Symposium Addresses Naltrexone Indications

Symposium #1, "Naltrexone: New Formulations and Indications," drew an overflow crowd Friday morning as attendees found room on the floor to hear presentations.

Symposium #1, “Naltrexone: New Formulations and Indications,” drew an overflow crowd Friday morning as attendees found room on the floor to hear presentations.

Oral naltrexone had once been viewed as a magic bullet because it is highly selective for opioid receptors, but the major clinical obstacles for this agent occur in the induction and adherence phases. This was a conclusion presented by Sandra D. Comer, Ph.D., one of 13 speakers to address attendees of the Friday symposium “Naltrexone: New Formulations and Indications.”

In her presentation “Oral Naltrexone for Opioid Dependence,” Dr. Comer said that naltrexone completely antagonizes opioid effects, is orally bioavailable, and reaches peak blood levels in one hour. Naltrexone has a half-life of four hours compared with 6-B-naltrexol, which has a half-life of 13 hours.

“Nevertheless, daily dosing with naltrexone is possible,” said Dr. Comer, Professor of Clinical Neurobiology, College of Physicians & Surgeons, Columbia University, New York State Psychiatric Institute. “Naltrexone is primarily metabolized by the liver and reaches target plasma concentration of 1 to 2 ng/ml, providing good clinical benefit. Antagonist effects don’t appear to diminish over time.”

With oral naltrexone, two different dosing regimens are used: 50 mg daily or 100-100-150 mg every Monday, Wednesday and Friday. Naltrexone is also safe to administer over long periods, Dr. Comer noted. Treatment with naltrexone begins after initial detoxification with first an induction and then a maintenance phase.

“Our group has found that the use of supplemental medications is really critical during detox,” she said. “Buprenorphine, clonazepam, and clonidine are useful supplemental medications during detox. It’s also important to start with small doses of naltrexone at 3 mg or 6 mg.”

During the maintenance phase, adherence is the major obstacle to naltrexone treatment, Dr. Comer said. No consequence comes from stopping naltrexone, so discontinuing the medication is easy for patients.

“The biggest risk with discontinuance is that they will resume heroin use and overdose,” she said. “Pain relief for the patient who has an acute medical condition requiring opioid agonist treatment can be an issue and tricky to manage.”

The clinical experience with naltrexone is that the outcomes are clinically poor primarily because of poor medication adherence, Dr. Comer said.

“Nevertheless, the drug can be effective in highly motivated individuals,” she said. “Behavior therapy has been shown to improve outcomes as well.”

Good candidates for naltrexone are those with high motivation for abstinence, while poor candidates are those with a history of overdoses especially following detox. Also poor candidates are those who need opiate agonists to feel normal, those in chronic pain requiring chronic opioid treatment, and those with severe GI or cardiovascular disorders exacerbated by opioid withdrawal or abstinence.

“A possible solution to the obstacles in the induction and adherence phases may be the sustained release formulation naltrexone,” Dr. Comer concluded.

In his presentation “Opioid Modulators: Future Research Directions,” Elliot Ehrich, M.D., Senior Vice President of R&D and Chief Medical Officer, Alkermes Inc., said that opioid receptors may be good targets for drug development. He set the stage by describing receptors in the endogenous opioid system, including the G-protein coupled receptors of Mu, Delta, Kappa, and nociceptin (NOP). These interact with opioid peptides and cause signaling. Receptors differ in their actions, depending on where they are located. The Mu and Kappa opioid receptors, for example, are largely located in the limbic system, including the hypothalamus, which is part of the reward system.

“As we begin to understand more about the opioid receptor, we have the potential to develop a variety of therapies to target different parts of the body with different specificity,” Dr. Ehrich said. “There is the ability to leverage our knowledge of opiate receptor systems, particularly the Kappa and the NOP receptors, to develop new, improved therapies for addiction.”