Synthetic Form of Snail Venom Toxin Has Strong Analgesic Effects Against Cancer Pain

SAN FRANCISCO—The predatory sea snail (conus magnus) compensates for its lack of speed by stunning its prey with a fast-acting neurotoxin. Ziconotide, a synthetic peptide derived from that toxin, proves to have strong analgesic effects in many patients with otherwise intractable cancer pain and may be the vanguard of a new class of pain drugs.

Michael S. Leong, MD, assistant professor of anesthesia at Stanford University School of Medicine in California, reported that Visual Analogue Scale of Pain Intensity (VASPI) scores improved 53% for patients treated with ziconotide vs 18% for patients receiving placebo. These data came from a double blind, placebo-controlled trial in 108 patients, 88% with intractable pain from cancer and 12% with AIDS. The study was sponsored by Elan Pharmaceuticals, Inc.

Previously Unresponsive

"Nearly 75% of cancer patients report moderate to severe pain, yet fewer than half receive adequate analgesic therapy," Dr. Leong said. He told Oncology News International that new analgesic options are particularly needed for patients such as those in this study, whose pain was rated severe on the VASPI scale (mean 7.8) despite median daily oral morphine equivalents of 0.3-0.6 g/day. Nearly 60% of the patients in this study were unresponsive to previous intrathecal (IT) morphine.

Dr. Leong said that patients in the study had pain unresponsive not only to high-dose morphine but also to tricyclic antidepressants, high-dose gabapentin (Neurontin), and/or to lidocaine.

Common cancer diagnoses included breast (25%), lung (16%), and colon (12%); 43.5% of cancer patients had metastatic disease.

Ziconotide efficacy was slightly higher for cancer patients (55% ziconotide, 18% placebo) than for AIDS patients (44% ziconotide, 22% placebo). Ziconotide was equally effective in relieving pain from metastatic disease and from localized disease. The degree of improvement with ziconotide was unaffected by age or sex, but was somewhat greater in white patients than in those who were other than white.

Prior use of intrathecal morphine did not alter responses. "Ziconotide is effective in a large proportion of patients with intractable pain of malignant origin. Efficacy is robust and not affected by patient age, gender, or disease status. We think that patients unresponsive to IT morphine may benefit from ziconotide therapy," Dr. Leong said.

Calcium Channel Blocker

Ziconotide is a specific blocker of neuronal N-type calcium channels. It also affects voltage-sensitive sodium channels and so might be synergistic with morphine. It is an analgesic, rather than an anesthetic, and reduces pain without numbing the affected area.

Dr. Leong told ONI that there is so far no evidence that tolerance to ziconotide develops, but that clinical utility may be limited somewhat by the need for intrathecal administration. He said that previous studies showed ziconotide to be too toxic for intravenous administration, mostly due to cognitive side effects and hypotension.

‘Approvable’ Says FDA

Dr. Leong said that the FDA has issued an "approvable" letter for ziconotide and that the drug is expected to be available later this year for intrathecal usage. The key to successful initiation of ziconotide therapy appears to be to titrate the drug slowly, over a 3-day period, from 0.2 mg/h up to 24 mg/h.

"We expect that ziconotide will find a role as an adjunct to IT morphine for treating chronic, severe pain," Dr. Leong said. "A reasonable approach would be to start with IT opioids and add small amounts of ziconotide to improve pain control."