Aetna considers intrathecal 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 intrathecal 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 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). 

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/h or 7.0 ug/h) was started and continued for 48 to 72 hours post-operatively.  Primary and secondary effectiveness variables were the mean daily patient controlled analgesia (PCA) morphine equivalent consumption and visual analog 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 hours (p = 0.04).  VASPI scores during the first 8 hours post-operatively were markedly lower in ziconotide-treated than in placebo-treated patients.  In 4 of 6 patients receiving the 7 ug/h-dose of ziconotide, side effects such as dizziness, blurred vision, nystagmus and sedation contributed to discontinuation of drug after 24 hours.  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/h-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/d for the ziconotide group and 600 mg/d 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 1254 patients with acute or chronic pain.  The duration of treatment has ranged from a 1-hour 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/h).  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.