Ziconotide (Prialt)

Number: 0712

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 ziconotide (Prialt).

1. Medical Necessity

   1. Aetna considers intra-thecal (IT) administration of ziconotide (Prialt) medically necessary for members with severe chronic pain that is intolerant of or refractory to other treatments such as systemic analgesics, adjunctive therapies, or IT morphine.
      
      
   2. Ziconotide intrathecal infusion (Prialt) is considered not medically necessary for members with the following contraindications:
      
      
      1. Pre‐existing history of psychosis; or
      2. Contraindications to IT analgesia including:
         1. The presence of infection at the microinfusion injection site; or
         2. Uncontrolled bleeding diathesis; or
         3. Spinal canal obstruction.

2. Experimental and Investigational

   1. Aetna considers IT administration (or other routes of administration) of ziconotide experimental and investigational as a treatment for the following (not an all-inclusive list), and for other indications because its effectiveness for these indications has not been established:
      
      
      1. Autism
      2. Epilepsy
      3. Irukandji syndrome
      4. Migraines
      5. Primary lateral sclerosis
      6. Stroke;
         
         
   2. Intrathecal combination of ziconotide, morphine, and levobupivacaine is considered experimental and investigational for the treatment of cancer-related refractory pain because the effectiveness of this approach has not been established.

Dosing Recommendations

Ziconotide intrathecal infusion is available as Prialt in 100 mcg/ml, 500 mcg/5 ml, and 500 mcg/20 ml solution in a single use vial.

The maximum dose of Prialt (ziconotide intrathecal infusion) is 19.2 mcg/day, to which the initiation dose of 2.4 mcg/day is titrated by day 21.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
62320 - 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, cervical or thoracic, lumbar or sacral (caudal), without or with imaging guidance (ie, fluoroscopy or CT
62324 - 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, cervical or thoracic, lumbar or sacral (caudal), without or with imaging guidance (ie, fluoroscopy or CT)
62350 - 62351	Implantation, revision or repositioning of tunneled intrathecal or epidural catheter, for long-term medication administration via an external pump or implantable reservoir/infusion pump; without or with laminectomy
62360 - 62362	Implantation or replacement of device for intrathecal or epidural drug infusion
99601 - 99602	Home infusion/specialty drug administration
HCPCS codes covered if selection criteria are met:
J2278	Injection, ziconotide, 1 mcg
Other HCPCS codes related to the CPB:
E0779	Ambulatory infusion pump, mechanical, reusable, for infusion 8 hours or greater
E0780	Ambulatory infusion pump, mechanical, reusable, for infusion less than 8 hours
E0781	Ambulatory infusion pump, single or multiple channels, electric or battery operated, with administrative equipment, worn by patient
E0783	Infusion pump system, implantable, programmable (includes all components, e.g., pump, catheter, connectors, etc.)
E0785	Implantable intraspinal (epidural/intrathecal) catheter used with implantable infusion pump, replacement
E0786	Implantable programmable infusion pump, replacement (excludes implantable intraspinal catheter)
J2270	Injection, morphine sulfate, up to 10 mg
J2272	Injection, morphine sulfate (fresenius kabi) not therapeutically equivalent to J2270, up to 10 mg
S0093	Injection, morphine sulfate, 500 mg (loading dose for infusion pump)
ICD-10 codes covered if selection criteria are met:
G89.0 - G89.4	Pain, not elsewhere classified [severed chronic pain that is intolerant of or refractory to other treatments]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C72.0	Malignant neoplasm of spinal cord [spinal canal obstruction]
D33.4	Benign neoplasm of spinal cord [spinal canal obstruction]
D69.9	Hemorrhagic condition, unspecified [uncontrolled bleeding diathesis]
F23	Brief psychotic disorder
F24	Shared psychotic disorder
F28	Other psychotic disorder not due to a substance or known physiological condition
F29	Unspecified psychosis not due to a substance or known physiological condition
F84.0	Autistic disorder
G12.23	Primary lateral sclerosis
G40.001 - G40.B19	Epilepsy and recurrent seizures
G43.001 – G43.919	Migraine
G45.0 - G45.9	Transient cerebral ischemic attack and related syndromes
G46.0 - G46.2	Cerebral artery syndrome
I63.00 - I63.9	Cerebral infarction
I65.01 - I66.9	Occlusion and stenosis of precerebral and cerebral arteries
I67.0 - I68.8	Other cerebrovascular diseases
M48.00 - M48.08	Spinal stenosis [spinal canal obstruction]
T63.621A - T63.624S	Toxic effect if contact with other jellyfish
Z86.59	Personal history of other mental and behavioral disorders [pre‐existing history of psychosis]
Intrathecal combination of ziconotide, morphine, and levobupivacaine:
Other CPT codes related to the CPB:
62320 - 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, cervical or thoracic, lumbar or sacral (caudal), without or with imaging guidance (ie, fluoroscopy or CT)
62324 - 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, cervical or thoracic, lumbar or sacral (caudal), without or with imaging guidance (ie, fluoroscopy or CT)
62350 - 62351	Catheter implantation
62360 - 62362	Reservoir/pump implantation
99601 - 99602	Home infusion/specialty drug administration
HCPCS codes not covered for indications listed in the CPB:
Levopuvicaine- no specific code
J2270	Injection, morphine sulfate, up to 10 mg
J2272	Injection, morphine sulfate (fresenius kabi) not therapeutically equivalent to J2270, up to 10 mg
S0093	Injection, morphine sulfate, 500 mg (loading dose for infusion pump)
Other HCPCS codes related to the CPB:
E0779	Ambulatory infusion pump, mechanical, reusable, for infusion 8 hours or greater
E0780	Ambulatory infusion pump, mechanical, reusable, for infusion less than 8 hours
E0781	Ambulatory infusion pump, single or multiple channels, electric or battery operated, with administrative equipment, worn by patient
E0783	Infusion pump system, implantable, programmable (includes all components, e.g., pump, catheter, connectors, etc.)
E0785	Implantable intraspinal (epidural/intrathecal) catheter used with implantable infusion pump, replacement
E0786	Implantable programmable infusion pump, replacement (excludes implantable intraspinal catheter)
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C00.0 - D09.9	Malignant neoplasms and carcinoma in situ
G89.3	Neoplasm related pain (acute) (chronic)

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Ziconotide intrathecal infusion is indicated for the management of severe chronic pain in adult patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. 

Pain is the most common complaint that leads patients to seek medical care. Chronic pain is not uncommon. Approximately 35% of Americans have some element of chronic pain, and approximately 50 million Americans are disabled partially or totally due to chronic pain.

Pharmacologic therapy used for the treatment of chronic pain includes opioid analgesics such as morphine and fentanyl, and adjuvant analgesics/coanalgesics such as antiepileptic drugs, tricyclic antidepressants and local anesthetics.

Prialt (ziconotide intrathecal infusion) is a non‐opioid N‐type calcium channel blocker analgesic. It is a synthetic conopeptide derived from the venom of the piscivorous marine snail, Conus magus. Prialt (ziconotide intrathecal infusion) is a calcium channel blocker specific to the neuronal calcium channels that regulate synaptic transmission in nociceptive neurons.

Prialt (ziconotide intrathecal infusion) has been approved by the U.S. Food and Drug Administration for the management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or IT morphine.

Voltage-sensitive calcium channel conductance is essential for the nervous system to signal a painful event.  However, intrathecal administration of L-type calcium channel blockers does not provide analgesia.  On December 28, 2004, ziconotide (Prialt), a peptide with analgesic and neuroprotective effect, gained approval from the Food and Drug Administration (FDA) for the treatment of severe chronic pain that is intolerant of or refractory to other treatments.  Ziconotide is the synthetic equivalent of omega-MVIIA, a component of the venom of the marine snail, Conus magus.  The mechanism of action underlying ziconotide's therapeutic profile derives from its potent and selective blockade of a neuron-specific N-type voltage-sensitive calcium channels (N-VSCCs).  Direct blockade of N-VSCCs inhibits the activity of a subset of neurons, including pain-sensing primary nociceptors.  This mechanism of action distinguishes ziconotide from all other analgesics, including opioid analgesics.  Clinical studies have reported that spinally administered ziconotide provides significant pain relief to severe chronic pain patients who have failed to obtain relief from opioid therapy.  Systemic toxicity is markedly decreased by administration of smaller doses of ziconotide intrathecally.  Furthermore, development of tolerance is not observed following chronic use of ziconotide in these subjects.  Nevertheless, there are neurological adverse effects due to delay in clearance of ziconotide from the neural tissues (Miljanich 2004). 

Black Box Warnings

• Severe psychiatric symptoms and neurological impairment may occur during treatment.
• Patients with a pre‐existing history of psychosis should not be treated with Prialt (ziconotide intrathecal infusion).
• All patients receiving Prialt (ziconotide intrathecal infusion) should be monitored frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness, and therapy be interrupted or discontinued in the event that these signs/symptoms occur. Prialt (ziconotide intrathecal infusion) therapy can be interrupted or discontinued abruptly without evidence of withdrawal effects.

Prialt (ziconotide intrathecal infusion) dose selection for an elderly member should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Data is unavailable regarding dosage adjustments in renal or hepatic impairment.

Safety and effectiveness in pediatric patients have not been established for Prialt (ziconotide intrathecal infusion).

Periodic monitoring of serum creatine kinase in members receiving Prialt (ziconotide intrathecal infusion) due to potential elevation of creatine kinase. Patients should be evaluated in the setting of new neuromuscular symptoms (myalgias, myasthenia, muscle cramp, asthenia) or a reduction in physical activity.

Prialt (ziconotide intrathecal infusion) may be used in treatment of a select subset of patients with refractory chronic pain, notably postherpetic neuralgia nonresponsive to previous therapies.

In a randomized, double-blind, pilot study, Atanassoff and colleagues (2000) evaluated the safety and analgesic effectiveness of intrathecal ziconotide in patients with acute post-operative pain following total abdominal hysterectomy, radical prostatectomy, or total hip replacement.  After intrathecal injection of local anesthetic and before surgical incision, a continuous intrathecal infusion of either placebo or 1 of 2 doses of ziconotide (0.7 ug/hr or 7.0 ug/hr) was started and continued for 48 to 72 hrs post-operatively.  Primary and secondary effectiveness variables were the mean daily patient controlled analgesia (PCA) morphine equivalent consumption and visual analog scale pain intensity (VASPI) scores, respectively.  Of the 30 patients who received study drug; 26 were evaluable for effectiveness.  Mean daily PCA morphine equivalent consumption was less in patients receiving ziconotide than in placebo-treated patients, and the difference was statistically significant between 24 and 48 hrs (p = 0.04).  VASPI scores during the first 8 hrs post-operatively were markedly lower in ziconotide-treated than in placebo-treated patients.  In 4 of 6 patients receiving the 7 ug/hr-dose of ziconotide, side effects such as dizziness, blurred vision, nystagmus and sedation contributed to discontinuation of drug after 24 hrs.  These symptoms resolved following ziconotide discontinuation.  Ziconotide showed analgesic activity, as indexed by reduced PCA morphine equivalent consumption and lower VASPI scores.  Because of a favorable trend of decreased morphine consumption with an acceptable side effect profile in the 0.7 ug/hr-dose ziconotide group, the lower dosage may be closer to the ideal dose than the higher dosage.  Large-scale studies are needed to clarify this issue.

In a multi-center, double-blind, placebo-controlled study, Staats and associates (2004) evaluated the safety and effectiveness of ziconotide in patients with pain that is refractory to conventional treatment (n = 111).  Patients were individuals aged 24 to 85 years with cancer or AIDS and a mean VASPI score of 50 mm or greater.  Subjects were randomly assigned in a 2:1 ratio to receive ziconotide or placebo treatment.  Intrathecal ziconotide was titrated over 5 to 6 days, followed by a 5-day maintenance phase for responders and crossover of non-responders to the opposite treatment group.  The main outcome measure was mean percentage change in VASPI score from baseline to the end of the initial titration period.  Of the evaluable population, 67 (98.5 %) of 68 patients receiving ziconotide and 38 (95 %) of 40 patients receiving placebo were taking opioids at baseline (median morphine equivalent dosage of 300 mg/day for the ziconotide group and 600 mg/day for the placebo group; p = 0.63, based on mean values), and 36 had used intrathecal morphine.  Mean VASPI scores were 73.6 mm in the ziconotide group and 77.9 mm in the placebo group (p = 0.18).  Mean VASPI scores improved 53.1 % (95 % confidence interval [CI]: 44.0 to 62.2 %) in the ziconotide group and 18.1 % (95 % CI: 4.8 to 31.4 %) in the placebo group (p < 0.001), with no loss of effectiveness of ziconotide in the maintenance phase.  Pain relief was moderate to complete in 52.9 % of patients in the ziconotide group compared with 17.5 % in the placebo group (p < 0.001).  Five patients receiving ziconotide achieved complete pain relief, and 50.0 % of patients receiving ziconotide responded to therapy compared with 17.5 % of those receiving placebo (p = 0.001).  The authors concluded that intrathecal ziconotide provided clinically and statistically significant analgesia in patients with pain from cancer or AIDS.

According to the manufacturer, the safety of Prialt administered as a continuous infusion has been examined in 1,254 patients with acute or chronic pain.  The duration of treatment has ranged from a 1-hr intrathecal infusion to treatment lasting for over 7.5 years.  The mean duration of treatment was 193 days with 173 patients (14 %) treated for at least 1 year.  The average final dose was 17 ug/day (0.73 ug/hr).  The most common side effects associated with the use of ziconotide are dizziness, nausea, confusion and headache.  Prialt carries a black box warning that severe psychiatric symptoms and neurological impairment may occur during treatment.  Patients with a pre-existing history of psychosis should not be treated with Prialt.

In a case-series study, Saulino et al (2009) reported the findings of intrathecal (IT) ziconotide and baclofen in 7 patients with neuropathic pain and spasticity; 5 of the 7 adult patients were receiving IT baclofen treatment when ziconotide was initiated.  All 5 patients had experienced at least one previous failed IT treatment regimen.  Pain intensity scores improved by a mean of 50.3 % with the use of ziconotide-baclofen therapy.  Mean time to onset of pain relief was 15 weeks, at a mean ziconotide dose of 3.7 mcg/day.  Within this group of patients, adverse events were observed in 1 patient, but they were not considered to be ziconotide-related and subsequently resolved.  The remaining 2 patients were receiving ziconotide treatment when baclofen was initiated.  Pain intensity scores improved by 75 % and 30 %, respectively.  Pain relief was evident at 2 weeks and 1 week, with corresponding ziconotide doses of 2.4 mcg/day and 14.4 mcg/day, respectively.  One patient in this group reported adverse events, but all resolved during continued treatment with the study drugs.  Treatment regimens varied between patients in these case series; each regimen used a different titration strategy and different concentrations of ziconotide and baclofen.  The authors concluded that combination IT ziconotide and baclofen therapy may be a treatment option for patients with neuropathic pain and spasticity.  Moreover, they stated that future studies are needed to determine the optimal dosing and titration schedules for ziconotide-baclofen usage.

Yamamoto and Takahara (2009) noted that a blockade of N-VSCCs has been suggested for reducing the neuronal injury occurring from ischemia/reperfusion events.  Thus, many efforts have been made to develop systemically available small-molecule N-type calcium channel blockers.  These researchers reviewed the latest updates concerning small-molecule N-type calcium channel blockers as potential candidates for the next generation of therapeutics for neuropathic pain and ischemic stroke.

Kress and associates (2009) noted that although morphine and ziconotide are the only intrathecal analgesics currently approved by regulatory authorities in the United States (FDA) and Europe (national-level approval by individual countries for morphine and European Agency for the Evaluation of Medicinal Products approval for ziconotide), a wide variety of opioid and non-opioid drugs are being used in this way.  There is no official guidance concerning the selection of these drugs or their use in combinations and a paucity of safety and effectiveness data from randomized controlled trials (RCTs).

In a retrospective, observational study, Deer and colleagues (2009) evaluated the safety and tolerability of ziconotide combination therapy.  Patients with severe chronic pain of non-cancer origin who were receiving inadequate analgesia with intrathecal opioid therapy (with or without intrathecal adjuvants) and who had ziconotide added to their intrathecal regimens were included.  Patient characteristics, intrathecal ziconotide doses, concomitant intrathecal and systemic drug use, VAS pain scores, Oswestry Disability Index scores, mini-mental status examination scores, neurological examination results, clinical observations (including adverse event reports), and equipment complications were reviewed for 12 weeks after ziconotide initiation.  A total of 16 patients were identified.  Ziconotide was initiated at a dose of 0.5 mcg/day and titrated to a mean dose of 2.64 mcg/day at week 12.  Intrathecal opioids were fentanyl (n = 3), hydromorphone (n = 7), morphine (n = 5), and sufentanil (n = 1).  Adverse events were noted in 1 patient, who reported increased depression and pain during combination therapy; ziconotide treatment was discontinued, and all adverse events resolved over a 4-week period.  Substantial pain relief (greater than or equal to 4-point decrease in VAS score) was reported in 3 of 15 patients (20.0 %) and increased functional capacity was evident in 3 of 15 patients (20.0 %).  The drawbacks of this study were that it was a retrospective study with a limited number of patients from a single center.  The authors concluded that results from this observational study suggest that combination intrathecal ziconotide and opioid therapy may be a safe and potentially effective treatment option for patients with refractory chronic pain.  They stated that prospective RCTs are needed to evaluate ziconotide combination therapy.

Wallace and colleagues (2010) noted that there is a need for a critical assessment of the currently available published literature on ziconotide combination therapy.  They summarized and evaluated the publications from pre-clinical and clinical peer-reviewed experiments that have examined the safety and effectiveness of ziconotide in combination with a variety of other drugs.  A total of 11 relevant publications were identified through a systematic search of multiple databases.  In pre-clinical studies, additive or synergistic anti-nociceptive effects were discovered when ziconotide was used in combination with baclofen, clonidine, or morphine; however, no additional anti-nociceptive effects were observed when bupivacaine was added to ziconotide therapy.  Safety data from animal studies revealed that ziconotide did not exacerbate morphine-induced respiratory depression, or clonidine-induced hypotension or bradycardia; however, ziconotide did potentiate morphine-induced hypotension and inhibition of gastrointestinal tract motility.  Results from 2 open-label trials indicated that combination ziconotide and morphine therapy produced greater analgesia than was produced by the use of either drug alone.  Preliminary support for the use of ziconotide in combination with baclofen, morphine, or hydromorphone was provided by case studies.  The authors concluded that although clinical and pre-clinical studies provide some support for the use of ziconotide in combination with baclofen, clonidine, morephine, or hydromorphone, strong evidence-based data are limited.  They stated that RCTs with long-term outcomes are needed.

Andras et al (2011) stated that the Irukandji syndrome is caused by the sting of some small jellyfish species.  The syndrome has severe life-threatening consequences.  The exacerbating pain and cardiovascular symptoms (tachycardia and hypertension) are hard to control in many cases.  These researcehers proposed a new possible therapy for Irukandji syndrome -- intravenously administered ziconotide.  The proposed experimental plasma concentration of ziconotide for rats is in the range of 0 to 6 μg/ml.  Based on a molecular biological scenario of the venom action mechanism at cellular level, these investigators suggested that the proposed method should be functional in re-establishing the normal cardiovascular parameters of the experimental animals and concomitantly it should abolish the severe pain caused by envenomation.  The authors expected that positive experimental results in agreement with their theory will lead to the possibility of a new therapy for the Irukandji syndrome and possibly for other envenomations with similar etiology.

In a pilot study, Mohammed et al (2013) evaluated the safety and effectiveness of bolus doses of ziconotide to assess the option of continuous administration of this drug via an implanted IT drug delivery system.  A total of 20 adults with severe chronic pain who were under consideration for IT therapy were enrolled in this open label, non-randomized study.  Informed consent was obtained.  Demographics, medical/pain history, pain scores, and concomitant medications were recorded.  A physical examination was performed.  Creatine kinase was measured.  Initial VAS, blood pressure, heart rate, and respiratory rate were recorded.  All patients received an initial bolus dose of 2.5-mcg ziconotide; the dose in the subsequent visits was modified according to response.  Subsequent doses were 2.5-mcg, 1.2-mcg, or 3.75-mcg as per protocol.  A good response (greater than or equal to30 % reduction in baseline pain VAS) with no side-effects on 2 occasions was considered a successful trial.  Data were analyzed using a generalized estimating equations model, with pain VAS as the outcome and time (7 time-points; pre-injection and 1 to 6 hours post-injection) as the predictor.  Generalized estimating equations analysis of summary measures showed a mean reduction of pain VAS of approximately 25 % at the group level; of 11 responders, 7 underwent pump implantation procedure, 2 withdrew because of adverse effects, 1 refused an implant, and 1 could not have an implant (lack of funding from the Primary Care Trust).  The authors concluded that these findings demonstrated that mean VAS was reduced by approximately 25 % at the group level after IT ziconotide bolus.  Treatment effectiveness did not vary with sex, center, age, or pain etiology.  Ziconotide bolus was generally well-tolerated.  The authors concluded that larger studies are needed to determine if bolus dosing with ziconotide is a good predictor of response to continuous IT ziconotide via an intrathecal drug delivery system.

Webster (2015) characterized safety profiles associated with the IT administration of morphine and ziconotide and discussed how they relate to mechanisms of action.  Published data were evaluated to identify potential relationships between safety profiles of IT morphine and IT ziconotide and their mechanisms of action.  Potentially severe and clinically relevant adverse events (AEs) associated with IT morphine include respiratory depression, tolerance, and granuloma formulation, whereas IT ziconotide is associated with neuropsychiatric AEs, such as cognitive impairment, hallucinations, and changes in mood or consciousness, particularly with high doses and rapid titration.  Adverse events associated with these IT therapies may result from spread of the medication out of the IT space into areas of the central and peripheral nervous systems and systemic circulation.  Adverse events that occur usually can be managed and, in some cases, prevented.  To mitigate risk, patients' histories should be reviewed to identify potential complicating factors (e.g., obesity or other risk factors for respiratory dysfunction in patients receiving IT morphine; a history of psychosis in patients receiving IT ziconotide).  Also, treatment should be initiated at a low dose, titrated slowly, and patients should be closely monitored during treatment.  The authors concluded that IT morphine and IT ziconotide are approved by the FDA for patients who do not respond to less invasive treatments, but the safety profiles of each may make them more or less appropriate for certain patient populations.

Hayek et al (2015) stated that the safety and effectiveness of ziconotide as a single agent has been evaluated in few short-term clinical trials and open-label studies.  Ziconotide use is challenging given its AE profile.  These researchers described the long-term effectiveness and AEs of ziconotide used as an adjunct to other IT agents in chronic non-cancer pain patients who had suboptimal pain control from IT therapy.  Ziconotide was introduced in the IT infusion mixture after a successful ziconotide trial.  Pain scores, IT doses, as well as AEs were recorded and analyzed from trial to initial ziconotide infusion and up to 24 months.  A total of 15 patients underwent ziconotide trials; 4 subjects failed the trial, and 11 proceeded to continuous ziconotide treatment.  Seven out of 11 patients experienced AEs resulting in ziconotide discontinuation; 2 of the 7 subjects who required discontinuation of ziconotide had improved pain; 4 subjects were able to continue IT ziconotide through 24 months.  The authors concluded that a high incidence of AEs limited the usefulness of IT ziconotide as adjunct therapy.  They stated that these results were limited by the size of this patient population; however, they represented a long follow-up period, which is limited in most current publications on this IT peptide.  These researchers stated that while ziconotide is a needed IT agent, more studies are needed to better understand the factors that would improve the treatment to trial ratio as well as the long-term effectiveness of IT ziconotide treatment.

Deer and colleagues (2019) evaluated the evidence for morphine and ziconotide as 1st-line IT analgesia agents for patients with chronic pain.  Medline was searched (through July 2017) for "ziconotide" or "morphine" and "intrathecal" and "chronic pain" with results limited to studies in human populations.  The literature supports the use of morphine (based primarily on non-controlled, prospective, and retrospective studies) and ziconotide (based on RCTs and prospective observational studies) as 1st-choice IT therapies.  The 2016 Polyanalgesic Consensus Conference (PACC) guidelines recommended both morphine and ziconotide as 1st-line IT monotherapy for localized and diffuse chronic pain of cancer-related and non-cancer-related etiologies; however, one consensus point emphasized ziconotide use, unless contraindicated, as 1st-line IT therapy in patients with chronic non-cancer-related pain.  Initial IT therapy choice should take into consideration individual patient characteristics (e.g., pain location, response to previous therapies, co-morbid medical conditions, psychiatric history).  Trialing is recommended to assess medication efficacy and tolerability.  For both morphine and ziconotide, the PACC guidelines recommended conservative initial dosing strategies.  Due to its narrow therapeutic window, ziconotide requires careful dose-titration.  Ziconotide is contraindicated in patients with a history of psychosis; IT morphine administration may be associated with serious side effects (e.g., respiratory depression, catheter tip granuloma), require dose increases, and cause dependence over time.  The authors concluded that based on the available evidence, morphine and ziconotide are recommended as 1st-line IT monotherapy for cancer-related and non-cancer-related pain.  The choice of first-in-pump therapy should take into consideration patient characteristics and the advantages and disadvantages of each medication.  Moreover, these researchers stated that the interim analysis data of the PRIZM registry suggested sustained effectiveness when ziconotide is used as the 1st-line agent in the pump; however, increased patient numbers and additional analyses of these data will contribute to the knowledge of and comfort in using non-opioid IT analgesics.  In addition, further investigation is needed to better understand the risks and benefits associated with the choice of initial IT medication (i.e., morphine or ziconotide) in diverse chronic pain populations.

Epilepsy

Zamani and colleagues (2020) stated that ziconotide is a novel analgesic agent acting on voltage-gated calcium channels and is administered intrathecally for neuropathic pain.  While anti-epileptic activities of other types of calcium channel blockers (T- or L-type) are well-established, there is no information regarding the effect of ziconotide as an N-type calcium channel antagonist in pentylenetetrazol-induced seizures or its anxiolytic and sedative activities.  The present study was the 1st to report on these effects.  In a pre-clinical and pilot study, these researchers examined the anti-convulsant activity of ziconotide in the pentylenetetrazol (60 mg/kg) seizure model.  Ziconotide was administered intracerebroventricular (i.c.v.) as a single-dose (1 μg/rat) or repeatedly (chronic administration: 0.1, 0.3, or 1 μg/rat once-daily for 7 days).  The anxiolytic and sedative actions of ziconotide were evaluated with the elevated plus maze, light/dark (LD) box, and pentobarbital-induced sleep tests.  Immediately after behavioral testing, the amygdala was completely removed bilaterally to determine corticosterone levels by immunoassay.  In all dosing regimens, ziconotide significantly decreased the seizure frequency and also delayed the latency period compared with control.  Chronic administration affected the percentage of mortality protection, while a single-dose of ziconotide did not.  In behavioral tests, ziconotide significantly increased both the number of entries and the percentage of time spent in the open arms of the elevated plus maze.  Furthermore, ziconotide significantly increased the latency period and the number of entries into the light compartment during the LD box examination.  Chronic administration of ziconotide significantly reduced the latency to sleep and increased sleeping time, whereas these parameters were not affected by a single-dose.  Furthermore, amygdala corticosterone levels were significantly decreased in rats treated with ziconotide compared with control.  The authors concluded that ziconotide displayed beneficial neurobehavioral effects in a model of epilepsy with anxiety as its co-morbid event.  It appeared that at least one of the mechanisms involved in these effects was associated with a decrease in brain corticosterone levels.  The main advantage of ziconotide over benzodiazepines (routine anxiolytic and sedative drugs) was that it did not cause tolerance, dependency, and addiction.  Thus, more than ever, it is necessary to improve the convenience of drug delivery protocols and attenuate the adverse effects associated with ziconotide-based therapies.

Migraines

Holden et al (2022) stated that migraine is one of the most prevalent and debilitating illnesses globally.  There are a wide variety of options for the treatment of migraines.  One of the emerging therapeutic options for migraine, refractory to conventional treatment modalities, is IT Ziconotide.  Ziconotide enforces selective block of N-type calcium channels, which control neurotransmission at many synapses.  Ziconotide is proposed to be effective for chronic neuropathic pain, with a favorable lack of tolerance and chemical dependency.  The authors noted that few studies in the literature reported the successful resolution of migraine headaches with ziconotide.  In a single-case study, these investigators reported the successful use IT ziconotide therapy for the treatment of chronic refractory migraines.  They stated that this case added to the evidence that ziconotide may be a useful therapeutic option for managing severe refractory migraines.

Primary Lateral Sclerosis

Zhu and colleagues (2019) noted that spasticity can be very debilitating and painful.  These investigators presented the findings of a case of severe spasticity from primary lateral sclerosis refractory to IT baclofen in doses up to 1,100 μg/day.  Baclofen was weaned down and switched to IT ziconotide at 0.6 μg/day.  The dose was then titrated up to 3 μg/day with excellent control of spasticity.  The authors concluded that the findings of this case suggested that low-dose IT ziconotide should be considered in patients with lower extremity (LE) spasticity refractory to IT baclofen.  These preliminary findings need to be validated by well-designed studies.

Intrathecal Combination of Ziconotide, Morphine, and Levobupivacaine for the Treatment of Cancer-Related Refractory Pain

Puntillo and colleagues (2020) stated that in cancer-related pain refractory to systemic opioids, IT administration of morphine can be a useful strategy.  In clinical practice, IT morphine is usually combined with other drugs with different mechanisms of action, in order to obtain a synergistic analgesic effect.  However, the discussion on safety and effectiveness of IT combination therapy is still ongoing.  In an observational, single-arm study, these investigators reported the effects of an IT combination of low doses of ziconotide, morphine, and levobupivacaine in end-stage cancer refractory pain.  A total of 60 adult patients, 21 females and 39 males, were enrolled to an IT device implant.  The mean VASPI score was 88 ± 20 mm.  All subjects started with a triple combination therapy: the initial IT dose of morphine was calculated for each subject based on the equivalent daily dose of morphine; an oral/IT ratio of 400/1 was used.  For ziconotide, a standard slow titration schedule was started at 1.2 μg/day and the initial dose of levobupivacaine was 3 mg/day.  The initial IT mean doses of morphine, ziconotide, and levobupivacaine were 0.8 ± 0.3 mg/day, 1.2 mcg/day and 3 mg/day, respectively.  At day 2, a significant reduction in VASPI score was registered (49 ± 17, p < 0.001), and this significant reduction persisted at 56 days (mean VASPI score 44 ± 9, p < 0.001), with mean doses of morphine 2 ± 1 mg/day, ziconotide 2.8 ± 1 mcg/day, and levobupivacaine 3.8 ± 2 mg/day.  Very few AEs were observed; and subjects' satisfaction was very high during the entire study period.  The authors concluded that these findings, within the limit of the study design, suggested that the IT combination of ziconotide, morphine, and levobupivacaine, at low doses, allowed safe and rapid control of refractory cancer pain, with high levels of patient satisfaction.

The authors stated that this study had several drawbacks related to the study design (observational, single-arm study), the small number of patients included due to the very difficult-to-treat category of patients enrolled.  The non-randomized nature of the study did not allow firm conclusions to be reached, nor to clearly examine the synergistic effect of the association.  The short life expectancy due to cancer progression limited the time of observation to 2 months, as only 13 patients survived after the 3ird month.  However, this strategy suggested rapid and effective pain control and called for more studies enrolling a larger population of oncological patients with refractory pain.

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