as a prophylaxis.  Men and women, aged 18 to 65 years, with migraine but otherwise healthy, experiencing 2 to 7 attacks per month, were recruited from the general population.  After a 4-week run-in phase, 48 subjects were randomized to receive either placebo or extended-release melatonin (Circadin®, Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) at a dose of 2-mg 1 hour before bedtime for 8 weeks.  After a 6-week washout treatment was switched.  The primary outcome was migraine attack frequency (AF).  A secondary end point was sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI).  A total of 46 subjects completed the study (96 %).  During the run-in phase, the average AF was 4.2 (+/- 1.2) per month and during melatonin treatment the AF was 2.8 (+/- 1.6).  However, the reduction in AF during placebo was almost equal (p = 0.497).  Absolute risk reduction was 3 % (95 % CI: -15 to 21, number needed to treat = 33).  A highly significant time effect was found.  The mean global PSQI score did not improve during treatment (p = 0.09).  The authors concluded that these findings provided evidence that prolonged-release melatonin (2-mg 1 hour before bedtime) does not provide any significant effect over placebo as migraine prophylaxis; thus, such treatment can not be recommended.

Aurora and associates (2011) evaluated the tolerability and effectiveness of MAP0004 (an orally inhaled formulation of DHE delivered to the systemic circulation) compared with placebo for a single migraine in adult migraineurs.  MAP0004 provided significant early onset of pain relief (10 mins, p < 0.05) and sustained pain relief for up to 48 hours with a favorable adverse event profile.  This study was conducted at 102 sites in 903 adults with a history of episodic migraine.  Patients were randomized (1:1) to receive MAP0004 (0.63-mg emitted dose; 1.0-mg nominal dose) or placebo, administered after onset of a migraine headache with moderate to severe pain.  The co-primary end points were patient-assessed pain relief and absence of photophobia, phonophobia, and nausea at 2 hours after treatment.  A total of 903 patients (450 active, 453 placebo) were randomized, and 792 (395 active, 397 placebo) experienced a qualifying migraine.  MAP0004 was superior to placebo in all 4 co-primary end points: pain relief (58.7 % versus 34.5 %, p < 0.0001), phonophobia-free (52.9 % versus 33.8 %, p < 0.0001), photophobia-free (46.6 % versus 27.2 %, p < 0.0001), and nausea-free (67.1 % versus 58.7 %, p = 0.0210).  Additionally, significantly more patients were pain-free at 2 hours following treatment with MAP0004 than with placebo (28.4 % versus 10.1 %, p < 0.0001).  MAP0004 was well-tolerated; no drug-related serious adverse events occurred.  The authors concluded that MAP0004 was effective and well-tolerated for the acute treatment of migraine with or without aura, providing statistically significant pain relief and freedom from photophobia, phonophobia, and nausea in adults with migraine compared with placebo.

Baron and Tepper (2010) noted that triptans are very effective for many migraineurs, and since their widespread use, use of ergots has significantly declined.  Unfortunately, there remain many migraineurs who benefit little from triptans, yet respond very well to ergots.  Ergots interact with a broader spectrum of receptors than triptans.  This lack of receptor specificity explains potential ergot side effects, but may also account for efficacy.  The authors stated that the role of ergots in headache should be revisited, especially in view of newer ergot formulations with improved tolerability and side effect profiles, such as orally inhaled DHE.  They noted that re-defining where in the headache treatment spectrum ergots belong and deciding when they may be the optimal choice of treatment is necessary.  Additionally, in a review new drugs and new approaches for acute migraine therapy, Monteith and Goadsby (2011) stated that current pharmacotherapies of acute migraine consist of non-specific and relatively specific agents.  Migraine-specific drugs comprise 2 classes: the ergot alkaloid derivatives and the triptans, serotonin 5-HT(1B/1D) receptor agonists.  The ergots, consisting of ergotamine and DHE, are the oldest specific anti-migraine drugs available and are considered relatively safe and effective.  Ergotamine has been used less extensively because of its adverse effects; DHE is better tolerated.  The triptan era, beginning in the 1990s, was a period of considerable change, although these medicines retained vasoconstrictor actions.  New methods of delivering older drugs include orally inhaled DHE as well as the trans-dermal formulation of sumatriptan, both currently under study.  Furthermore, orally inhaled formulation DHE for the treatment of migraine has not received FDA approval yet.

In a prospective observational study, Bond et al (2011) examined whether weight loss after bariatric surgery is associated with improvements in migraine headaches.  A total of 24 patients who had migraine according to the ID-Migraine screener were assessed before and 6 months after bariatric surgery.  At both time points, patients had their weight measured and reported on frequency of headache days, average headache pain severity, and headache-related disability over the past 90 days via the Migraine Disability Assessment questionnaire.  Changes in headache measures and the relation of weight loss to these changes were assessed using paired-sample t tests and logistic regression, respectively.  Patients were mostly female (88 %), middle-aged (mean age of 39.3 years), and severely obese (mean body mass index of 46.6) at baseline.  Mean (+/- SD) number of headache days was reduced from 11.1 +/- 10.3 pre-operatively to 6.7 +/- 8.2 post-operatively (p < 0.05), after a mean percent excess weight loss (% EWL) of 49.4 %.  The odds of experiencing a greater than or equal to 50 % reduction in headache days was related to greater % EWL, independent of surgery type (p < 0.05).  Reductions in severity were also observed (p < 0.05) and the number of patients reporting moderate to severe disability decreased from 12 (50.0 %) before surgery to 3 (12.5 %) after surgery (p < 0.01).  The authors occluded that severely obese migraineurs experience marked alleviation of headaches after significant weight reduction via bariatric surgery.  However, they stated that more studies are needed to examine if more modest, behaviorally produced weight losses can effect similar migraine improvements.  The findings of this small, retrospective, uncontrolled study need to be confirmed by randomized controlled trials.  Furthermore, it would be interesting to ascertain if there is a dose-response relationship (i.e., if greater weight loss would lead to greater improvement of migraine headaches).

Posadzki and Ernst (2011) evaluated the effectiveness of spinal manipulations as a treatment for migraine headaches.  A total of 7 databases were searched from inception to November 2010.  All randomized clinical trials (RCTs) investigating spinal manipulations performed by any type of healthcare professional for treating migraine headaches in human subjects were considered.  The selection of studies, data extraction and validation were performed independently by 2 reviewers.  A total of 3 RCTs met the inclusion criteria.  Their methodological quality was mostly poor and ranged between 1 and 3 on the Jadad scale.  Two RCTs suggested no effect of spinal manipulations in terms of Headache Index or migraine duration and disability compared with drug therapy, spinal manipulation plus drug therapy, or mobilization.  One RCT showed significant improvements in migraine frequency, intensity, duration and disability associated with migraine compared with detuned interferential therapy.  The most rigorous RCT demonstrated no effect of chiropractic spinal manipulation compared with mobilization or spinal manipulation by medical practitioner or physiotherapist on migraine duration or disability.  The authors concluded that current evidence does not support the use of spinal manipulations for the treatment for migraine headaches.

Khatami et al (2011) stated that cluster headache (CH) manifests with periodic attacks of severe unilateral pain and autonomic symptoms.  Nocturnal attacks may cause severe sleep disruption.  In about 10 % of cases, patients present with a chronic CH (CCH), which is often medically intractable.  Few attempts have been made to improve headache via pharmacological modulation of sleep.  In an open-label study, 4 patients with CCH and disturbed sleep received increasing dosages of sodium oxybate (SO), a compound known to consolidate sleep and to increase slow-wave sleep.  Response to SO was monitored by serial polysomnography, and actimetry, along with pain and sleep diaries.  Sodium oxybate was effective in all 4 patients as shown by an immediate reduction in frequency (up to 90 %) and intensity (greater than 50 %) of nocturnal pain attacks and improved sleep quality.  These effects were long-lasting in 3 patients (mean 19 months, range of 12 to 29 months) and transient (for 8 months) in 1 patient.  Long-lasting improvement of daytime headaches was achieved with a latency of weeks in 2 patients.  Sodium oxybate was safe, with mild-to-moderate adverse effects (e.g., amnesia, dizziness, vomiting, and weight loss).  The authors concluded that SO may represent a new treatment option to reduce nocturnal and diurnal pain attacks and improve sleep quality in CCH.  This study provides Class IV evidence that oral SO at night improves sleep and reduces the intensity and frequency of headaches in patients with CCH.  Drawbacks of this study included;
  1. open-label study with small number of subjects (n = 4),
  2. study was not placebo-controlled,
  3. SO did not completely eliminate headaches, and effects on daytime headaches were delayed and less sustained, and
  4. some adverse events needed long-term supervision and symptomatic treatments.
Well-designed studies are needed to confirm the effectiveness of SO in the treatment of CCH.

The updated evidence-based guidelines on "Pharmacologic treatments and NSAIDs and other complementary treatments for episodic migraine prevention in adults" of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society (Silberstein et al, 2012) states that "Data from older studies regarding verapamil and nimodipine are insufficient when current AAN classification criteria are applied .... Evidence is conflicting or inadequate to support or refute the use of nicardipine, nimodipine, or verapamil for migraine prevention".

In a single-blinded, randomized trial, Bell et al (1990) evaluated the relative effectiveness of 3 non-narcotic agents, chloropromazine, lidocaine, and dihydroergotamine, in the treatment of migraine headache in an emergency department setting.  All patients had an isolated diagnosis of common or classic migraine.  Patients were pre-treated with 500 ml intravenous (IV) normal saline before randomization.  Study drugs as administered were dihydroergotamine 1 mg IV repeated after 30 minutes if the initial response was inadequate; lidocaine 50 mg IV at 20-minute intervals to a maximum total dose of 150 mg as required; or chloropromazine 12.5 mg IV repeated at 20-minute intervals to a total maximum dose of 37.5 mg as required.  Patients were asked to grade headache severity on a 10-point scale before and 1 hour after the initiation of therapy.  Follow-up by phone was sought the following day.  Of 76 patients completing the trial, 24 were randomized to receive chloropromazine, 26 to receive dihydroergotamine, and 26 to receive lidocaine.  Reduction in mean headache intensity was significantly better among those treated with chloropromazine (p < 0 .005).  Persistent headache relief was experienced by 16 of the chloropromazine-treated patients (88.9 %) contacted at 12 to 24 hours follow-up compared with 10 of the dihydroergotamine-treated patients (52.6 %) and 5 of the lidocaine-treated group (29.4 %).  The authors concluded that the relative effectiveness of these 3 anti-migraine therapies appears to favor chloropromazine in measures of headache relief, incidence of headache rebound, and patient satisfaction with therapy.

Reutens et al (1991) performed a prospective, randomized, double-blind, placebo-controlled trial of IV lidocaine (1 mg/kg) in the treatment of acute migraine.  A total of 13 subjects were randomly allocated to receive IV lidocaine; while 12 control subjects received IV normal saline.   Subjects scored the intensity of headache and nausea on separate VAS before the injection and at 10 and 20 mins after injection.  At 20 mins, the mean pain intensity score was 80 % of initial intensity in the lidocaine group and 82 % in the placebo group.  The difference was not statistically significant; at 20 mins, the 95 % CI for the difference between the 2 groups in mean percentage of initial pain score was 2 +/- 29 %.  At the dose studied, IV lidocaine has, at best, only a modest effect in acute migraine.

In a double-blind, randomized, controlled trial, Afridi et al (2013) tested the hypothesis that intranasal ketamine would affect migraine with prolonged aura.  These researchers examined the effect of 25-mg intranasal ketamine on migraine with prolonged aura in 30 migraineurs using 2-mg intranasal midazolam as an active control.  Each subject recorded data from 3 episodes of migraine.  A total of 18 subjects completed the study.  Ketamine reduced the severity (p = 0.032) but not duration of aura in this group, whereas midazolam had no effect.  The authors concluded that these data provided translational evidence for the potential importance of glutamatergic mechanisms in migraine aura and offer a pharmacologic parallel between animal experimental work on cortical spreading depression and the clinical problem.  Drawbacks of this study included small number of patients and the design of the study did not exclude an effect of midazolam.  These findings need to be validate by well-designed studies with more patients, higher doses of ketamine and subjects with more migraine attacks.  The authors stated that their study does not endorse the widespread use of ketamine in migraine aura.

Dimitriou et al (2002) evaluated the effectiveness of the blockade of branches of ophthalmic nerve in the management of the acute attack of migraine headache localized to the ocular region.  The study included 70 female patients aged 23 to 60 years who presented to the pain clinic at our hospital with an acute attack of migraine headache localized to the ocular and retro-ocular region.  A targeted history and a neurologic examination were performed in all patients to confirm the diagnosis and at the same time to rule out life-threatening neurological dysfunction.  The method applied was the blockade of the supra-orbital and supra-trochlear nerves which are branches of the ophthalmic nerve.  By the use of a fine short needle 27G the nerves were sought for until paraesthesia is obtained and then 1 ml of lignocaine 2 % with adrenaline 1:200,000 was injected in every 1 of the 3 sites of the nerves.  The migraine acute attack was relieved in 58/70 patients (82 %), while in 12/70 patients (18 %) the results were poor.  The pain relief started 3 to 4 mins after the injection and was completed in 10 to 15 mins.  The authors concluded that these findings supported that the blockade of the branches of the ophthalmic nerve seems to be a safe and effective technique in the management of the acute attack of migraine localized to the ocular and retro-ocular region.  The main drawback of this study was the lack of a control group.  Furthermore, UpToDate reviews on "Acute treatment of migraine in adults" (Bajwa and Sabahat, 2013a) and "Preventive treatment of migraine in adults" (Bajwa and Sabahat, 2013b) do not mention the use of lidocaine injection as a therapeutic option.

In a double-blinded, randomized, sham-controlled trial, Schoenen and colleagues (2013) evaluated the safety and effectiveness of trigeminal neurostimulation with a supraorbital transcutaneous stimulator (Cefaly, STX-Med., Herstal, Belgium) in migraine prevention.  After a 1-month run-in, patients with at least 2 migraine attacks/month were randomized 1:1 to verum or sham stimulation, and applied the stimulator daily for 20 minutes during 3 months.  Primary outcome measures were change in monthly migraine days and 50 % responder rate.  A total of 67 patients were randomized and included in the intention-to-treat analysis.  Between run-in and third month of treatment, the mean number of migraine days decreased significantly in the verum (6.94 versus 4.88; p = 0.023), but not in the sham group (6.54 versus 6.22; p = 0.608).  The 50 % responder rate was significantly greater (p = 0.023) in the verum (38.1 %) than in the sham group (12.1 %).  Monthly migraine attacks (p = 0.044), monthly headache days (p = 0.041), and monthly acute anti-migraine drug intake (p = 0.007) were also significantly reduced in the verum but not in the sham group.  There were no adverse events in either group.  The authors concluded that supraorbital transcutaneous stimulation with the device used in this trial is effective and safe as a preventive therapy for migraine.  The therapeutic gain (26 %) is within the range of those reported for other preventive drug and non-drug anti-migraine treatments.  Drawbacks of this study included
  1. partial unblinding may have occurred in this trial, and
  2. patients in the verum group were on average younger than those in the sham group and the duration of their migraine was somewhat shorter, and
  3. it is unclear whether supraorbital transcutaneous stimulation is effective in patients with more frequent attacks or with chronic migraines, and
  4. compliance did not exceed 62 %.

The authors noted that despite methodologic precautions including concealed allocation, partial un-blinding may have occurred in this trial.  It was difficult to blind peripheral neurostimulation trials because the effective electrical stimulation produces intense paresthesia.  These investigators doubted, however, that un-blinding markedly influenced their results for the following reasons.  The sham response was within the range of that found in other trials with neurostimulation devices.  Compared to the ONSTIM trial of occipital nerve stimulation, it was even higher for the 50 % responder rate: 6 % in ONSTIM, 12.8 % in PREMICE.  Un-blinding could thus have been twice more pronounced in ONSTIM than in PREMICE, if one assumed that it was inversely proportional to the percentage of responders in a sham group.  The rather small difference (7.3 %) in compliance rates between verum and sham groups also did not favor massive un-blinding.  If this were the case, one would expect a much lower compliance in the sham group.  Another possible weakness of this trial appeared when data from the different centers were analyzed: patients in the verum group were on average younger than those in the sham group and the duration of their migraine was somewhat shorter.  On post-hoc statistical analyses these researchers were unable, however, to detect an influence of age or of disease duration on treatment outcome.  In the ONSTIM trial, the difference in mean age between the effectively stimulated patients and the smaller "ancillary" group was 9 years.  Overall, both patient groups in PREMICE were well in the age range of migraine patients included in other trials.  These researchers stated that beyond statistics, the question whether the results of the PREMICE trial were clinically relevant merits consideration.  Besides the therapeutic gain for 50 % responders, other outcome measures suggested that STS could be of benefit to migraine patients.  It decreased significantly consumption of acute anti-migraine drugs, which is a pharmaco-economical advantage.  In addition, more than 70 % of effectively stimulated patients were satisfied with the treatment.  The patients recruited for PREMICE were not the most disabled migraineurs.  Having 4 migraine attacks or 7 migraine days per month, they were similar, however, to those included in topiramate trials and representative of the majority of migraine patients in the general population who are in need of preventive treatment according to international recommendations.  Whether STS treatment is effective in patients with more frequent attacks or with chronic migraine remains to be determined.

In an editorial that accompanied the aforementioned study, Asano and Goadsby (2013) "new therapies are needed in migraines, and further studies of neurostimulation using innovative study designes are warranted to explore the optimum way to create an acceptable evidence base for widespread use of this potentially valuable treatment modality".

Ashkenazi and Levin (2007) stated that peripheral nerve blocks have long been used in headache treatment.  The most widely used procedure for this purpose has been greater occipital nerve (GON) block.  The rationale for using GON block in headache treatment comes from evidence for convergence of sensory input to trigeminal nucleus caudalis neurons from both cervical and trigeminal fibers.  Although there is no standardized procedure for GON blockade, the nerve is usually infiltrated with a local anesthetic (lidocaine, bupivacaine, or both).  A corticosteroid is sometimes added.  Several studies suggested efficacy of GON block in the treatment of migraine, cluster headache, and chronic daily headache.  However, few were controlled and blinded.  Despite a favorable clinical experience, little evidence exists for the efficacy of GON block in migraine treatment.  Controlled studies are needed to better assess the role of GON block in the treatment of migraine and other headaches.

In a retrospective case series, Rosen et al (2009) examined the use of IV lidocaine for refractory chronic daily headache (CDH) patients in an inpatient setting.  This was an open-label, retrospective, uncontrolled study of IV lidocaine for 68 intractable headache patients in an inpatient setting.  These investigators reviewed the medical records of patients receiving IV lidocaine between February 6, 2003 and June 29, 2005.  Pre-treatment headache scores averaged 7.9 on an 11-point scale and post-treatment scores averaged 3.9 representing an average change of 4.  Average length of treatment was 8.5 days.  Lidocaine infusion was generally well-tolerated with a low incidence of adverse events leading to discontinuation of treatment.  The authors concluded that the results of this study suggested benefit of lidocaine treatment and the need for further prospective analyses.  The mechanism of lidocaine in treating headache is unknown.

Also, the European handbook of neurological management of cluster headache and other trigemino-autonomic cephalgias (Evers et al, 2011) stated that "The following were considered but not recommended for treatment of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome: lamotrigine, gabapentin, topiramate, oxcarbazepine, verapamil, intravenous lidocaine, steroids, intravenous phenytoin, and stimulation of the hypothalamus. Lamotrigine is considered first-line treatment".

The AAN’s updated guidelines on "Pharmacologic treatment for episodic migraine prevention in adults" (Silberstein et al, 2012a) and "NSAIDs and other complementary treatments for episodic migraine prevention in adults" (Holland et al, 2012)  had no recommendation for intravenous methylprednisolone or other steroids, or for nalbuphine (Nubain) or other opioid agonist-antagonists for migraine treatment.  Furthermore, the U.S. Headache Consortium’s guidelines on "Migraine headache in the primary care setting" (Matchar et al, 2014) concluded that the clinical and statistical benefits of IV steroids are unknown (insufficient evidence available).

Colombo et al (2013) stated that patients affected by chronic forms of headache are often very difficult to treat.  Refractory patients are so defined when adequate trials of specific drugs (for acute or prophylactic treatment) failed both to reduce the burden of disease and to improve headache-related quality of life.  An escalating approach is suggested to test different kinds of therapies.  All co-morbid factors should be addressed.  The authors concluded that more invasive modalities (such as neurostimulation) or promising approaches such as repetitive transcranial magnetic stimulation (rTMS) could be a future major step as third line therapies.

On March 11, 2014, the FDA allowed marketing of the first device (the Cefaly Migraine Headband) as a preventative treatment for migraine headaches.  This is also the first transcutaneous electrical nerve stimulation (TENS) device specifically authorized for use prior to the onset of pain.  Cefaly is a small, portable, battery-powered, prescription device that resembles a plastic headband worn across the forehead and atop the ears.  The user positions the device in the center of the forehead, just above the eyes, using a self-adhesive electrode.  The device applies an electric current to the skin and underlying body tissues to stimulate branches of the trigeminal nerve, which has been associated with migraine headaches.  The user may feel a tingling or massaging sensation where the electrode is applied.  Cefaly is indicated for patients 18 years of age and older and should only be used once-daily for 20 minutes.

The FDA reviewed the data for Cefaly through the de-novo pre-market review pathway, a regulatory pathway for generally low- to moderate-risk medical devices that are not substantially equivalent to an already legally marketed device (i.e., it did not even go through the 510(k) process).  The agency evaluated the safety and effectiveness of the device based on data from a clinical study conducted in Belgium involving 67 individuals who experienced more than 2 migraine headache attacks a month and who had not taken any medications to prevent migraines for 3 months prior to using Cefaly, as well as a patient satisfaction study of 2,313 Cefaly users in France and Belgium.  The 67-person study showed that those who used Cefaly experienced significantly fewer days with migraines per month and used less migraine attack medication than those who used a placebo device.  The device did not completely prevent migraines and did not reduce the intensity of migraines that did occur.  The patient satisfaction study showed that a little more than 53 % of patients were satisfied with Cefaly treatment and willing to buy the device for continued use.  The most commonly reported complaints were dislike of the feeling and not wanting to continue using the device, sleepiness during the treatment session, and headache after the treatment session.  No serious adverse events occurred during either study.

An UpToDate review on "Preventive treatment of migraine in adults" (Bajwa and Sabahat, 2014) states that "Recommendations from the AAN practice parameter published in 2000 regarding cognitive and behavioral treatment for migraine prevention are as follows: Evidence-based recommendations regarding the use of hypnosis, acupuncture, transcutaneous electrical nerve stimulation, chiropractic or osteopathic cervical manipulation, occlusal adjustment, or hyperbaric oxygen could not be made".

Tso and Goadsby (2014) noted that the shift in the understanding of migraine as a vascular disorder to a brain disorder has opened new avenues for the development of novel therapeutics with neural targets.  The advent of 5-HT1B/1D receptor agonists, the triptans, in the 1990s was a crucial step in the modern evolution of treatment.  The use of triptans, like their predecessors, is limited by their vasoconstrictor effects, and new development has been slowed by poor academic research funding to identify new targets.  The development of agents without vascular effects, such as calcitonin gene-related peptide receptor antagonists and selective serotonin 5-HT1F receptor agonists, will bring more effective treatments to a population currently without migraine-specific options.  In addition, advances in understanding migraine pathophysiology have identified new potential pharmacologic targets such as acid-sensing ion channels, glutamate and orexin receptors, nitric oxide synthase (NOS), and transient receptor potential (TRP) channels.  Although previous attempts to block subtypes of glutamate receptors, NOS, and TRP channels have had mixed outcomes, new molecules for the same targets are currently under investigation.  Finally, an entirely new approach to migraine treatment with non-invasive neuromodulation via transcutaneous neurostimulation (e.g., TENS) or TMS is just beginning.

Conforto et al (2014) stated that high-frequency rTMS of the left dorsolateral prefrontal cortex (rTMS-DLPFC) is an effective treatment for depression.  Preliminary studies indicated beneficial effects of rTMS-DLPFC on pain relief in patients treated for depression, and in patients with chronic migraine.  In this randomized, double-blind, parallel-group, single-center, proof-of-principle clinical trial, these researchers tested the hypothesis that 23 sessions of active rTMS-DLPFC delivered over 8 weeks would be feasible, safe and superior to sham rTMS to decrease the number of headache days in 18 patients with chronic migraine without severe depression.  Per-protocol analysis was performed.  rTMS-DLPFC applied over 8 weeks was feasible and safe in patients with chronic migraine.  Contrary to the primary hypothesis, the number of headache days decreased significantly more in the sham group than in the group treated with active rTMS-DLPFC at 8 weeks.  Average decrease in headache days was greater than 50 % in the sham group, indicating a powerful placebo response.  Pain intensity improved in both groups to a similar extent.  The authors concluded that positive results of M1 stimulation in other studies, and the absence of significant benefits of active high-frequency rTMS of the DLPFC in the present study, point to M1 as a more promising target than the DLPFC, for larger trials of non-invasive brain stimulation in patients with chronic migraine.

On July 11, 2014, the California Technology Assessment Forum (CTAF) held a meeting in Los Angeles on "Controversies in Migraine Management" (Tice et al, 2014).  The CTAF Panel discussed the clinical effectiveness and reviewed economic analyses of 4 migraine treatments; 2 devices were considered.  First, for the treatment of acute migraine headache accompanied by aura, 1 well-designed, moderate size study of a single-pulse transcranial magnetic stimulation device (SpringTMS™ by eNeura) showed superior pain relief compared with a sham device, but no benefit was found in several other common outcome measures.  Economic modeling comparing the device with a commonly-used generic triptan found a high relative cost for its potential benefit.  Second, only 1 small trial has been reported of a TENS device (Cefaly) for the prevention of frequent migraine headaches.  This trial, further limited by concerns about unblinding and incomplete reporting of adverse effects, showed improvement in some commonly measured headache outcomes.  At current pricing and with the best estimate of Cefaly’s clinical effectiveness compared with a commonly used generic, oral medication, modeling suggested lower overall benefit and higher cost.  For both devices, the CTAF panel voted that the evidence is inadequate to demonstrate that they are as effective as other currently available care options.

The Work Loss Data Institute’s clinical practice guideline on "Pain (chronic)" (2013) stated that ketamine subanesthetic infusion is not recommended for complex regional pain syndrome (CRPS) and ketamine, in general, is not recommended.  Furthermore, an UpToDate review on "Chronic migraine" (Garza and Schwedt, 2015) does not mention ketamine as a therapeutic option.

Lee and Huh (2013) stated that a headache is a common neurological disorder, and large numbers of patients suffer from intractable headaches including migraine, tension headache and cluster headache, etc., with no clear therapeutic options.  Despite the advances made in the treatment of headaches over the last few decades, subsets of patients either do not achieve adequate pain relief or cannot tolerate the side effects of typical migraine medications.  An electrical stimulation of the peripheral nerves via an implantable pulse generator appears to be good alternative option for patients with treatment-refractory headaches.  A number of clinical trials showed considerable evidence supporting the use of peripheral nerve stimulator (PNS) for headaches not responding to conservative therapies.  However, the mechanism by which PNS improves headaches or predicts who will benefit from PNS remains uncertain.  The decision to use PNS should be individualized based on patient suffering and disability.  The authors concluded that further work is imperative.

Huang et al (2014) described the current data evaluating the safety and effectiveness of memantine for the prevention of primary headache disorders.  They performed a literature search using MEDLINE (1966-July 2014) and EMBASE (1973-July 2014) using the search terms memantine, headache, migraine, glutamate, and NMDA.  References of identified articles were reviewed for additional, relevant citations.  All English-language articles dealing with the use of memantine for prevention of primary headache disorders were included.  Data from several retrospective reports and 2 prospective clinical trials suggested that memantine may be a useful treatment option for the prevention of primary headache disorders.  The majority of available literature focused specifically on chronic migraine prevention in refractory patients who had failed multiple previous prophylactic therapies.  In these patients, 10 to 20 mg of memantine daily reduced the frequency and intensity of migraine headaches and was generally well-tolerated, with few adverse events.  Data regarding the effectiveness of memantine for other primary headache disorders such as chronic tension type and cluster headaches were limited.  The authors concluded that "Although further studies evaluating the efficacy of memantine for prevention of primary headache disorders are warranted, memantine may be a reasonable option, used either as monotherapy or adjunctive therapy, in the refractory chronic migraine prophylaxis setting.

An AHRQ assessment of pharmacologic agents for migraine prevention in adults (Shamliyan, et al., 2013) reported that published randomized controlled trials did not examine antidementia drugs. Retrospective review of case series and case reports demonstrated that with memantine treatment, 60 percent of the patients experienced ≥50 percent reduction in monthly migraine frequency, and 80 percent experienced a significant reduction in frequency of aura.

Jurgens et al (2014) noted that CCH is a debilitating headache disorder with a significant impairment of the patients' lives.  Within the past decade, various invasive neuromodulatory approaches have been proposed for the treatment of CCH refractory to standard preventive drug, but only very few RCTs exist in the field of neuromodulation for the treatment of drug-refractory headaches.  Based on the prominent role of the cranial parasympathetic system in acute CH attacks, high-frequency sphenopalatine ganglion (SPG) stimulation has been shown to abort ongoing attacks in some patients in a first small study.  As preventive effects of SPG-stimulation have been suggested and the rate of long-term side effects was moderate, SPG stimulation appears to be a promising new treatment strategy.  The authors stated that as SPG stimulation is effective in some patients and the first commercially available CE-marked SPG neurostimulator system has been introduced for CH, patient selection and care should be standardized to ensure maximal safety and effectiveness.  They noted that as only limited data have been published on SPG stimulation, standards of care based on expert consensus were proposed to ensure homogeneous patient selection and treatment across international headache centers.  These investigators concluded that given that SPG stimulation is still a novel approach, all expert-based consensuses on patient selection and standards of care should be re-reviewed when more long-term data are available.

An UpToDate review on "Chronic migraine" (Garza and Schwedt, 2015) states that "There are inconsistent data from small randomized trials regarding the benefit of occipital nerve stimulation for the treatment of chronic migraine.  In the largest trial, there was no significant difference at 12 weeks for the primary endpoint, the percentage of patients that had a ≥ 50 % reduction in mean daily pain score in the active compared with the control group.  However, there were statistically significant if modest improvements with active stimulation for a number of secondary endpoints, including the percentage of patients with a ≥ 30 % reduction in mean daily pain score, and reduction in the mean number of headache days and migraine-related disability.  The findings from these reports are limited by concerns about blinding in the control (sham treatment) groups, given that active treatment causes paresthesia, and relatively high rates of complications, including lead migration in 14 to 24 % of subjects.  Further trials are needed to determine if occipital nerve stimulation is a useful therapy for chronic migraine".

Tx360 Nasal Applicator (Spheno-Palatine Ganglion Blockade) for the Treatment of Migraine

Candido et al (2013) stated that the spheno-palatine ganglion (SPG) is located with some degree of variability near the tail or posterior aspect of the middle nasal turbinate.  The SPG has been implicated as a strategic target in the treatment of various headache and facial pain conditions, some of which are featured in this manuscript.  Interventions for blocking the SPG range from minimally to highly invasive procedures often associated with great cost and unfavorable risk profiles.  In a pilot study, these researchers presented a novel, FDA-cleared medication delivery device, the Tx360® nasal applicator, incorporating a trans-nasal needleless topical approach for SPG blocks.  This case-series study featured the technical aspects of this new device and presented some limited clinical experience observed in a small series of head and face pain cases.  After Institutional Review Board (IRB) approval, the technical aspects of this technique were examined on 3 patients presenting with various head and face pain conditions including trigeminal neuralgia (TN), chronic migraine headache (CM), and post-herpetic neuralgia (PHN).  The subsequent response to treatment and quality of life was quantified using the following tools: the 11-point Numeric Rating Scale (NRS), Modified Brief Pain Inventory - short form (MBPI-sf), Patient Global Impression of Change (PGIC), and patient satisfaction surveys.  The Tx360® nasal applicator was used to deliver 0.5 ml of ropivacaine 0.5 % and 2 mg of dexamethasone for SPG block.  Post-procedural assessments were repeated at 15 and 30 minutes, and on days 1, 7, 14, and 21 with a final assessment at 28 days post-treatment.  All patients were followed for 1 year. Individual patients received up to 10 SPG blocks, as clinically indicated, after the initial 28 days.  Three women, aged 43, 18, and 15, presented with a variety of headache and face pain disorders including TN, CM, and PHN were included in this study.  All patients reported significant pain relief within the first 15 minutes post-treatment.  A high degree of pain relief was sustained throughout the 28 day follow-up period for 2 of the 3 study participants.  All 3 patients reported a high degree of satisfaction with this procedure.  One patient developed minimal bleeding from the nose immediately post-treatment that resolved spontaneously in less than 5 minutes.  Longer term follow-up (up to 1 year) demonstrated that additional SPG blocks over time provided a higher degree and longer lasting pain relief.  The authors concluded that SPG block with the Tx360® is a rapid, safe, easy, and reliable technique to accurately deliver topical trans-nasal analgesics to the area of mucosa associated with the SPG.  This intervention can be delivered in as little as 10 seconds with the novice provider developing proficiency very quickly.  They stated that further investigation is certainly warranted related to technique efficacy, especially studies comparing efficacy of Tx360 and standard cotton swab techniques.  Well-designed controlled double-blind studies with a higher number of patients are needed to prove the effectiveness of the Tx360 nasal applicator for the treatment of headache.

In a double-blind, parallel-arm, placebo-controlled, randomized pilot study, Cady et al (2015) examined if repetitive SPG blocks with 0.5 % bupivacaine delivered through the Tx360 are superior in reducing pain associated with CM compared with saline.  Up to 41 subjects could be enrolled at 2 headache specialty clinics in the US.  Eligible subjects were between 18 and 80 years of age and had a history of CM defined by the second edition of the International Classification of Headache Disorders appendix definition.  They were allowed a stable dose of migraine preventive medications that was maintained throughout the study.  Following a 28-day baseline period, subjects were randomized by computer-generated lists of 2:1 to receive 0.5 % bupivacaine or saline, respectively.  The primary end-point was to compare numeric rating scale scores at pre-treatment baseline versus 15 minutes, 30 minutes, and 24 hours post-procedure for all 12 treatments.  Spheno-palatine ganglion blockade was accomplished with the Tx360, which allows a small flexible soft plastic tube that is advanced below the middle turbinate just past the pterygopalatine fossa into the intranasal space.  A 0.3 cc of anesthetic or saline was injected into the mucosa covering the SPG.  The procedure was performed similarly in each nostril.  The active phase of the study consisted of a series of 12 SPG blocks with 0.3 cc of 0.5 % bupivacaine or saline provided 2 times per week for 6 weeks.  Subjects were re-evaluated at 1 and 6 months post-final procedure.  The final dataset included 38 subjects, 26 in the bupivacaine group and 12 in the saline group.  A repeated measures analysis of variance showed that subjects receiving treatment with bupivacaine experienced a significant reduction in the numeric rating scale scores compared with those receiving saline at baseline (M = 3.78 versus M = 3.18, p = 0.10), 15 minutes (M = 3.51 versus M = 2.53, p < 0.001), 30 minutes (M = 3.45 versus M = 2.41, p < 0.001), and 24 hours after treatment (M = 4.20 versus M = 2.85, p < 0.001), respectively.  Headache Impact Test-6 scores were statistically significantly decreased in subjects receiving treatments with bupivacaine from before treatment to the final treatment (Mdiff = -4.52, p = 0.005), whereas no significant change was seen in the saline group (Mdiff = -1.50, p = 0.13).  The authors concluded that SPG blockade with bupivacaine delivered repetitively for 6 weeks with the Tx360 device demonstrated promise as an acute treatment of headache in some subjects with CM.  Statistically significant headache relief is noted at 15 and 30 minutes and sustained at 24 hours for SPG blockade with bupivacaine vs saline.  They stated that the Tx360 device was simple to use and not associated with any significant or lasting adverse events; further research on SPG blockade is warranted.

In a randomized placebo-controlled trial, Schaffer et al (2015) examined the effectiveness of non-invasive SPG block for the treatment of acute anterior headache in the emergency department (ED) using a novel non-invasive delivery device.  This study was completed in 2 large academic EDs.  Bupivacaine or normal saline solution was delivered intra-nasally (0.3 ml per side) with the Tx360 device.  Pain and nausea were measured at 0, 5, and 15 minutes by a 100-mm visual analog scale.  The primary end-point was a 50 % reduction in pain at 15 minutes.  Telephone follow-up assessed 24-hour pain and nausea through a 0- to 10-point verbal scale and adverse effects.  The median reported baseline pain in the bupivacaine group was 80 mm (interquartile range [IQR] 66 mm to 93 mm) and 78.5 mm (IQR 64 mm to 91.75 mm) in the normal saline solution group.  A 50 % reduction in pain was achieved in 48.8 % of the bupivacaine group (20/41 patients) versus 41.3 % in the normal saline solution group (19/46 patients), for an absolute risk difference of 7.5 % (95 % confidence interval [CI]: -13 % to 27.1 %).  As a secondary outcome, at 24 hours, more patients in the bupivacaine group were headache free (24.7 % difference; 95 % CI: 2.6 % to 43.6 %) and more were nausea free (16.9 % difference; 95 % CI: 0.8 % to 32.5 %).  The authors concluded that for patients with acute anterior headache, SPG block with the Tx360 device with bupivacaine did not result in a significant increase in the proportion of patients achieving a greater than or equal to 50 % reduction in headache severity at 15 minutes compared with saline solution applied in the same manner.

Calcitonin Gene-Related Peptide Antagonists

Cui and associates (2015) stated that calcitonin gene-related peptide (CGRP) receptor antagonists, such as telcagepant, have been under investigation as a treatment for acute migraine. In a meta-analysis, these researchers evaluated the effectiveness of telcagepant versus placebo and triptans (zolmitriptan or rizatriptan).  Randomized controlled trials were identified from databases using the following search terms: migraine; calcitonin gene-related peptide; calcitonin gene-related peptide receptor antagonists; efficacy; safety, and telcagepant.  The primary outcome measure was pain freedom 2 hours after first treatment.  The secondary outcome measure was pain relief 2 hours after first treatment.  A total of 8 trials were included in the meta-analysis (telcagepant = 4,011 participants).  The difference in pain freedom at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.70, 95 % confidence interval = 2.27-3.21, P < 0.001) and triptans over telcagepant (odds ratio = 0.68, 95% confidence interval = 0.56-0.83, P < 0.001). The difference in pain relief at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.48, 95% confidence interval = 2.18-2.81, P < 0.001). The difference in pain relief at 2 hours did not significantly favor telcagepant over triptans or vice versa (OR = 0.76, 95 % CI: 0.57 to 1.01, p = 0.061). The authors concluded that these findings indicated that telcagepant can be effective for treating acute migraine; and CGRP receptor antagonists represent a potentially important alternative means of treating acute migraine.

In a meta-analysis, Hong and Liu (2017) evaluated the effectiveness of CGRP antagonisms in treating acute migraine attack. PubMed, Cochrane Library, Web of Science and OvidSP were systematically searched up to April 9, 2015 for RCTs that dealt with the effectiveness of CGRP antagonisms in treating acute migraine attack.  The bias and quality of RCTs were assessed with Cochrane collaboration's tool for assessing risk of bias.  Reviewer manager 5.2 was utilized for data analysis.  A total of 13 publications matched the inclusion criteria, including 10 independent RCTs and 6,803 patients.  Pooled analysis indicated that CGRP antagonisms had better outcomes in number of patients with pain free at 2 hours, 2 to 24 hours sustained pain free, phonophobia free at 2 hours, patients with photophobia free at 2 hours and nausea free at 2 hours post-dose, as compared with placebo.  However, CGRP antagonisms were no superior than 5-HT agonists in the aforementioned indices.  The authors concluded that CGRP antagonisms may be an effective and promising treatment for acute migraine attack.

An UpToDate review on "Acute treatment of migraine in adults" (Bajwa and Smith, 2016) states that "Pharmacologic modulation of calcitonin-gene related peptide (CGRP) activity offers the promise of future treatment options for acute migraine attacks. A number of randomized trials suggested that the investigational CGRP receptor antagonists telcagepant (MK-0974) and olcegepant (BIBN 4096 BS) were beneficial for acute migraine attacks.  However, development of telcagepant was stopped due to concerns regarding hepatotoxicity, and development of olcegepant was halted because of poor oral bioavailability.  It remains unclear whether other orally bioavailable CGRP receptor antagonists still in development will be hampered by liver toxicity".

Bigal and colleagues (2016) evaluated the onset of effectiveness of TEV-48125, a monoclonal antibody against CGRP, recently shown to be effective for the preventive treatment of CM and high-frequency episodic migraine.  A randomized placebo-controlled study tested once-monthly injections of TEV-48125 675/225 mg or 900 mg versus placebo.  Headache information was captured daily using an electronic headache diary.  The primary end-point was change from baseline in the number of headache hours in month 3.  These researchers evaluated the effectiveness of each dose at earlier time-points.  The sample consisted of 261 patients.  For headache hours, the 675/225-mg dose separated from placebo on day 7 and the 900-mg dose separated from placebo after 3 days of therapy (p = 0.048 and p = 0.033, respectively).  For both the 675/225-mg and 900-mg doses, the improvement was sustained through the second (p = 0.004 and p < 0.001) and third (p = 0.025 and p < 0.001) weeks of therapy and throughout the study (month 3, p = 0.0386 and p = 0.0057).  For change in weekly headache days of at least moderate intensity, both doses were superior to placebo at week 2 (p = 0.031 and p = 0.005).  The authors concluded that TEV-48125 demonstrated a significant improvement within 1 week of therapy initiation in patients with CM.

The study had several drawbacks:
  1. The analyses reported in this article had not been a priori defined; Nonetheless, post-hoc analyses have an important role in further defining the benefits of any drug, including subsets of patients experiencing particular benefit or, as in this case, providing preliminary evidence for future rigorous assessments;
  2. These researchers had not interviewed patients to check whether the effect size at early time-points was clinically meaningful, and they did not suggest that they were for the early time-points, although they certainly were for what was seen after 1 month of therapy, as the therapeutic gain (placebo-subtracted difference) appeared to suggest so;
  3. In the pooled analyses of the onabotulinumtoxinA pivotal trials, the therapeutic gain for moderate or severe headache days after 6 months of therapy was −1.9.31 In the present study, after 1 month of therapy, 900-mg and 675/225-mg doses yielded a therapeutic gain of values of −2.8 and −2.0 days, respectively; Since clinical benefit may be a function of absolute response rather than placebo-adjusted response, future studies should incorporate patients' subjective assessment of improvement.
The authors stated that since clinical benefit may be a function of absolute response rather than placebo-adjusted response, future studies should incorporate patients' subjective assessment of improvement.

Intramuscular Bupivacaine

Mellick and colleagues (2006) described the 1-year experience of an academic emergency department (ED) in treating a wide spectrum of headache classifications with intramuscular injections of 0.5 % bupivacaine bilateral to the spinous process of the lower cervical vertebrae. These investigators performed a retrospective review of over 2,805 ED patients with the discharge diagnosis of headache and over 771 patients who were coded as having had an anesthetic injection between June 30, 2003 and July 1, 2004.  All adult patients who had undergone para-spinous intramuscular injection with bupivacaine for the treatment of their headache were gleaned from these 2 larger databases and were included in this retrospective chart review.  A systematic review of the medical records was accomplished for these patients.  Lower cervical para-spinous intramuscular injections with bupivacaine were performed in 417 patients.  Complete headache relief occurred in 271 (65.1 %) and partial headache relief in 85 patients (20.4 %).  No significant relief was reported in 57 patients (13.7 %) and headache worsening was described in 4 patients (1 %).  Overall a therapeutic response was reported in 356 of 417 patients (85.4 %).  Headache relief was typically rapid with many patients reporting complete headache relief in 5 to 10 minutes.  Associated signs and symptoms such as nausea, vomiting, photophobia, phonophobia, and allodynia were also commonly relieved.  The authors concluded that their observations suggested that the intramuscular injection of small amounts of 0.5 % bupivacaine bilateral to the sixth or seventh cervical spinous process appeared to be an effective therapeutic intervention for the treatment of headache pain in the outpatient setting.

Mellick and Pleasant (2010) performed a retrospective review of all pediatric patients with headaches who were treated with this technique in an ED setting over a 16-month period. A total of 3 separate databases were reviewed to capture all patients younger than 18 years with a diagnosis of headache who received bilateral cervical injections between June 30, 2003, and December 1, 2004, in the Medical College of Georgia and Children's Medical Center EDs.  Their medical records were retrospectively reviewed to determine their response to this procedure.  The headaches of 13 patients younger than 18 years were treated with this procedure.  The mean headache severity was 9.15, and the mean duration of headache was 3.16 days; 6 (46.2 %) of 13 patients had complete relief of their headaches, whereas 5 (38.4 %) of 13 patients had partial relief.  No significant relief was documented in 2 (15.4 %) of 13 patients.  A therapeutic response was documented in 11 (84.6 %) of 13 of the patients.  The authors concluded that these retrospective observations suggested that bilateral lower cervical para-spinous intramuscular injections with small amounts of bupivacaine may have a therapeutic role in the management of headache pain in children, and their rate of therapeutic response may be similar to that recently reported for adult headache patients.

Patniyot and Gelfand (2016) performed a qualitative systematic review to evaluate the safety and effectiveness of available treatments for pediatric patients with migraine or benign primary headache in the ED. Scopus, Medline, and PubMed databases were searched for RCTs, retrospective reviews, review articles, and case studies discussing migraine or benign primary headache management that were conducted in the emergency room or outpatient acute care setting in pediatric patients (less than 18 years old).  Meeting abstracts and cited references within articles were also evaluated.  Multiple variables were recorded, including type of treatment, study design, dosing, primary outcome, and side effects.  Therapeutic gain was calculated in studies with a placebo arm.  Treatments were subjectively assessed based on methodology and number of trials for a particular therapy.  A total of 31 studies were included in the final analysis.  Of these, 17 were RCTs, 9 were retrospective reviews, and 5 were prospective chart review studies.  One pertained to IV fluids, 2 to non-specific analgesic use, 5 to dopamine receptor antagonists, 2 to valproic acid, 1 to propofol, 1 to magnesium, 1 to bupivacaine, 13 to triptan medications, and 3 to DHE.  Treatments considered effective for acute migraine or benign primary headache in the analgesic category include ibuprofen, and to a lesser degree acetaminophen.  Ketorolac was not compared to other NSAIDs, but was found to be less effective than prochlorperazine.  Of the phenothiazines, prochlorperazine was considered most effective.  Of the triptan medications, almotriptan, rizatriptan, zolmitriptan nasal spray, sumatriptan nasal spray, and combination sumatriptan/naproxen are effective agents for acute treatment.  Treatments considered probably effective included IV fluids, chlorpromazine, valproate sodium, injectable sumatriptan, and IV DHE.  Treatments with oral zolmitriptan showed inconsistent results, while treatments considered ineffective included isolated oral sumatriptan and oral DHE.  Moreover, there is insufficient evidence to comment on propofol, magnesium, and bupivacaine efficacy.  The authors concluded that of the available evidence, ibuprofen, prochlorperazine, and certain triptan medications are the most effective and safe agents for acute management of migraine and other benign headache disorders in the pediatric population.  They stated that additional studies in this population are needed, and should take into consideration variables such as dosing, co-administered medications, treatment duration, and length of treatment effect.

Furthermore, UpToDate reviews on "Acute treatment of migraine in adults" (Bajwa and Smith, 2016a), "Preventive treatment of migraine in adults" (Bajwa and Smith, 2016b) and "Chronic migraine" (Garza and Schwedt, 2016) do not mention the use of bupivacaine injection as a therapeutic option.

Intramuscular Nalbuphine

Tek and Mellon (1987) noted that the present treatment for acute attacks of headache is empiric. Intramuscular nalbuphine (Nubain) and hydroxyzine (Vistaril) were assessed for pain relief in a prospective, double-blind clinical trial.  A total of 94 patients were assigned randomly to treatment groups receiving nalbuphine 10 mg, nalbuphine 10 mg plus hydroxyzine 50 mg, hydroxyzine 50 mg, or placebo.  The treatment groups were found to be adequately homogenous with regard to age, sex, type and duration of headaches, and history of prior narcotic use.  All data were analyzed by 1-way analysis of variance.  Patients who had headaches diagnosed as other than classic migraine had significantly greater pain relief with nalbuphine compared to placebo (p < 0.01).  The combination of nalbuphine and hydroxyzine was not significantly more effective than other treatment groups.  In 20 patients with classic migraine, none of the treatment regimens significantly outperformed placebo.  There were no clinically significant adverse effects attributed to the study drugs.  The authors concluded that these findings were similar to others that showed a lack of effectiveness of kappa receptor agonists in classic migraineurs.  They stated that nalbuphine appeared to be clinically useful in other types of severe headache; the findings of this study did not support the routine addition of hydroxyzine for presumed synergistic effect.

Furthermore, UpToDate reviews on "Acute treatment of migraine in adults" (Bajwa and Smith, 2016a), "Preventive treatment of migraine in adults" (Bajwa and Smith, 2016b) and "Chronic migraine" (Garza and Schwedt, 2016) do not mention the use of nalbuphine injection as a therapeutic option.

Intravenous Propofol

Mosier et al (2013) stated that migraine headaches requiring an ED visit due to failed outpatient rescue therapy present a significant challenge in terms of length of stay (LOS) and financial costs. These researchers hypothesized that propofol therapy may be effective at pain reduction and reduce that length of stay given its pharmacokinetic properties as a short acting intravenous sedative anesthetic and pharmacodynamics on GABA mediated chloride flux.  These investigators presented findings of case series of 4 patients with migraine headache failing outpatient therapy.  Each patient was given a sedation dose (1 mg/kg) of propofol under standard procedural sedation precautions.  Each of the 4 patients experienced dramatic reductions or complete resolution of headache severity; LOS for 3 of the 4 patients was 50 % less than the average LOS for patients with similar chief complaints to the authors’ ED; 1 patient required further treatment with standard therapy but had a significant reduction in pain and a shorter LOS.  There were no episodes of hypotension, hypoxia, or apnea during the sedations.  The authors concluded that the finding of this small case series showed a promising reduction in headache symptoms using sedative dosing of propofol.  Moreover, they stated that future research should more formally evaluate the safety, effectiveness, and cost-effectiveness of sedation dosing of propofol for refractory migraines.

On behalf of the Canadian Headache Society, Orr and colleagues (2015) performed a peer-reviewed search of databases (MEDLINE, Embase, CENTRAL) to identify rRCTs and quasi-RCTs of interventions for acute pain relief in adults presenting with migraine to emergency settings. Where possible, data were pooled into meta-analyses.  Two independent reviewers screened 831 titles and abstracts for eligibility; 3 independent reviewers subsequently evaluated 120 full text articles for inclusion, of which 44 were included.  Individual studies were then assigned a US Preventive Services Task Force quality rating.  The grading of recommendations, assessment, development, and evaluation (GRADE) scheme was used to assign a level of evidence and recommendation strength for each intervention.  The authors strongly recommended the use of prochlorperazine based on a high level of evidence, lysine acetylsalicylic acid, metoclopramide and sumatriptan, based on a moderate level of evidence, and ketorolac, based on a low level of evidence.  They weakly recommended the use of chlorpromazine based on a moderate level of evidence, and ergotamine, dihydroergotamine, lidocaine intranasal and meperidine, based on a low level of evidence.  The authors found evidence to recommend strongly against the use of dexamethasone, based on a moderate level of evidence, and granisetron, haloperidol and trimethobenzamide based on a low level of evidence.  Based on moderate-quality evidence, they recommended weakly against the use of acetaminophen and magnesium sulfate.  Based on low-quality evidence, they recommended weakly against the use of diclofenac, droperidol, lidocaine intravenous, lysine clonixinate, morphine, propofol, sodium valproate and tramadol.

In a qualitative systematic review to evaluate the safety and effectiveness of available treatments for pediatric patients with migraine or benign primary headache, Patniyot and Gelfand (2016) noted that there is insufficient evidence to comment on propofol, magnesium, and bupivacaine efficacy.

Furthermore, UpToDate reviews on "Acute treatment of migraine in adults" (Bajwa and Smith, 2016a), "Preventive treatment of migraine in adults" (Bajwa and Smith, 2016b) and "Chronic migraine" (Garza and Schwedt, 2016) do not mention the use of propofol as a therapeutic option.

Oral Magnesium

Teigen and Boes (2015) performed a review of the literature from 1990 to the present on magnesium and migraine. These investigators identified 16 studies aimed at magnesium status assessment in migraine, and 4 intervention trials evaluating the effectiveness of oral magnesium supplementation, independent of other therapies, in the prevention of migraine.  The authors concluded that the strength of evidence supporting oral magnesium supplementation is limited at this time.  They stated that with such limited evidence, a more advantageous alternative to magnesium supplementation, in patients willing to make lifestyle changes, may be to focus on increasing dietary magnesium intake.

Intranasal Lidocaine

In a randomized, double-blind, placebo-controlled clinical trial, Blanda et al (2001) evaluated the effect of intranasal lidocaine for immediate relief (5 minutes) of migraine headache pain.  Patients 18 to 50 years old with migraine headache as defined by the International Headache Society were enrolled in this study.  Patients who were pregnant, lactating, known to abuse alcohol or drugs, or allergic to one of the study drugs, those who used analgesics within 2 hours, or those with a first headache were excluded.  Statistical significance was assessed by using chi-square or Fisher's exact test for categorical variables and Student's t-test for continuous variables.  Patients rated their pain on a 10-centimeter VAS prior to drug administration and at 5, 10, 15, 20, and 30 minutes after the initial dose.  Medication was either 1 ml of 4 % lidocaine or normal saline (placebo) intranasally in split doses 2 minutes apart and intravenous prochlorperazine.  Medications were packaged so physicians and patients were unaware of the contents.  Successful pain relief was achieved if there was a 50 % reduction in pain score or a score below 2.5 cm on the VAS.  A total of 27 patients received lidocaine and 22 received placebo.  No significant difference was observed between groups in initial pain scores, 8.4 (95 % CI: 7.8 to 9.0) lidocaine and 8.6 (95 % CI: 8.0 to 9.2) placebo (p = 0.75).  Two of 27 patients (7.4 %, 95 % CI: 0.8, 24.3) in the lidocaine group and 3of 22 patients (13.6 %, 95 % CI: 2.8 to 34.9) in the placebo group had immediate successful pain relief (p = 0.47), with average pain scores of 6.9 (95 % CI: 5.9 to 7.8) and 7.0 (95 % CI: 5.8 to 8.2), respectively.  No difference in pain relief was detected at subsequent measurements.  The authors concluded that there was no evidence that intranasal lidocaine provided rapid relief for migraine headache pain in the emergency department setting.

In a single-center, double-blind, RCT, Avcu and colleagues (2017) evaluated the safety and effectiveness of intranasal lidocaine administration for migraine treatment.  This study was conducted in a tertiary care ED.  Included patients met the migraine criteria of the International Headache Society.  Patients were randomized to intranasal lidocaine or saline solution; all participants received 10 mg of IV metoclopramide.  Patient pain intensity was assessed with an 11-point numeric rating scale score.  The primary outcome measure was the change in pain scores at 15 minutes; secondary outcomes were changes in pain intensity after pain onset and need for rescue medication.  Patients (n = 162) were randomized into 2 groups with similar baseline migraine characteristics and numeric rating scale scores.  The median reduction in numeric rating scale score at 15 minutes was 3 (IQR 2 to 5) for the lidocaine group and 2 (IQR 1 to 4) for the saline solution group (median difference [MD] = 1.0; 95 % CI: 0.1 to 2.1).  The reduction in pain score at 30 minutes was 4 (IQR 3 to 7) for the lidocaine group and 5 (IQR 2 to 7) for the saline solution group (MD = 1.0; 95 % CI: 0.1 to 2.1).  Need for rescue medication did not differ between the groups, and local irritation was the most common AE in the lidocaine group.  The authors concluded that although intranasal lidocaine was found no more effective than normal saline solution in this study, future studies should focus on patients who present earlier after headache onset.

In a systematic review, Dagenais and Zed (2018) examined the safety and efficacy of intranasal lidocaine in the acute management of primary headaches.  The Medline (1946 to May 2018), Embase (1974 to May 2018), Cochrane Central Register of Controlled Trials (2008 to May 2018), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to May 2018), and ClincialTrials.gov online databases were searched.  Studies conducted in patients with acute primary headache were included if lidocaine was compared with placebo or alternative treatments, lidocaine dosing was specified, and patients' pain before and after treatment were clearly reported.  A total of 6 studies met the inclusion criteria.  Intranasal lidocaine demonstrated potential benefit over placebo in acute pain reduction and need for rescue medication only in the 4 studies deemed to be of poor quality, not in the 2 fair-quality studies.  No study reported benefit in preventing headache recurrence or repeat visits to the ED.  Lidocaine was associated with significantly higher rates of AEs compared with placebo and may result in lower rates of patient satisfaction.  The authors concluded that there is insufficient evidence to support the use of intranasal lidocaine in acute management of primary headaches.  They stated that further research is needed to better examine if intranasal lidocaine has a role in the management of specific primary headache subtypes and whether there is an optimal regimen.

Occipital Nerve Stimulation

Reed et al (2010) developed a novel approach to the treatment of chronic migraine (CM) headaches based on neurostimulation of both occipital and supraorbital.  Following positive trials, a total of 7 patients with CM and refractory CM headaches had permanent combined occipital nerve-supraorbital nerve neurostimulation systems implanted.  The relative responses to 2 stimulation programs were evaluated:
  1. one that stimulated only the occipital leads and
  2. one that stimulated both the occipital and supraorbital leads together.
With follow-up ranging from 1 to 35 months, all patients reported a full therapeutic response but only to combined supraorbital-occipital neurostimulation.  Occipital nerve stimulation alone provided a markedly inferior and inadequate response.  Combined occipital nerve-supraorbital nerve neurostimulation systems may provide effective treatment for patients with CM and refractory CM headaches.  For patients with CM headaches the response to combined systems appears to be substantially better than occipital nerve stimulation alone.  The authors stated that further studies are needed.

Saper et al (2011) noted that medically intractable CM is a disabling illness characterized by headache greater than or equal to 15 days per month.  A multi-center, randomized, blinded, controlled feasibility study was conducted to obtain preliminary safety and efficacy data on occipital nerve stimulation (ONS) in CM.  Eligible subjects received an occipital nerve block, and responders were randomized to adjustable stimulation (AS), preset stimulation (PS) or medical management (MM) groups.  Seventy-five of 110 subjects were assigned to a treatment group; complete diary data were available for 66.  A responder was defined as a subject who achieved a 50 % or greater reduction in number of headache days per month or a 3-point or greater reduction in average overall pain intensity compared with baseline.  Three-month responder rates were 39 % for AS, 6 % for PS and 0 % for MM.  No unanticipated adverse device events occurred.  Lead migration occurred in 12 of 51 (24 %) subjects.  The authors concluded that the results of this feasibility study offer promise and should prompt further controlled studies of ONS in CM.

Silberstein et al (2012) stated that CM is a debilitating neurological disorder with few treatment options.  Peripheral nerve stimulation (PNS) of the occipital nerves is a potentially promising therapy for CM patients.  In this randomized, controlled, multi-center study, patients diagnosed with CM were implanted with a neurostimulation device near the occipital nerves and randomized 2:1 to active (n = 105) or sham (n = 52) stimulation.  The primary endpoint was a difference in the percentage of responders (defined as patients that achieved a greater than or equal to 50 % reduction in mean daily visual analog scale scores) in each group at 12 weeks.  There was not a significant difference in the percentage of responders in the Active compared with the Control group (95 % lower confidence bound (LCB) of -0.06; p = 0.55).  However, there was a significant difference in the percentage of patients that achieved a 30 % reduction (p = 0.01).  Importantly, compared with sham-treated patients, there were also significant differences in reduction of number of headache days (Active Group = 6.1, baseline = 22.4; Control Group = 3.0, baseline = 20.1; p = 0.008), migraine-related disability (p = 0.001) and direct reports of pain relief (p = 0.001).  The most common adverse event was persistent implant site pain.  The authors concluded that although this study failed to meet its primary endpoint, this is the first large-scale study of PNS of the occipital nerves in CM patients that showed significant reductions in pain, headache days, and migraine-related disability.  They stated that additional controlled studies using endpoints that have recently been identified and accepted as clinically meaningful are warranted in this highly disabled patient population with a large unmet medical need.

Lambru and Matharu (2012) stated that chronic daily headache is a major worldwide health problem that affects 3 to 5 % of the population and results in substantial disability.  Advances in the management of headache disorders have meant that a substantial proportion of patients can be effectively treated with medical treatments.  However, a significant minority of these patients are intractable to conventional medical treatments.  Occipital nerve stimulation is emerging as a promising treatment for patients with medically intractable, highly disabling chronic headache disorders, including migraine, cluster headache and other less common headache syndromes.  Open-label studies have suggested that this treatment modality is effective and recent controlled trial data are also encouraging.  The procedure is performed using several technical variations that have been reviewed along with the complications, which are usually minor and tolerable.  The mechanism of action is poorly understood, though recent data suggest that ONS could restore the balance within the impaired central pain system through slow neuromodulatory processes in the pain neuromatrix.  While the available data are very encouraging, the ultimate confirmation of the utility of a new therapeutic modality should come from controlled trials before widespread use can be advocated; more controlled data are still needed to properly assess the role of ONS in the management of medically intractable headache disorders.  The authors noted that future studies also need to address the variables that are predictors of response, including clinical phenotypes, surgical techniques and stimulation parameters.  Finally, the mode of action of ONS is poorly understood and further studies are required to elucidate the underlying mechanisms by which the anti-nociceptive effect is exerted.

The International Association for the Study of Pain's review on "Neuromodulation in Primary Headaches" (2012) states that "After an initial focus on hypothalamic deep brain stimulation (DBS), the less invasive technique of ONS is now widely considered the neuromodulatory approach of first choice in many primary headache disorders.  Despite their increasing popularity, most approaches lack methodologically sound randomized multicenter studies using an appropriate sham paradigm.  Especially in ONS, blinding remains an unresolved issue because effective stimulation induces paresthesias, unlike in hypothalamic DBS.  SPG stimulation represents an emerging alternative in the acute and possibly prophylactic treatment of chronic cluster headache.  The efficacy of various devices for transcutaneous peripheral nerve stimulation (such as the vagal and supraorbital nerves) and their role relative to implantable devices will have to be evaluated in future studies". 

A clinical trial on "Occipital Nerve Stimulation in Medically Intractable Chronic Cluster Headache" (NCT011516531) is recruiting subjects.

Yang and colleagues (2016) noted that patients who suffer from migraines often report impaired quality of life (QOL); ONS is a novel treatment modality for migraines, although few systematic reviews have evaluated whether this therapy is effective.  These researchers evaluated the safety and effectiveness of ONS for treating migraine through a literature review.  They performed a literature search to identify studies that examined ONS for migraine treatment.  Evidence levels of these studies were assessed by recommendations set by the University of Oxford Centre for Evidence-Based Medicine.  A total of 5 RCTs, 4 retrospective studies, and 1 prospective study met the inclusion criteria.  Results from the retrospective studies and case series indicated that ONS significantly reduced the pain intensity and the number of days with headache in patients with migraine.  However, the evidence of ONS effectiveness established by RCTs was limited.  Improvement in the migraine disability assessment (MIDAS) score was more dramatic than improvement in the SF-36 score at follow-up.  The mean complication incidence of ONS was 66 % for the reviewed studies.  The authors concluded that future clinical studies should optimize and standardize the ONS intervention process and identify the relationship among the surgical process, effectiveness, and complications resulting from the procedure.

Clark and co-workers (2016) presented functional outcome studies of combined supra-orbital nerve stimulation (SONS) and ONS for CM using verified metrics.  Consecutive patients with both SONS and ONS assessed with MIDAS and Beck Depression Index (BDI) both pre-operatively and post-operatively were studied.  Selected predictor variables included patients with greater than  50 % improvement of pain, disability status, number of years from diagnosis to implantation, and narcotic use.  Functional outcome variables included net improvement of ranked MIDAS and BDI scores.  Multi-variate analysis of variance was performed to assess the correlation between the outcome and predictor variables.  A total of 16 patients (12 females; average age of 52 years) were studied.  Follow-up ranged from 5 to 80 months (average of 44.5; σ = 21.4 months).  At most recent follow-up, 8 patients had a positive response (greater than or equal to 50 % improvement in headache), which was the only predictor of functional outcome (total MIDAS, MIDAS-B, and BDI) (p = 0.021).  Of note, improvement in functional outcome was only significant during the peri-operative 3 to 6 months period and not throughout long-term follow-up.  Among the predictor variables, a strong inverse correlation was found between disability status and positive response to stimulation (r = -0.582).  The authors concluded that there is a paucity of studies in QOL, productivity, and psychosocial aspects with peripheral nerve stimulation therapy for headache.  Patients with a positive response to SONS and ONS also reported overall improvement in their functional status as reflected by MIDAS and BDI in the peri-operative period; however, this effect waned over the long-term follow-up.

Miller and associates (2016) stated that CM affects up to 2 % of the general population and has a substantial impact on sufferers; ONS has been investigated as a potential treatment for refractory CM.  Results from RCTs and open label studies have been inconclusive with little long-term data available.  In an uncontrolled, open-label, prospective study, these investigators examined the safety, long-term effectiveness, and functional outcome of ONS in 53 patients with intractable CM.  Subjects were implanted in a single center between 2007 and 2013; they had a mean age of 47.75 years (range of 26 to 70), had suffered CM for around 12 years and had failed a mean of 9 (range of 4 to 19) preventative treatments prior to implant; 18 patients had other chronic headache phenotypes in addition to CM.  After a median follow-up of 42 months (range of 6 to 97) monthly moderate-to-severe headache days (i.e., days on which pain was more than 4 on the verbal rating score and lasted at least 4 hours) reduced by 8.51 days (p < 0.001) in the whole cohort, 5.80 days (p < 0.01) in those with CM alone and 12.16 days (p < 0.001) in those with multiple phenotypes including CM.  Response rate of the whole group (defined as a greater than 30 % reduction in monthly moderate-to-severe headache days) was observed in 45.3 % of the whole cohort, 34.3 % of those with CM alone and 66.7 % in those with multiple headache types.  Mean subjective patient estimate of improvement was 31.7 %.  Significant reductions were also seen in outcome measures such as pain intensity (1.34 points, p < 0.001), all monthly headache days (5.66 days, p < 0.001) and pain duration (4.54 hours, p < 0.001).  Responders showed substantial reductions in headache-related disability, affect scores and QOL measures; AEs rates were favorable with no episodes of lead migration and only 1 minor infection reported.  The authors concluded that ONS may be a safe and effective treatment for highly intractable CM patients even after relatively prolonged follow-up of a median of over 3 years.  Moreover, these researchers stated that there are still concerns over the risk to benefit ratio and cost-effectiveness of ONS despite positive open-label data, and a well-designed, double-blind, controlled trial with long-term follow-up is needed to clarify the position of neuromodulation in CM.

Spheno-Palatine Ganglion Stimulation

Puledda and Goadsby (2016) stated that neuromodulation is a promising, novel approach for the treatment of primary headache disorders.  Neuromodulation offers a new dimension in the treatment that is both easily reversible and tends to be very well-tolerated.  The autonomic nervous system is a logical target given the neurobiology of common primary headache disorders, such as migraine and the trigeminal autonomic cephalalgias (TACs).  These investigators reviewed new encouraging results of studies from the most recent literature on neuromodulation as acute and preventive treatment in primary headache disorders, and discussed some possible underlying mechanisms.  These researchers focused on vagal nerve stimulation (VNS) and spheno-palatine ganglion stimulation (SPGS) since they have targeted autonomic pathways that are cranial and can modulate relevant pathophysiological mechanisms.  The initial data suggested that these approaches will find an important role in headache disorder management going forward.  The authors concluded that the armamentarium for the treatment of migraine and the TACs is rapidly expanding thanks to neuromodulation techniques.  The newer methods appear much better tolerated and offer important therapeutic benefits.  Equally attractive in many ways is that bench-based understanding is being applied to neuromodulation to yield bedside advances in treatment.  They stated that clinicians can look forward to the results of a number of ongoing studies and the real possibility to add these exciting methods to their practice.

Robbins et al (2016) noted that CH is an extremely debilitating primary headache disorder that is often not optimally treated.  New evidence-based treatment guidelines for CH will assist clinicians with identifying and choosing among current treatment options.  In a systematic review, these researchers examined the available evidence for the acute and prophylactic treatment of CH; and provided an update of the 2010 American Academy of Neurology (AAN) endorsed systematic review.  Medline, PubMed, and Embase databases were searched for double-blind, randomized controlled trials (RCTs) that examined treatments of CH in adults.  Exclusion and inclusion criteria were identical to those utilized in the 2010 AAN systematic review.  For acute treatment, sumatriptan subcutaneous, zolmitriptan nasal spray, and high flow oxygen remain the treatments with a Level A recommendation.  Since the 2010 review, a study of sphenopalatine ganglion stimulation was added to the current guideline and has been administered a Level B recommendation for acute treatment.  For prophylactic therapy, previously there were no treatments that were administered a Level A recommendation.  For the current guidelines, suboccipital steroid injections have emerged as the only treatment to receive a Level A recommendation with the addition of a 2nd Class I study.  Other newly evaluated treatments since the 2010 guidelines have been given a Level B recommendation (negative study: deep brain stimulation [DBS]), a Level C recommendation (positive study: warfarin; negative studies: cimetidine/chlorpheniramine, candesartan), or a Level U recommendation (frovatriptan).  The authors concluded that this AHS guideline can be used for understanding which therapies have superiority to placebo or sham treatment in the management of CH.  In clinical practice, these recommendations should be considered in concert with other variables including safety, side effects, patient preferences, clinician experience, cost, and the invasiveness of the intervention.  Given the lack of Class I evidence and Level A recommendations, particularly for a number of commonly used preventive therapies, further studies are warranted to demonstrate safety and efficacy for established and emerging therapies (including neurostimulation).

The authors noted that a study examining the use of a novel nVNS was recently published.  It compared adjunctive stimulation as a prophylactic treatment with medical SoC versus SoC alone in a sample of patients with cCH.  The study was not blinded; thus, was excluded from this systematic review.  However, during the randomized phase of the study there was a significant reduction of weekly attack frequency in those treated with VNS, with no serious adverse events (AEs) attributed to the device.  These investigators stated that future studies that are blinded with a sham control are needed to examine the safety and effectiveness of nVNS for treatment of CH.

In a recent review, Lainez and Guillamon (2017) summarized CH pathophysiology and the effectiveness of various neuromodulating techniques.  In patients with cCH, VNS with a portable device used in conjunction with SoC in CH patients resulted in a reduction in the number of attacks.  The authors concluded that new recent non-invasive approaches such as nVNS have shown effectiveness in a few trials and could be an interesting alternative in the management of CH, but require more testing and positive RCTs.

Miller and colleagues (2017) noted that there is growing interest in neuromodulation for primary headache conditions.  Invasive modalities such as ONS, deep brain stimulation (DBS) and SPGS are reserved for the most severe and intractable patients.  Non-invasive options such as VNS, SONS and TMS have all emerged as potentially useful headache treatments.  These researchers examined the evidence base for non-invasive neuromodulation in TACs and migraine.  Although a number of open-label series of non-invasive neuromodulation devices have been published, there is very little controlled evidence for their use in any headache condition.  Open-label evidence suggested that VNS may have a role in the prophylactic treatment of CH and there is limited evidence to suggest it may be useful in the acute treatment of cluster and potentially migraine attacks.  There is limited controlled evidence to suggest a role for SONS in the prophylactic treatment of episodic migraine, however, there is no evidence to support its use in CH; TMS may be effective in the acute treatment of episodic migraine; but there is no controlled evidence to support its use as a preventative in any headache condition.  The authors concluded that non-invasive neuromodulation techniques are an attractive treatment option with excellent safety profiles, however, their use is not yet supported by high-quality RCTs.

Furthermore, an UpToDate review on "Cluster headache: Treatment and prognosis" (May, 2017) states that "When chronic cluster headache is unresponsive to medical treatments, various surgical interventions and neurostimulation techniques are potential treatment options, though none are clearly established as effective. In such cases, it is particularly important to exclude potential causes of secondary cluster headache.  Neurostimulation techniques, including sphenopalatine ganglion stimulation and vagus nerve stimulation, appear promising but remain investigational.  Destructive surgical procedures are unproven and should be viewed with great caution".

National Institute for Health and Care Excellence (NICE)’s interventional procedures guidance on "Transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine" (2016) stated that "Current evidence on the safety of transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine raises no major concerns.  The evidence on efficacy is limited in quantity and quality.  Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research … Clinicians wishing to do transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine should ensure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information … NICE encourages further research on transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine.  Studies should describe whether the procedure is used for treatment or prevention, and whether it is used for cluster headache or migraine.  Clinicians should clearly document details of patient selection and the treatment regimen.  Outcome measures should include changes in the number and severity of cluster headache or migraine episodes, medication use, quality of life in the short and long term, side effects, acceptability, and device durability".

Silberstein and colleagues (2017) noted that a panel of 9 experts, including neurologists, other headache specialists, and medical and pharmacy directors, from 4 health plans (1 integrated delivery network and 3 plans with commercial, Medicare, and Medicaid lines of business), convened to discuss CH.  Topics covered included the current treatment landscape, treatment challenges, economic impact of disease, and gaps in care for patients with CH.  One major challenge in the management of CH is that it is under-recognized and frequently misdiagnosed, leading to delays in and suboptimal treatment for patients who suffer from this painful and disabling condition.  The management of CH is challenging due to the lack of a robust evidence base for preventive treatment, the AEs associated with conventional preventive treatments, the variability of response to acute treatments, and the challenging reimbursement landscape for well-accepted treatments (e.g., oxygen).  The lack of effective prevention for many patients may lead to the excessive use of acute therapies, often multiple times each day, which drives the cost of illness up significantly.  The goal of the panel discussion was to discuss the role of gammaCore, the recently released first nVNS therapy in the acute treatment of patients with eCH, in the management of CH.  The panel reviewed current practices and formulated recommendations on incorporating a newly released therapy into CH management. The panel explored the role of traditional management strategies as well as that of gammaCore in the acute treatment of patients with eCH.  The panel agreed that the treatment guidelines should be updated to reflect the role of gammaCore as a first-line, acute therapeutic option for patients with eCH and that payers should offer coverage of gammaCore to their members who have a diagnosis of eCH.  Healthcare providers, including headache specialists and neurologists, and payers are encouraged to remain up-to-date regarding the results of ongoing clinical trials evaluating the use of gammaCore for the acute and/or preventive treatment of migraine to ensure that patients are being appropriately treated for these conditions and that they have access to treatment through their insurers.  Moreover, the panel noted that additional studies need to be conducted in the United States to verify the role of gammaCore in the preventive therapy of eCH and cCH.

Ho and co-workers (2017) noted that SPG is the largest collection of neurons in the calvarium outside of the brain.  Over the past century, it has been a target for interventional treatment of head and facial pain due to its ease of access.  Block, radiofrequency ablation (RFA), and neuro-stimulation have all been applied to treat a myriad of painful syndromes.  Despite the routine use of these interventions, the literature supporting their use has not been systematically summarized.  These investigators summarized the level of evidence supporting the use of SPG block, RFA and neuro-stimulation.  Medline, Google Scholar, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were reviewed for studies on SPG block, RFA and neuro-stimulation. Studies included in this review were compiled and analyzed for their treated medical conditions, study design, outcomes and procedural details.  Studies were graded using Oxford Center for Evidence-Based Medicine for level of evidence.  Based on the level of evidence, grades of recommendations are provided for each intervention and its associated medical conditions.  A total of 83 publications were included in this review, of which 60 were studies on SPG block, 15 were on RFA, and 8 were on neuro-stimulation.  Of all the studies, 23 had evidence level above case series.  Of the 23 studies, 19 were on SPG block, 1 study on RFA, and 3 studies on neuro-stimulation.  The rest of the available literature was case reports and case series.  The strongest evidence lied in using SPG block, RFA and neuro-stimulation for CH; SPG block also had evidence in treating trigeminal neuralgia, migraines, reducing the needs of analgesics after endoscopic sinus surgery and reducing pain associated with nasal packing removal after nasal operations.  The authors concluded that SPG is a promising target for treating CH using blocks, RFA and neuro-stimulation; SPG block also had some evidence supporting its use in a few other conditions.  Moreover, they stated that most of the controlled studies were small and without replications; further controlled studies are needed to replicate and expand on these previous findings.

An UpToDate review on "Cluster headache: Treatment and prognosis" (May, 2018) states that "There are several promising but unproven methods using neurostimulation to treat medically refractory cluster headache, including sphenopalatine ganglion stimulation, occipital nerve stimulation, noninvasive vagus nerve stimulation, and deep brain stimulation.  All are investigational and require further study to confirm long-term benefit and safety".

Reuter et al (2019) noted that non-invasive neuromodulation therapies for migraine and CH are safe and practical alternative options to pharmacotherapies.  Comparisons of these therapies are difficult because of the heterogeneity in study designs.  In a systematic review of clinical trials, the scientific rigor and clinical relevance of the available data were examined to inform clinical decisions regarding non-invasive neuromodulation.  PubMed, Cochrane Library and ClinicalTrials.gov databases and the World health Organization (WHO)'s International Clinical Trials Registry Platform were searched for relevant clinical studies of non-invasive neuromodulation devices for migraine and CH January 1, 1990 to January 31, 2018), and 71 articles were identified.  This analysis compared study designs using recommendations of the International Headache Society (IHS) for pharmacological clinical trials, the only available guidelines for migraine and CH.  nVNS (3 studies with 350 subjects for CH – 2 for treatment, and 1 for prevention), single-transcranial magnetic stimulation and external trigeminal nerve stimulation (all with regulatory clearance) were well studied compared with the other devices, for which studies frequently lacked proper blinding, sham controls and sufficient population sizes.  nVNS studies demonstrated the most consistent adherence to available guidelines.  Studies of all neuromodulation devices should strive to achieve the same high level of scientific rigor to allow for proper comparison across devices.  Future trials should be rigorously designed to facilitate comparisons across devices.  Well-designed studies, such as those for nVNS that consistently adhere to stringent IHS recommendations for pharmacological trials, may help in the design of future clinical trials until neuromodulation-specific guidelines are established.  Device-specific guidelines for migraine and CH will be soon available; however, adherence to current guidelines for pharmacological trials will remain a key consideration for investigators and clinicians.

The authors stated that the scope of this systematic review was limited by the heterogeneity among the clinical trials analyzed and the unavailability of many of the study results, which precluded a formal systematic meta-analysis of all identified studies; 37 of the 41 studies that were registered with ClinicalTrials.gov or another registry but not published did not have results available, and some did not comprehensively report all study design components examined.  Studies evaluated in this review were heterogeneous in both study design and statistical power (i.e., patient population sample size), which affected the ability to interpret and compare the true effects.  Uniform use of pre-specified outcome measures and other study design components is essential for conducting meta-analyses and cost-benefit analyses to compare different treatment interventions.  It was not the scope of this review to compare the results of these clinical trials as they were heterogeneous.  The results of this review suggested several considerations for the ongoing development of clinical trial guidelines for non-invasive neuromodulation devices in primary headache.  First, in an acute setting, the IHS emphasis on the 1st attack may not be optimal for non-invasive neuromodulation devices.  These devices require patient training to ensure proper administration, which may not be complete at the 1st attack.  To allow for complete patient training with non-invasive neuromodulation devices, it may be advisable to assess the effectiveness of multiple attacks or after proper administration is demonstrated.  Second, the mechanisms of preventive neuromodulation (e.g., electrical or magnetic) treatments in primary headache are indirect, and effectiveness may be multi-dimensional when considering the different pathophysiologies of migraine and CH.  The full preventive potential of a neuromodulation regimen may be best captured with an observational time period equal to that of the IHS-recommended period for pharmacological therapies (i.e., a minimum of 12 weeks).  Third, reproducibility is needed to support the validity of effectiveness outcomes in all therapeutic trials.  Many neuromodulation devices have not yet been evaluated in multiple RCTs.  The field of neuromodulation would benefit if more devices were evaluated in more than 1 rigorous study to support effectiveness outcomes.  Finally, appropriate blinding is a particular challenge in non-invasive neuromodulation trials.  Ideally, the sham device should mimic the active device as closely as possible while avoiding any inadvertent nerve activity.  Sham devices with an active signal risk producing an active therapeutic effect, which could diminish the ability to achieve significant treatment differences.  The suggested modifications to clinical design elements recommended in this review could support scientific rigor and inform the development of recommendations for non-invasive neuromodulation studies in migraine and CH.

NICE’s guideline on “gammaCore for cluster headache” (2019) provided the following recommendations:

  • Evidence supports the case for adopting gammaCore to treat cluster headache in the NHS. gammaCore reduces the frequency and intensity of cluster headache attacks and improves quality of life.
  • gammaCore is not effective in everyone with cluster headache. Treatment with gammaCore should only continue for people whose symptoms reduce in the first 3 months.

Sanchez-Gomez and colleagues (2021) evaluated the safety and effectiveness of peripheral neurostimulation of the SPG in the treatment of refractory CCH.  Various medical databases were used to perform a systematic review of the scientific literature.  The search for articles continued until October 31, 2016, and included clinical trials, systematic reviews and/or meta-analyses, health technology assessment reports, and clinical practice guidelines that included measurements of efficiency/effectiveness or adverse effects associated with the treatment.  The review excluded cohort studies, case-control studies, case series, literature reviews, letters to the editor, opinion pieces, editorials, and studies that had been duplicated or outdated by later publications from the same institution.  Regarding effectiveness, these investigators found that SPG stimulation had positive results for pain relief, attack frequency, medication use, and patients' QOL.  In the results regarding safety, these researchers found a significant number of AEs in the first 30 days following the intervention.  Removal of the device was necessary in some patients.  Little follow-up data, and no long-term data, were available.  The authors concluded that these findings are promising, despite the limited evidence available.  They considered it essential for research to continue into the safety and efficacy of SPG stimulation for patients with refractory CCH.  In cases where this intervention may be indicated, treatment should be closely monitored.

An UpToDate review on “Chronic migraine” (Garza and Schwed, 2021) states that “Noninvasive vagus nerve stimulation -- A noninvasive vagus nerve stimulation (nVNS) device is approved by the US Food and Drug Administration (FDA) for migraine prevention in adult patients.  However, the efficacy of nVNS for migraine prevention is not established.  In 2 randomized controlled trials, the mean reduction in the number of headache days per month was greater for patients assigned to nVNS compared with sham stimulation, but the difference was modest and did not reach statistical significance”.

Furthermore, UpToDate review on “Preventive treatment of episodic migraine in adults” (Smith, 2021) and “Preventive treatment of migraine in children” (Mack, 2021) do not mention gammaCore / vagus nerve stimulation as a management / therapeutic option.

Evers and Summ (2021) examined the current literature on neurostimulation methods in the treatment of cCH.  These neurostimulation methods include DBS, VNS, greater occipital nerve stimulation, sphenopalatine ganglion stimulation, transcranial magnetic stimulation, transcranial direct current stimulation, supraorbital nerve stimulation, and cervical spinal cord stimulation.  Altogether, only nVNS and SPG stimulation are supported by at least 1 positive sham-controlled clinical trial for preventive and acute attack (only SPG stimulation) treatment.  Other clinical trials either did not control at all or controlled by differences in the stimulation technique itself but not by a sham-control.  Case series reported higher responder rates.  The evidence for these neurostimulation methods in the treatment of cCH is poor and in part contradictive.  However, except DBS, tolerability and safety of these methods are good so that in refractory situations application might be justified in individual cases.

Coppola et al (2022) examined the literature on the use of central and peripheral neuromodulation techniques for chronic daily headache (CDH) treatment.  Although the more invasive DBS is effective in CCH, it should be reserved for extremely difficult-to-treat patients.  Percutaneous occipital nerve stimulation has shown similar efficacy to DBS and is less risky in both cCH and chronic migraine (CM).  nVNS is a promising add-on treatment for CCH but not for CM.  Transcutaneous external trigeminal nerve stimulation may be effective in treating CM; however, it has not yet been tested for CH.  Transcranial magnetic and electric stimulations have promising preventive effects against CM and cCH.  Although the precise mode of action of non-invasive neuromodulation techniques remains largely unknown and there is a paucity of controlled trials, they should be preferred to more invasive techniques for treating CDH.

The current UpToDate review on “Cluster headache: Treatment and prognosis” (May, 2021; April 2022) still states that “Neurostimulation techniques, including sphenopalatine ganglion stimulation and vagus nerve stimulation, appear promising but remain investigational.  Destructive surgical procedures are unproven and should be viewed with great caution”.

Anti-Calcitonin Gene-Related Peptide (CGRP) Monoclonal Antibodies (e.g., Eptinezumab, Erenumab, Fremanezumab, and Galcanezumab)

In a randomized, double-blind, placebo-controlled, phase II clinical trial, Tepper and associates (2017) examined the safety and efficacy of erenumab, a fully human monoclonal antibody against the calcitonin gene-related peptide (CGRP) receptor, in patients with chronic migraine.  This was a multi-center study of erenumab for adults aged 18 to 65 years with chronic migraine, enrolled from 69 headache and clinical research centers in North America and Europe.  Chronic migraine was defined as 15 or more headache days per month, of which 8 or more were migraine days.  Patients were randomly assigned (3:2:2) to subcutaneous placebo, erenumab 70-mg, or erenumab 140-mg, given every 4 weeks for 12 weeks.  Randomization was centrally executed using an interactive voice or web response system.  Patients, study investigators, and study sponsor personnel were masked to treatment assignment.  The primary end-point was the change in monthly migraine days from baseline to the last 4 weeks of double-blind treatment (weeks 9 to 12).  Safety end-points were AEs, clinical laboratory values, vital signs, and anti-erenumab antibodies.  The efficacy analysis set included patients who received at least 1 dose of investigational product and completed at least 1 post-baseline monthly measurement.  The safety analysis set included patients who received at least 1 dose of investigational product.  From April 3, 2014, to December 4, 2015, a total of 667 patients were randomly assigned to receive placebo (n = 286), erenumab 70-mg (n = 191), or erenumab 140 mg (n = 190).  Erenumab 70-mg and 140-mg reduced monthly migraine days versus placebo (both doses -6·6 days versus placebo -4.2 days; difference -2.5, 95 % CI: -3.5 to -1.4, p < 0.0001); AEs were reported in 110 (39 %) of 282 patients, 83 (44 %) of 190 patients, and 88 (47 %) of 188 patients in the placebo, 70-mg, and 140-mg groups, respectively.  The most frequent AEs were injection-site pain, upper respiratory tract infection, and nausea.  Serious AEs were reported by 7 (2 %), 6 (3 %), and 2 (1 %) patients, respectively; none were reported in more than 1 patient in any group or led to discontinuation.  A total of 11 patients in the 70-mg group and 3 in the 140-mg group had anti-erenumab binding antibodies; none had anti-erenumab neutralizing antibodies.  No clinically significant abnormalities in vital signs, laboratory results, or electrocardiogram findings were identified.  Of 667 patients randomly assigned to treatment, 637 completed treatment; 4 withdrew because of AEs, 2 each in the placebo and 140-mg groups.  The authors concluded that in patients with chronic migraine, erenumab 70-mg and 140-mg reduced the number of monthly migraine days with a safety profile similar to placebo, providing evidence that erenumab could be a potential therapy for migraine prevention.  Moreover, they stated that further research is needed to understand long-term safety and efficacy of erenumab, and the applicability of this study to real-world settings.

In an open-label study, Ashina and colleagues (2017) evaluated the long-term safety and efficacy of erenumab in patients with episodic migraine (EM).  Patients enrolled in a 12-week, double-blind, placebo-controlled clinical trial who continued in an open-label extension (OLE) study will receive erenumab 70-mg every 4 weeks for up to 5 years.  This pre-planned interim analysis, conducted after all participants had completed the 1-year open-label follow-up, evaluated changes in monthly migraine days (MMD), achievement of greater than or equal to 50 %, greater than or equal to 75 %, and 100 % reductions.  HIT-6 score, Migraine-Specific Quality of Life (MSQ), Migraine Disability Assessment (MIDAS), and safety.  Data reported as observed without imputation for missing data.  Of 472 patients enrolled in the parent study, 383 continued in the OLE with a median exposure to erenumab of 575 days (range of 28 to 822 days).  Mean (SD) MMD were 8.8 (2.6) at parent study baseline, 6.3 (4.2) at week 12 (beginning of OLE), and 3.7 (4.0) at week 64 (mean change from baseline [reduction] of 5.0 days).  At week 64, 65 %, 42 %, and 26 % achieved greater than or equal to 50 %, greater than or equal to 75 %, and 100 % reduction in MMD, respectively.  Mean HIT-6 scores were 60.2 (6.3) at baseline and 51.7 (9.2) at week 64.  MSQ and MIDAS improvements from baseline were maintained through week 64.  Safety profiles during the OLE were similar to those in the double-blind phase, which overall were similar to placebo.  The authors stated that a drawback of the study was the lack of a placebo group for efficacy and safety comparisons.  It was therefore difficult to interpret the possible relatedness of an AE without a placebo arm, and it is difficult to distinguish spontaneously occurring AEs from AEs due to erenumab.  However, the OLE study is ongoing and will continue to provide a long-term safety experience for erenumab.  Moreover, they noted that retention rates, efficacy, patient-reported outcomes, and safety results after 1 year for erenumab in patients with EM appeared promising; thus, these data support further investigation of erenumab as a potential preventive treatment option for patients with EM.

Goadsby and co-workers (2017) examined the effectiveness of erenumab for the prevention of EM.  These researchers randomly assigned patients to receive a subcutaneous injection of either erenumab, at a dose of 70-mg or 140-mg, or placebo monthly for 6 months.  The primary end-point was the change from baseline to months 4 through 6 in the mean number of migraine days per month.  Secondary end-points were a 50 % or greater reduction in mean migraine days per month, change in the number of days of use of acute migraine-specific medication, and change in scores on the physical-impairment and everyday-activities domains of the Migraine Physical Function Impact Diary (scale transformed to 0 to 100, with higher scores representing greater migraine burden on functioning).  A total of 955 patients underwent randomization: 317 were assigned to the 70-mg erenumab group, 319 to the 140-mg erenumab group, and 319 to the placebo group.  The mean number of migraine days per month at baseline was 8.3 in the overall population; by months 4 through 6, the number of days was reduced by 3.2 in the 70-mg erenumab group and by 3.7 in the 140-mg erenumab group, as compared with 1.8 days in the placebo group (p < 0.001 for each dose versus placebo).  A 50 % or greater reduction in the mean number of migraine days per month was achieved for 43.3 % of patients in the 70-mg erenumab group and 50.0 % of patients in the 140-mg erenumab group, as compared with 26.6 % in the placebo group (p < 0.001 for each dose versus placebo), and the number of days of use of acute migraine-specific medication was reduced by 1.1 days in the 70-mg erenumab group and by 1.6 days in the 140-mg erenumab group, as compared with 0.2 days in the placebo group (p < 0.001 for each dose versus placebo).  Physical-impairment scores improved by 4.2 and 4.8 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 2.4 points in the placebo group (p < 0.001 for each dose versus placebo), and every day activities scores improved by 5.5 and 5.9 points in the 70-mg and 140-mg erenumab groups, respectively, as compared with 3.3 points in the placebo group (p <0.001 for each dose versus placebo). The rates of AEs were similar between erenumab and placebo.  The authors concluded that erenumab administered subcutaneously at a monthly dose of 70-mg or 140-mg significantly reduced migraine frequency, the effects of migraines on daily activities, and the use of acute migraine-specific medication over a period of 6 months.  Moreover, they stated that the long-term safety and durability of the effect of erenumab require further study.

Khan and colleagues (2019) stated that migraine and CH are challenging to manage, with no tailored preventive medications available.  Targeting the calcitonin gene-related peptide (CGRP) pathway to treat these headaches may be the first focused therapeutic option to-date, with the potential for promising efficacy.  These investigators systematically searched PubMed and clinicaltrials.gov for RCTs examining the preventive potential of monoclonal antibodies against the CGRP pathway in the treatment of migraine and CH.  The literature search returned a total of 136 records, of which 32 were eligible for review.  Clinical data from phase II and III clinical trials of the 4 monoclonal antibodies targeting the CGRP pathway: eptinezumab, erenumab, fremanezumab, and galcanezumab, collectively showed a positive effect in the preventive treatment of episodic and chronic migraine.  Multiple phase II and III clinical trials are under way to further determine the efficacy and safety of this new drug class.  It may be particularly important to evaluate the cardiovascular effects of long-term CGRP blockade.  In addition, phase III clinical trials are also currently in progress for the preventive treatment of CH.  The authors concluded that efficacy of anti-CGRP monoclonal antibodies suggested a promising future for the many patients suffering from migraine, and possibly also for the smaller but severely-affected population with CH.

Intravenous Valproic Acid for the Treatment of Intractable Migraine

Reiter and colleagues (2005) described the tolerability and effectiveness of rapid intravenous (IV) valproic acid (VPA) infusions in children with severe migraine headache.  These investigators conducted a retrospective chart review of all children who received intravenous VPA at The Children's Hospital Headache Clinic during an 18-month study period.  Baseline intensity of headache pain, time at which maximum relief was attained, pain reduction following therapy, dose and duration of VPA infusion(s), patient's pulse, blood pressure, respiratory rate, and pulse oximetry were collected; adverse events (AEs) were also recorded.  A total of 31 children (age = 15 +/- 2 years; 81 % female) requiring 58 clinic visits and 71 VPA infusions were included.  Most visits (n = 45; 78 %) resulted in only 1 dose of VPA (976 +/- 85 mg infused over 12 +/- 4 minutes) for desired pain relief.  Percent pain reduction in those children was 39.8 %, with time to maximum relief of 63 +/- 31 minutes.  Some children required a second dose of 500 mg (n = 13 visits; 22 %), that was infused over 14 +/- 6 minutes and produced a 57 % reduction in pain intensity from baseline; VPA infusions were well-tolerated; AEs described included cold sensation (n = 1), dizziness (n = 3), nausea (n = 1), possible absence seizure (n = 1), paresthesia (n = 2), and tachycardia (n = 2).  The authors concluded that rapid infusion of IV VPA is generally well-tolerated and may play a role in the management of children with acute migraine headache.  Moreover, they stated that prospective, controlled trials to further investigate this treatment in children are needed.

Frazee and Foraker (2008) reviewed the literature regarding the use of IV valproic acid in aborting an acute migraine attack.  A Medline (1967 to June 2007) and bibliographic search of the English-language literature was conducted using the search terms valproic acid and migraine disorders.  All articles identified through the search were included.  Divalproex sodium is approved by the Food and Drug Administration (FDA) for the prevention of migraine headaches.  The use of IV valproic acid has been studied as a possible treatment for acute migraine.  Available studies are small, mostly open-label and non-placebo-controlled, and used variable doses.  Valproic acid has not been shown to be superior to comparator drugs and was inferior to prochlorperazine in 1 trial.  The authors concluded that IV valproic acid has not been proven effective for acute migraine treatment.  They stated that future trials should be larger, placebo-controlled, and use a standardized dose and outcome measures.

Avraham et al (2010) stated that acute confusional migraine (ACM) is a dramatic, rare manifestation of migraine described mostly for children and adolescents.  There are few data on the treatment of an ACM attack.  Prochlorperazine has been suggested as an effective drug.  The authors of some reports have suggested that valproic acid may play a role in the prevention of ACM and as treatment for acute migraine headache in the adult population.  However, this medication has not been reported as first-line, acute therapy for ACM.  The authors reported on the case of a 12-year old girl who presented with an ACM attack that resolved rapidly after IV administration of valproic acid.  (This was a single-case study on the treatment of acute migraine).

Ketamine Infusion Combined With Magnesium for the Treatment of Cluster Headache

Moisset and colleagues (2017) noted that CH is a rare, highly disabling primary headache condition.  As NMDA receptors are possibly overactive in CH, NMDA receptor antagonists, such as ketamine, could be of interest in patients with intractable CH.  These researchers reported the findings of 2 Caucasian men, aged 28 and 45 years, with chronic intractable CH, received a single ketamine infusion (0.5 mg/kg over 2 hours) combined with magnesium sulfate (3,000 mg over 30 minutes) in an out-patient setting.  This treatment led to a complete relief from symptoms (attack frequency and pain intensity) for 1 patient and partial relief (50 %) for the second patient, for 6 weeks in both cases.  The authors concluded that the NMDA receptor is a potential target for the treatment of chronic CH; randomized, placebo-controlled studies are needed to establish both safety and efficacy of this approach.

Ketamine Intra-Nasal Administration / Intravenous Infusion for the Treatment of Migraines

In a systematic review and meta-analysis, Orhurhu et al (2019) synthesized evidence from RCTs to evaluate the effectiveness of IV ketamine infusions for pain relief in chronic conditions and examined if any pain classifications or treatment regimens are associated with greater benefit.  These investigators searched Medline, Embase, and Google Scholar, as well as the clinicaltrials.gov website from inception through December 16, 2017 for RCTs comparing IV ketamine to placebo infusions for chronic pain that reported outcomes for greater than or equal to 48 hours after the intervention.  A total of 3 reviewers independently screened the studies, pooled the data, and appraised risk of bias.  Random-effects model was used to calculate weighted mean differences (WMDs) for pain scores and secondary outcomes.  The primary outcome was the lowest recorded pain score at greater than or equal to 48 hours after cessation of treatment.  Secondary outcomes included responder rate and adverse effects.  Among 696 studies assessed for eligibility, 7 met inclusion criteria.  All studies except 1 were at high risk of bias.  These studies randomly assigned 211 patients with neuropathic (n = 2), mixed (n = 2), and non-neuropathic (nociplastic or nociceptive) (n = 3) pain; 3 studies reported significant analgesic benefit favoring ketamine, with the meta-analysis revealing a small effect up to 2 weeks after the infusion (p < 0.0001).  In the 3 studies that reported responder rates, the proportion with a positive outcome was greater in the ketamine than in the placebo group (p = 0.029; I = 0.0 %).  No differences were noted based on pain classification or condition.  Compared to low-dose ketamine studies and investigations that evaluated non-CRPS conditions, a small but non-significant greater reduction in pain scores was found among studies that either employed high-dose ketamine therapy (p = 0.213) or enrolled CRPS patients (p = 0.079).  The authors concluded that evidence suggested that IV ketamine provided significant short-term analgesic benefit in patients with refractory chronic pain, with some evidence of a dose-response relationship.  Moreover, these researchers stated that larger, multi-center studies with longer follow-ups are needed to better select patients and determine the optimal therapeutic protocol.  Based on the quality of the evidence from studies in this review and the strength of effect, it is recommended that IV ketamine be used, on a case-by-case basis, as a primary analgesic in patients with chronic pain refractory to more conventional treatments (GRADE: Weak recommendation; low evidence)

The authors stated that this review had several drawbacks including the small number of patients enrolled in trials (median sample size of 24 subjects), which may be attributed to the lack of industry funding for a generic medication, and the lack of standardization for infusion regimens, patient selection, and follow-up periods.  In general, studies for medications that receive FDA approval go through a well-defined process that includes determining the optimal dose via phase-I and -II clinical trials, followed by large-scale randomized trials with stringent selection criteria that typically evaluate participants for 12 weeks.  In contrast, the studies in this review treated small number of patients with refractory pain using myriad dose regimens, and often failed to include secondary outcomes or evaluate intermediate-term effects.  Clinical heterogeneity in the studies included in this review was a significant challenge they attempted to examine but were unable to identify causes.  Furthermore, the difference in effect size required to detect a statistically significant improvement in pain score may not fully reflect the true clinical effect.  For example, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines note, “… in evaluating a new analgesic, if a 2-point decrease on a 0 to 10 numerical rating scale of pain intensity is considered a clinically important improvement for an individual, it should not be inferred that a 2-point difference in pain reduction between the analgesic and placebo must occur before the treatment benefit can be considered clinically important”.  Due to the subjectivity of reported pain scores among patients, wide variations in response, and high placebo response rates, the clinical relevance of the differences in effect size is hard to determine.  Finally, chronic pain management includes not only the reduction of pain but also improved QOL, which should be measured via validated instruments.  Unfortunately, their analysis could not account for these outcomes due to limited availability of outcome data.

Thompson et al (2019) conducted a meta-analysis of controlled trials that used experimental models of acute pain and hyperalgesia to examine the analgesic effects of NMDA receptor (NMDAR) antagonists.  A total of 6 major databases were systematically searched (to March 2018) for studies using human evoked pain models to compare NMDAR antagonists with no-intervention controls.  Pain outcome data were analyzed with random-effects meta-analysis.  Searches identified 70 eligible trials (n = 1,069).  Meta-analysis found that low-dose ketamine (less than 1 mg/kg) produced a decrease in hyperalgesic area (SMD 0.54, 95 % CI: 0.34 to 0.74, p < 0.001) and a 1.2-point decrease (95 % CI: 0.88 to 1.44, p < 0.001) in pain ratings from 4.6 to 3.4 on a 0-10 scale (a 26 % reduction).  Similar analgesia was observed for acute and hyperalgesic models and was constant across the dosing range (0.03 to 1.00 mg/kg).  Moderate-to-high variability in effect size was observed and mild side effects (e.g., sedation, sensory disturbance) were common.  No effects of dextromethorphan were found.  Findings provided robust evidence for analgesic and anti-hyperalgesic effects of ketamine, supporting its use for acute and chronic pain management.  However, pain relief was modest, suggesting ketamine may potentially be most useful when opioids are contraindicated, rapid analgesia is required, or for pain resistant to conventional medication.

Pribish et al (2020) stated that “Ketamine, a non-selective NMDA receptor antagonist, is used widely in medicine as an anesthetic agent.  However, ketamine's mechanisms of action lead to widespread physiological effects, some of which are now coming to the forefront of research for the treatment of diverse medical disorders.  This paper aims at reviewing recent data on key non-anesthetic uses of ketamine in the current literature.  MEDLINE, CINAHL, and Google Scholar databases were queried to find articles related to ketamine in the treatment of depression, pain syndromes including acute pain, chronic pain, and headache, neurologic applications including neuroprotection and seizures, and alcohol and substance use disorders.  It can be concluded that ketamine has a potential role in the treatment of all of these conditions.  However, research in this area is still in its early stages, and larger studies are required to evaluate ketamine's efficacy for non-anesthetic purposes in the general population”.

Turner et al (2020) noted that ketamine has recently emerged as a promising therapeutic alternative for abortive migraine therapy, likely secondary to N-methyl-d-aspartate antagonism.  Most reports examined adults and the IV route; few used intra-nasal administration or pediatric populations.  Given the limited evidence for intra-nasal ketamine in pediatric migraine populations, these researchers retrospectively reviewed their experience to further characterize safety and effectiveness of intra-nasal ketamine in this population.  They examined the use of intra-nasal ketamine at 0.1 to 0.2 mg/kg/dose up to 5 doses in pediatric migraineurs.  Pain scores (scale = 0 to 10) were recorded at baseline and after each dose.  Response was characterized as pain score reduction to 0 to -3 and/or reduction of at least 50 %.  A total of 25 encounters (25 of 34; 73.5 %) were responders (mean pain score reduction of -7.2 from admission to treatment completion).  Overall pain reduction from admission to discharge in the entire study population was 66.1 %; side effects were mild and transient.  The authors concluded that their experience with intra-nasal ketamine has promising outcomes in both pain relief and side effect minimization.

The authors stated the retrospective design of this study was its main drawback.  Moreover, these researchers stated that future studies to examine most effective regimen as well as sequence within current guideline recommendations are needed.  Head-to-head comparison with current standards of care, such as triptans and DHE, would further delineate intra-nasal ketamine’s true place within the abortive migraine treatment pathway.  For instance, a randomized, prospective head-to-head comparison of DHE and intra-nasal ketamine in patients presenting to an ED for abortive migraine therapy would be especially useful.  Alternative designs could include patients presenting to an ED for abortive migraine therapy; those with a contraindication to DHE would be assigned to intra-nasal ketamine while the remainder would receive IV DHE as usual.  Efficacy could then be more accurately compared in both designs.  Additional studies of merit include examining long-term effects such as depression scores, psychological side effects, tolerance, instances of rebound migraines, and propensity toward patterns of abuse given ketamine’s social stigma.

Chah et al (2021) stated that migraine headaches are the 2nd leading cause of disability worldwide and are responsible for significant morbidity, reduction in the QOL, and loss of productivity on a global scale.  In a systematic review and meta-analysis, these researchers examined the effectiveness of ketamine on migraines and other primary headache disorders compared to placebo and other active interventions, such as midazolam, metoclopramide/diphenhydramine, and prochlorperazine/diphenhydramine.  They carried out an electronic search of databases published up to February 2021, including Medline via PubMed, Embase, Web of Science, and Cochrane Library, a hand search of the bibliographies of the included studies, as well as literature and systematic reviews found through the search to identify RCTs examining ketamine in the treatment of migraine/headache disorders compared to the placebo.  These investigators evaluated the risk of bias according to the Cochrane Handbook guidelines.  The initial search strategy yielded 398 unduplicated references, which were independently assessed by 3 review authors.  After evaluation, this number was reduced to 5 RCTs (2 unclear risk of bias and 3 high risk of bias).  The total number of patients in all the studies was 193.  Due to the high risk of bias, small sample size, heterogeneity of the outcomes reported, and heterogeneity of the comparison groups, the quality of the evidence was very low.  One RCT reported that intra-nasal ketamine was superior to intra-nasal midazolam in improving the aura attack severity, but not duration, while another reported that intra-nasal ketamine was not superior to metoclopramide and diphenhydramine in reducing the headache severity.  In one trial, subcutaneous ketamine was superior to saline in migraine severity reduction; however, IV ketamine was inferior to IV prochlorperazine and diphenhydramine in another study.  The authors concluded that further double-blind controlled studies are needed to examine the effectiveness of ketamine in treating acute and chronic refractory migraines and other primary headaches using intra-nasal and subcutaneous routes.  These studies should include a long-term follow-up and different ketamine dosages in diagnosed patients following international standards for diagnosing headache/migraine.

These researchers stated that the drawbacks of this study included the small number of included studies.  The method of delivery varied throughout the studies, which made the dose comparison difficult.  Furthermore, in many of the control groups, the route of the delivery (such as with IV saline) and the additional medications could potentially have a confounding effect in the comparison of ketamine with control therapies.

Mojica et al (2021) discussed the available evidence and therapeutic considerations for IV drug therapy for refractory chronic migraine (rCM).  The use of aggressive inpatient infusion therapy consisting of IV lidocaine or ketamine, along with other adjunctive medications, has become increasingly common for these patients when all other treatments have failed.  There is a clear need for prospective studies in this population comprised of patients who have largely been excluded from other studies.  These researchers noted that most, if not all, patients with rCM have experienced failure with the Raskin protocol when used without the co-administration of multiple other infusions.  Therefore, a modified, multi-day, aggressive inpatient infusion approach has become increasingly common for rCM and incorporates a variety of other medications, including co-administration with continuous lidocaine or ketamine infusions in a closely monitored setting to mitigate serious AEs.  These investigators stated that a widely accepted standardized set of criteria for rCM diagnosis is needed to further examine the unique demographics, pathophysiological mechanisms, risk factors, and prognostic factors for rCM.  This will facilitate the future research that is needed to identify more effective, safe, and tailored therapeutic approaches to better complement a holistic, multi-disciplinary plan of care.  In addition, these investigators stated that a variety of concerns regarding potentially harmful effects of ketamine arose from data in patients chronically abusing the drug.  Studies have identified long-term effects, including focal decrease in brain connectivity, focal decrease in cortical volumes, impairment within certain cognitive domains, and white matter changes.  However, there are several confounding variables in these studies, and it is not possible to establish causality or implications of the findings from this relatively weak evidence.  These researchers stated that large, controlled longitudinal studies are needed to further examine the long-term effects of ketamine.

In a prospective, observational pilot study (n = 6 patients), Schwenk et al (2021) compared the effects of lidocaine and (R,S)-ketamine infusions and performed metabolite analyses of (R,S)-ketamine to determine its metabolic profile patients with refractory chronic migraine.  One of (R,S)-ketamine's metabolites, (2R,6R)-hydroxynorketamine, has been shown in animal studies to reduce pain, but human studies in patients undergoing continuous (R,S)-ketamine infusions for migraine are lacking.  All 6 patients tolerated both infusions well with mild adverse effects.  The baseline mean pain rating (0 to 10 NRS) decreased from 7.5 ± 2.2 to 4.7 ± 2.8 by end of lidocaine treatment (p ≤ 0.05); but increased to 7.0 ± 1.4 by the post-discharge visit at 4 weeks (p > 0.05 versus baseline).  The baseline mean pain rating before ketamine treatment was 7.4 ± 1.4, which decreased to 3.7 ± 2.3 by the end of the hospitalization (p ≤ 0.05); but increased to 7.2 ± 1.7 by the post-discharge visit at 6 weeks (p > 0.05 versus baseline).  For the primary outcome the change in pain from baseline to end of treatment was greater for ketamine than lidocaine (-3.7 versus -2.8; p ≤ 0.05); but this has minimal clinical significance.  The authors stated that patients with refractory chronic migraine have continuous pain and substantial disability.  These investigators have shown that both lidocaine and (R,S)-ketamine infusions hold potential to reduce short-term pain and “break the cycle” of constant symptoms, with a more pronounced reduction in pain score with (R,S)-ketamine treatment.  In this pilot study, no statistically significant correlation was found between pain scores and circulating levels of (R,S)-ketamine or its metabolites.  Circulating concentrations of (2R,6R)-HNK, however, were at their highest between days 3 and 5, the period of time when pain was at its lowest, suggesting the possibility that this molecule could hold promise as an analgesic that lacks (R,S)-ketamine’s psychomimetic adverse effects, although this should be interpreted with caution given the small sample size.  These results suggested that future studies should be performed to further investigate this.

The authors stated that this study had several drawbacks.  In addition to the small sample size, retrospectively collected pain ratings from the lidocaine hospitalizations were not always assessed at consistent intervals and could be subject to influence based on the time of day and medications given just before assessment.  Follow-up pain ratings were in some cases obtained via telephone call several months following treatment and could be subject to recall bias.  These findings may not be generalizable to other practices where lower (R,S)-ketamine or lidocaine doses were used, or different adjunctive medications were used.  These findings also may not apply to less refractory patients.  Finally, this was an open-label study, and these researchers were unable to control for the additional medications that patients were given during admission, such as dihydroergotamine and ketorolac.  It was unknown how these or other medications might have influenced pain.  These researchers stated that future studies including pre-treatment and post-treatment metabolic phenotyping for CYP2B6 and CYP2A6 activity and urinary excretion are needed to aid in examining if those enzymes play a role in the pharmacological mechanisms responsible for the observed effects.

Ray et al (2022) noted that the use of lidocaine (lignocaine) and ketamine infusion in the inpatient treatment of patients with headache disorders is supported by small case series.  In a retrospective, cohort study, these researchers examined the effectiveness, duration and safety of lidocaine and ketamine infusions.  Patients admitted between January 1, 2018 and July 31, 2021 were identified by ICD code and electronic prescription.  Effectiveness of infusion was determined by reduction in VAS, and patient demographics were collected from review of the hospital electronic medical record.  Through the study period, a total of 83 infusions (50 lidocaine, 33 ketamine) were initiated for a headache disorder (77 migraine, 3 NDPH, 2 SUNCT, 1 cluster headache).  In migraine, lidocaine infusion achieved a greater than or equal to 50 % reduction in pain in 51.1 % over a mean of 6.2 days (SD 2.4).  Ketamine infusion was associated with a greater than or equal to 50 % reduction in pain in 34.4 % over a mean of 5.1 days (SD 1.5).  Side effects were observed in 32 % and 42.4 %, respectively.  Infusion for MOH resulted in successful withdrawal of analgesia in 61.1 % of lidocaine, and 41.7 % of ketamine infusions.  The authors concluded that lidocaine and ketamine infusions were an effective inpatient treatment for headache disorders; however, these approaches were associated with prolonged LOS and possible side-effects.  Moreover, these researchers stated that further prospective study is needed to confirm these findings.  These investigators noted that overall adverse effects of both infusions in this cohort was high; and further prospective, controlled studies are needed to guide treatment decisions in the inpatient treatment of migraine and headache disorders.

The main drawback of this study was its retrospective design.  Data such as the presence of complications of migraine such as status migrainosus or MOH relied upon the accuracy of documentation at the time, and as such were most liable to under-reporting in this study.  Data detailing all trialed alternate therapies, timing of treatment failure, and duration of symptoms before commencement of infusion was not available.  Similarly, data following discharge was also unavailable, and as such duration of effect, MOH withdrawal or pain freedom was unknown.  Finally, the choice of IV infusion for individual patient was made by the treating neurologist at the time; thus, was subject to patient factors, as well as individual prescribing habits and biases.

Transcutaneous Supraorbital Neurostimulation for the treatment of Migraines

Piquet et al (2011) stated that transcutaneous neurostimulation (TNS) at extra-cephalic sites is a well-known treatment of pain.  Thanks to recent technical progress, the Cefaly device now also allows supraorbital TNS.  During observational clinical studies, several patients reported decreased vigilance or even sleepiness during a session of supraorbital TNS.  These researchers examined in more detail the potential sedative effect of supraorbital TNS, using standardized psychophysical tests in healthy volunteers.  They performed a double-blind, cross-over, sham-controlled study on 30 healthy subjects.  Subjects underwent a series of 4 vigilance tests (Psychomotor Vigilance Task, Critical Flicker Fusion Frequency, Fatigue Visual Numeric Scale, d2 test).  Each subject was tested under 4 different experimental conditions: without the neurostimulation device, with sham supraorbital TNS, with low frequency supraorbital TNS and with high frequency supraorbital TNS.  As judged by the results of 3 tests (Psychomotor Vigilance Task, Critical Flicker Fusion Frequency, Fatigue Visual Numeric Scale) there was a statistically significant (p < 0.001) decrease in vigilance and attention during high frequency TNS, while there were no changes during the other experimental conditions.  Similarly, performance on the d2 test was impaired during high frequency TNS, but this change was not statistically significant.  The authors concluded that supraorbital high frequency TNS applied with the Cefaly device decreased vigilance in healthy volunteers.  They stated that additional studies are needed to determine the duration of this effect, the underlying mechanisms and the possible relation with the stimulation parameters.  Meanwhile, this effect opened interesting perspectives for the treatment of hyperarousal states and, possibly, insomnia.  This study did not address the use of Cefaly for the treatment of migraines.

Russo and Tessitore (2015) noted that transcutaneous supraorbital neurostimulation (tSNS) has been recently found superior to sham stimulation for episodic migraine prevention in a randomized trial.  These researchers evaluated both the safety and efficacy of a brief period of tSNS in a group of patients with migraine without aura (MwoA).  They enrolled 24 consecutive patients with MwoA experiencing a low frequency of attacks, which had never taken migraine preventive drugs in the course of their life.  Patients performed a high frequency tSNS and were considered "compliant" if they used the tSNS for greater than or equal to 2/3 of the total time expected.  For this reason, 4 patients were excluded from the final statistical analysis.  Primary outcome measures were the reduction migraine attacks and migraine days per month (p < 0.05).  Furthermore, these investigators evaluated the percentage of patients having at least 50 % reduction of monthly migraine attacks and migraine days.  Secondary outcome measures were the reduction of headache severity during migraine attacks and HIT-6 (Headache Impact Test) rating as well as in monthly intake of rescue medication (p < 0.05).  Finally, compliance and satisfaction to treatment and potential adverse effects related to tSNS have been evaluated.  Between run-in and second month of tSNS treatment, both primary and secondary end-points were met.  Indeed, these researchers observed a statistically significant decrease in the frequency of migraine attacks (p < 0.001) and migraine days (p < 0.001) per month.  They also demonstrated at least 50 % reduction of monthly migraine attacks and migraine days in respectively 81 % and 75 % of patients.  Furthermore, a statistically significant reduction in average of pain intensity during migraine attacks (p = 0.002) and HIT-6 rating (p < 0.001) and intake of rescue medication (p < 0.001) has been shown.  All patients showed good compliance levels and no relevant AEs.  The authors concluded that in patients experiencing a low frequency of attacks, significant improvements in multiple migraine severity parameters were observed following a brief period of high frequency tSNS.  Thus, tSNS may be considered a valid option for the preventive treatment of migraine attacks in patients who cannot or are not willing to take daily medications, or in whom low migraine frequency and/or intensity would not require pharmacological preventive therapies.

The authors stated that this study had several drawbacks.  First, these researchers did not use a tSNS sham device and, therefore, they could not rule-out the possible role of a placebo-effect on primary and secondary outcomes in this study.  In particular, several factors may contribute to the remedial efficacy of tSNS in these patients such as alternative form of medical therapy, patients naïve to preventive treatment and observation period limited to no more than 2 months.  However, the placebo-effect appeared to have a lower impact in the prophylactic treatment than in the acute treatment of migraine attacks.  This could be due to the inherent variability in response measured over a period of months compared with one measured over a period of hours.  Moreover, the effective tSNS superiority respect to sham stimulation for the prevention of migraine headaches has been extensively demonstrated in a previous RCT in a large cohort of patients with migraine.  Nevertheless, in partial disagreement with these findings, Schoenen and colleagues (2013) did not show statistically significant effect on migraine attacks at 2 months, although ameliorating effect on migraine severity vanished in sham treated patients and amplified in effectively treated patients at this time of the study.  These investigators suggested that a greater migraine severity (i.e., frequency of migraine per month and disease duration) and, probably, previous pharmacological anti-migraine preventive therapies may cause a different impact on pain pathways in the 2 migraine populations and consequent different response to the tSNS treatment.  Second, the lack of blinding may weaken the results of the present study.  However, empirical evidence showed that although double-blind RCTs are the gold standard for proving efficacy of a therapeutic procedure, they often suffer from lack of generalizability.  Therefore, the authors believed that these data, in addition to the previous effectiveness and safety results of double-blind RCTs (Schoenen and colleagues, 2013) could provide additional information which may be useful in everyday clinical practice.  Finally, although these findings were consistent with previous studies, the sample size was relatively small (n = 20 available for final analysis).  Thys, they stated that further studies are needed to corroborate these findings and to explore tSNS efficacy and tolerability in patients with migraine compared with preventive treatments used in clinical practice.

The authors stated that this study had several drawbacks.  Because of the small number of evaluable patients (n = 14), the results must be taken with caution.  As discussed, the study design did not allow assessing a direct causal effect of eTNS on brain metabolism since a sham condition is missing.  These investigators found sham stimulation for 3 months would be unethical knowing that there is evidence for eTNS efficacy from an RCT.  The compliance rate with eTNS therapy was rather low.  For preventive drug treatments, adherence varies from 48 % to 94 % between studies.  Neurostimulation was more time consuming (20 mins daily in this study), which provoked lower compliance.  In the PREMICE trial, patients had a compliance rate of 62 %, while participants renting the eTNS Cefaly device via the internet used it on average 58 % of the recommended time.  In this study, the authors considered patients who performed at least 30 % of the sessions as "compliant"; this threshold was chosen on an empirical basis and experience from clinical practice showing that patients may benefit from eTNS with non-daily use of the device.  However, the minimal time of use to obtain a clinical improvement in migraine is unknown, and may vary between patients.  Although the headache diaries allowed monitoring global intake of acute medications for each patient, they did not allow these researchers to determine the precise proportion of drugs taken within each of the pharmacological classes, analgesics, NSAIDs, triptans, nor its possible change after eTNS. I t is unlikely, however, that such a change would have influenced brain metabolism.

Russo et al (2017) examined the functional re-organization of the pain processing network during trigeminal heat stimulation (THS) after 60 days of eTNS in migraine without aura (MwoA) patients between attacks.  Using whole-brain BOLD-fMRI, functional response to THS at 2 different intensities (41 and 51°C) was investigated interictally in 16 adults MwoA patients before and after eTNS with the Cefaly device.  These researchers calculated the percentage of patients having at least a 50 % reduction of monthly migraine attacks and migraine days between baseline and the last month of eTNS.  Secondary analyses evaluated associations between BOLD signal changes and clinical features of migraine.  Before eTNS treatment, there was no difference in BOLD response between MwoA patients and healthy controls (HC) during low-innocuous THS at 41°C, whereas the perigenual part of the right anterior cingulate cortex (ACC) revealed a greater BOLD response to noxious THS at 51°C in MwoA patients when compared to HC.  The same area demonstrated a significant reduced BOLD response induced by the noxious THS in MwoA patients after eTNS (p = 0.008).  Correlation analyses showed a significant positive correlation between ACC BOLD response to noxious THS before eTNS treatment and the decrease of ACC BOLD response to noxious THS after eTNS.  Moreover, a significant negative correlation in the migraine group after eTNS treatment between ACC functional activity changes and both the perceived pain ratings during noxious THS and pre-treatment migraine attack frequency has been found.  The authors concluded that the findings of this study suggested that eTNS treatment with the Cefaly® device induced a functional anti-nociceptive modulation in the ACC that is involved in the mechanisms underlying its preventive anti-migraine efficacy.  Nevertheless, these researchers stated that further observations to confirm whether the observed fMRI effects of eTNS are both related to clinical improvement and specific to anti-nociceptive modulation in migraine patients are mandatory.

The authors noted that this study had several drawbacks.  First, these investigators did not use an eTNS sham device and, therefore, they could not rule out the possible role of a placebo effect in imaging and clinical data.  However, the superiority of effective eTNS respect to sham stimulation for the prevention of migraine headaches has already been demonstrated in a randomized, sham-controlled trial.  Second, the HC did not undergo eTNS treatment, thus, the authors could not determine if the eTNS-induced changes in ACC activation by THS were specific to migraineurs.  By corollary, these researchers could not exclude that these changes could be due to the clinical improvement of patients after eTNS, rather than to the neurostimulation treatment itself.

An UpToDate review on "Preventive treatment of migraine in adults" (Bajwa and Smith, 2019a) states that "Transcutaneous nerve stimulation – Although data are limited, the findings of a controlled trial conducted at 5 tertiary headache centers in Belgium suggest that treatment with a supraorbital transcutaneous electrical nerve stimulator is beneficial for patients with episodic migraine.  The trial randomly assigned 69 adults with migraine (with or without aura) to active or sham stimulation for 20 minutes daily for three months.  Exclusion criteria included the use of preventive treatment for migraine in the 3 months prior to enrollment.  At 3 months of treatment, the responder rate, defined as the percentage of subjects with a ≥ 50 % reduction in migraine days per month, was significantly higher for the active stimulation compared with the sham stimulation group (38.2 versus 12.1 %), as was the mean reduction in monthly migraine days (-2.1 versus +0.3 days).  There were no adverse events in either group.  Limitations to this trial include small effect size, low patient numbers, and uncertainty in concealing treatment allocation, given that active stimulation causes intense paresthesia. The device used in this trial is approved for marketing in the United States, Canada, Europe, and several additional countries … Non-pharmacologic measures that may be beneficial for migraine headache prevention include aerobic exercise, biofeedback, other forms of relaxation training, cognitive-behavioral therapies, acupuncture, and transcutaneous electrical nerve stimulation".

Furthermore, an UpToDate review on "Preventive treatment of migraine in children" (Mack, 2019a) does not mention "Cefaly / supraorbital transcutaneous electrical nerve stimulation" as a management option.

Intramuscular Injection of Toradol (Ketorolac tromethamine) for the treatment of Migraines

In a prospective, randomized, double-blind trial, Duarte et al (1992) compared the effectiveness of IM ketorolac with that of meperidine and hydroxyzine in the treatment of acute migraine headache.  A total of 47 adult patients with migraines enrolled on 50 visits.  Patients were randomly assigned to receive a single injection of either 60 mg ketorolac (group 1) or 100 mg meperidine and 50 mg hydroxyzine (group 2).  Pain assessment was made using both visual-analog scale (VAS) and verbal descriptor scale.  At 60 mins, 15 patients (60 %) from group 1 (n = 25) and 14 patients (56 %) from group 2 (n = 25) reported a great deal of complete relief (p = 0.77; 60-min mean pain relief scores (3.35 versus 3.37) were [not] different (p = 0.76); 9 patients (36 %) from group 1 and 7 patients (28 %) from group 2 required additional analgesia (p = 0.76).  The authors concluded that ketorolac was as effective as meperidine and hydroxyzine for the treatment of acute migraine headache.

Turkewitz et al (1992) noted that 61 separate self-injections of ketorolac tromethamine (Toradol) by 16 patients diagnosed with episodic migraine with or without aura were evaluated over a 90-day period for safety, efficacy of pain reduction, and the ability of this therapy program to prevent the necessitation of ED acute care.  Prior to initiation of treatment, patients were formally instructed on IM injection techniques by a member of the nursing staff.  Patients were instructed to call upon the onset of a severe headache interfering with daily functioning and, then, were permitted to proceed with the injection.  Headache intensity ratings were collected prior to injection and intermittently for the following 24 hours.  The results demonstrated safety and efficacy of this form of therapy.  A significant percent of ketorolac usages (64 %) resulted in a good response and significant reduction in head pain; 23 % of ketorolac usages resulted in a mild response; and only 13 % of usages provided no relief.  Furthermore, 13 % of all usages failed to prevent the use for ED treatment.

In a prospective, randomized, double-blind trial, Shrestha et al (1996) compared IM ketorolac troinethamine with intravenous (IV) chlorpromazine hydrochloride in treating acute migraine.  These researchers examined the clinical effectiveness of 60 mg of IM ketorolac tromethamine with 25 mg of IV chlorpromazine hydrochloride in patients with acute migraine headache seen in the ED.  Pain intensity, quantitated using the Wong-Baker Faces Rating Scale, was measured every 30 mins for 2 hours in the ED.  Patients returned pain scores at 6, 12, 24, and 48 hours by mail.  A total of 15 patients were entered into each treatment arm.  No differences were seen between the mean pain scores or the mean change in pain scores.  The ketorolac group mean (+/- SEM) pain score decreased from 4.07 +/- 0.18 to 0.73 +/- 0.3 in 2 hours.  The chlorpromazine group pain score decreased from 4.47 +/- 0.17 to 0.87 +/- 0.4; 2 of the 3 non-responders responded to the alternate group's treatment.  No side effects were seen.  The authors concluded that using 60 mg of IM ketorolac tromethamine was as effective as 25 mg of IV chlorpromazine hydrochloride in the treatment of acute migraine headache.  They noted that patients who did not respond to one of these medications may respond to the other.

A paper entitled "Evidence-Based Guidelines for Migraine Headache in the Primary Care Setting: Pharmacological Management of Acute Attacks" (Matchar et al, 2000) stated that "Ketorolac IM is an option that may be used in a physician-supervised setting, although conclusions regarding clinical efficacy cannot be made at this time (Grade C)".

Furthermore, an UpToDate review on "Acute treatment of migraine in adults" (Bajwa and Smith, 2019b) states that "Emergency settings – Patients who present with migraine in emergency settings generally have unusually severe attacks, and in many cases their customary acute migraine treatment has failed to provide relief.  The treatment of migraine attacks in the emergency department or other urgent care settings follows the same principles as treatment in non-urgent settings with the obvious difference that parenteral medications are more readily available.  The following are reasonable options, with evidence of efficacy from randomized trials [ketorolac 30 mg IV or 60 mg IM is listed as one of the options].  A 2013 systematic review of 8 randomized trials found that parenteral ketorolac (30 mg intravenous or 60 mg intramuscular) was effective for acute migraine in comparison with other agents, including intranasal sumatriptan, IV prochlorperazine, IV chlorpromazine, and IV dihydroergotamine combined with metoclopramide"

Also, an UpToDate review on "Acute treatment of migraine in children " (Mack, 2019b) states that "Ketorolac (intravenous [IV]) may also be beneficial for pediatric migraine.  A randomized trial comparing prochlorperazine with ketorolac found that IV ketorolac (0.5 mg/kg, maximum 30 mg) successfully treated migraine within 60 minutes in 55 %  of 29 children, with a 50 %or greater reduction in the pain score.  However, IV prochlorperazine was more effective.  In children 2 to 16 years of age, ketorolac is approved for use only as a single intramuscular or IV dose".

According to the product labeling, ketorolac tromethamine is indicated for the short-term (≤5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a post-operative setting. Therapy should always be initiated with intravenous or intramuscular dosing of ketorolac tromethamine, and oral ketorolac tromethamine is to be used only as continuation treatment, if necessary. The labeling states that the total combined duration of use of ketorolac tromethamine injection and oral ketorolac tromethamine is not to exceed 5 days of use because of the potential of increasing the frequency and severity of adverse reactions associated with the recommended doses. The labeling states that patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine therapy is not to exceed 5 days.

Intramuscular Magnesium for the Treatment of Migraines

An UpToDate review on "Preventive treatment of migraine in adults" (Bajwa and Smith, 2019a) states that "There is only limited evidence supporting magnesium supplementation for migraine prevention in adults.  Several small randomized controlled trials using variable formulations of oral magnesium produced mixed results, with 3 trials finding a statistically significant benefit for magnesium, and 1 trial finding no benefit.  Diarrhea and gastrointestinal discomfort were the most common side effects of magnesium supplementation in these trials".

An UpToDate review on "Preventive treatment of migraine in children" (Mack, 2019a) states that "Other nutraceuticals sometimes used for the pediatric migraine prevention include coenzyme Q10, butterbur, ginkgolide B, magnesium, and polyunsaturated fats, though supporting data are limited and generally low-quality".

UpToDate review on "Acute treatment of migraine in adults" (Bajwa and Smith, 201ba), and "Acute treatment of migraine in children" (Mack, 2018a) do not mention intramuscular magnesium as a therapeutic option.

An UpToDate review on "Chronic migraine" (Garza and Schwedt, 2019) states that "Second-line pharmacologic agents for chronic migraine include botulinum toxin injections, verapamil, other beta blockers, gabapentin, magnesium, riboflavin, candesartan, and other tricyclic antidepressants.  Third-line agents include feverfew, tizanidine, memantine, pregabalin, cyproheptadine, and zonisamide.  Botulinum toxin injections are modestly superior to placebo for the treatment of chronic migraine.  The remaining drugs have been studied only on a limited basis, and their effectiveness in migraine prophylaxis is uncertain.  For patients with chronic migraine who have failed treatment with first-line agents, we suggest use of onabotulinumtoxinA injections (Grade 2B) or other second-line agents (Grade 2C).  Third-line agents are alternatives for those who fail treatment with first and second-line agents".

Manual Trigger Point Treatment for Cluster Headache and Migraines

Garcia-Leiva et al (2007) stated that tenderness and referred pain have been described in migraine and involved in its pathogenesis.  These researchers examined the prophylactic effectiveness of ropivacaine injections during a 12-week period.  A total of 52 patients agreed to participate in the study; trigger points (TrPs) were examined by manual palpation and injected weekly with 10-mg ropivacaine.  The frequencies of migraine attacks were recorded from 4 weeks before the beginning of injections until 4 weeks after the last one, and a Clinical Global Impression improvement scale was completed in the final visit.  All of the subjects had 1 or more TrPs, located in temporal and/or suboccipital areas in most of the cases.  In 9 (17.3 %) patients the frequency of attacks was reduced greater than or equal to 50 %, and in 19 (36.5 %) cases the reduction was comprised between 11 % and 49 %.  A total of 31 (59.6 %) patients reported to be much or very much improved after finishing the injection period.  In 11 cases rescue medication intake was reduced greater than or equal to 50 % in comparison with baseline period, and the attacks of severe intensity decreased significantly; 8 (26.6 %) out of 30 patients suffering chronic migraine reverted to episodic migraine.  Local pain in injection sites was reported by 14 patients, and 13 subjects (25.5 %) experienced post-injection soreness.  The authors concluded that TrPs inactivation could be an effective palliative measure in the prophylactic management of severe refractory migraine.  The main drawbacks of this trial were its relatively small sample size (n = 52) and the lack of a control group.

Blumenfeld et al (2010) noted that many clinicians use peripheral nerve blocks (NBs) and TrPs injections (TPIs) for the treatment of headaches.  Little is known, however, regarding the patterns of use of these procedures among practitioners in the U.S.  These researchers obtained information on patterns of office-based use of peripheral NBs and TPIs by headache practitioners in the U.S.  Using an Internet-based questionnaire, the Interventional Procedures Special Interest Section of the American Headache Society (AHS) conducted a survey among practitioners who were members of AHS on patterns of use of NBs and TPIs for headache treatment.  Electronic invitations were sent to 1,230 AHS members and 161 provided usable data (13.1 %).  Of the responders, 69 % performed NBs and 75 % performed TPIs.  The most common indications for the use of NBs were occipital neuralgia and CM, and the most common indications for the use of TPIs were chronic tension-type headache and CM.  The most common symptom prompting the clinician to perform these procedures was local tenderness at the intended injection site.  The most common local anesthetics used for these procedures were lidocaine and bupivacaine.  Dosing regimens, volumes of injection, and injection schedules varied greatly.  There was also a wide variation in the use of corticosteroids when performing the injections.  Both NBs and TPIs were generally well-tolerated.  The authors concluded that NBs and TPIs are commonly used by headache practitioners in the U.S. for the treatment of various headache disorders, although the patterns of their use varied greatly.  The main drawback of this study was the low response rate (13.1 %) of the survey.  Moreover, of the responders, 75 % performed TPIs; and the most common indications for the use of NBs were occipital neuralgia and CM.  It was unclear if CM was the most common indication for TPIs.

Szperka et al (2016) stated that peripheral NBs are often used to treat headaches in adults and children; however, available evidence and practice data from adult headache specialists have shown wide variability in diagnostic indications, sites injected, and medication(s) used.  These investigators described current practice patterns in the use of NBs and TPIs for pediatric headache disorders.  A survey was created in REDCap; it was emailed to the 82 members of the Pediatric and Adolescent Section of the AHS in June 2015.  The survey queried about current practice and use of NBs, as well as respondents' opinions regarding gaps in the evidence for use of NBs in this patient population.  A total of 41 complete, 5 incomplete, and 3 duplicate responses were submitted (response rate complete 50 %).  About 78 % of the respondents identified their primary specialty as Child Neurology, and 51 % were certified in headache medicine; 26 (63 %) respondents performed NBs themselves, and 7 (17 %) referred patients to another provider for NBs.  Chronic migraine with status migrainosus was the most common indication for NBs (82 %), although occipital neuralgia (79 %), status migrainosus (73 %), CM without flare (70 %), post-traumatic headache (70 %), and new daily persistent headache (67 %) were also common indications.  The most commonly selected clinically meaningful response for status migrainosus was greater than or equal to 50 % reduction in severity, while for CM this was a greater than or equal to 50 % decrease in frequency at 4 weeks.  Respondents injected the following locations: 100 % injected the greater occipital nerve (GON), 69 % lesser occipital nerve, 50 % supra-orbital, 46 % TPIs, 42 % auriculo-temporal, and 34 % supra-trochlear.  All respondents used local anesthetic, while 12 (46 %) also used corticosteroid (8 bupivacaine only, 4 each lidocaine + bupivacaine, lidocaine + corticosteroid, bupivacaine + corticosteroid, lidocaine + bupivacaine + corticosteroid, and 2 lidocaine only).  The authors concluded that despite limited evidence, NBs were commonly used by pediatric headache specialists.  There was considerable variability among clinicians as to injection site(s) and medication selection, indicating a substantial gap in the literature to guide practice, and supporting the need for additional placebo-controlled studies in this area. 

The authors stated that this study had several drawbacks.  The survey response rate was approximately 50 %.  Because these researchers used a distribution list without names, they did not have any information on non-responders to the survey, and they did not know if any respondents were not members of the original distribution list.  Even if all pediatric headache specialists who performed NBs answered the survey, this still represented an estimated 1/3 of known pediatric headache specialists.  The survey was emailed only to the members of the AHS Pediatric and Adolescent Section; therefore, the results described use among headache specialists, but did not account for use among other specialists such as concussion specialists.

Falsiroli Maistrello and colleagues (2018) noted that various interventions has been proposed for symptomatology relief in primary headaches.  Among these, manual trigger points (TrPs) treatment gains popularity, however its effects have not been examined yet.  These researchers examined the effectiveness of manual TrP compared to minimal active or no active interventions in terms of frequency, intensity, and duration of attacks in adult people with primary headaches.  They searched Medline, Cochrane, Web Of Science, and PEDro databases up to November 2017 for RCTs.  Two independent reviewers appraised the risk-of-bias (RoB) and the GRADE to evaluate the overall quality of evidence.  A total of 7 RCTs that compared manual treatment versus minimal active intervention were included: 5 focused on tension-type headache (TTH) and 2 on migraine headache (MH); 3 out of 7 RCTs had high RoB.  Combined TTH and MH results showed statistically significant reduction for all outcomes after treatment compared to controls, but the level of evidence was very low.  Subgroup analysis showed a statistically significant reduction in attack frequency (number of attacks per month) after treatment in TTH (MD -3.50; 95 % CI: -4.91 to -2.09; 4 RCTs) and in MH (MD -1.92; 95 % CI: -3.03 to -0.80; 2 RCTs).  Pain intensity (0 to 100 scale) was reduced in TTH (MD -12.83; 95 % CI: -19.49 to -6.17; 4 RCTs) and in MH (MD -13.60; 95 % CI: -19.54 to -7.66; 2RCTs).  Duration of attacks (hours) was reduced in TTH (MD -0.51; 95 % CI: -0.97 to -0.04; 2 RCTs) and in MH (MD -10.68; 95 % CI: -14.41 to -6.95; 1 RCT).  The authors concluded that manual TrPs treatment of head and neck muscles may reduce frequency, intensity, and duration of attacks in TTH and MH, but the quality of evidence according to GRADE approach was very low for the presence of few studies, high RoB, and imprecision of results.  These researchers also noted that the included studies did not report any additional negative effects, while positive effects regarding reduction of medicine consumption were controversial.

The authors stated that this review had several drawbacks that need to be addressed.  Because these investigators did not attempt to identify unpublished RCTs and their inclusion criteria were limited to only 3 languages, a publication bias could have occurred.  The high variability of the delivered treatments prevented them from identifying the most effective technique among those proposed.  Even if epidemiological studies have determined that women are more likely to suffer from TTH and that female gender constitutes a risk factor for this disease, the higher prevalence of women in the TTH subgroup could make the results less applicable to the general population.

Laube et al (2020) noted that CDH is a group of headache syndromes including most commonly CM and chronic tension-type headache, which often overlap, are complicated by medication overuse and are disabling, costly, and variable responsive to Western pharmacotherapies.  There is growing research and awareness of integrative health approaches and therapies to address patients with chronic headache, yet limited examples of how to deliver this approach.  These investigators reviewed a commonly observed challenging case of a patient with overlapping CM and chronic tension-type headache complicated by medication overuse managed with an integrative East-West medicine intervention.  This included person-centered biopsychosocial history taking, traditional Chinese medicine informed acupuncture, TPIs, and contributing factors modifications.  The authors also presented a narrative review of the literature to demonstrate an evidence-informed rationale for incorporating non-pharmacologic approaches to effectively help reduce the symptom burden of this patient population.  Moreover, these investigators advocated for further research into the use of integrative, comprehensive, multi-disciplinary approaches in the routine, and compassionate care of CDH patients.

Melatonin for the Treatment of Cluster Headache and Migraines

In a systematic review, Leite Pacheco and colleagues (2018) evaluated the safety and effectiveness of melatonin for primary headache.  This systematic review followed the Cochrane Handbook for Systematic Reviews of Interventions recommendations and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement.  A total of 4 RCTs were included (351 subjects).  According to the GRADE approach the quality of evidence was very low.  The use of melatonin for migraine showed reduced the number of days with pain and the analgesic consumption when compared with placebo; no benefits on headache intensity, number of headache days and analgesics consumption when compared with amitriptyline; reduced the number of analgesic consumption, the attack frequency and the headache intensity when associated with propranolol plus nortriptyline versus placebo plus propranolol plus nortriptyline; and no difference for any of the interest outcomes when associated with propranolol plus nortriptyline vs sodium valproate plus propranolol plus nortriptyline.  The use of melatonin for cluster headache when compared with placebo showed a reduction in the daily number of analgesic consumption and no difference in the number of daily attacks; AEs were poorly reported by all of the studies.  The authors concluded that the findings of this review showed that so far there are few clinical trials, with poor methodological quality about melatonin for primary headaches.  The available evidence is insufficient to support the use of melatonin in clinical practice for this population.  These researchers stated that further research is needed to evaluate its effects (benefits and harms) for primary headaches patients.

Trigeminal Nerve Stimulation for Migraine

Magis et al (2017) noted that a recent sham-controlled trial showed that external trigeminal nerve stimulation (eTNS) is effective in episodic migraine (MO) prevention.  However, its mechanism of action remains unknown.  These researchers performed 18-fluorodeoxyglucose positron emission tomography (FDG-PET) to evaluate brain metabolic changes before and after eTNS in episodic migraineurs.  A total of 28 individuals were recruited: 14 with MO and 20 healthy volunteers (HVs).  HVs underwent a single FDG-PET, whereas patients were scanned at baseline, directly after a first prolonged session of eTNS (Cefaly) and after 3 months of treatment (uncontrolled study).  The frequency of migraine attacks significantly decreased in compliant patients (n = 10).  Baseline FDG-PET revealed a significant hypo-metabolism in fronto-temporal areas, especially in the orbito-frontal (OFC) and rostral anterior cingulate cortices (rACC) in MO patients.  This hypo-metabolism was reduced after 3 months of eTNS treatment.  The authors concluded that the findings of this study suggested that OFC and rACC are hypo-metabolic in MO patients at rest.  After a 3-month treatment with eTNS, this hypo-metabolism was reduced and the changes were associated with a significant decrease of migraine attack frequency.  It is known that neurostimulation can modulate OFC and rACC activity.  Like cluster and medication overuse headache, MO appeared to be associated with dysfunction of medial frontal cortex areas involved in affective and cognitive dimensions of pain control.  Because this study was under-powered and had no sham arm, these researchers were unable to formally attribute the metabolic changes to the non-invasive neurostimulation treatment.  Nonetheless, the observed effect was likely similar to that found with invasive neurostimulation of peri-cranial nerves, such as pONS.  These researchers stated that further trials are needed to confirm these findings.

An assessment by the Ludwig Boltzmann Institute for Health Technology Assessment on "External stimulation of the trigeminal nerve for the prevention and acute treatment of episodic and chronic migraine" (2018) concluded that "Given the small size of the highly selective sample of patients included in the evidence base (as compared to the large burden of disease that migraine creates), the conclusions about effectiveness and the positive safety profile appear to be inflated.  The target population of e-TNS are not only patients refractory to medication, but mainly drug responsive patients, which makes replacing the use of medication a main objective of e-TNS.  That is why larger controlled trials with best practice interventions (for prevention as well as acute treatment use of e-TNS) as comparators are necessary for potentially considering e-TNS to be part of the standard practice".

Blockade / Stimulation of the Sphenopalatine Ganglion and Its Branches for the Treatment of Cluster and Migraine Headaches

Rosso and colleagues (2019) stated that among cephalgias, CH is the rarest and the most disabling, explaining the appellation of "suicide headache".  Up to 20 % of chronic CH are resistant to pharmacotherapies, in which case interventional procedures should be considered.  Many reports evaluated invasive approaches and a wide strand of research is dedicated to the SPG.  These investigators provided an overview on modern applications on the SPG, their outcomes, and their feasibility in terms of risks and benefits.  They reviewed the international literature systematically for procedures targeting the SPG and its branches for episodic CH (ECH) and CCH, including block, stimulation, radiofrequency, stereotactic radiosurgery, and vidian neurectomy.  A total of 17 articles met inclusion criteria.  Comparing the outcomes that have been analyzed, it was possible to notice how the most successful procedure for the treatment of refractory CCH and ECH was the SPG block, which reached 76. 5% and 87 % of efficacy, respectively.  Radiofrequency had a wide range of outcomes, from 33 % to 70.3 % in CCH.  Stimulation of SPG only achieved up to 55 % of outcomes in significant reduction in attack frequency in CCH and 71 % in ECH.  Radiosurgery and vidian neurectomy on SPG have also been analyzed.  Generally, ECH patients showed better response to standard medical therapies; nevertheless, even this more manageable condition may sometimes benefit from interventional therapies mostly reserved for CCH.  First results appeared promising and considering the low frequency of side effects or complications, one should think of expanding the indications of the procedures also to those conditions.  The authors concluded that outcomes certainly suggested that further studies are needed to understand which method is the most effective and with less side effects.  These researchers stated that placebo-controlled studies would be pivotal, and tight collaboration between neurologists and otorhinolaryngologists should also be central in order to give correct indications, which allow clinicians to expect procedures on the SPG to be an effective and mostly safe method to control either refractory ECH or CCH.

An UpToDate review of cluster headache treatment (May, 2020) said: "Neurostimulation techniques, including sphenopalatine ganglion stimulation and vagus nerve stimulation, appear promising but remain investigational. Destructive surgical procedures are unproven and should be viewed with great caution".

Burkett and colleagues (2020) noted that the SPG is a known current and historical target for therapeutic intervention in headache disorders because of its role in cranial autonomics and vasodilation.  There remains an overall lack of well-established SPG treatment protocols, especially with the advent of newer commercial devices.  A 22 multiple-choice question survey was created to evaluate clinical practice patterns with SPG block and sent to members of the American Headache Society (AHS).  Questions focused on determining indications, preferred applicators, medications applied, perceived efficacy, tolerability, and reimbursement.  A total of 172 of 1,346 (12.8 %) AHS members participated; 93 respondents (56.3 %) had performed SPG blocks on 50 or fewer patients.  The SphenoCath (42.4 %) and the Tx360 (41.8 %) were the most common methods of application.  Ease of use was the top reason for provider preference in applicator type.  SPG blocks were mostly used as an as-needed 1-time procedure.  When a scheduled protocol was used, twice-weekly for 6 weeks was most common.  Chronic migraine was the most commonly treated headache disorder and rated the most likely to respond to SPG block.  Experienced clinicians found SPG more helpful as a stand-alone treatment and tended to report that acute relief was not predictive of enduring response.  The authors concluded that the variety of responses strongly suggested that clinicians would benefit from formalized protocols for SPG blocks.  More experienced clinicians may have developed individualized protocols that they felt were more effective.  The authors concluded that the lack of evidence-based protocols contribute to clinicians not performing SPG blocks more frequently.  Moreover, these researchers stated that it is important to determine where SPG block fits into the toolbox of the headache practitioner.  The findings of this survey suggested that according to headache specialists already performing SPG blocks, there is no clear consensus in the therapeutic strategy using SPG blocks as acute versus preventive therapy.  It is notable that the Tx360 applicator has had 4 studies examining its efficacy in chronic migraine and its efficacy in the emergency department setting for treatment of anterior or global headaches.  These studies may offer some possible protocols for treatment, dosing, and scheduling of blocks.  The Allevio and SphenoCath catheters have, thus far, not had any randomized trials examining their use as treatment delivery devices.  Because trials have only been performed on 1 of the 3 commercially available devices, it is also unclear what the basis for the initial protocol development for the Tx360 was and whether it truly represents the best possible protocol.  These investigators stated that prospective, comparative studies as well as systematic assessments of delivery devices, medications used, frequency of use, and efficacy may better refine the indications of SPG blockade as a therapy for headache disorders.

The authors stated that this study had several drawbacks.  First, the way the survey was written allowed those who were infrequent users of SPG blocks to continue answering questions despite limited use.  After the survey was closed, 32 participants were removed from the analyses because of concerns that they represented non-users.  Second, because this was a voluntary survey of clinical practice, these investigators were limited by both the recall bias of the respondents and selection bias as the clinicians who filled out the survey may not represent the larger population using the SPG blocks; i.e., clinicians with either high satisfaction or high dissatisfaction with the procedure may have been more motivated to participate in this survey.  However, these researchers’ stratification by frequency of use may help to alleviate this limitation some because they were able to analyze the opinions of the more experienced (and possibly more satisfied) users separately.  Survey items were also created by the authors and were not previously validated in previous research; thus, it could be possible that responders did not fully understand an item or the item did not accurately examine what it was intended to.  Conflicts of interest of responders were not ascertained, which could include free samples of blocking devices provided to practitioners.  Finally, these investigators wished that they could have taken the opportunity to ask the providers with limited experience (fewer than 25 patients) why they were not using SPG blocks more frequently.  These researchers could only speculate whether their infrequent use was driven by the lack of familiarity with the procedure, an impression of low clinical response, issues of cost/reimbursement, or other reasons.  It must also be considered that more experienced clinicians had the higher number of patients seen because they believed that the procedure is effective; therefore, used it more frequently, regardless of whether this is true or not.

Manual Therapy for the Treatment of Migraines

Falsiroli Maistrello and colleagues (2019) noted that individuals with headache usually experienced significantly lower HR-QOL than the healthy subjects.  In a systematic review, these researchers examined the effectiveness of manual therapy on HR-QOL in patients with TTH, MH or cervicogenic headache (CGH).  They searched RCTs on Medline, Cochrane and PEDro databases.  Treatment was manual therapy compared to usual care or placebo.  The outcome was the HR-QOL that could be measured by HIT-6) Headache Disability Inventory (HDI), MIDAS and Short Form Health Survey 12/36 (SF-12/36).  For the RCT internal validity, these investigators used the Cochrane risk of bias (RoB) tool.  For the level of evidence, they used the GRADE.  These researchers identified a total of 10 RCTs, 7 of which were included into the meta-analysis.  For HIT-6 scale, meta-analysis showed statistically significant differences in favor of manual therapy both after treatment (MD - 3.67; 95 % CI: - 5.71 to - 1.63) and at follow-up (MD - 2.47; 95 % CI: - 3.27 to - 1.68).  For HDI scale, meta-analysis showed statistically significant differences in favor of manual therapy both after treatment (MD - 4.01; 95 % CI: - 5.82 to - 2.20) and at follow-up (MD - 5.62; 95 % CI: - 10.69 to - 0.54).  Other scales provided inconclusive results.  The authors concluded that manual therapy should be considered as an effective approach in improving the QOL in patients with TTH and MH, while in patients with CGH, the results were inconsistent.  Moreover, these researchers stated that those positive results should be considered with caution due to the very low level of evidence.  They stated that researchers should in future design primary studies using valid and reliable disease-specific outcome measures.

Chemodenervation with P2G (Phenol-Glycerine-Glucose) for Migraine Prophylaxis

An UpToDate review on “Preventive treatment of episodic migraine in adults” (Smith, 2021) does not mention chemodenervation with P2G / phenol-glycerine-glucose as a management option.

Greater Occipital Nerve Block for the Treatment of Cervicogenic and Cluster Headaches

Ornello and colleagues (2020) noted that the treatment of CH is challenging in view of the few evidence-based treatments.  In a systematic review and meta-analysis, these researchers examined the safety and efficacy of greater occipital nerve blocks (GONBs) in CH.  They included studies indexed in PubMed and Web of Science from the beginning of indexing to May 5, 2020; they included both observational and randomized studies referring to patients with episodic and/or chronic CH.  These researchers identified 12 studies on 365 patients; 5 studies (2 RCTs) could be included in the meta-analyses.  The pooled proportion of pain-free subjects at 1 month was 50 % (95 % CI: 24 % to 76 %) with considerable heterogeneity (I2 = 88 %; p < 0.01).  The pooled relative risk ratio of pain freedom at 1 month in active versus control groups in the 2 included RCTs was 4.86 (95 % CI: 1.35 to 17.55) without statistical heterogeneity (I2 = 0 %; p = 0.39); 3 studies showed decreased attack intensity, frequency, and duration after GONBs.  The studies reported mild and transient AEs.  The authors concluded that despite several drawbacks and considerable heterogeneity, the available data supported the safety and efficacy GONBs for the treatment of CH.  Moreover, these researchers stated that further large randomized trials are needed to establish protocols and indications for GONBs in patients with episodic or chronic CH.

Caponnetto and associates (2021) stated that cervicogenic headache (CGH) is a secondary headache disorder caused by cervical spine or neck soft tissue lesions.  Despite few available evidence-based pharmacological treatments are available, GONBs are considered as therapeutic option.  In June 2020, these investigators carried out a systematic review on PubMed and Scopus, to examine the safety and effectiveness of GONBs in treating CGH.  They included 5 observational studies and 3 non-randomized trials reporting clinical outcomes of 140 CGH patients following GONBs.  Authors performed unilateral GONBs during inter-ictal phase (5 studies) or during pain, injecting local anesthetic (4 studies) or both local anesthetic and steroid (3 studies) at variable time-points.  In 5 studies mean pain reduction ranged from -8.2 (at 2 weeks after the 1st block) to -0.1 (at 1 month after the 3rd block); 1 study documented 66.6 % reduction of pain intensity and another study documented a significant median reduction of pain intensity at 3 months (decreased from 5.5 to 2.3), but not at 9 months; and 3 studies reported minor AEs.  The authors concluded that few available studies suggested that GONBs are safe and effective in the treatment of CGH; GONB is a highly tolerable, low cost and repeatable procedure.  Moreover, these researchers stated that larger, randomized studies are needed to confirm the efficacy of the procedure, refine patient selection and injection protocols.

Greater Occipital Nerve Block for the Management of Migraines

Yang et al (2017) noted that greater occipital nerve (GON) block may be a promising approach to treat migraine.  However, the results remained controversial.  These investigators conducted a systematic review and meta-analysis to examine the efficacy of GON block in migraine patients.  PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched.  Randomized controlled trials (RCTs) assessing the efficacy of GON block versus placebo in migraine patients were included; 2 investigators independently searched articles, extracted data, and assessed the quality of included studies.  Meta-analysis was performed using the random-effect model.  A total of 6 RCTs were included in the meta-analysis.  Overall, compared with control intervention in migraine patients, GON block intervention was found to significantly reduce pain score (standardized mean difference [SMD] = -0.51; 95 % confidence interval [CI]: -0.81 to -0.21; p = 0.0008), number of headache days (SMD = -0.68; 95 % CI: -1.02 to -0.35; p < 0.0001), and medication consumption (SMD = -0.35; 95 % CI: -0.67 to -0.02; p = 0.04), but demonstrated no influence on duration of headache per 4 weeks (SMD = -0.07; 95 % CI: -0.41 to 0.27; p = 0.70).  The authors concluded that compared to control intervention, GON block intervention could significantly alleviate pain, reduce the number of headache days and medication consumption, but have no significant influence on the duration of headache per 4 weeks for migraine patients.

Zhang et al (2018) GON block has some potential in treating migraine.  These researchers performed a systematic review and meta-analysis to examine the impact of GON block on pain management of migraine.  They have systematically searched RCTs assessing the efficacy of GON block versus placebo for migraine in various databases including PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases.  The primary outcome is pain intensity.  Meta-analysis is performed using the random-effect model; a total of 7 RCTs were included in the meta-analysis.  Compared with control intervention in migraine patients, GON block intervention could significantly reduce pain intensity (MD = -1.24; 95 % CI: -1.98 to -0.49; p = 0.001) and analgesic medication consumption (MD = -1.10; 95 % CI: -2.07 to -0.14; p = 0.02), but has no remarkable impact on head duration (MD = -6.96; 95 % CI: -14.09 to 0.18; p = 0.0.06) and adverse events (AEs) (relative risk [RR] = 0.93; 95 % CI: 0.52 to 1.65; p = 0.80).  The authors concluded that GON block intervention was able to significantly reduce pain intensity and analgesic medication consumption in migraine patients.  These researchers noted that GON block had no remarkable impact on headache duration and adverse events for migraine.

In a prospective RCT, Korucu et al (2018) examined the effectiveness of a GON blockade against a placebo and classical treatments (non-steroidal anti-inflammatory drugs [NSAIDs] + metoclopramide) among patients who were admitted to the emergency department (ED) with acute migraine headaches.  This study was conducted on patients with acute migraine headaches; they were randomly assigned to 3 treatment groups: the GON blockade group (nerve blockade with bupivacaine), the placebo group (injection of normal saline into the GON area), and the intravenous (IV) treatment group (IV dexketoprofen and metoclopramide).  A total of 60 acute migraine attack patients were assigned to 3 groups of 20 patients each.  The pain severity was assessed at 5, 15, 30, and 45 mins with a 10-point pain scale score (PSS).  The mean decreases in the 5-, 15-, 30-, and 45-minu PSS scores were greater in the GON blockade group than in the dexketoprofen and placebo groups.  When comparing the 30- and 45-min PSS changes, a statistically significant difference was found among the 3 groups (p = 0.03 and p = 0.03, respectively).  The authors concluded that a GON blockade was as effective as an IV dexketoprofen + metoclopramide treatment and superior to a placebo in patients with acute migraine headaches.  These researchers stated that despite being an invasive procedure, a GON blockade might be an effective option for acute migraine treatment in the ED due to its rapid, easy, and safe application.

Allen et al (2018) stated that GON blocks are frequently used to treat migraine headaches, although a paucity of supporting clinical evidence exists.  In a large, retrospective, cohort study, these researchers examined the efficacy of GON block in acute treatment of migraine headache, with a focus on pain relief.  This study was undertaken between January 2009 and August 2014 and included patients who underwent at least 1 GON block and attended at least 1 follow-up appointment.  Change in the 11-point numeric pain rating scale (NPRS) was used to assess the response to GON block.  Response was defined as "minimal" (less than 30 % NPRS point reduction), "moderate" (31 to 50 % NPRS point reduction), or "significant" (greater than 50 % NPRS point reduction).  A total of 562 patients met inclusion criteria; 423 were women (75 %).  Mean age was 58.6 ± 16.7 years.  Of these 562, 459 patients (82 %) rated their response to GON block as moderate or significant.  No statistically significant relationship existed between previous treatment regimens and response to GON block; GON block was equally effective across the different age and sex groups.  The authors concluded that GON block appeared to be an effective option for acute management of migraine headache, with promising reductions in pain scores.  Moreover, these researchers stated that large, placebo-controlled clinical trials are needed to confirm these findings, along with those from several smaller observational studies and randomized trials.  They noted that further data would help to solidify the use of GON block in the treatment of migraine headache and potentially assist with its inclusion within future treatment guidelines.

Inan et al (2019) carried out a search of PubMed for English-language RCT and open studies on GON block between 1995 and 2018 using greater occipital nerve, headache, and migraine as keywords.  A total of 242 potentially relevant PubMed studies were found; 228 of them which were non-English articles and reviews, case reports, letters and meta-analyses were excluded.  The remaining articles were reviewed, and 14 clinical trials, 7 of which were randomized-controlled on GON block in migraine patients, were identified and reviewed.  The authors concluded that although clinicians commonly use GON block in migraine patients, the procedure has yet to be standardized.

An UpToDate review on “Acute treatment of migraine in adults” (Smith, 2021a) noted that the evidence of efficacy for occipital nerve blocks is limited mainly to small, low-quality trials.  “Preventive treatment of episodic migraine in adults” (Smith, 2021b), “Acute treatment of migraine in children” (Mack, 2021a) and “Preventive treatment of migraine in children” (Mack, 2021b) do not mention greater occipital nerve block as a therapeutic option.

Furthermore, an UpToDate review on “Chronic migraine” (Garza and Schwedt, 2019) states that “Occipital nerve stimulation -- There are inconsistent data from small randomized trials regarding the benefit of occipital nerve stimulation for the treatment of chronic migraine [80,81]. In the largest trial, there was no significant difference at 12 weeks for the primary endpoint, the percentage of patients that had a ≥50 percent reduction in mean daily pain score in the active compared with the control group [81]. However, there were statistically significant if modest improvements with active stimulation for a number of secondary endpoints, including the percentage of patients with a ≥30 percent reduction in mean daily pain score, and reduction in the mean number of headache days and migraine-related disability. The findings from these reports are limited by concerns about blinding in the control (sham treatment) groups, given that active treatment causes paresthesia, and relatively high rates of complications, including lead migration in 14 to 24 percent of subjects”.

Nerivio - Remote Electrical Neuromodulation (REN) for the Treatment of Migraines

Rapoport and Lin (2019) stated that non-invasive neuromodulation devices represent an emerging field in the acute treatment of migraine.  High efficacy, favorable safety profile, good tolerability and low cost are important factors for the desired shift to non-pharmacological treatments.  This will have the potential to improve the quality of life (QOL) of individuals with migraine; and reduce the risk for adverse events (AEs) and medication overuse headache (MOH).  Nerivio (Theranica Bio-Electronics, Israel) is a novel FDA-cleared (via 510(k)) remote electrical neuromodulation (REN) device for acute treatment of migraine.  These investigators highlighted the mechanism of action of REN and summarized the clinical data.  Nerivio has been studied in 2 randomized trials that provided support for the safety and efficacy of the device.  Post-hoc analyses suggested that the efficacy of REN is non-inferior to usual care in general and to acute pharmacological treatments specifically.  The authors concluded that Nerivio integrates clinically meaningful efficacy with a high safety profile, satisfying a great unmet need in migraine acute care.  The unique mechanism of action, in which the electrical stimulation is applied to peripheral nerves in the upper arm, allows the introduction of an innovative device with high efficacy and superior and improved usability aspects compared with acute pharmacological treatments and other approved devices. 

In a randomized, double-blind, placebo-controlled, multi-center trial, Yarnitsky et al (2019) examined the safety and efficacy of a REN device for the acute treatment of migraine.  This trial was carried out at 7 sites in the U.S. and 5 sites in Israel.  A total of 252 adults meeting the International Classification of Headache Disorders criteria for migraine with 2 to 8 migraine headaches per month were randomized in a 1:1 ratio to active or sham stimulation.  A smartphone-controlled wireless device was applied for 30 to 45 mins on the upper arm within 1 hour of attack onset; electrical stimulation was at a perceptible but non-painful intensity level.  Migraine pain levels were recorded at baseline, 2 hours, and 48 hours post-treatment.  Most bothersome symptoms (MBS) were also recorded.  The primary efficacy endpoint was the proportion of participants achieving pain relief at 2 hours post-treatment (improvement from severe or moderate pain to mild or none, or from mild pain to none).  Relief of MBS and pain-free at 2 hours were key secondary endpoints.  Active stimulation was more effective than sham stimulation in achieving pain relief (66.7 % [66/99] versus 38.8 % [40/103]; therapeutic gain of 27.9 % [95 % CI: 15.6 to 40.2]; p < 0.0001), pain-free (37.4 % versus 18.4 %, p = 0.003), and MBS relief (46.3 % versus 22.2 %, p = 0.0008) at 2 hours post-treatment.  The pain relief and pain-free superiority of the active treatment was sustained 48 hours post-treatment.  The incidence of device-related AEs was low and similar between treatment groups (4.8 % [6/126] versus 2.4 % [3/126], p = 0.499).  The authors concluded that the findings of this study suggested that REN is an effective acute migraine treatment with a favorable safety and tolerability profile; REN may be an alternative acute migraine treatment with comparable or superior efficacy to commercially available neuromodulation devices.  These researchers stated that REN has the potential to increase patient adherence, improve migraine management, and improve the health and QOL of individuals with migraine.

The authors stated that this study had several drawbacks.  First, there was a low rate of severe baseline pain intensity and high rate of mild pain intensity, presumably due to the early treatment.  Yet, the rates of pain relief were as high for attacks treated at a moderate pain level, as for those treated at a mild pain level.  Second, these investigators did not study the efficacy of the device at intervention periods over 1 hour of symptoms onset.  Finally, selecting an appropriate sham device for successful blinding in neuromodulation studies in migraine is a great challenge.  However, in the current study the sham device produced a solid perceivable stimulus.  As in other neuromodulation studies in migraine, the placebo effect was higher than drug trials.  Yet, the therapeutic gain in the current study was impressive and was not significantly affected by the participants' treatment‐assigned response, providing acceptable evidence that REN treatment is safe and effective as an acute treatment for migraine.

Nierenburg et al (2020) stated that REN is a novel acute treatment of migraine.  Upper arm peripheral nerves are stimulated to induce conditioned pain modulation (CPM) -- an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions.  The REN (Nerivio) is a device cleared by the FDA for acute treatment of migraine in adults who do not have chronic migraine.  In an open-label, single-arm, dual-center, pilot study, these researchers examined the consistency of response over multiple migraine attacks in individuals with chronic migraine who are typically characterized with severe pain intensity, high disability, and less robust response to triptans.  This trial was carried out on adults with chronic migraine.  Participants underwent a 4-week treatment phase in which they treated their migraine headaches with the device for 45 mins within 1 hour of attack onset.  Pain levels were recorded at baseline, 2 hours, and 24 hours post-treatment.  Efficacy outcomes (pain relief and pain-free responses at 2 hours, sustained pain relief and sustained pain-free responses at 24 hours) focused on intra-individual consistency of response across multiple attacks, which was defined as response in at least 50 % of the treatments.  A total of 42 participants were enrolled, and 38 participants were evaluable for analyses; 73.7 % (28/38) achieved pain relief at 2 hours, 26.3 % (10/38) were pain-free at 2 hours, 84.4 % (27/32) had sustained pain relief response at 24 hours and 45.0 % (9/20) had sustained pain relief response at 24 hours in at least 50 % of their treated attacks.  The effects of REN on associated symptoms and improvement in function were also consistent.  The incidence of device-related adverse events (AEs) was low (1.8 %).  The authors concluded that REN used for a series of migraine attacks was effective and well-tolerated across attacks.  These researchers stated that REN may offer a safe and effective non-pharmacological alternative for acute treatment in patients with chronic migraine.  These researchers stated that further studies in a larger sample size are needed.

Grazzi et al (2021) noted that significant side effects or drug interactions can make pharmacotherapy for headache disorders very difficult.  Non-conventional and non-pharmacological treatments are becoming increasingly used to overcome these issues.  In particular, non-invasive neuromodulation (including remote electrical skin stimulation), nutraceuticals, and behavioral approaches are well-tolerated and indicated for specific patient categories such as adolescents and pregnant women.  These investigators presented the main approaches reported in the literature in the management of headache disorders.  They reviewed the available literature published between 2010 and 2020 and carried out a narrative presentation for each of the 3 categories (non-invasive neuromodulation, nutraceuticals, and behavioral therapies).  Regarding non-invasive neuromodulation, these researchers selected transcranial magnetic stimulation, supraorbital nerve stimulation, transcranial direct current stimulation, non-invasive vagal nerve stimulation, and caloric vestibular stimulation.  For nutraceuticals, they selected feverfew, butterbur, riboflavin, magnesium, and coenzyme Q10.  Finally, for behavioral approaches, these investigators selected biofeedback, cognitive behavioral therapy (CBT), relaxation techniques, mindfulness-based therapy, and acceptance and commitment therapy.  These approaches are increasingly seen as a valid therapeutic option in headache management, especially for patients with medication overuse or contra-indications to drug treatment; however, further investigations are needed to consider the effectiveness of these approaches also with respect to the long-term effects.

Furthermore, an UpToDate review on “Estrogen-associated migraine, including menstrual migraine” (O’Neal, 2021) states that “Neurostimulator treatment -- There are several neurostimulator devices approved for acute migraine treatment: the CEFALY device, gammaCore (vagal nerve stimulator), and Nerivio (a remote electrical modulation).  Prescribing a neurostimulator device is a useful option when there is a concern for polypharmacy; these are not typically first-line therapies.  While these devices should theoretically be safe in pregnancy, they have not been tested in this population”.

Caffeine Citrate Infusion for the Treatment of Post Lumbar Puncture Headache

Zeger and colleagues (2012) noted that cosyntropin has been reported to be effective in the treatment of post-dural puncture headaches (PDPHs); however, there is a lack of data regarding its effectiveness.  In a prospective, randomized, double-blind trial, these researchers compared the effectiveness of cosyntropin with that of caffeine in the treatment of PDPH.  They carried out an interim analysis of a study of adult patients presenting to the emergency department with a PDPH.  Patients were randomized to receive either IV caffeine or IV cosyntropin.  Values on a 100-mm VAS were recorded at 0, 60, and 120 mins to evaluate pain.  Rescue therapy was documented on the study data forms.  Its effectiveness was determined by the need for this therapy.  A total of 37 patients were included and 4 patients were excluded from the analysis because of protocol violations or incomplete data; analysis was based on ITT.  Caffeine was 80 % (95 % CI: 60 % to 100 %) effective and cosyntropin was 56 % (95 % CI: 33 % to 79 %) effective in treating PDPHs.  The group's VAS scores at 0, 60, and 120 mins were 80 mm, 41 mm, 31 mm for caffeine; and 80 mm, 40 mm, 33 mm for cosyntropin, respectively (p = 0.66).  The authors concluded that caffeine was not more effective than cosyntropin in treating patients with PDPHs, and there was no difference in the degree of pain relief on VAS assessment.

The authors stated that this study had several drawbacks.  Needle size and type were reported to be factors in preventing PDPHs.  The typical kits used by these researchers had 20-G cutting needles, but some of the lumbar punctures in this study were carried out with 22-G cutting needles.  These investigators were unable to control this potential confounder.  Furthermore, since increasing volume of CSF is thought to be one of the mechanisms, through which cosyntropin works, these researchers did not study potential delayed effects and/or may not have allotted enough time to maximize its effectiveness.

In a Cochrane review, Ona and associates (2015) examined the safety and effectiveness of drugs for the treatment of PDPH in adults and children.  This was an updated version of the original Cochrane review published in Issue 8, 2011, on “Drug therapy for treating post-dural puncture headache”.  These investigators included 13 small RCTs (479 participants) in this review (at least 274 participants were women, with 118 parturients after a lumbar puncture for regional anesthesia).  In the original version of this Cochrane review, only 7 small RCTs (200 participants) were included.  Pharmacological drugs assessed were oral and IV caffeine, subcutaneous sumatriptan, oral gabapentin, oral pregabalin, oral theophylline, IV hydrocortisone, IV cosyntropin and IM adrenocorticotropic hormone (ACTH). Two RCTs reported data for PDPH persistence of any severity at follow-up (primary outcome).  Caffeine reduced the number of participants with PDPH at 1 to 2 hours when compared to placebo.  Treatment with caffeine also decreased the need for a conservative supplementary therapeutic option.  Treatment with gabapentin resulted in better VAS scores after 1, 2, 3, and 4 days when compared with placebo and also when compared with ergotamine plus caffeine at 2, 3, and 4 days.  Treatment with hydrocortisone plus conventional treatment showed better VAS scores at 6, 24 and 48 hours when compared with conventional treatment alone and also when compared with placebo.  Treatment with theophylline showed better VAS scores compared with acetaminophen at 2, 6 and 12 hours and also compared with conservative treatment at 8, 16 and 24 hours.  Theophylline also showed a lower mean "sum of pain" when compared with placebo.  Sumatriptan and ACTH did not show any relevant effect for this outcome.  Theophylline resulted in a higher proportion of participants reporting an improvement in pain scores when compared with conservative treatment.  There were no clinically significant drug AEs.  The rest of the outcomes were not reported by the included RCTs or did not show any relevant effect.  Moreover, these researchers stated that these findings should be interpreted with caution due to the quality of the evidence found: the limited number of studies, the diversity of drugs assessed, and outcomes measured, the small sample sizes (13 studies involving a total of 479 participants) and the bias presented as well as their limited generalizability, as nearly 50 % of the participants were post-partum women in their 30s.

Furthermore, an UpToDate review on “Post dural puncture headache” (Bateman et al, 2022) states that “A number of drugs have been investigated for the treatment of PDPH in small trials and studies, but none have been proven beneficial for this specific indication.  Nevertheless, oral caffeine is a low-risk option for most patients, and caffeine and oral analgesics are options for the symptomatic treatment of PDPH.  Caffeine has commonly been used for treatment of PDPH (sometimes in combination with butalbital and/or acetaminophen), without high-quality supporting evidence.  We encourage self-administered oral caffeine in patients who normally drink caffeinated beverages on a daily basis, in order to avoid headache and other symptoms of caffeine withdrawal.  A 2015 systematic review of the literature on drug therapy for PDPH found 2 small randomized trials (approximately 40 patients in each) that compared oral and IV caffeine with placebo for PDPH after neuraxial anesthesia.  The trials had methodologic flaws and meta-analysis was not performed because of heterogeneity.  One of these trials reported lower pain scores at 4 hours in patients who received a single dose of 300 mg of caffeine orally, with no difference in pain scores at 24 hours or the need for EBP.  In the other trial, PDPH was relieved in 75 % of patients who received IV caffeine 500 mg IV, but 24 hours after treatment there was no difference in pain scores between patients who received caffeine and placebo, and no difference in the number of patients who required EBP.  Neither of these trials reported significant complications of caffeine administration.  However, there are case reports of grand mal seizures after IV administration of caffeine for treatment of PDPH”.

A statement on post-dural lumbar puncture headache from the American Society of Anesthesiologists (2021) states that "Oral caffeine in the dose of 300-500 mg is recommended once or twice a day. Intravenous caffeine can be given if the parturient is unable to drink."

Intravenous Magnesium for the Treatment of Migraine

Choi and Parmar (2014) evaluated the effectiveness and tolerability of intravenous magnesium for the treatment of acute migraine in adults.  Double-blind, randomized controlled trials (RCTs) of intravenous magnesium for acute migraine in adults were selected for analysis.  Cochrane Central Register of Controlled Trials, Medline, EMBASE, CINAHL, National Research Register Archive, ACP Journal Club, the US Government's Clinical Trial Database, Conference Proceedings, and other sources were data sources used for selection of studies.  Overall, 1,203 abstracts were reviewed and 5 RCTs totaling 295 patients were eligible for the meta-analyses.  The percentage of patients who experienced relief from headache 30 mins following treatment was 7 % lower in the magnesium groups compared with the controls [pooled risk difference = -0.07, 95 % CI: -0.23 to 0.09].  The percentage of patients who experienced side-effects or adverse events was greater in the magnesium groups compared with controls by 37 % (pooled risk difference = 0.370, 95 % CI: 0.06 to 0.68).  The percentage of patients who needed rescue analgesic medications was slightly lower in the control groups, but this was not significant (pooled risk difference = -0.021, 95 % CI: -0.16 to 0.12).  The authors concluded that these meta-analyses have failed to demonstrate a beneficial effect of intravenous magnesium in terms of reduction in pain relief in acute migraine in adults, showed no benefit in terms of the need for rescue medication and in fact have shown that patients treated with magnesium were significantly more likely to report side-effects/adverse events.

Orr et al (2015) note that there is a considerable amount of practice variation in managing migraines in emergency settings, and evidence-based therapies are often not used 1st line.  These researchers carried out a peer-reviewed search of databases (Medline, Embase, CENTRAL) to identify randomized controlled trials (RCTs) and quasi-RCTs of interventions for acute pain relief in adults presenting with migraine to emergency settings.  Where possible, data were pooled into meta-analyses.  Two independent reviewers screened 831 titles and abstracts for eligibility.  Three independent reviewers subsequently evaluated 120 full text articles for inclusion, of which 44 were included.  Individual studies were then assigned a U.S. Preventive Services Task Force quality rating.  The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to assign a level of evidence and recommendation strength for each intervention.  The authors strongly recommended the use of prochlorperazine based on a high level of evidence, lysine acetylsalicylic acid, metoclopramide and sumatriptan, based on a moderate level of evidence, and ketorolac, based on a low level of evidence.  They weakly recommended the use of chlorpromazine based on a moderate level of evidence, and ergotamine, dihydroergotamine, lidocaine intra-nasal and meperidine, based on a low level of evidence.  They found evidence to recommend strongly against the use of dexamethasone, based on a moderate level of evidence, and granisetron, haloperidol and trimethobenzamide based on a low level of evidence.  Based on moderate-quality evidence, these investigators recommended weakly against the use of acetaminophen and magnesium sulfate.  Based on low-quality evidence, they recommended weakly against the use of diclofenac, droperidol, lidocaine intravenous, lysine clonixinate, morphine, propofol, sodium valproate and tramadol.

Miller et al (2019) stated that non-traumatic headaches comprise up to 4 % of all emergency department (ED) visits.  Current practice is moving toward multi-modal analgesia regimens that limit narcotic use.  In a systematic review, these investigators examined the following research question: In patients with non-traumatic headaches (Population), does administration of intravenous (IV) magnesium sulfate (Intervention) compared to placebo, corticosteroids, dopamine antagonists, ergot alkaloids, non-steroidal anti-inflammatory drugs (NSAIDs), triptans, or usual care result in better pain control, lower rate of recurrence at 24 hours, lower requirements for rescue analgesia, and less adverse medication effects (Outcomes)?  Scholarly databases and relevant bibliographies were searched, as were clinical trial registries and relevant conference proceedings to limit publication bias.  Studies were not limited by date, language, or publication status.  Inclusion criteria were: (i) RCT, (ii) patients age 18 years or older, (iii) non-traumatic headache, (iv) patients treated in ED or an outpatient acute care treatment center, and (v) magnesium sulfate administered intravenously.  Eligible comparison groups included: placebo, conventional therapy, dopamine antagonist, NSAID, corticosteroid, ergot alkaloid, or triptans.  Out of 4,018 identified references, 7 RCTs (545 participants) that treated migraine headaches (n = 6) and benign non-traumatic headaches (n = 1) met inclusion criteria.  Pain intensity was improved with magnesium sulfate versus comparators at 60 to 120 mins, but not at earlier time-points.  Result for the endpoint of pain reduction by 50 % were conflicting as 3 studies reported that headache was improved, unchanged, and less with magnesium sulfate.  Complete pain relief was improved with magnesium sulfate in 1 study, and in the migraine with aura (MA) subgroup in another.  The need for rescue analgesia at any point was improved with magnesium sulfate in 1 study, and in the MA subgroup in another; and 24-hour headache recurrence was improved with magnesium sulfate in 1 study, but unchanged in a second.  The intended meta-analysis was not performed due to the clinical heterogeneity among studies.  The authors concluded that while they could not draw a firm conclusion on the effectiveness or benefit of IV magnesium sulfate in the treatment of acute non-traumatic headaches, the existing evidence indicated potential benefits in pain control beyond 1 hour, aura duration, and need for rescue analgesia.

Kandil et al (2021) noted that due to the healthcare burden associated with migraines, prompt and effective treatment is vital to improve patient outcomes and ED workflow.  A prospective, randomized, double-blind trial enrolled adults who presented to the ED with a diagnosis of migraine from August of 2019 to March of 2020.  Pregnant patients, or those with renal impairment were excluded.  Patients were randomized to receive IV magnesium, prochlorperazine, or metoclopramide.  The primary outcome was change in pain from baseline on a numeric rating scale (NRS) evaluated at 30 mins after initiation of infusion of study drug.  Secondary outcomes included NRS at 60 and 120 mins, ED length of stay (LOS), necessity for rescue analgesia, and adverse effects.  A total of 157 patients were analyzed in this study: 61 patients received magnesium, 52 received prochlorperazine, and 44 received metoclopramide.  Most patients were white females, and the median age was 36 years.  Hypertension and migraines were the most common co-morbidities, with a third of the patients reporting an aura.  There was a median decrease in NRS at 30 mins of 3 points across all 3 treatment arms.  The median decrease in NRS (inter-quartile range [IQR]) at 60 mins was -4 (2 to 6) in the magnesium group, -3 (2 to 5) in the metoclopramide group, and -4.5 (2 to7) in the prochlorperazine group (p = 0.27).  There were no statistically significant differences in ED LOS, rescue analgesia, or adverse effects.  The authors concluded that IV magnesium was not inferior to prochlorperazine or metoclopramide at 30 mins when treating headaches and migraines in the ED despite patients requiring greater rescue analgesia.  Although prochlorperazine may be more effective at controlling pain at 1 hour, it may also result in greater adverse effects.  These researchers stated that IV magnesium may be used as an adjunctive agent for the treatment of migraines; or may serve as a safe alternative when agents such as prochloperazine or metoclopramide are not appropriate.

The authors stated that drawbacks of the study included the unexpected premature termination of recruitment, which ultimately lead to unequal treatment arms and the study being underpowered.  This made it difficult to draw conclusions regarding if one agent fared better for migraine abortion.  In addition, there was no uniform protocol for time to initiation of medications in the ED before study drug administration or for rescue therapy.  This ultimately could have confounded the results of this study since it is unknown if pain relief was related to the administration of the study drug versus adjunctive therapies.  Furthermore, the choice of adjunctive therapies was at the physician's discretion.  Approximately 1/3 of patients received additional therapies before 120 mins, which may have also confounded migraine relief.  Finally, although there was no difference in ED LOS between groups, the LOS may have varied due to the timing of presentation to the ED, and prioritization for high acuity patients.

Urits et al (2021) stated that the International Association for the Study of Pain (IASP) defines chronic pain as pain that persists or recurs for longer than 3 months.  Chronic pain has a significant global disease burden with profound effects on health, quality of life (QOL), and socio-economic costs.  There are several therapeutic options, including pharmacological therapy, physical rehabilitation, psychological therapies, and surgical interventions, for chronic pain management.  Magnesium has been FDA-approved for several indications including hypomagnesemia, arrhythmia, prevention of seizures in eclampsia/preeclampsia, and constipation.  Magnesium has been used for numerous off-label uses, notably for acute and chronic pain management.  The mechanism of magnesium in pain management is primarily via its action as a voltage-gated antagonist of NMDA receptors, which are involved in pain transduction.  The authors stated that mixed trials and case reports of using magnesium to treat migraines have been reported; they stated that further investigation is needed to confirm the effectiveness of magnesium in the treatment of migraines.

An UpToDate reviews on “Preventive treatment of episodic migraine in adults” (Schwedt and Garza, 2023a) states that “There is only limited evidence supporting magnesium supplementation for migraine prevention in adults.  Several small randomized controlled trials using variable formulations of oral magnesium produced mixed results, with three trials finding a statistically significant benefit for magnesium, and one trial finding no benefit.  Magnesium is typically used at 400 to 600 mg daily for migraine prevention.  Diarrhea and gastrointestinal discomfort were the most common side effects of magnesium supplementation in these trials”. 

Furthermore, UpToDate reviews on “Acute treatment of migraine in adults” (Schwedt and Garza, 2023b) does not mention IV magnesium as a management/therapeutic option.  

Preventive Treatment of Refractory Chronic Cluster Headache

Membrilla et al (2023) stated that preventive treatment for refractory chronic cluster headache (rCCH) is challenging and many therapies have been tried.  In a systematic review and meta-analysis, these investigators examined what could be considered the therapy of choice in rCCH.  This review was carried out following the PRISMA guidelines.  They conducted a systematic search in Medline, Embase, Cochrane, clinicaltrials.gov, and the WHO's-International-Clinical-Trials-Registry-Platform.  Studies on the preventive treatment for rCCH as defined by the European Headache Federation consensus statement were included.  A meta-analysis of the pooled response rate was conducted for the different therapies.  Of 336 results, 45 were eligible for inclusion.  Most studies examined the effect of neuromodulation as a preventive treatment for rCCH.  The most studied neuromodulation technique was occipital nerve stimulation (ONS), with a pooled response rate in the meta-analysis of 57.3 % (95 % CI: 0.481 to 0.665).  Deep brain stimulation (DBS) was the 2nd most studied treatment with a pooled response rate of 77.0 % (95 % CI: 0.594 to 0.957).  DBS results were more heterogeneous than ONS, which could be related to the different stimulation targets in DBS studies; and reported more serious AEs than in ONS studies.  The remaining therapies (anti-CGRP pathway drugs, warfarin, ketamine-magnesium infusions, serial occipital nerve blocks, clomiphene, onabotulinum toxin A, ketogenic diet, sphenopalatine ganglion radiofrequency or stimulation, vagus nerve stimulation, percutaneous bioelectric current stimulation, upper cervical cord stimulation, and vidian neurectomy) presented weaker results or have less quality of evidence.  The authors concluded that the findings of this systematic review and meta-analysis suggested that ONS could be the 1st therapeutic strategy for patients with rCCH based on the current evidence.

Epidural Steroid Injection and Radiofrequency Ablation for the Treatment of Cervicogenic Headache and Neck Pain

Orhurhu et al (2021) noted that headache is a very common condition that affects 5 % to 9 % of men and 12 % to 25 % of women in North America and Europe.  Globally, the prevalence of active headaches among adults is 47 %.  The most common type of headache is tension headaches (38 % of adults), followed by migraines (10 %), and chronic headaches (3 %).  While the majority of headaches are benign, the disorder can severely influence a patients' QOL, which is directly reflected in societal costs.  In a systematic review, these investigators examined available evidence on the use of radiofrequency ablation (RFA) for the treatment of headache, including pain outcome measures, secondary outcomes, and complications.  This systematic review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.  Two reviewers independently scored the methodological quality of the selected studies.  Due to heterogeneity of studies, a best-evidence synthesis of the available prognostic factors was provided.  In the present investigation, these researchers evaluated 18 studies composed of 6 RCTs, 6 prospective studies, and 6 retrospective studies.  All the studies assessed pain improvement with RFA in patients with headache.  Most studies targeted the occipital nerve for treatment.  Complications were mostly mild and self-limiting, including eyelid swelling, rash, superficial infection of the procedural site, and worsening of headache.  The authors concluded that this review discussed several studies that suggested the effectiveness of RFA in the treatment of headaches.  Outcomes varied based on the difference in approaches regarding continuous RF versus pulsed RF, temperature, and duration of administration.  The majority of the studies discussed in this review indicated a therapeutic benefit of RFA for headaches over a short-term period.  Pain outcomes beyond 1 year were under-studied and further studies are needed to determine the long-term effects of RFA for headaches.

The authors stated that the drawbacks of this review included a large variability in definitions of trigeminal neuralgia, RF technique, and patient selection bias was observed in the selected cohort of studies.  Furthermore, there was a paucity of strong longitudinal RCTs and prospective studies.

Suer et al (2022) stated that chronic neck pain is often multi-factorial and is a leading cause of pain and disability.  Cervical facet joint pain is a common cause of neck pain and, in addition to more conservative modalities, can be treated with RFA of the respective medial branch nerves.  Cervicogenic headaches (CHAs) are a frequent complaint in pain clinics in the U.S. and can be targeted via a similar procedural approach.  In a systematic review, these researchers evaluated RCTs of cervical facet joint pain and CHAs with the objective of establishing a current level of evidence for the treatment of these etiologies of pain with RFA.  Database search, from inception through July 2021, was carried out identifying RCTs for cervical medial branch RFA.  Two reviewers independently evaluated the studies to identify those meeting criteria.  Primary outcome measures included pain relief and duration of pain relief.  Secondary outcome measures included function, sleep, mood, return-to-work, additional treatments, and complications.  A total of 4 RCTs met inclusion criteria and were selected for this review, each showed low risk of bias.  Of these studies, 3 were unique with the 4th being a subgroup analysis.  Primary outcome measures of pain relief and duration of relief were variable with successful relief ranging from 30 % to 50 % and median duration of pain relief also showing a wide variety.  Function and psychological distress were also variably reported and found variable relief to treatment with no difference between groups in 2 of the studies.  The authors concluded that based on this systematic review, the effectiveness of cervical facet RFA in treatment of chronic neck pain has Level II evidence.  These investigators stated that the primary limitations of the review were the paucity of adequately powered RCTs, variability in patient population, heterogeneous treatment outcomes, and follow-up intervals did not allow for meta-analyses.  These researchers stated that there remain many questions going forward in relation to cervical RFA that highlight the need for further research into this treatment for chronic neck pain.

Ekhator et al (2023) noted that dysfunction of the cervical spine and its anatomical features, mostly innervated by the C1, C2, and C3 spinal nerves, could result in a secondary headache known as CHA, mainly characterized by unilateral pain.  The effectiveness of pharmacotherapies and physical therapy (PT) is currently the subject of scant literature.  Interventional pain management techniques can be applied when conservative treatments fail.  In a systematic review and meta-analysis, these investigators examined the safety and effectiveness of RFA and epidural steroid injection (ESI) in the treatment of patients with CHA and neck pain.  A total of 3 databases -- PubMed, Cochrane CENTRAL Library, and Embase were searched, and 110 studies were identified.  A total of 9 screening processes were included for review and meta-analysis.  Statistical evaluation was performed via STATA version 17 (College Station, TX: StataCorp LLC) and effect measures were reported via random effects model risk ratios.  The main subject of focus included the following 3 outcomes: incidences of pain relief, degree and duration of pain, as well as incidences of AEs.  The findings showed both interventions relieved pain by a factor of greater than 50 %, demonstrating a relative effects RR of 1.45 (-0.50 to 3.39) for RFA: pain relief, 84.76 (82.82 to 86.69) RFA: AEs, and 19.46 (18.80 to 20.11) ESI: pain relief at 95 % CI; and the effectiveness of RFA and ESI differ.  Both interventions were effective in the reduction of CHA pain intensity; however, their complication rates and pain duration were considerably different.  With ESI, the headaches could still recur weekly, demanding the use of oral analgesics to deal with them.  On the other hand, RFA exhibited a low complication rate.  The authors concluded that improving guidance from imaging technologies, RFA has the potential to be the most effective interventional treatment.

The authors stated that this study could not arrive at conclusive decisions because few studies examined the effectiveness of RFA and ESI in the treatment of CHAs . The included studies generalized pain and injection; thus, lacking the specificity needed to arrive at distinct results.  The difficulty in diagnosing CHAs typically contributed to the study's limitations, as different headaches fundamentally share characteristics and symptoms such as cervical pain.  The difficulty in diagnosis essentially resulted in few subjects in the research for CHA interventions.  Moreover, the study was limited by the subjectivity of pain, which demanded that the research depends on the subjects' feelings.  The difficulty in diagnosis resulted in a small sample size, affecting the accuracy of the studies included in the research.

Photo-Biomodulation for the Treatment of Primary Headache

In a systematic review, Gomez et al (2022)examined  the safety and effectiveness of photo-biomodulation as an adjuvant treatment for primary headache.  These investigators carried out a systematic review of randomized clinical trials.  For such, electronic searches were conducted in the Medline, Embase, Cochrane Library, LILACS, PEDro, PsycInfo, Clinicaltrials.gov., and WHO/ICTRP databases, with no restrictions imposed regarding language or year of publication.  These researchers included studies that examined any photo-biomodulation therapy as an adjuvant treatment for primary headache compared to sham treatment, no treatment, or another intervention.  The methodological assessment was carried out using the Cochrane Risk of Bias tool.  The certainty of the evidence was classified using the GRADE approach.  A total of 4 randomized clinical trials were included; most of the included studies had an overall high risk of bias.  Compared to sham treatment, photo-biomodulation had a clinically important effect on pain in individuals with primary headache.  The authors concluded that despite the benefits reported for other outcomes, the estimates were imprecise, and the certainty of the evidence was graded as low.  These researchers stated that these findings were considered insufficient to support the use of photo-biomodulation in the treatment of primary headache; they stated that randomized clinical trials, with higher methodological quality, are needed to enhance the reliability of the estimated effects.

Appendix

The diagnostic criteria for medication overuse headache from the International Classification of Headache Disorders, third edition (ICHD-3) are as follows:

  • Headache occurring on 15 or more days per month in a patient with a pre-existing headache disorder; and
  • Regular overuse for more than three months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache:

    • Regular intake, for ≥10 days per month for >3 months, of ergotamines, triptans, opioids, or combination analgesics, or any combination of ergotamines, triptans, simple analgesics, nonsteroidal anti-inflammatory drugs (NSAID) and/or opioids without overuse of any single drug or drug class alone or when the pattern of overuse cannot be reliably established; or
    • Regular intake, for ≥15 days per month for >3 months, of simple analgesics (ie, acetaminophen, aspirin, or NSAID); and

  • Not better accounted for by another ICHD-3 diagnosis.

Patients who meet criteria for both medication overuse headache and chronic migraine are given both diagnoses.

Source: Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, third edition (beta version). Cephalalgia. 2013;33(9):629-808. 

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