Post-Herpetic Neuralgia

Number: 0725

Table Of Contents

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

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses post-herpetic neuralgia.

1. Medical Necessity

   Aetna considers the use of antivirals (oral), gabapentin, intrathecal, interlaminar or transforaminal epidural corticosteroids, lidocaine patch, opioids (oral), pregabalin, and tricyclic anti-depressants medically necessary for post-herpetic neuralgia (PHN). 

2. Experimental and Investigational

   Aetna considers any the following therapeutic modalities for PHN experimental and investigational because their effectiveness for this indication has not been established (not an all-inclusive list):

   1. Acupuncture
   2. Angiotensin II type 2 receptor antagonists
   3. Botulinum toxin (see CPB 0113 - Botulinum Toxin)
   4. Combined therapy of nerve block and pulsed radiofrequency
   5. Combination of trigeminal ganglion and retrobulbar nerve block
   6. Cryocautery
   7. Dorsal root entry zone lesions/dorsal root ganglion destruction
   8. Epidural morphine
   9. Extracorporeal shockwave therapy
   10. Fulranumab
   11. Ganglioside GM1
   12. Intercostal nerve block
   13. Intralesional corticosteroid
   14. Intravenous antiviral therapy
   15. Intravenous ketamine
   16. Intravenous lidocaine
   17. Intravenous vitamin C
   18. Intravenous zinc sulfate
   19. Iontophoresis of vincristine
   20. Laser irradiation
   21. Narrow-band ultraviolet light B
   22. Peripheral nerve stimulation
   23. Pulsed radiofrequency of the dorsal root ganglion
   24. Stellate ganglion blockade
   25. Sympathectomy
   26. Thermotherapy (including fire needle and moxibustion)
   27. Topical ketamine
   28. Topical piroxicam
   29. Transcranial magnetic stimulation
   30. Transcutaneous electrical nerve stimulation (TENS)
   31. Transdermal oxycodone patch
   32. Trigeminal nerve block
   33. Use of gabapentin and low-level laser for prevention of PHN
   34. Use of any of the following pharmacotherapies for treatment of PHN:
       
       
       • Biperiden
       • Carbamazepine
       • Chlorprothixene
       • Ganoderma lucidum extract
       • Nicardipine

   35. Vitamin B-12 injection (see CPB 0536 - Vitamin B-12 Therapy);

3. Related Policies

   Refer to applicable pharmacy benefit plan for capsaicin topical (Qutenza).

   See also:

   • CPB 0011 - Electrical Stimulation for Pain
   • CPB 0113 - Botulinum Toxin
   • CPB 0115 - Varicella and Herpes Zoster Vaccines
   • CPB 0135 - Acupuncture
   • CPB 0194 - Spinal Cord Stimulation
   • CPB 0297 - Cryoanalgesia and Therapeutic Cold
   • CPB 0536 - Vitamin B-12 Therapy
   • CPB 0735 - Pulsed Radiofrequency.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
62320 - 62321	Injection(s), of diagnostic or therapeutic substance(s) (eg, anesthetic, antispasmodic, opioid, steroid, other solution), not including neurolytic substances, including needle or catheter placement, interlaminar epidural or subarachnoid, cervical or thoracic
62322 - 62323	Injection(s), of diagnostic or therapeutic substance(s) (eg, anesthetic, antispasmodic, opioid, steroid, other solution), not including neurolytic substances, including needle or catheter placement, interlaminar epidural or subarachnoid, lumbar or sacral (caudal)
62324 - 62325	Injection(s), including indwelling catheter placement, continuous infusion or intermittent bolus, of diagnostic or therapeutic substance(s) (eg, anesthetic, antispasmodic, opioid, steroid, other solution), not including neurolytic substances, interlaminar epidural or subarachnoid, cervical or thoracic
62326 - 62327	Injection(s), including indwelling catheter placement, continuous infusion or intermittent bolus, of diagnostic or therapeutic substance(s) (eg, anesthetic, antispasmodic, opioid, steroid, other solution), not including neurolytic substances, interlaminar epidural or subarachnoid, lumbar or sacral (caudal)
64479	Injection(s), anesthetic agent and/or steroid, transforaminal epidural, with imaging guidance (fluoroscopy or CT); cervical or thoracic, single level
+ 64480	cervical or thoracic, each additional level (List separately in addition to code for primary procedure)
64483	lumbar or sacral, single level
+ 64484	lumbar or sacral, each additional level (List separately in addition to code for primary procedure)
CPT codes not covered for indications listed in the CPB (not all-inclusive):
Pulsed radiofrequency of the dorsal root ganglion, Angiotensin II type 2 receptor antagonist, Thermotherapy (including fire needle, moxibustion) – no specific code
0101T	Extracorporeal shock wave involving musculoskeletal system, not otherwise specified, high energy
0228T	Injection(s), anesthetic agent and/or steroid, transforaminal epidural, with ultrasound guidance, cervical or thoracic; single level
+ 0229T	each additional level
0230T	Injection(s), anesthetic agent and/or steroid, transforaminal epidural, with ultrasound guidance, lumbar or sacral; single level
+ 0231T	each additional level
62281	Injection/infusion of neurolytic substance (eg, alcohol, phenol, iced saline solutions), with or without other therapeutic substance; epidural, cervical or thoracic
62282	epidural, lumbar, sacral (caudal)
63650	Percutaneous implantation of neurostimulator electrode array, epidural
63655	Laminectomy for implantation of neurostimulator electrodes, plate/paddle, epidural
64400	Injection, anesthetic agent; trigeminal nerve, any division or branch
64420	Injection, anesthetic agent; intercostal nerve, single
64421	intercostal nerves, multiple, regional block
64510	Injection, anesthetic agent; stellate ganglion (cervical sympathetic)
64555	Percutaneous implantation of neurostimulator electrodes; peripheral nerve (excludes sacral nerve)
64575	Incision for implantation of neurostimulator electrodes; peripheral nerve (excludes sacral nerve)
64600 - 64640	Destruction by neurolytic agent (eg, chemical, thermal, electrical or radiofrequency, somatic nerves
64650	Chemodenervation of eccrine glands; both axillae
64653	other area(s) (eg, scalp, face, neck), per day
64680 - 64681	Destruction by neurolytic agent, with or without radiologic monitoring, sympathetic nerves
64802 - 64818	Sympathectomy
67500	Retrobulbar injection; medication (separate procedure, does not include supply of medication)
67505	Retrobulbar injection; alcohol
90867 - 90869	Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment
+ 95873	Electrical stimulation for guidance in conjunction with chemodenervation (List separately in addition to code for primary procedure)
+ 95874	Needle electromyography for guidance in conjunction with chemodenervation (List separately in addition to code for primary procedure)
96910	Photochemotherapy; tar and ultraviolet B (Goeckerman treatment) or petrolatum and ultraviolet B
97033	Application of a modality to one or more areas; iontophoresis, each 15 minutes
97810 - 97814	Acupuncture
Other CPT codes related to the CPB:
96365 - 96379	Therapeutic, prophylactic, and diagnostic injections and infusions (excludes chemotherapy and other highly complex drug or higly complex biologic agent administration)
99601 - 99602	Home infusion/specialty drug administration, per visit
HCPCS codes covered if selection criteria are met:
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
J1320	Injection, amitriptyline HCL, up to 20 mg
J1700	Injection, hydrocortisone acetate, up to 25 mg (Hydrocortone Acetate)
J1710	Injection, hydrocortisone sodium phosphate, up to 50 mg (Hydrocortone Phosphate)
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg (Solu-Cortef)
J2650	Injection, prednisolone acetate, up to 1 ml (Key-Pred 25, Key-Pred 50, Predcor-25, Predcor-50, Predoject-50, Predalone-50, Predicort-50)
J2920	Injection, methylprednisolone sodium succinate, up to 40 mg (Solu-Medrol)
J2930	Injection, methylprednisolone sodium succinate, up to 125 mg (Solu-Medrol)
J3300	Injection, triamcinolone acetonide, preservative free, 1 mg
J3301	Injection, triamcinolone acetonide, not otherwise specified, 10 mg
J3302	Injection, triamcinolone diacetate, per 5 mg (Aristocort)
J3303	Injection, triamcinolone hexacetonide, per 5 mg (Aristospan)
HCPCS codes not covered for indications listed in the CPB (not all-inclusive):
Fulranumab, Ganglioside GM1, transdermal oxycodone patch - no specific code
A4595	Electrical stimulator supplies, 2 lead, per month, (e.g. TENS, NMES)
E0720	Transcutaneous electrical nerve stimulation (TENS) device, two lead, localized stimulation
E0730	Transcutaneous electrical nerve stimulation (TENS) device, four or more leads, for multiple nerve stimulation
E0731	Form-fitting conductive garment for delivery of TENS or NMES (with conductive fibers separated from the patient's skin by layers of fabric)
J0133	Injection, acyclovir, 5 mg
J0190	Injection, biperiden lactate, per 5 mg
J0585	Botulinum toxin type A, per unit
J0587	Botulinum toxin type B, per 100 units
J2001	Injection, lidocaine HCL for intravenous infusion, 10 mg
J2060	Injection, lorazepam, 2 mg
J2270	Injection, morphine sulfate, up to 10 mg
J2271	Injection, morphine sulfate, 100 mg
J2272	Injection, morphine sulfate (fresenius kabi) not therapeutically equivalent to J2270, up to 10 mg
J2274	Injection, morphine sulfate, preservative-free for epidural or intrathecal use, 10 mg
J2275	Injection, morphine sulfate (preservative-free sterile solution), per 10 mg
J2404	Injection, nicardipine, 0.1 mg
J3420	Injection, vitamin B-12 cyanocobalamin, up to 1,000 mcg
J3425	Injection, hydroxocobalamin, 10 mcg
J9370	Vincristine sulfate, 1 mg
S0093	Injection, morphine sulfate, 500 mg (loading dose for infusion pump)
ICD-10 codes covered if selection criteria are met:
B02.21 - B02.29	Zoster [herpes zoster] with other nervous system involvement

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Background

Herpes zoster (HZ) is the consequence of re-activation of the varicella zoster virus that remains latent since primary infection (varicella).Once infected with herpes zoster, the virus sequesters itself in the nerve roots. The virus has the potential to reappear, traveling down the dermatome in which it resides. This flair is typically characterized by local and radiating pain throughout the dermatome. Patients will be treated with antivirals such as acyclovir or valcyclovir. In some of these patients, the virus causes noticeable nerve damage and results in moderate to severe pain which radiates as most neuropathies do. This condition is referred to as postherpetic neuralgia.

The overall incidence of HZ is about 3 per 1000 of the population per year increasing to 10 per 1000 per year by age 80. Approximately half of persons reaching age 90 years will have had HZ. In approximately 6%, a second episode of HZ may occur; usually several decades after the first attack. The most common complication of HZ is post-herpetic neuralgia (PHN), defined as significant pain or dysaesthesia present 3 months or more following HZ. More than 5% of the elderly have PHN at 1 year after acute HZ. Reduced cell-mediated immunity to HZ occurs with aging, which may be responsible for the increased incidence in the elderly and from other causes such as tumors, human immunodeficiency virus infection as well as immunosuppressant drugs. Diagnosis of PHN is usually clinical from typical unilateral dermatomal pain and rash. Prodromal symptoms, pain, itching and malaise, are common (Johnson and Whitton, 2004).

The observation that patients with PHN experience different types of pain (e.g., continuous burning or intense paroxysmal; most often with tactile allodynia) suggests that multiple pathophysiological mechanisms are involved, which may include the peripheral as well as the central nervous systems. Traditional treatments for PHN usually entail tricyclic antidepressants (TCA) such as amitriptyline, nortriptyline, desipramine and maprotiline; antiepileptic drugs such as gabapentin and pregabalin; topical 5% lidocaine patches (Lidoderm), which frequently reduce allodynia; as well as long-acting oral opioid preparations and tramadol (Ultram). Oral antiviral agents (aciclovir, famciclovir, valaciclovir) are used during an acute attack of herpes zoster to prevent postherpetic neuralgia (Wareham, 2006). There is evidence that intrathecal corticosteroids may be effective in patients who are refractory to conservative measures (Wu and Raja, 2008; Hempenstall et al, 2005), but the potential for neurological sequelae should prompt caution with their application (Christo et al, 2007). Epidural corticosteroids have not been shown to provide effective analgesia for PHN (Christo et al, 2007). Many alternative treatments for PHN such as cryocautery, dorsal column (spinal cord) stimulation, iontophoresis of vincristine, intravenous administration of ketamine, an N-methyl-D-aspartate (NMDA) antagonist; laser; peripheral nerve stimulation as well as transcutaneous electrical nerve stimulation (TENS) have not been adequately studied.

Iontophoresis has been suggested to be effective in treating PHN (Ozawa et al, 1999). However, in a randomized controlled trial, Dowd et al (1999) reported that that iontophoresed vincristine is no better than iontophoresed saline in the treatment of this condition. Although TENS has been reported to benefit some patients with PHN (Milligan and Nash, 1985; Robertson and George, 1990), these findings have not been validated by randomized controlled studies. Furthermore, on behalf of the Canadian Coordinating Office for Health Technology Assessment (CCOHTA), Reeve and Corabian (1995) evaluated the scientific evidence of the clinical effectiveness of TENS for the treatment of acute, chronic as well as labor and delivery pain. These researchers concluded that there is little evidence that TENS is effective in treating chronic pain.

In a review on sympathectomy for neuropathic pain, Mailis and Furlan (2003) stated that the practice of surgical and chemical sympathectomy is based on poor quality evidence, uncontrolled studies and anecdotal experience. In addition, complications of the procedure may be significant, in terms of both worsening the pain or producing a new pain syndrome; and abnormal forms of sweating (e.g., compensatory hyperhidrosis and pathological gustatory sweating). The authors concluded that more clinical studies of sympathectomy are needed to establish the potential risks and overall effectiveness of this procedure.

In a pilot study (n = 10), Johnson and Burchiel (2004) found that peripheral nerve stimulation of the supra-orbital or infra-orbital branches of the trigeminal nerve is effective in relieving trigeminal neuropathic pain following facial trauma or herpetic infection. These investigators stated that a prospective clinical trial using this novel approach to treat these disorders is thus warranted. A recent Cochrane review (Mailis-Gagnon et al, 2004) on spinal cord stimulation (SCS) concluded that although there is limited evidence in favor of SCS for failed back surgery syndrome and complex regional pain syndrome (also known as reflex sympathetic dystrophy), more research is needed to confirm whether SCS is an effective treatment for other types of chronic pain. Gilden et al (2005) noted that because only a few studies have used antiviral therapy to manage PHN and with conflicting results, larger, double-blind studies, which give intravenous antiviral drug, are needed. Thus, well-designed, multi-center, controlled clinical trials are needed to ascertain the effectiveness of various alternative treatments in the treatment of PHN.

An earlier systematic review of randomized controlled trials on treatments for PHN (Volmink et al, 1996) reported that pooled analysis of the effect of TCA demonstrated statistically significant pain relief. Pooling of the results of the 3 studies comparing the effects of capsaicin and placebo could not be performed due to heterogeneity, which was mainly attributable to an unpublished trial which differed in terms of the dosage and duration of treatment. When this study was omitted, no heterogeneity was found and the pooled analysis revealed a statistically significant benefit. However, problems with blinding in patients using capsaicin may have accounted for the positive effect. One small study of iontophoresis of vincristine compared to placebo yielded a favorable result. Other therapies evaluated included lorazepam, acyclovir, topical benzydamine as well as acupuncture. There was no evidence that these treatments are effective in relieving pain associated with PHN. These investigators concluded that based on evidence from randomized trials, TCA appear to be the only agents of proven benefit for established PHN.

A more recent evidence-based report on treatment of PHN was developed by the Quality Standards Subcommittee of the American Academy of Neurology (Dubinsky et al, 2004) and it had the following recommendations:

1. Acupuncture, benzydamine cream, dextromethorphan, indomethacin, epidural methylprednisolone, epidural morphine sulfate, iontophoresis of vincristine, lorazepam, vitamin E and zimelidine are not of benefit.
2. Aspirin cream or ointment is possibly effective in the relief of pain in patients with PHN but the magnitude of benefit is low, as is seen with topical capsaicin.
3. The effectiveness of carbamazepine, nicardipine, biperiden, chlorprothixene, ketamine, Helium:Neon (He:Ne) laser irradiation, intralesional triamcinolone, cryocautery, topical piroxicam, extract of Ganoderma lucidum, dorsal root entry zone lesions and stellate ganglion block are unproven in the treatment of PHN.
4. Tricyclic antidepressants, gabapentin, pregabalin, opioids and lidocaine patch are effective and should be used in the treatment of PHN.

In a multi-center, randomized controlled study, van Wijck and colleagues (2006) reported that a single epidural injection of 80 mg methylprednisolone and 10 mg bupivacaine within the first days of herpes zoster has a modest effect in reducing zoster-associated pain for one month; however there were no significant differences in pain level between the two groups at subsequent follow-ups. At 1 month, 137 (48%) patients in the epidural group (plus standard therapy given to the control group) reported pain compared with 164 (58%) in the control group (oral antivirals and analgesics). After 3 months these values were 58 (21%) and 63 (24%) respectively, and at 6 months, 39 (15%) and 44 (17%). The main drawback of this study was that it was neither double-blinded nor placebo-controlled, which decreased the validity of the already modest anti-nociceptive effects of the treatment within the first month. Moreover, this treatment is ineffective in preventing the development of long-term PHN. Furthermore, Baron and Wasner (2006) stated that large, well-designed prospective studies are needed to estimate the preemptive effect of neuropathic pain treatment on PHN.

In a Cochrane review, Khaliq et al (2007) examined the safety and effectiveness of topical lidocaine in the treatment of PHN. The investigators identified three trials meeting inclusion criteria, involving 182 topical lidocaine treated participants and 132 control participants. Two trials gave data on pain relief, and the remaining study provided data on secondary outcome measures. The largest trial compared topical lidocaine patch to a placebo patch and accounted for 150 of the 314 patients included in the analysis. A meta-analysis combining two of the three studies identified a significant difference between the topical lidocaine and control groups for the primary outcome measure -- a mean improvement in pain relief according to a pain relief scale. Topical lidocaine relieved pain better than placebo (p = 0.003). The investigators also found a statistical difference between the groups for the secondary outcome measure of mean visual analog scale (VAS) score reduction (p = 0.03), but only for a single small trial. In the selected studies, there were a similar number of adverse skin reactions in both treatment and placebo groups. The investigators reported that the highest recorded blood lidocaine concentration varied between 59 ng/ml and 431 ng/ml between trials. The investigators noted that the latter figure is high and posited that it may have been due to contamination of the sample during the assay procedure.

Christo et al (2007) stated that epidural corticosteroids have not been shown to provide effective analgesia for PHN.  Furthermore, Wu and Raja (2008) stated that the majority of interventional therapies show equivocal analgesic efficacy although some data indicate that intrathecal methylprednisolone may be effective.  The author stated that further randomized, controlled trials will be needed to confirm the analgesic efficacy of analgesic and interventional therapies (e.g., sympathetic nerve blocks/other nerve blocks, intrathecal methylprednisolone, and spinal cord stimulation) to determine their role in the overall treatment of patients with PHN.

In a Cochrane review, He et al (2008) examined the effectiveness of corticosteroids in preventing PHN. People of all ages with herpes zoster of all degrees of severity within 7 days after onset were included. Interventions include corticosteroids given by oral, intramuscular or intravenous routes during the acute stage (starting within 1 week of onset of the rash) compared with no treatment or placebo, but not with other treatments. Primary outcome measure was the presence of PHN 6 months after the onset of the acute herpetic rash. Secondary outcome measure was pain severity measured by a validated VAS or numerical descriptive scale after 3, 6 and 12 months; quality of life measured with the Short Form 36 questionnaire after 6 months; adverse events during or within 2 weeks after stopping treatment. Five trials were included with altogether 787 participants. All were randomized, double-blind, placebo-controlled parallel group studies. There was no significant difference between the corticosteroid and control groups for the primary outcome (risk ratio [RR] 1.27, 95% confidence interval [CI]: 0.20 to 7.97). There was also no significant difference between the corticosteroid plus anti-viral agents and placebo plus anti-viral agents groups for the primary outcome (RR 0.90, 95% CI: 0.40 to 2.03). No included trials evaluated pain severity with a validated VAS or numerical descriptive scale and also no trials measured quality of life with the Short Form 36 questionnaire. Adverse events during or within 2 weeks after stopping treatment were reported by all 5 included trials, but after meta-analysis, there was no significant difference in any serious adverse event (e.g., death, acute cardiac insufficiency, rash dissemination, bacterial pneumonia or hematemesis) or non-serious adverse event (e.g., dizziness, nausea, vomiting, hypertension or hyperglycemia). The authors concluded that there was insufficient evidence that corticosteroids are safe or effective in the prevention of PHN. They stated that more randomized controlled trials with a greater number of participants are needed to determine reliably whether there is real benefit (or harm) from the use of corticosteroid therapy to prevent PHN; and that future trials should measure function and quality of life.

A Clinical Evidence systematic evidence review concluded that corticosteroids for post-herpetic neuralgia are likely to be ineffective or harmful in preventing post-herpetic neuralgia (Wareham, 2006). The evidence review noted that, not only have corticosteroids not been proven to be effective for this indication, but they may cause dissemination of herpes zoster.

Schencking and associates (2010) reported the findings of intravenous administration of vitamin C in the treatment of 2 patients with PHN. These 2 subjects (females aged 67 and 53 years) were from an average and unselected patient group of a general practice with confirmed acute herpetic neuralgia who were observed in the course of their illness. They received the basic analgesic (according to the WHO step scheme) and viral-static therapy. Furthermore, 15-g of vitamin C was administered intravenously every second day over a period of 2 weeks. Sudden and total remission of the neuropathic pain (measured on the basis of VAS) could be observed. Remission of the cutaneous lesions was noted within 10 days. The use of the vitamin C appears to be an interesting component of alternative therapeutic strategies in the treatment of HZ. Especially for therapy-resistant cases of PHN, vitamin C administration should be examined as an additional option. The authors concluded that to test and confirm these clinical findings, randomized clinical trials regarding the use of vitamin C in the concomitant treatment of zoster-associated neuralgia should be performed.

Rullan and colleagues (2017) stated that PHN is a chronic neuropathic pain that results from alterations of the peripheral nervous system in areas affected by the herpes zoster virus.  The symptoms include pain, paresthesia, dysesthesia, hyperalgesia, and allodynia.  Despite the availability of pharmacological treatments to control these symptoms, no treatments are available to control the underlying pathophysiology responsible for this disabling condition.  These researchers described the study protocol for a randomized controlled clinical trial that will examine the effectiveness of gabapentin for prevention of PHN.  Patients with herpes zoster who are at least 50 years old and have a pain score of 4 or higher on a VAS will be recruited.  The aim is to recruit 134 patients from the practices of general physicians.  Participants will be randomized to receive gabapentin to a maximum of 1,800 mg/day for 5 weeks or placebo.  Both arms will receive 1,000-mg caplets of valacyclovir 3 times daily for 7 days (initiated within 72 hours of the onset of symptoms) and analgesics as needed.  The primary outcome measure is the percentage of patients with a VAS pain score of 0 at 12 weeks from rash onset.  The secondary outcomes measures are changes in quality of life (QOL; measured by the SF-12 questionnaire), sleep disturbance (measured by the Medical Outcomes Study Sleep Scale), and percentage of patients with neuropathic pain (measured by the Douleur Neuropathique in 4 Questions).

In a randomized, double-blind study, Backonja et al (2008) examined the safety and effectiveness of one application of NGX-4010, a high-concentration (8%) capsaicin dermal patch, in the treatment of patients with PHN. A total of 402 patients were randomly assigned to one 60-min application of NGX-4010 (640 microg/cm(2) or a low-concentration capsaicin control patch (3.2 microg/cm(2) [0.04% capsaicin]). Patients were aged 18 to 90 years, had had PHN for at least 6 months, and had an average baseline numeric pain rating scale (NPRS) score of 3 to 9. The primary efficacy end point was percentage change in NPRS score from baseline to weeks 2 to 8. Analysis was by intention-to-treat. Patients who were randomly assigned to NGX-4010 (n = 206) had a significantly greater reduction in pain during weeks 2 to 8 than did patients who had the control patch (n = 196). The mean changes in NPRS score were -29.6% versus -19.9% (difference -9.7%, 95% CI: -15.47 to -3.95; p = 0.001). A total of 87 (42%) patients who received NGX-4010 and 63 (32%) controls had a 30% or greater reduction in mean NPRS score (odds ratio [OR] 1.56, 95% CI: 1.03 to 2.37; p = 0.03). Patients who had NGX-4010 had significant improvements in pain during weeks 2 to 12 (mean change in NPRS score -29.9% versus -20.4%, difference -9.5, -15.39 to -3.61; p = 0.002). Transient blood pressure changes associated with changes in pain level were recorded on the day of treatment, and short-lasting erythema and pain at the site of application were common, self-limited, and generally mild-to-moderate in the NGX-4010 group and less frequent and severe in the controls. The authors concluded that one 60-min application of NGX-4010 provided rapid and sustained pain relief in patients with PHN. No adverse events were associated with treatment except for local reactions at the site of application and those related to treatment-associated pain.

In a Cochrane review, Derry et al (2009) reviewed the evidence from controlled trials on the efficacy and tolerability of topically applied capsaicin in chronic neuropathic pain in adults. Randomized, double-blind, placebo-controlled studies of at least 6 weeks' duration, using topical capsaicin to treat neuropathic pain were included in this analysis. A total of 6 studies (389 participants in total) compared regular application of low dose (0.075%) capsaicin cream with placebo cream; the numbers needed to treat to benefit (NNT) for any pain relief over 6 to 8 weeks was 6.6 (4.1 to 17). Two studies (709 participants in total) compared a single application of high dose (8%) capsaicin patch with placebo patch; the NNT for greater than or equal to 30% pain relief over 12 weeks was 12 (6.4 to 70). Local skin reactions were more common with capsaicin, usually tolerable, and attenuated with time; the numbers needed to treat to harm (NNH) for repeated low dose application was 2.5 (2.1 to 3.1). There were insufficient data to analyse either data set by condition or outcome definition. All studies satisfied minimum criteria for quality and validity, but maintenance of blinding remains a potential problem. The authors concluded that capsaicin, either as repeated application of a low dose (0.075%) cream, or a single application of a high dose (8%) patch may provide a degree of pain relief to some patients with painful neuropathic conditions. Local skin irritation, which is often mild and transient but may lead to withdrawal, is common. Systemic adverse effects are rare. Estimates of benefit and harm are not robust due to limited amounts of data for different neuropathic conditions and inconsistent outcome definition.

In a randomized, double-blind, controlled study with an open-label extension, Backonja et al (2010) evaluated the safety, effectiveness and tolerability of NGX-4010 in patients with PHN. Patients were randomized to receive NGX-4010 or control patch in a 4-week, double-blind study. This was followed by an open-label extension phase (up to 48 weeks total) where patients could receive up to 3 additional treatments no sooner than 12 weeks after initial treatment. The primary efficacy variable was mean change from baseline in mean morning and evening NPRS scores. During days 8 to 28 after the double-blind treatment, NGX-4010 patients had a mean change in NPRS scores from baseline of -32.7% compared with -4.4% for control patients (p = 0.003). Mean NPRS scores decreased from baseline during week 1 in both treatment groups, remained relatively stable through week 12 in NXG-4010 patients, but returned to near baseline during weeks 2 to 4 in controls. Mean change in NPRS scores from baseline during weeks 2 to 12 was -33.8% for NGX-4010 and +4.9% for control recipients. A similar decrease in NPRS scores from baseline was maintained with subsequent NGX-4010 treatments, regardless of the number of treatments received. Transient increases in application site pain were adequately managed with analgesics. No increases in application site reactions or adverse events were observed with repeated treatments. No patients discontinued the study due to an adverse event. The authors concluded that NGX-4010 is a promising topical treatment for PHN patients, which appears to be tolerable, generally safe, and effective.

In an open-label study, Simpson and associates (2010) assessed the safety of repeated applications of NGX-4010 over 1 year in patients with moderate to severe PHN or human immunodeficiency virus-associated distal sensory polyneuropathy (HIV-DSP). Patients had successfully completed a previous NGX-4010 study and had a pain level appropriate for further treatment. Eligible patients had not been treated with NGX-4010 within 12 weeks of study initiation. Patients received pre-treatment with a topical local anesthetic (lidocaine 4%) for 60 minutes followed by either a 60-minute (PHN and HIV-DSP patients) or a 90-minute (HIV-DSP patients) treatment with NGX-4010. Patients could receive up to 3 additional treatments at intervals of greater than or equal to 12 weeks. Regardless of the number of treatments received, all patients were followed-up for 48 weeks except for those withdrawing early. A total of 106 patients were enrolled and received a total of 293 NGX-4010 treatments. The most frequently reported treatment-emergent adverse events were transient, mild-to-moderate application site erythema, pain, edema, and papules. Small, transient pain-related increases in blood pressure during and immediately after NGX-4010 application were observed. There was no evidence of an increased incidence of adverse events, dermal irritation, intolerability, or impaired neurological function with repeated treatments. The authors concluded that repeated treatments with NGX-4010 administered over a 1-year period are generally safe and well-tolerated.

McCormack (2010) stated that capsaicin dermal patch is an adhesive patch containing a high concentration (8% w/w) of synthetic capsaicin. It is indicated in the European Union for the treatment of peripheral neuropathic pain in non-diabetic adults using a single 30- or 60-minute application repeated every 90 days, as required, and in the United States for the treatment of neuropathic pain associated with PHN. In pivotal, randomized, double-blind, multi-center trials in adults with PHN, a single 60-minute application of capsaicin dermal patch reduced the mean NPRS scores from baseline to a significantly greater extent than a low-concentration (0.04% w/w capsaicin) control patch during weeks 2 to 8. In randomized, double-blind, multi-center trials in patients with HIV-associated neuropathy, capsaicin dermal patch reduced the mean NPRS scores from baseline significantly more than control in 1 study for the 30- and 90-minute, but not the 60-minute, application during weeks 2 to 12. In another study, the differences between capsaicin (30- and 60-minute applications) and control did not reach statistical significance. An integrated analysis of both studies showed that the 30-minute application of capsaicin dermal patch was significantly better than control for the reduction from baseline in mean NPRS scores during weeks 2 to 12. The efficacy of capsaicin dermal patch was maintained for up to 1 year in extension studies in which patients could receive up to 3 or 3 repeat treatments. Capsaicin dermal patch was generally well-tolerated in clinical trials. The most common adverse events were transient, mostly mild-to-moderate, application-site reactions.

On November 16, 2009, the Food and Drug Administration approved Qutenza (capsaicin, 8% patch) for the treatment of neuropathic pain associated with PHN. The capsaicin in Qutenza (capsaicin) 8% patch is a synthetic equivalent of the naturally occurring compound found in chili peppers. Capsaicin is an agonist for the transient receptor potential vanilloid 1 receptor (TRPV1), which is an ion channel‐receptor complex expressed on nociceptive nerve fibers in the skin. Topical administration of capsaicin causes an initial enhanced stimulation of the TRPV1‐expressing cutaneous nociceptors that may be associated with painful sensations. This is followed by pain relief thought to be mediated by a reduction in TRPV1‐expressing nociceptive nerve endings. Over the course of several months, there may be a gradual re‐emergence of painful neuropathy thought to be due to TRPV1 nerve fiber reinnervation of the treated area.

Qutenza must be applied to the skin by a health care professional since placement of the patch can be quite painful, requiring use of a local topical anesthetic, as well as additional pain relief such as ice or use of opioid pain relievers. The patient must also be monitored for at least 1 hour since there is a risk of a significant rise in blood pressure following patch placement. The product insert of Qutenza states that the patches should be applied to the most painful skin areas, using up to 4 patches.  Furthermore, the patches should be applied for 60 minutes and repeat every 3 months or as warranted by the return of pain (not more frequently than every 3 months).

There are no controlled studies with pregnant or lactating mothers. The safety and efficacy of Qutenza in patients under the age of 18 has also not been studied. Studies did involve patients over 75 years of age with similar efficacy and safety profiles. Therefore no dose adjustments are required in the geriatric population.

According to the 2004 American Academy of Neurology treatment guidelines for postherpetic neuralgia, the magnitude of benefit for topical capsaicin is below the level that is considered clinically important in the treatment of chronic pain related to post‐herpetic neuralgia. Since the guidelines have not been updated since 2004, the same AAN evidence rating tool was used to evaluate the two Qutenza trials cited in the package insert. Both studies were prospective, randomized, double‐blind controlled trials. Primary outcomes and drop‐out rationale were clearly defined. The endpoints were mean percent reductions in Numeric Pain Rating Scale (NPRS) score from baseline. Pain endpoints such as these, are subject to user bias. In addition possible confounders in these studies were the fact that half of the patients were allowed to continue taking their current pain regimen and the subjects were also allowed to take extra pain medications during the treatment period as well. Both endpoints did not reach statistically significance, only showed pain improvement. The patients who did not complete the trials were assigned to 0% improvement which is a conservative approach when evaluating outcomes. These trials would be classified as AAN Class II because of the potential bias and the lack of convincing evidence to support Qutenza’ use in PHN.

Young and colleagues (2017) noted that capsaicin has been traditionally used to manage pain; however, the safety and effectiveness of this practice is still elusive.  These researchers examined the effect of topical capsaicin in pain management.  All double-blinded, randomized placebo- or vehicle-controlled trials that were published in English addressing PHN were included.  Meta-analysis was performed using Revman version 5.3.  Upon application of the inclusion and exclusion criteria, only 6 trials fulfilled all the criteria and were included in the review for qualitative analysis.  The difference in mean percentage change in NPRS score ranged from -31 to -4.3.  This demonstrated high efficacy of topical capsaicin application and implied that capsaicin could result in pain reduction.  Furthermore, meta-analysis was performed on 5 of the included studies.  All the results of studies were in favor of the treatment using capsaicin.  The incidence of side effects from using topical capsaicin is consistently higher in all included studies, but the significance of safety data cannot be quantified due to a lack of p-values in the original studies.  The authors concluded that topical capsaicin is a promising therapeutic option for specific patient groups or certain neuropathic pain conditions such as PHN.

In a pilot study, Nabarawy et al (2011) evaluated the effect of narrow-band ultra-violet light B (nbUVB) in the treatment PHN.  The study included 17 patients with distressing PHN.  Patients were evaluated using the Verbal Rating Scale (VRS).  They received nbUVB sessions, 3 times a week, for a total of 15 sessions or until the pain disappeared.  Patients were followed-up for a period of 3 months after the end of therapy.  Using intention-to-treat analysis, more than 50% improvement was achieved in 6 (35.29%) and 8 (47.06%) patients, at the end of therapy and after 3 months follow-up, respectively.  An improvement of less than 50% was achieved in 11 (64.71%) and 9 (52.94%) patients, at the end of therapy and after 3 months follow-up, respectively.  The pain severity assessed by the VRS significantly improved both at the end of sessions (p = 0.005) and after 3 months follow-up (p = 0.005).  The authors concluded that nbUVB may be of beneficial use in the treatment of PHN.  The drawbacks of this pilot study were small number of patients and limited follow-up period.  These preliminary findings need to be validated by well-designed studies.

Barros et al (2012) stated that herpes zoster infection may cause PHN.  This phenomenon may be reversed by (S)-ketamine (SKET), but its use results in intolerable side effects, while its topical administration seems to be safe.  In a cross-over study, these researchers examined the effectiveness of topical (S)-ketamine for pain management of PHN.  A total of 12 patients were randomly divided into 2 groups.  There was a significant effect of time on pain intensity, but no statistical difference in pain scores for SKET or placebo use in this sample in this treatment regimen.  Only few mild cutaneous reactions were observed with topical SKET use.

In a Cochrane review, Han and colleagues (2013) examined the effectiveness of corticosteroids in preventing PHN.  These researchers updated the searches for randomized controlled trials (RCTs) of corticosteroids for preventing PHN in the Cochrane Neuromuscular Disease Group Specialized Register (April 16, 2012), CENTRAL (2012, Issue 3), MEDLINE (January 1966 to April 2012), EMBASE (January 1980 to April 2012), LILACS (January 1982 to April 2012), and the Chinese Biomedical Retrieval System (1978 to 2012).  They also reviewed the bibliographies of identified trials, contacted authors and approached pharmaceutical companies to identify additional published or unpublished data.  These investigators included all RCTs involving corticosteroids given by oral, intramuscular, or intravenous routes for people of all ages with HZ of all degrees of severity within 7 days after onset, compared with no treatment or placebo but not with other treatments.  They did not include quasi-RCTs (trials in which a systematic method of randomization such as alternation or hospital number was used).  Two authors identified potential articles, extracted data, and independently assessed the risk of bias of each trial.  Disagreement was resolved by discussion among the co-authors.  A total of 5 trials were included with 787 participants in total.  All were randomized, double-blind, placebo-controlled, parallel-group studies.  They conducted a meta-analysis of 2 trials (114 participants) and the results gave moderate quality evidence that oral corticosteroids did not prevent PHN 6 months after the onset of herpes (RR 0.95, 95% CI: 0.45 to 1.99).  One of these trials was at high-risk of bias because of incomplete outcome data, the other was at low-risk of bias overall.  The 3 other trials that fulfilled inclusion criteria were not included in the meta-analysis because the outcomes were reported at less than 1 month or not in sufficient detail to add to the meta-analysis.  These 3 trials were generally at low-risk of bias.  Adverse events during or within 2 weeks after stopping treatment were reported in all 5 included trials.  There were no significant differences in serious or non-serious adverse events between the corticosteroid and placebo groups.  There was also no significant difference between the treatment groups and placebo groups in other secondary outcome analyses and subgroup analyses.  The review was first published in 2008 and no new RCTs were identified for inclusion in subsequent updates in 2010 and 2012.  The authors concluded that there is moderate quality evidence that corticosteroids given acutely during zoster infection are ineffective in preventing PHN.  In people with acute HZ the risks of administration of corticosteroids do not appear to be greater than with placebo, based on moderate quality evidence.  Corticosteroids have been recommended to relieve the zoster-associated pain in the acute phase of disease.  These investigators stated that if further research is designed to evaluate the effectiveness of corticosteroids for HZ, long-term follow-up should be included to observe their effect on the transition from acute pain to PHN; and future trials should include measurements of function and quality of life.

Reviews on “Evidence-based guidance for the management of postherpetic neuralgia in primary car” (Harden et al, 2013), “Management of herpes zoster and post-herpetic neuralgia” (Gan et al, 2013) and “Herpes zoster: Diagnostic, therapeutic, preventive approaches” (Bader, 2013), and “Options for treating postherpetic neuralgia in the medically complicated patient” (Bruckenthal and Barkin, 2013) mentioned the use of topical lidocaine, but not intravenous lidocaine, as a therapeutic option.

Furthermore, an UpToDate review on “Postherpetic neuralgia” (Bajwa et al, 2014) states that “The effectiveness of therapies such as TENS and acupuncture has not been proven.  Intravenous lidocaine may provide benefit in patients who do not respond to other therapies; however, small controlled trials have not convincingly demonstrated that this therapy is superior to placebo”.

In a Cochrane review, Wiffen et al (2104) evaluated the analgesic effectiveness and adverse events of levetiracetam in chronic neuropathic pain conditions in adults.  These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 6) (via the Cochrane Library), MEDLINE, EMBASE, and two clinical trials databases (ClinicalTrials.gov. and the World Health Organization Clinical Trials Registry Platform) to July 3, 2014, together with reference lists of retrieved papers and reviews.  They included randomized, double-blind studies of 2 weeks duration or longer, comparing levetiracetam with placebo or another active treatment in adults with chronic neuropathic pain conditions.  Studies had to have a minimum of 10 participants per treatments arm.  Two review authors independently extracted effectiveness and adverse event data, and examined issues of study quality.  They performed analysis using 3 tiers of evidence.  First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction; intention-to-treat analysis without imputation for drop-outs; at least 200 participants in the comparison; 8 to 12 weeks duration; parallel design); 2nd tier evidence from data that failed to meet 1 or more of these criteria and that these researchers considered at some risk of bias but with at least 200 participants in the comparison; and 3d tier evidence from data involving fewer than 200 participants that was considered very likely to be biased or used outcomes of limited clinical utility, or both.  These investigators included 6 studies: 5 small, cross-over studies with 174 participants, and 1 parallel group study with 170 participants.  Subjects were treated with levetiracetam (2,000 mg to 3,000 mg daily) or placebo for between four and 14 weeks.  Each study included participants with a different type of neuropathic pain; central pain due to multiple sclerosis, pain following spinal cord injury, painful polyneuropathy, central post-stroke pain, PHN, and post-mastectomy pain.  None of the included studies provided 1st or 2nd tier evidence.  The evidence was very low quality, down-graded because of the small size of the treatment arms, and because studies reported results using last observation carried forward (LOCF) imputation for withdrawals or using only participants who completed the study according to the protocol, where there were greater than 10% withdrawals.  There were insufficient data for a pooled efficacy analysis in particular neuropathic pain conditions, but individual studies did not show any analgesic effect of levetiracetam compared with placebo.  These researchers did pool results for any outcome considered substantial pain relief (greater than or equal to 50% pain intensity reduction or “complete” or “good” responses on the verbal rating scale) for 4 studies with dichotomous data; response rates across different types of neuropathic pain was similar with levetiracetam (10%) and placebo (12%), with no statistical difference (RR 0.9; 95% CI: 0.4 to1.7).  They pooled data across different conditions for adverse events and withdrawals.  Based on very limited data, significantly more participants experienced an adverse event with levetiracetam than with placebo (number needed to treat for an additional harmful event (NNH) 8.0 (95% CI: 4.6 to 32)).  There were significantly more adverse event withdrawals with levetiracetam (NNH 9.7 (6.7 to 18)).  The authors concluded that the amount of evidence for levetiracetam in neuropathic pain conditions was very small and potentially biased because of the methods of analysis used in the studies.  There was no indication that levetiracetam was effective in reducing neuropathic pain, but it was associated with an increase in participants who experienced adverse events and who withdrew due to adverse events.

In a Cochrane review, Gaskell et al (2014) evaluated the analgesic effectiveness and adverse events of oxycodone for chronic neuropathic pain and fibromyalgia.  On November 6, 2013, these investigators searched CENTRAL, MEDLINE and EMBASE databases.  They reviewed the bibliographies of all included studies and of reviews, and also searched 2 clinical trial databases, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform, to identify additional published or unpublished data.  They included RCTs with double-blind assessment of participant outcomes following 2 weeks of treatment or longer (although the emphasis of the review was on studies of 8 weeks or longer) that used a placebo or active comparator.  Two review authors independently extracted efficacy and adverse event data, examined issues of study quality, and assessed risk of bias.  They performed analysis using 3 tiers of evidence.  First tier evidence was derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design), 2nd tier from data that failed to meet 1 or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and 3rd tier from data involving small numbers of participants that was considered very likely to be biased or used outcomes of limited clinical utility, or both.  These researchers included 3 studies with 254 participants; 204 had painful diabetic neuropathy and 50 PHN.  Study size ranged from 45 to 159 participants.  Two studies used a cross-over design and 1 a parallel group design; study duration was 4 or six weeks.  Controlled release oxycodone (oxycodone CR) was used in all 3 studies, with doses titrated up to a maximum of between 60 and 120 mg daily; mean doses achieved ranged between 37 and 45 mg daily.  All studies used a placebo comparator, although in 1 study, an active placebo (benztropine) was used.  All studies had 1 or more sources of potential major bias.  No study reported the proportion of participants experiencing at least 50% pain relief or who were very much improved, while 1 reported the proportion with at least 30% pain relief, 2 reported at least moderate pain relief, and 1 reported the number of participants who considered treatment to be moderately effective.  No study provided 1st or 2nd tier evidence for an efficacy outcome.  Third tier evidence indicated greater pain intensity reduction and better patient satisfaction with oxycodone than with placebo in all 3 studies, but such evidence was derived mainly from group mean data, with LOCF imputation or completer analysis, in small studies lasting less than 8 weeks (very low quality evidence).  Adverse events were more common with oxycodone CR than with placebo.  At least 1 adverse event was experienced by 86% of participants taking oxycodone CR and 63% taking placebo, and the NNH was 4.3.  The effect of oxycodone on serious adverse events reported was uncertain in comparison with placebo (oxycodone 3.4% versus placebo: 7.0%; RR 0.48 (95% CI: 0.18 to 1.23; very low quality evidence); 1 death was reported with oxycodone CR, but was not attributed to treatment.  Adverse event withdrawals did not differ significantly between groups, occurring in 11% of participants with oxycodone CR and 6.4% with placebo (RR 1.69 (0.83 to 3.43); very low quality evidence).  Withdrawals due to lack of efficacy were less frequent with oxycodone CR (1.1%) than placebo (11%), with an NNT to prevent 1 withdrawal of 10 (RR 0.12 (0.03 to 0.45); very low quality evidence).  These investigators found no relevant studies in chronic neuropathic pain conditions other than painful diabetic neuropathy or PHN, or in fibromyalgia.  The authors concluded that no convincing, unbiased evidence suggests that oxycodone (as oxycodone CR) is of value in treating people with painful diabetic neuropathy or PHN.  There is no evidence at all for other neuropathic pain conditions, or for fibromyalgia.  Adverse events typical of opioids appear to be common.

Ing and colleagues (2015) stated that PHN remains a therapeutic challenge for the clinician.  Many modalities have been utilized with limited success.  In this pilot randomized study of patients who were refractory to previous medicinal treatment, the patients were treated with TENS with a biofeedback capability.  After every 2 treatments with the sham and true device, the patients were required to fill out a standard neuropathic pain scale score.  The patients were allowed to select the other device after 3 consecutive treatments if they felt an inadequate decrease in their pain.  The true device was chosen over the sham device by all patients.  The majority of these patients treated by the true device reported a statistically significant decrease in pain scores (p < 0.001).  The authors concluded that further investigation of this Food and Drug Administration (FDA)-class 2 electronic device for relief of pain is needed for patients with a history of recalcitrant PHN.

Angiotensin II Type 2 Receptor Antagonist for the Treatment of Post-Herpetic Neuralgia

Rice and colleagues (2021) reported the safety and efficacy of 2 phase-IIb clinical trials of EMA401 (a highly selective angiotensin II type 2 receptor [AT2R] antagonist), in patients with PHN; EMPHENE) and painful diabetic neuropathy (EMPADINE).  They were randomized, double-blind, multi-center studies carried out in subjects with PHN or type I/II diabetes mellitus (DM) with painful distal symmetrical sensorimotor neuropathy.  Subjects were randomized 1:1:1 to either placebo, EMA401 25 mg, or 100 mg twice-daily (b.i.d) in the EMPHENE and 1:1 to placebo or EMA401 100 mg b.i.d. in the EMPADINE.  The primary outcome for both the studies was change in weekly mean of the 24-hour average pain score, using a NRS, from baseline to Week 12.  Both the studies were prematurely terminated due to pre-clinical hepatotoxicity on long-term dosing, although not observed in these studies.  Out of the planned subjects, a total of 129/360 (EMPHENE) and 137/400 (EMPADINE) subjects were enrolled.  The least square mean reduction in NRS pain score was numerically in favor of EMA401 100 mg arm in both EMPHENE (treatment difference [TD]: -0.5; 95% CI: -1.6 to 0.6; p value: 0.35) and EMPADINE (TD: -0.6; 95% CI: -1.4 to 0.1; p value: 0.10) at the end of Week 12.  However, as the studies were terminated prematurely, no firm conclusion could be drawn but the consistent clinical improvement in pain intensity reduction across these 2 studies in 2 different populations is worth noting.

Guo and associates (2021) stated that the AT2R has attracted much attention as a potential target for the relief of neuropathic pain, which represents an area of unmet clinical need.  A series of 1,2,3,4-tetrahydroisoquinolines with a benzoxazole sidechain were discovered as potent AT2R antagonists.  Rational optimization resulted in compound 15, which demonstrated both excellent antagonistic activity against AT2R in-vitro and analgesic efficacy in a rat chronic constriction injury (CCI) model.  Its favorable physicochemical properties and oral bioavailability make it a promising therapeutic candidate for neuropathic pain.  These researchers stated that compound 15 demonstrated an excellent pharmacokinetic profile in rodent/non-rodent species and analgesic efficacy in the CCI rat model.  They stated that further investigations including investigational new drug application (IND) enabling studies and development of compound 15 are in progress and will be reported in due course.

Combination of Trigeminal Ganglion and Retrobulbar Nerve Block for the Treatment of Post-Herpetic Neuralgia

Huang and colleagues (2017) noted that varicella zoster virus reactivation can cause permanent histological changes in the central and peripheral nervous system.  Neural inflammatory changes or damage to the dorsal root ganglia sensory nerve fibers during reactivation can lead to PHN.  For PHN of the first division of the 5th cranial nerve (ophthalmic division of the trigeminal ganglion), there is evidence of inflammatory change in the ganglion and adjacent ocular neural structures.  First division trigeminal nerve PHN can prove to be difficult and sometimes even impossible to manage despite the use of a wide range of conservative measures, including anti-convulsant and anti-depressant medication.   Steroids have been shown to play an important role by suppressing neural inflammatory processes.  Thus, these researchers chose the trigeminal ganglion as an interventional target for an 88-year old woman with severe ophthalmic division PHN after she failed to respond to conservative treatment.  Under fluoroscopic guidance, a trigeminal ganglion nerve block was performed with lidocaine combined with dexamethasone; and a retrobulbar block with lidocaine and triamcinolone settled residual oculodynia.  At 1-year follow-up, the patient remained pain-free and did not require analgesic medication.  The authors concluded that to their knowledge, this was the first reported case of ophthalmic division PHN successfully treated with a combination of trigeminal ganglion and retrobulbar nerve block using a local anesthetic agent and steroid for central and peripheral neural inflammatory processes.  This preliminary finding need to be validated by well-designed studies.

CT-Guided Pulsed Radiofrequency for the Treatment of Postherpetic Neuralgia

In a retrospective study, Han and colleagues (2020) compared the safety and effectiveness of computed tomography (CT)-guided PRF at 3 different voltages for the treatment of patients with PHN.  This trial included 109 patients with PHN involving the thoracic dermatome who were treated from January 2017 to May 2019.  They were divided into 3 groups based on the PRF voltage used: group A (45 V), group B (55 V), and group C (65 V).  The PRF therapy (voltage 45, 55, and 65 V) was carried out in all patients by targeting the thoracic dorsal root ganglion.  After surgery, patients were followed at 3 days, 1 month, 3 months, 6 months, and 12 months.  Observation at each follow-up included basic patient characteristics, VAS, SF-36 scores, patient satisfaction, complications, and side effects.  Visual analog scale scores decreased; and SF-36 scores increased for all patients in the 3 groups at each post-operative time-point (1, 3, 6, and 12 months; all p < 0.01).  Pain relief, improvement in QOL, and overall satisfaction were more significant for patients in group C than for those in groups A and B at the 3-, 6-, and 12-month follow-ups (all p < 0.05).  Patients in group B had lower VAS scores and higher overall satisfaction levels than those in group A (both p < 0.01).  A small number of patients from each group (n less than or equal to 3) experienced mild intra-operative and post-operative complications, which bore no relationship with group assignment (all p > 0.05).  At post-operative day 3, patients in group C had skin numbness affecting a larger area than patients in the other 2 groups (both p < 0.05), but the differences were no longer statistically significant at day 30 after the operation.  All patients experienced a drop in numbness area of more than 30% after surgery.  The authors concluded that compared with PFR at 45 and 55 V, PFR at 65 V had superior efficacy in treating PNH, with a favorable safety profile.  Moreover, these researchers stated that large, multi-center studies are needed to further verify these findings.

The authors stated that this study had several drawbacks.  First, the sample size in this study was small.  Second, these investigators did not carry out subgroup analysis based on patients’ disease stage and age.  They continued to collect cases and intend to refine the groupings and get more in-depth results in the future.  Third, these researchers did not increase the PRF voltage beyond 65 V.  If the voltage was further increased, the temperature could not be maintained below 50° C, which might cause protein degeneration and nerve damage; meanwhile, the objective of this trial was also to distinguish It from the CRF technology.  In future studies, these researchers will further refine the PRF voltage parameters and expand parameter range as long as it can be tolerated by the patients.

Ganglioside GM1 for the Treatment of Post-Herpetic Neuralgia

Koju and Lei (2016) noted that PHN is a commonest and difficult-to-manage complication of Herpes zoster.  This comparative study included 140 cases of PHN admitted in the department of dermatology in Renmin Hospital of Wuhan University, Wuhan, China, from March 2014 to February 2015, divided into a control and a study group.  In addition to the combination of anti-viral, analgesic, and neurotrophic agents given to the control group, additional ganglioside GM1 was given to patients in the study group.  Pain assessment was performed at the time of admission, and then on the 3rd, 7th and 10th day of treatment, on both groups, using a 10 cm VAS.  There was a significant statistical difference between the pain VAS score of the 2 groups, on the 7th day (3.73 ± 1.66 versus 3.03 ± 1.86, p = 0.024) and on the 10th day (3.25 ± 1.78 versus 2.20 ± 1.59, p = 0.006) of treatment.  The number of patients who have good/and complete response (37.5%) were largely higher in the study group than those in the control group (15%, p < 0.05).  The authors concluded that these findings demonstrated that the administration of ganglioside GM1 may potentially serve as a neoadjuvant therapy to reduce the severity and duration of pain in PHN patients.

Fulranumab for the Treatment of Post-Herpetic Neuralgia

Wang and colleagues (2017) stated that fulranumab is an antibody that specifically neutralizes the biological activity of human nerve growth factor.  In a multi-center, phase II, randomized, double-blind, placebo-controlled study, these researchers evaluated the safety and effectiveness of fulranumab in PHN and post-traumatic neuropathy (PTN) patients.  Patients (18 to 80 years of age) with inadequately controlled moderate-to-severe pain received study medication (subcutaneous injection) every 4 weeks.  Patients with PHN were randomized (3:2:2:3) to receive either placebo or one of 3 doses of fulranumab: 1 mg (1 mgQ4 wk), 3 mg (3 mgQ4 wk), or 10 mg (10 mgQ4 wk); PTN patients were randomized (1:1) to receive either placebo or fulranumab 10 mgQ4 wk.  The FDA placed a clinical hold (December 23, 2010) on all trials of anti-nerve growth factor drugs, including fulranumab, due to identified risks of osteonecrosis or rapidly progressing osteoarthritis; therefore, only 49 (of 150 planned) PHN patients and 34 (of 50 planned) PTN patients completed the double-blind efficacy evaluation.  There was no significant difference (p > 0.05, fulranumab versus placebo) for change in 7-day average of daily pain intensity scores from double-blind baseline to end of 12-week double-blind efficacy phase in PHN or PTN patients (primary end-point).  No significant difference was found with fulranumab versus placebo (p > 0.05) in other efficacy measures in either PHN or PTN patients.  The most common treatment-emergent adverse events (AEs; greater than 10% incidence) in PTN patients were sinusitis, carpal tunnel syndrome, and headache, whereas in PHN patients it was arthralgia.  The authors concluded that fulranumab did not demonstrate effectiveness in either PHN or PTN patients, but was generally well-tolerated in this small under-powered and abbreviated study.

Low-Level Laser for the Prevention of Post-Herpetic Neuralgia

Transdermal Oxycodone Patch for the Treatment of Post-Herpetic Neuralgia

In a Cochrane review, Gaskell and associates (2016) evaluated the analgesic effectiveness and adverse events (AEs) of oxycodone for chronic neuropathic pain in adults.  These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, and Embase from inception to November 6, 2013 for the original review and from January 2013 to December 21, 2015 for this update.  They also searched the reference lists of retrieved studies and reviews, and 2 online clinical trial registries.  This update differed from the earlier review in that these researchers included studies using oxycodone in combination with naloxone, and oxycodone used as add-on treatment to stable, but inadequate, treatment with another class of drug.  They included randomized, double-blind studies of 2-week duration or longer, comparing any dose or formulation of oxycodone with placebo or another active treatment in chronic neuropathic pain.  The authors concluded that there was only very low quality evidence that oxycodone (as oxycodone MR) is of value in the treatment of painful diabetic neuropathy or PHN.  There was no evidence for other neuropathic pain conditions; and AEs typical of opioids appeared to be common.

In a randomized, double-blind, multi-center, phase IIa vehicle-controlled cross-over trial, Gavin and colleagues (2017) evaluated the effectiveness, systemic exposure, safety and tolerability of a transdermal oxycodone patch containing tocopheryl phosphate mixture (TPM) in patients with PHN.  While the TPM/oxycodone patch did not significantly improve “average” NPRS scores versus vehicle patch, patients reporting high levels of paresthesia (n = 9) showed a trend toward improved pain reduction.  The TPM/oxycodone patch resulted in a low systemic exposure to oxycodone and was well-tolerated.  The authors concluded that  TPM/oxycodone patch delivered oxycodone to the site of perceived pain in subjects suffering from PHN, but did not provide analgesia for the broad PHN indication.

Combined Therapy of Nerve Block and Pulsed Radiofrequency

In a prospective, randomized clinical trial, Li and co-workers (2018) examined the combined effects of nerve block therapy (NBT) and pulsed radiofrequency (PRF) in patients with PHN.  A total of 60 PHN patients were divided into 4 groups (n = 15 each): the conventional puncture group (group CP), the nerve block therapy group (group NB), the PRF group (group PRF), and the combined treatment group (PRF combined with nerve block therapy (group CT).  To evaluate the extent of remission of hyperalgesia, these investigators recorded the VAS scores during cotton swab reaction before and after treatment and in the resting and active pain states.  In addition, blood samples were collected and plasma cytokine and neuropeptides such as interleukin-6 (IL-6), substance P (SP), and β-endorphin (β-EP) were measured by enzyme-linked immunosorbent assay (ELISA) at the admission (basic state), before the operation, and at 12 hours post-operatively.  The number of AEs (nausea, vomiting, constipation, puncture point hemorrhage, swelling and redness) within 12 hours of the treatment were also documented.  The results showed that VAS scores during cotton swab reaction decreased after treatment in all patients (p < 0.05).  Compared to group CP, plasma IL-6 and SP levels decreased (p < 0.05) and β-EP levels increased (p < 0.05) in groups NB, PRF, and CT.  There were no significant differences in AEs among groups (p > 0.05).  These researchers found that PRF in combination with NBT increased β-EP levels and decreased plasma IL-6 and SP, thereby alleviating pain and hyperalgesia in PHN patients.  The authors concluded that these findings suggested that combined therapy of NBT and PRF was safe and effective for PHN patients.

The authors stated that the drawbacks of this study included its design as a single-center study and its small sample size (n = 15 in the combined NBT and PRF group).  They did not evaluate the effects of liver or renal dysfunction on the treatment effects either.  These researchers stated that their study might have limited statistical power to detect difference among the groups.  They stated that future multi-center studies with larger sample sizes are needed to validate these findings.

Intravenous Zinc Sulfate

Lin and colleagues (2018) noted that gabapentinoids (gabapentin and pregabalin) are 1st-line drugs for PHN, but some PHN patients have inadequate therapeutic response.  Zinc deficiency has been identified as a risk factor for PHN.  Zinc can alleviate pain through binding to Ca(v)3.2 T-channels and N-methyl-D-aspartate receptors.  Mechanisms of gabapentinoids on neuropathic pain include inhibiting N-methyl-D-aspartate receptors and calcium channels.  The afore-mentioned findings provided a molecular pain-relieving basis for zinc supplements as an add-on therapy to pregabalin.  These investigators report 2 zinc-deficient PHN patients who received zinc sulfate intravenously as an add-on therapy to pregabalin and responded well.  These preliminary findings need to be validated by well-designed studies.

Dorsal Root Ganglion Pulsed Radiofrequency Lesioning

Huang and colleagues (2018) examined the clinical effects of selective dorsal root ganglion pulsed radiofrequency lesioning in combination with oral administration of gabapentin in the treatment PHN.  A total of 116 consecutive cases of initially diagnosed patients with PHN were randomly divided into the control and the observation groups, with each group consisting of 58 patients.  The control group was treated with oral gabapentin (2,400 mg/day, tid), while the observation group received gabapentin and pulsed radiofrequency lesioning of the dorsal root ganglion.  The clinical efficacy of both the regimens was compared after a follow-up period of 6 months.  The observation group had a significantly lower score on the VAS than the control group (p ≤ 0.05, with no significant complications occurring in both the groups) at a 1, 2, and 4 week post-treatment duration.  The percentage of cluster of differentiation (CD) 4+ cells and the CD4+/CD8+ ratio increased gradually, while the percentage of CD8 + cells decreased in the observation group (p ≤ 0.05).  No significant alterations were observed in the control group (p > 0.05).  The observation group had significantly lower serum IL-6, C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) levels than the control group (p < 0.05) at 1, 2, and 4 weeks after the treatment was instituted.  The observation group also demonstrated a superior total effective rate and efficiency than the control group (p ≤ 0.05).  The authors concluded that the findings of this study demonstrated that radiofrequency combined with gabapentin in the treatment of PHN had a good safety and efficacy profile.  The effects of this treatment may be related to an increased T-cell immunity and an inhibited inflammatory response.

In a commentary regarding the afore-mentioned study, Dauffenbach and Sharma (2018) stated that there are a number of clinically relevant questions that need to be addressed.  The outcomes chosen for this observational study were not entirely well-defined, aside from the ubiquitous VAS and “no severe complications”.  The total effective rate appeared to be either a novel or a rarely used assessment of the objective response rate.  It may be argued that this was a mere extrapolation of the VAS data as anything above a VAS change of 50% was classified as “effective”.  Incorporating robustly validated and commonly reported pain indices such as the Brief Pain Inventory-Short Form, Neuropathic Pain Scale, and/or the McGill Pain Scale would have added greater clarity to the conclusions.  On the contrary, the emphasis on immune and inflammatory indices shifted the focus away from reported clinical observations that the title of the article clearly highlighted.  The commentators noted that additional data regarding the technique used for trigeminal nerve pulsed radiofrequency lesioning, which was carried out in 9 of 58 observational subjects, would have been useful.  Although, the chosen parameters for pulsed radiofrequency fell within commonly reported and recommended ranges, the authors failed to clarify the rationale for repeating the 120-second therapy cycle and whether this could have impacted the clinical outcomes.  The rationale behind using a dosing regimen of gabapentin at 2,400-mg, administered thrice-daily, was also not explained.  Common clinical practice for dosing of neuromodulating medications is to reach a maximal daily dose (3,600 mg/day of gabapentin in this case) or a maximum tolerable dose (MTD), as limited by the side effects of the medication.  Furthermore, the authors failed to report the presence or absence of adverse side effects in either the control or observational groups.  Although, the inclusion criteria outlined “good treatment compliance”, the article did not reveal medication tolerance or adherence.  As regards, dorsal root ganglion pulsed radiofrequency lesioning improving the immune functioning of these patients, the authors fele that this reasoning may be a trifle over-arching.  It was possible that the difference in the reported immune and inflammatory indices between the control and observational groups may reflect a natural response to procedural stress.  It was also interesting to note that, in this group of largely healthy individuals with severe PHN, the mean age was essentially in the mid-40s.  This was far younger than that reported in world literature.  Finally, the reader was left without the ability to infer a dose-dependent effect of gabapentin and the unanswered question regarding whether or not the observed results of the use of selective dorsal root ganglion pulsed radiofrequency lesioning would vary in patients taking lower or higher doses of this neuromodulating agent.

In a retrospective study, Huang and associates (2021) examined the safety and efficacy of US-guided PRF modulation on thoracic DRG or intercostal nerve (ICN) for PHN in elderly patients and provided a theoretical basis for clinical treatment.  These investigators classified elderly patients into 2 groups, DRG group and ICN group, based on the needle tip position; VAS and concise health status questionnaire (SF-36) were used to examine the pain intensity and the QOL of the patients before and 2, 4 and 12 weeks after the PRF treatments.  These investigators also recorded the adverse reactions during the treatments.  After the PRF treatment, the scores of VAS and SF-36 (assessing general health perception, social function, emotional role, mental health, and pain) improved significantly in both groups (p < 0.05).  The mean VAS score in the DRG group was significantly lower than that in the ICN group 2 weeks after treatment; and remained for 12 weeks.  The SF-36 scores in the DRG group were significantly higher than those in the ICN group (p < 0.05).  These researchers found a similar incidence of adverse reactions between the 2 groups (p > 0.05).  The authors concluded that PRF therapy was safe and effective for elderly patients with PHN; however, PRF treatment in DRG was superior to that in ICN with improving VAS and SF-36 scores to a greater extent in elderly patients.

The authors stated that the findings of this study showed that the scores of VAS and SF-36 in the DRG group were better than those in the ICN group.  DRG neurons have the primary receptors of pain and temperature perceptions.  The electrical signals of pain in the trunk are first integrated at DRGs and then transmitted to the spinal cord, which finally arrive in the central nervous system.  PRF can stimulate DRGs by intermittent pulse currents and block the pain signal transduction.  Furthermore, PRF could form a high voltage field around DRGs, which further inhibits the activation of glial cells.  However, the mechanism that PRF of DRG is better than that of ICN to treat PHN still needs further researches.  Besides, as a retrospective study, it was difficult to avoid selectivity bias.  These researchers stated that prospective studies are still needed to confirm the findings of this retrospective study.

Transforaminal Epidural Steroid Injection

Mehta and colleagues (2015) reported on the case of a 64-year old man with a history of herpes zoster exposure presented with severe, constant, burning pain in the left T10 dermatome consistent PHN.  Previous treatment included oral and topical medications as well as an intercostal nerve block; however, these therapeutic options did not provide significant relief.  The patient was treated with a single-level T10 thoracic transforaminal epidural steroid injection for refractory PHN.  He reported complete resolution of his symptoms at 2- and 12-week follow-ups.  The authors concluded that this case illustrated transforaminal epidural steroid injections may be a successful therapeutic option for PHN.

Fujiwara et al (2018) stated the acute phase of shingles is characterized by severe pain, and one of the complications of shingles known as postherpetic neuralgia (PHN) is associated with prolonged pain. Although factors predicting the development of PHN, as well as its preventative measures, have been investigated, there is no single treatment effective for PHN. Some studies showed effectiveness of epidural injection to alleviate pain associated with acute-phase shingles. In these studies, epidural injection was performed by interlaminar (IL) approach. However, transforaminal (TF) approach may be more effective as it enables injection of steroids and local anesthetics closer to the dorsal root ganglion where inflammation primarily occurs. There have not been any studies comparing the analgesic effects of epidural injection approaches for pain associated with acute-phase shingles. This randomized prospective trial study compared the analgesic effects of IL and TF epidural injection approaches for pain associated with acute-phase shingles. Nara Medical University Hospital, Department of Anesthesiology. Forty patients with acute-phase shingles were randomly assigned to receive epidural steroid injections by TF or IL approaches. Patients were evaluated at the baseline, as well as at 1 month and 3 months after the treatment using the VAS and 36-Item Short-Form Health Survey (SF-36) scores. Patients with VAS score of over 40 at the 3-month follow-up were considered as having PHN, and the number of patients with PHN was compared between the IL and TF groups. Except the mental component of the SF-36 score and severity of skin rash, patient characteristics were not significantly different between the groups. VAS scores at 1 and 3-month follow-up were significantly lower than those at the baseline, and there was no difference between the groups. All SF-36 scores were not significantly different between groups at 1- and 3-month. There was no significant difference in the occurrence of PHN between the groups. Study limitations included a small sample size that did not reach the number of patients needed by the power analysis in the study. Also, the follow-up period of 3 months was relatively short. The authors concluded that VAS scores, the SF-36 RCS and MCS scores improved in both groups, however, there was no difference in the analgesic effects of the IL and TF epidural steroid injections at 1 and 3 months for acute-phase shingles patients.

Park and associates (2019) noted that despite the high frequency of nerve blocks in the acute phase of herpes zoster, factors associated with intervention, such as response to epidural block, have not been analyzed as predictive factors of PHN.  These  researchers determined the predictive factors of progression to PHN in the presence of interventions; they analyzed the medical records of 145 patients who underwent transforaminal epidural injection (TFEI) in the acute phase of herpes zoster.  A total volume of 5 ml (a mixture of 0.5% lidocaine and 5-mg dexamethasone) was injected during TFEI.  Corticosteroid was used only for the first TFEI.  Clinical data of age, sex, involved dermatome, presence of co-morbidity, time from zoster onset to first TFEI, numerical rating scale (NRS) before TFEI, NRS at 1 week and 1, 3, and 6 months after the first TFEI, and number of TFEI were collected and analyzed.  Through multi-variate logistic regression analysis, pain improvement less than 50% at 1 week after the first TFEI was a strong predictive factor of progression of PHN at all time-points.  Response to TFEI appeared to be a stronger predictive factor of progression to PHN than patient factors of sex, age, degree of initial pain, and presence of co-morbidity.

Extracorporeal Shockwave Therapy

Chen and colleagues (2020) noted that PHN is one of the most common types of chronic neuropathic pain, which seriously affects QOL because of pain severity and poor response to the currently available treatments.  The main strategies for PHN management are medication and invasive interventional therapies; however, these approaches have many adverse effects, so it is important to find another safe and effective treatment for PHN.  These researchers presented the study protocol of a RCT that will examine the safety and effectiveness of extracorporeal shockwave therapy (ESWT) in patients with PHN.  A single-blind, single-center RCT will evaluate 98 study participants randomized in a 1:1 ratio into control and experimental groups.  The control group will receive conventional treatment including medication therapy and invasive interventional therapy.  The experimental group will receive ESWT in addition to conventional therapy.  The primary outcome is pain intensity assessed on a VAS; the secondary outcomes are QOL assessed by the SF-36, psychological state for anxiety and depression measured by the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS), and sleep quality (SQ) measured by the Pittsburgh Sleep Quality Index (PSQI).  Assessors blinded to the randomization will collect data during the intervention period at baseline and weeks 1, 4, and 12.  The plasma levels of TNF-α and IL-6 will be evaluated before and after ESWT to examine the biochemical mechanisms of ESWT in the treatment of PHN.  The authors stated that this RCT will examine the safety and effectiveness of ESWT in patients with PHN, and will provide clinical evidence for its use in the management of PHN and examine the potential biochemical mechanisms of this treatment.

The authors stated that the proposed study has several limitations.  First, it is a single-center clinical trial, which might influence participant recruitment.  Second, this clinical trial is single-blind because a double-blind design would be difficult to ensure considering the therapeutic properties of ESWT, which might cause patient bias.  In addition, the primary outcome measure is a subjective evaluation, which may be a potential risk for bias because participants will know in which arm of the trial they are enrolled.  Another limitation is that although the trial follow-up is 3 months after the treatment, extended follow-up may be needed to demonstrate the benefits of ESWT in further studies.

Pulsed Radiofrequency of the Dorsal Root Ganglion

In a systematic review, Vuka and colleagues (2020) examined the evidence regarding the safety and efficacy of PRF applied to the dorsal root ganglion (DRG) for the treatment of neuropathic pain.  These investigators searched Medline, CINAHL, Embase, and PsycINFO through January 8, 2019, as well as ClinicalTrials.gov and the clinical trial register of the World Health Organization (WHO); all study designs were eligible.  They evaluated risk of bias using the Cochrane tool for RCTs and the Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I).  These researchers examined level of evidence using the Oxford tool and quality of evidence with GRADE.  They included 28 studies with subjects suffering from lumbo-sacral, cervical, or thoracic radicular pain, PHN, neuropathic bone pain in cancer patients, or carpal tunnel syndrome.  Only 5 studies were RCTs, while others were of non-randomized designs, predominantly before and after comparisons.  A total of 991 subjects were included, with a median number (range) of 31 (1 to 101) subjects.  Only 204 subjects were included in the RCTs, with a median number (range) of 38 (23 to 62) subjects.  The overall quality of evidence was low, as the majority of the included studies were rated as evidence level IV or V; and the quality of evidence was very low.  The authors concluded that evidence regarding the safety and efficacy of PRF of the DRG for the treatment of neuropathic pain is based mainly on results from very small studies with low evidence quality.  Current research results regarding the benefits of PRF of the DRG for the treatment of neuropathic pain should be considered preliminary and confirmed in high-quality RCTs with sufficient numbers of subjects.

Transcranial Magnetic Stimulation

In a prospective RCT, Pei and colleagues (2020) examined the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) at different high frequencies (5-Hz and 10-Hz) for the treatment of PHN.  A total of 60 patients with PHN who were treated at the Department of Pain Management at Xuanwu Hospital of Capital Medical University were recruited.  Using a computer-created number list, the cases were equally divided into 3 groups (n = 20), namely, the sham rTMS group, 5-Hz rTMS group, and 10-Hz rTMS group.  The sham rTMS group received sham stimulation, and the other 2 groups received high-frequency (5-Hz and 10-Hz) rTMS, respectively.  The primary motor cortex (M1) on the healthy side was stimulated with an intensity of 80% transcranial magnetic stimulation (RMT).  For the 5-Hz rTMS group, each stimulation session consisted of a series of 300 1-second pulses with a frequency of 5-Hz and an interval of 2.5 seconds between each train, giving a total of 1,500 pulses per session.  For the 10-Hz rTMS group, each stimulation session consisted of a series of 300 0.5-second pulses with a frequency of 10-Hz and an interval of 3 seconds between each train, giving a total of 1,500 pulses per session; the total time of stimulations was 17.5 mins.  rTMS was performed once-daily for 10 days.  The 3 groups received conventional medication therapy.  Baseline data (gender, age, course of disease, affected side) were recorded in the 3 groups.  At different time-points (before treatment, T0; during treatment, T1-T10; 1 month after treatment, T11; and 3 months after treatment, T12), the patients were evaluated on the following scales: VAS, short-form McGill Pain Questionnaire (SF-MPQ), QOL scale, SQ scale, SDS, Patient Global Impression of Change (PGIC), and incidence of AEs.  Compared with the sham rTMS group, there was a significant reduction in VAS scores in the 5-Hz rTMS group and 10-Hz rTMS group at T2-T12 (p < 0.05).  VAS scores in the 10-Hz rTMS group at T7-T12 were significantly lower compared with the 5-Hz rTMS group (p < 0.05).  The average VAS reduction was significantly different between the 5-Hz and 10-Hz rTMS groups; 28.3% (95% CI: 19.48% to 49.35%), compared to 39.89% (95% CI: 22.47% to 58.64%), with (F = 5.289, p = 0.022).  The 3 groups did not differ significantly in general SF-MPQ, QOL, SQ, SDS, and PGIC scores.  However, the QQL, SQ, and PGIC scores of the 5-Hz rTMS group and the 10-HZ rTMS group at T12 were significantly higher than that of the sham rTMS group.  The authors concluded that rTMS at either frequency, 5-Hz or 10-Hz, relieved PHN and improved the patients' QOL; rTMS at 10-Hz was superior to rTMS at 5-Hz in terms of pain relief, QOL, and improvement in SQ, although the latter had higher safety.  These investigators stated that rTMS at either 5-Hz or 10-Hz can be used as an adjuvant therapy for PHN.

The authors stated that the main drawback of this study was that the patients were only followed-up for 3 months.  In future work, these researchers will follow patients for 6 months or even longer to observe the safety and effectiveness of rTMS at different high frequencies for PHN.  Furthermore, this study had a small sample (n = 20 in each of the 3 groups) size due to time limitations, and these investigators could have refined the screening for rTMS evaluation indicators.  In the future, these researchers will enlarge the sample size and confirm the current findings on the safety and effectiveness of rTMS for PHN.

Furthermore, an UpToDate review on “Postherpetic neuralgia” (Ortega, 2020) states that “The effectiveness of therapies such as transcutaneous electrical nerve stimulation (TENS), transcranial magnetic stimulation (TMS), and acupuncture has not been proven”.

Trigeminal Nerve Block

Moon et al (2016) stated that neuropathic pain includes PHN, painful diabetic neuropathy (PDN) and trigeminal neuralgia.  Although various drugs have been tried to treat neuropathic pain, the effectiveness of the drugs sometimes may be limited for chronic intractable neuropathic pain, especially when they cannot be used at an adequate dose, due to undesirable severe side effects and the underlying disease itself.  Botulinum toxin type A (BoNT-A) has been known for its analgesic effect in various pain conditions.  Nevertheless, there are no data of nerve block in PHN and PDN.  These investigators reported the findings of 2 patients who were successfully treated with ultrasound (US)-guided peripheral nerve block using BoNT-A for intractable PHN and PDN; 1 patient had PHN on the left upper extremity (UE) and the other patient had PDN on a lower extremity (LE).  Due to side effects of drugs, escalation of the drug dose could not be made.  The authors injected 50 Botox units (BOTOX) into brachial plexus and lumbar plexus, respectively, under US guidance.  Pain was significantly decreased for approximately 4 to 5 months.  These researchers concluded that US-guided nerve block with BoNT-A may be an effective analgesic modality in a chronic intractable neuropathic pain especially when conventional treatment failed to achieve adequate pain relief.

Huang et al (2017) noted that varicella zoster virus re-activation can cause permanent histological changes in the central and peripheral nervous system.  Neural inflammatory changes or damage to the dorsal root ganglia (DRG) sensory nerve fibers during re-activation can lead to PHN.  For PHN of the 1st division of the 5th cranial nerve (ophthalmic division of the trigeminal ganglion), there is evidence of inflammatory change in the ganglion and adjacent ocular neural structures.  First division trigeminal nerve PHN can prove to be difficult and sometimes even impossible to manage despite the use of a wide range of conservative measures, including anti-convulsant and anti-depressant medication.  Steroids have been shown to play an important role by suppressing neural inflammatory processes.  Therefore, these researchers chose the trigeminal ganglion as an interventional target for an 88-year old woman with severe ophthalmic division PHN after she failed to respond to conservative treatment.  Under fluoroscopic guidance, a trigeminal ganglion nerve block was carried out with lidocaine combined with dexamethasone.  A retrobulbar block with lidocaine and triamcinolone settled residual oculodynia.  At 1-year follow-up, the patient remained pain-free and did not require analgesic medication.  The authors concluded that to their knowledge, this was the 1st reported case of ophthalmic division PHN successfully treated with a combination of trigeminal ganglion and retrobulbar nerve block using a local anesthetic agent and steroid for central and peripheral neural inflammatory processes.  This was a single-case study and its findings were confounded by the combined use of trigeminal ganglion and retrobulbar nerve block.

Kodama-Takahashi et al (2018) reported a case of persistent corneal epithelial defect that had occurred after a trigeminal nerve block.  A 75-year old woman had suffered from PHN for 8 years.  She underwent Gasserian ganglion block surgery and noticed declining visual acuity (VA) in the right eye on the following day.  She presented with severe hyperemia and corneal epithelial defects in the right eye and experienced remarkable reduction of sensitivity in the right cornea.  She was diagnosed with neurotrophic keratopathy.  Ofloxacin eye ointment and rebamipide ophthalmic suspension ameliorated the corneal epithelial defects but superficial punctate keratopathy, corneal superficial neovascularization, and Descemet's fold persisted.  Although the epithelial defects occasionally recurred, the corneal sensation and epithelial defects, Descemet's fold, and corneal superficial neovascularization all improved around 5 months after trigeminal nerve block.  The HRT II Rostock Cornea Module (RCM) could not detect any corneal sub-basal nerve fibers at post-operative 4 months; however, it could detect them at post-operative 6 months.  The authors concluded that as the nerve block effect wore off, the corneal sub-basal nerve fibers slowly regenerated.  As the corneal sensation improved, the corneal epithelial defects and superficial neovascularization also improved.  The HRT II RCM appeared useful for observing loss and regeneration of the corneal sub-basal nerve fibers.

Furthermore, an UpToDate review on “Postherpetic neuralgia” (Ortega, 2020) does not mention trigeminal nerve block as a therapeutic option.

Thermotherapy (Including Fire Needle and Moxibustion)

Li et al (2021) stated that PHN, as the most frequent sequela of HZ, can persist a long time.  Both HZ and PHN may significantly impact the QOL and made great economical afford to affected patients.  The optimal treatment on HZ and PHN is still an urgent problem.  In China, thermotherapy (including fire needle and moxibustion) is widely used because they can quickly promote the recovery of shingles and reduce the occurrence of PHN.  Thermotherapy can also reduce pain intensity, relieve anxiety, and improve QOL of PHN.  Based on the current literatures, the safety and effectiveness of thermotherapy will be systematically evaluated to provide appropriate complementary therapies for HZ and PHN.  Studies search for eligible RCTs that use thermotherapy including fire needle and moxibustion for HZ or PHN from the following databases: PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biology Medicine Database (CBM), Technology Periodical database (VIP), and Wanfang database.  Language restrictions for retrieving literature are English and Chinese.  Their data extraction will be performed by 2 researchers.  Mean difference (MD) or RR with fixed or random effect model in terms of 95% CI will be adopted for the data synthesis.  To evaluate the risk of bias, the Cochrane's risk of bias assessment tool will be employed.  The sensitivity or subgroup analysis will also be carried out when meeting high heterogeneity (I2 > 50%).  This meta-analysis will provide an authentic synthesis of the thermotherapy's effect on HZ and PHN, including incidence of PHN and AEs.  The authors concluded that the findings of the review will offer updated evidence and identify whether thermotherapy can be an effective treatment for HZ and PHN for clinicians.

Wu et al (2021) noted that PHN is one of the most common complications of HZ, and there is still a lack of effective therapies.  An increasing number of studies have found that compared to traditional therapy, moxibustion treatment is beneficial for the treatment of PHN, although current evidence remains inconclusive.  In a systematic review and meta-analysis, these investigators examined the safety and effectiveness of moxibustion for PHN.  They carried out a broad literature review of a range of databases from inception to December 2020, including the Cochrane Library, PubMed, Embase, Web of Science, Clinical Trails, China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals (VIP), China Biomedical Network Information, and Wanfang databases.  These researchers included RCTs that compared moxibustion to pharmacological therapies, herbal medicine, or no treatment for in the treatment of PHN.  The main outcome measure was efficacy rate and VAS; the secondary outcome measure was AEs.  Data accumulation and synthesis included meta-analysis, publication bias, sensitivity analysis, risk-of-bias assessment, and AEs.  These investigators included 13 RCTs entailing 798 patients.  Compared with the controls (pharmacological therapies, herbal medicine, or no treatment), moxibustion achieved a significantly higher efficacy rate (OR: 3.65; 95% CI: 2.32 to 5.72; p < 0.00001).  Subgroup analysis of the distinct moxibustion modalities showed that both Zhuang medicine medicated thread and thunder-fire moxibustions obtained higher clinical efficacy than the control group.  Compared with the controls, moxibustion resulted in significantly lower scores on the VAS (weighted mean difference [WMD] = -1.79; 95% CI: -2.26 to -1.33; p < 0.00001).  However, there was no significant difference in terms of safety between moxibustion and the controls (OR = 0.33; 95% CI: 0.06 to 1.77; p = 0.19).  The authors concluded that due to the lack of methodological quality as well as the significant heterogeneity of the included studies, it was difficult to draw a firm conclusion regarding the safety and effectiveness of moxibustion for the treatment of PHN.  These researchers stated that future high-quality studies are needed to compare moxibustion to pharmacological treatments; and more attention should be paid to the selection of medications with well-established efficacy for neuropathic pain and longer treatment duration.  Furthermore, these investigators also noted that it is important to include a sufficiently large sample size to ensure statistical power is retained.

Capsaicin 8% Patch (Qutenza) for Neuropathic Pain not Associated with Post-Herpetic Neuralgia

Giaccari et al (2021) noted that surgery is a frequent cause of persistent pain, defined chronic post-surgical pain (CPSP).  The capsaicin 8% patch (Qutenza®) is approved for the treatment of post-herpetic neuralgia (PHN) and for diabetic peripheral neuropathy (DPN) of the feet.  These investigators examined a review of the literature on use of the capsaicin 8% patch to treat neuropathic pain associated with surgery.  They identified studies by searching electronic databases using a combination of such terms as "capsaicin 8% patch", "Qutenza®", and "chronic postsurgical pain".  They identified 14 selected studies reporting on a total of 632 CPSP cases treated with capsaicin 8% patch.  Treatment with the capsaicin 8% patch significantly reduced the average pain intensity.  Only 5 studies reported adverse events (AEs) after the patch application.  The most common AEs were erythema, burning sensation and pain.  The authors concluded that the findings of this review indicated that capsaicin 8% patch treatment for CPSP was effective, safe and well-tolerated; however, randomized controlled trials (RCTs) on efficacy, safety and tolerability should be conducted.

Ausín-Crespo et al (2022) stated that pain units manage approximately 20% of the patients with neuropathic pain, usually presenting with severe uncontrolled pain associated with substantial impairment of quality-of-life (QOL) and disability.  In a retrospective, observational study, these researchers analyzed the experience with the capsaicin 8% dermal patch for managing patients with neuropathic pain in a pain unit.  This trial was carried out at a single pain unit on patients with peripheral neuropathic pain under routine clinical care.  Diagnosis of neuropathic pain was based on the Douleur Neuropathique 4 (DN4) questionnaire.  Evaluations included pain intensity according to a visual analog scale (VAS) and the QOL as evaluated with the European Quality of Life-5 Dimensions (EQ-5D).  These researchers included 66 patients with neuropathic pain lasting for a median of 24 months.  The most frequent diagnosis was iatrogenic neuropathic pain (47%) and 2/3 of patients exhibited extreme pain or discomfort.  Pain intensity was reduced significantly from a mean (standard deviation [SD]) of 7.20 (1.95) at baseline to 6.02 (2.77) at month 3, leading to a mean change from baseline of 1.19 (95% confidence interval [CI]: 0.59 to 1.78; p < 0.001; Cohen's d 0.49).  The extent of the pain area was also significantly reduced from a median (inter-quartile range [IQR]) of 169.5 cm2 (69.3 to 299.9) at baseline to 121.2 cm2 (35.4 to 183.9) at month 3 (p < 0.001).  There was an improvement in most dimensions of QOL, especially regarding "usual activities", "pain/discomfort" and "anxiety/depression".  Tolerability was consistent with the known profile.  The authors concluded that the findings of this study suggested that the capsaicin 8% dermal patch was a useful and well-tolerated therapeutic option for managing peripheral neuropathic pain in pain units.

Dupoiron et al (2022) noted that data supporting the use of high-concentration capsaicin patches (HCCPs) in breast cancer (BC) patients and BC survivors (BCSs) with peripheral neuropathic pain (PNP) are limited.  In an observational study, these researchers examined the safety and effectiveness of HCCP applications in BCSs/BC patients with PNP.  Data from all patients treated with HCCP in the pain department of a French comprehensive cancer center were collected from January 1, 2014 to October 14, 2020.  Independent pain specialists completed the Clinical Global Impression of Change (CGIC) for each included patient based on data extracted from patient's electronic medical record compiled by the treating pain specialist after each HCCP application.  Patients (n = 279; mean age of 59.2 years; previous history of PNP medication: 54.5%) received on average 4.1 repeated HCCP applications (1,141 HCCP applications); 68.8% received HCCP as an add-on to systemic therapy and 27.9% as 1st-line therapy.  PNP was most frequently caused by surgery (62.4%) followed by chemotherapy (11.8%) and radiotherapy (6.5%).  A complete or important analgesic effect was reported at least once by 82.3% of patients.  A 6.0% reported no effect at all.  For post-surgical PNP existing for less than 12 months and greater than 10 years an important or complete effect was observed for 70.7% and 56.0% of applications.  For chemotherapy- or radiotherapy-induced PNP, this important or complete effect was observed for 52.7% and 52.3% of applications, respectively. The authors concluded that HCCP application was associated with site reactions in 54.4% of patients (mainly burning sensation or pain, 45.9%, or erythema, 30.8%) and high blood pressure [BP] in 7.2%.  The authors concluded that this real-world chart review provided important safety and effectiveness information to clinicians when considering topical options to treat PNP in BCSs/BC patients.

Vieira et al (2022) stated that chronic neuropathic pain is a disabling condition that affects QOL.  Despite recommendations and guidelines, treatment remains suboptimal as it often does not result in significant symptom relief.  Capsaicin 8% patch has been used for the treatment of several peripheral neuropathic pain etiologies with encouraging results.  In a retrospective, observational study, these researchers examined the results of capsaicin 8% patch on neuropathic pain by evaluating pain intensity and the painful treatment area.  Participants included all patients submitted to capsaicin treatment at the Chronic Pain Unit of the Hospital Center of Tondela Viseu, from 2011 through 2019.  Records of capsaicin treatments were reviewed, and the data collected.  The primary outcome was pain intensity and painful treatment area reduction between the 1st and last treatment.  Furthermore, the number of treatments performed, neuropathic pain duration, anatomic location, pain etiology, and concomitant oral pain medication at baseline and upon treatment conclusion was also listed.  Post-surgical neuropathic pain was the most common etiology (49%), followed by PHN (28%).  The median (inter-quartile range [IQR]) baseline pain intensity assessed by the Numeric Rating Scale (NRS-11) was 6 (5 to 8) and the median (IQR) final NRS-11 was 3 (1 to 5), with a median (IQR) relative difference of -0.5 (-0.85 to 0.17) with statistically significant differences (p < 0.001) between baseline and last pain intensity, regarding all groups.  In addition, there was a reduction in the painful treatment area between baseline and the last evaluation, with a median (IQR) relative difference of -0.4 (-0.625 to 0.167).  The authors concluded that capsaicin 8% patch was a valuable option for the treatment of peripheral neuropathic pain, providing a significant reduction in pain intensity and painful area.  It was well-tolerated and has a high treatment compliance.  These investigators stated that the limitations of this trial included relatively small sample (100 patients included, 66% were women), the co-existence of oral pain medication, the size asymmetry between groups as well as occasional different timing for pain intensity and pain treatment area assessment due to logistical difficulties.

Laude-Pagniez et al (2022) reported the findings of 13 patients with neuropathic CPSP after excision of a skin melanoma treated with capsaicin 8% patch (CP8) at a single academic institution over a 40-month period.  Response to treatment and adverse effects were presented.  The authors concluded that CP8 may be an additional effective and well-tolerated treatment for high neuropathic CPSP with a very impaired QOL after melanoma surgery.  Moreover, these researchers stated that this treatment could be included in the therapeutic arsenal if prospective RCTs confirms its effectiveness.  These investigators stated that limitations of this trial included a small sample size (n = 13) and the lack of a control group.  Furthermore, this cohort represented a selected group of patients compared to general melanoma patients because of hospital-based recruitment in a specialized institution.

Boden et al (2022) stated that neuropathic pain is common in cancer survivorship and is one of the most distressing symptoms for patients previously treated for head and neck cancer (HNNC).  Persistent neuropathic pain, when it is ongoing and uncontrolled, has a detrimental effect and erodes patients' QOL.  Patients treated for HNNC are chronic opioid users to manage their post-treatment pain, which may entail an increased risk of addiction and over-dose.  These researchers proposed to examine the analgesic activity of high-concentration capsaicin patches for the treatment of HNNC survivors presenting with neuropathic pain sequelae.  TEC-ORL is a comparative, parallel, randomized, multi-center, phase-II clinical trial examining if Capsaicin patches (Qutenza) would reduce neuropathic pain when compared to Amitriptyline (Laroxyl) in HNNC survivors presenting with neuropathic pain sequelae.  The primary efficacy outcome is the rate of patients with a pain reduction of at least 2 points at 9 months compared to baseline.  Assuming that 5% of patients become lost to follow-up, a total of 130 patients will need to be randomized to detect a 25% improvement (i.e., standard: 25%, experimental: 50%) using a 1-sided Chi-square test with an alpha of 0.05%.  According to the recommendations for comparative phase-II clinical trials, the target differences and type I error rates are relaxed.  Randomized patients will either be treated with a capsaicin 8% (Qutenza) patch applied at 3 time-intervals in the experimental arm or with Amitriptyline (Laroxyl) (oral solution 40 mg/ml) taken for 9 months at the recommended daily dose of 25 mg to 75 mg in the control arm.  The authors concluded that TEC-ORL is a randomized, comparative phase-II clinical trial designed to comprehensively examine the analgesic activity of capsaicin compared to Laroxyl in HNNC survivors presenting with neuropathic pain sequelae.

Olusanya et al (2023) stated that neuropathic pain (NP) after spinal cord injury (SCI) exacerbates disability, decreases QOL, and is often refractory to available therapies.  Patients report willingness to trade potential recovery of strength, bowel, bladder, or sexual function for pain relief.  One proposed mechanism causing NP is up-regulation of transient receptor potential vanilloid 1 (TRPV 1) protein in uninjured C fibers and dorsal root ganglia causing neuronal excitability.  Recent studies have found up-regulation of TRPV 1 proteins after SCI.   In a randomized, single-blind, cross-over study, these researchers hypothesized that the application of capsaicin 8% patch (C8P) would improve pain, function and QOL in persons with SCI.  This study included 11 patients with SCI and NP refractory to 2 oral pain medications who received C8P or a control low-dose capsaicin 0.025% patch (CON) over 2 12-week periods.  Pain (VAS, MPI-SCI), QOL (WHO-QOL), and functional status (SCIM) were measured at 2 to 4-week intervals.  There was a main treatment effect of C8P over CON on VAS and MPI-SCI outcomes with pain reduction of 35% and 29% at weeks 2 and 4, respectively.  C8P also demonstrated a main treatment effect over CON on the SCIM mobility subscale.  WHO-QOL scores did not improve with C8P.  The authors concluded that C8P improved pain and mobility for patients with SCI and refractory NP.  Moreover, these researchers stated that larger studies are needed to examine the impact of repeat applications and QOL outcomes.

Furthermore, an UpToDate review on “Overview of chronic widespread (centralized) pain in the rheumatic diseases” (Goldenberg, 2023) does not mention capsaicin patch as a management / therapeutic option.

Gabapentinoids During Acute Herpes Zoster for the Prevention of Post-Herpetic Neuralgia

Lu et al (2021) stated that herpes zoster (HZ)-associated pain (i.e., acute herpes zoster neuralgia (AHN) and PHN) has the potential to cause significant patients' burden and heath resource expenditure.  PHN is refractory to the existing treatments, and the consensus is preventing the transition of AHN to PHN is better than treating PHN.  Anti-convulsants (e.g., gabapentin, pregabalin) have been recommended as one of the 1st-line therapies for PHN.  In practice, anti-convulsants have also decreased the severity and duration of AHN and reduced the incidence of PHN.  Nevertheless, its clinical application to AHN is hampered by inadequate evidence for its safety and effectiveness.  These investigators carried out this protocol for a systematic review to examine the safety and effectiveness of anti-convulsants for AHN.  Furthermore, a benefit-risk assessment of anti-convulsants for AHN would be conducted to estimate the extent to which these drugs could relieve symptoms and whether the benefits outweigh harms.  The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) was used to prepare their protocol and the results will be reported according to the PRISMA.  These investigators will search the China National Knowledge Infrastructure (CNKI), Chinese VIP Information (VIP), Cochrane Library, Embase, and PubMed databases, from inception to August 2019.  In addition, Clinicaltrials and Chinese Clinical Trial Registry will also be searched for relevant studies.  Selection of eligible studies and data extraction will be independently carried out by reviewers.  They will record the characteristic information, pain outcomes, incidence of PHN and adverse effects.  Data synthesis and other statistical analyses will be carried out using Review Manager Software 5.3 and STATA13.0.  Furthermore, risk of bias assessment, meta-regression and subgroup analyses, publication bias assessment, grading of evidence will be conducted for included studies.  The authors noted that as this systematic review will be conducted based on published data, no ethical approval is needed.  The findings will be submitted in peer-reviewed journals for publication.

Menaldi et al (2022) noted that gabapentinoids (e.g., gabapentin and pregabalin) have been established as a treatment for PHN; however, their effects on the prevention of PHN are unclear.  In a systematic review, these investigators examined the effectiveness of gabapentinoids for acute HZ in preventing PHN.  PubMed, Embase, CENTRAL, and Web of Science were queried December 2020 to collect data on relevant RCTs.  A total of 4 RCTs (including 265 subjects) were retrieved.  Overall, the incidence of PHN was lower, but not statistically significant in the gabapentinoid-treated group compared to the control group.  Subjects treated with gabapentinoids were more likely to experience AEs (e.g., dizziness, somnolence, and gastro-intestinal [GI] symptoms).  The authors concluded that the findings of this systematic review of RCTs showed that the addition of gabapentinoids during acute HZ were not significantly effective in preventing PHN; the evidence on this subject remains limited.  These researchers stated that physicians should carefully weigh the risks and benefits of prescribing gabapentinoids during the acute phase of HZ owing to its side effects.

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References