Severe chronic pain - ziconotide
Severe chronic pain can result from a variety of conditions and injuries, and there remains a need for new, efficient, strong, side effect-free analgesics to treat severe chronic pain, particularly for cancer patients and those with severe neuropathic pain with no obvious physical cause.
One such compound under development by Elan is ziconotide, previously known as SNX-111. The synthetic peptide corresponds to the sequence of the omega-conopeptide MVIIA found in the venom of the marine snail Conus magnus.1 Ziconotide is the first in a new class of non-opioid painkillers that act by blocking the N-type calcium channels. Voltage sensitive calcium channel conductance is an essential part of the nervous system's pain signalling, and N-type calcium channel blockers have been shown to provide analgesia.
In a randomised double-blind pilot study, patients undergoing elective total abdominal hysterectomy, radical prostatectomy or total hip replacement were given a continuous intrathecal infusion of either placebo or 0.7 or 7.0µg/hr of ziconotide, after the intrathecal injection of local anaesthetic, but before the first incision was made.2 The infusion was continued for 48 to 72 hours after the operation. Patients given ziconotide needed smaller amounts of morphine to control their pain, and those given the lower dose had a lower incidence of side-effects, which included dizziness, blurred vision, sedation and nystagmus and led to four of the six patients who had been given the higher dose discontinuing therapy.
A multicentre double-blind placebo-controlled randomised trial has also been carried out in 111 patients.3 The subjects had cancer or AIDS, and were randomly assigned in a 2:1 ratio to receive ziconotide or placebo. Intrathecal ziconotide was titrated over 5-6 days, followed by a 5 day maintenance phase for those who responded to treatment, and a crossover of non-responders to the opposite treatment group. Mean visual analogue scale of pain intensity scores improved by 53% in those receiving the active, and 18% in those given placebo; no loss of efficacy was seen in the maintenance phase. Few serious side effects were seen, and the incidence was similar to that for placebo.
Ziconotide has now been submitted for regulatory approval under the trade name Prialt, and it could well prove to be a significant new addition to the analgesic arsenal.