Cautious dosing urged for intrathecal pain drug.

PALM SPRINGS, CALIF. -- Ziconotide is a welcome addition to alternatives for relieving pain via intrathecal infusion, but many questions remain about its dosing, side effects, and potential best use, pain specialists said at the annual meeting of the American Academy of Pain Medicine.

"There are a lot of nuances with this drug," said Samuel J. Hassenbusch III, M.D., professor of neurosurgery at the University of Texas, Houston.

"It's got to be on the market maybe 5 years before we can really say what its role is," he said.

The Food and Drug Administration approved the nonopioid, N-type calcium channel blocker in December for treating chronic, intractable pain via an implanted intrathecal pump, making it the only analgesic other than morphine approved for intrathecal use. (Baclofen, marketed as Lioresal, is approved for intrathecal use in the treatment of cerebral spasticity.)

In practice, ziconotide (Prialt) will probably be used alone or in combination with other drugs to treat intractable malignant and nonmalignant pain.

A synthetic equivalent of a peptide used by the Conus magus marine snail to numb its prey, ziconotide is said to be 1,000-fold more potent than morphine in blocking phase 2 pain responses.

A combined analysis of three controlled trials presented at the meeting found the mean Visual Analogue Scale of Pain Intensity (VASPI) scores of 402 patients with nonmalignant pain improved 23%, compared with an 8% improvement in patients receiving placebo from the initial dose to the end of titration. The difference between the groups was significant.

In 51 patients with malignant pain, VASPI scores improved by 37% with ziconotide treatment, compared with 9% for placebo.

Within the study conducted by Ronald Collins, M.D., in private practice in Hampton Cove, Ala., significant VASPI score improvement was found in patients with myelopathic pain (19% vs. 0.1%), neuropathic pain (29% vs. 9%), radiculopathic pain (44% vs. 4%), spinal pain (21% vs. 7%), and failed back surgery syndrome (22% vs. 7%).

A trend toward significance was seen for patients with bone pain, according to the study findings, which were presented in poster form.

Dizziness, nausea, headache, and confusion are commonly reported side effects of ziconotide. Serious adverse events have been reported, including neurologic problems (such as confusion and somnolence) and urinary retention. The incidence and severity of side effects are believed to be modifiable with careful dosing and titration.

Indeed, the ideal dosing of the powerful drug--specifically, the initial intrathecal dose and titration schedule--drew significant attention at the meeting.

Many early study patients received an initial dose of 0.4 mcg/hour, with upward dose adjustments at 12-hour intervals. However, a safety evaluation conducted after 48 patients had been enrolled in a phase III trial prompted investigators led by Peter S. Staats, M.D., to decrease the initial dose to 0.1 mcg/hr and schedule increases in titration at 24-hour intervals (JAMA 2004;291:63-70).

The FDA-approved package insert recommends initiation at a dose of no more than 0.1 mcg/hour (2.4 mcg/day), with dose increases at intervals of no more than 2-3 times per week.

Some specialists at the meeting cautioned that the dose in the package insert may still be too high and the titration schedule too fast.

"You really do have to go low and very slow," said Dr. Staats, chief of the division of pain medicine at Johns Hopkins University in Baltimore.

Aggressive dosing can trigger what Dr. Staats called a "fly by" effect; that is, the precipitation of side effects before pain relief sets in.

"The package insert says to change the dose every few days; I wouldn't even go there," said Dr. Staats, who consults for Elan Pharmaceuticals Inc., the maker of ziconotide, and receives research support from Medtronic Inc., maker of a pump used to infuse ziconotide.

An initial dose of 0.5 mcg/day with dose adjustments every other week was recommended by Elliot Krames, M.D., a private practitioner in San Francisco. Dr. Krames disclosed that he receives research support and is on an advisory/review panel for Elan.

BY BETSY BATES

Los Angeles Bureau