Buprenorphine, a medication being studied as a treatment for heroin and other opiate addiction, has crossed a major hurdle in the process of gaining Food and Drug Administration (FDA) approval. A large multicenter clinical trial to determine the safety and effectiveness of buprenorphine was completed earlier this year.
Although data from the study are still being analyzed, NIDA officials are encouraged by buprenorphine's performance. "It's looking very good," says Doralie Segal of NIDA's Medications Development Division, who directs the buprenorphine project.
The 16-week study, chaired by Dr. Walter Ling of the Los Angeles Addiction Treatment Research Center, compared the safety and effectiveness of buprenorphine in patients who were randomly assigned to receive daily doses of either 1, 4, 8, or 16 milligrams (mg) of the medication. A total of 733 patients participated in the study at 12 sites throughout the United States and Puerto Rico. While complete analyses of the specific findings from the clinical trial are not yet available, buprenorphine significantly reduced patients' craving for heroin, says Segal. Patients rated their levels of heroin craving during each week of the study by marking a visual scale, the ends of which represented minimum and maximum craving. "Regardless of the dose, heroin craving dropped dramatically within 4 weeks and remained very low for the remaining 12 weeks of the study," Segal says. "The effect was very pronounced."
Patients who completed the 16-week study phase were then allowed to continue on buprenorphine for another 36 weeks under a flexible-dosing schedule. During this time, patient dosages could be increased to 32 mg or decreased to 1 mg, and individual sites had the option of giving double doses on Friday or Saturday. Double-dosed patients would then receive their next dose on Monday.
If approved by the FDA, buprenorphine, an analgesic, would join methadone, naltrexone, and LAAM (l-alpha-acetyl-methadol) as the fourth medication available for treating opiate addiction. Buprenorphine's unique effects and pharmacology make it an attractive and clinically helpful treatment option. For example, buprenorphine produces less euphoria than morphine and heroin. When compared with other opiates, it also causes a significantly lower degree of sedation and respiratory depression, the slowing down of breathing that makes heroin overdoses so dangerous. Even high doses of buprenorphine--as much as 100 times the dose at which it produces analgesia--do not produce dangerous respiratory effects. "Respiratory depression caused by buprenorphine is not of clinical concern," says Segal, "which makes it an extremely attractive treatment alternative."
These limited side effects can be attributed to the fact that buprenorphine is a partial mu agonist, explains Dr. Eric Strain, a researcher in the Behavioral Pharmacology Research Unit at the Johns Hopkins University School of Medicine in Baltimore. Agonists are chemicals that bind to and stimulate opiate receptors. Antagonists block the effects of opiates by binding to receptors without stimulating them. By stimulating mu opiate receptors in the brain, mu agonists produce the effects associated with morphine: analgesia, euphoria, sedation, and respiratory depression. Because buprenorphine is a partial mu agonist, it also readily binds to mu opiate receptors. However, buprenorphine activates these receptors to a lesser degree than full mu receptor agonists such as morphine and heroin, says Dr. Strain.
Buprenorphine also is released slowly from the mu receptor, producing a long-lasting effect. Therefore, it may be possible to give buprenorphine to patients every other day, rather than in the daily doses that methadone patients must receive. Some studies also suggest that withdrawal effects are less severe with buprenorphine than with methadone. "Buprenorphine could bring more flexibility to the treatment of heroin addicts," says Dr. Strain.
Buprenorphine, a potential treatment for opiate addiction, is administered under the tongue via a small syringe. Patients do not swallow the medication but allow it to be absorbed through the mucous membranes that line the inside of the mouth.Research has shown that buprenorphine can perform favorably relative to methadone. A recent NIDA-funded clinical study by Dr. Strain and his colleagues Drs. Maxine Stitzer, George Bigelow, and Ira Liebson at Johns Hopkins University found that addicts who received buprenorphine remained in treatment as long as those who received methadone. The researchers studied 164 patients admitted to a 6-month opioid treatment research clinic operated by the Johns Hopkins Behavioral Pharmacology Research Unit. The patients were stabilized on daily doses of either 50 mg of methadone or 8 mg of buprenorphine. However, a notable methodological feature of the study was the use of a flexible, rather than fixed, dosing schedule. If urine tests repeatedly showed that a patient continued to use opioids, his or her dose could be increased to a maximum of 90 mg of methadone or 16 mg of buprenorphine. Flexible dosing, says Dr. Strain, more closely simulates clinical practice than does fixed dosing. The researchers reported that 56 percent of the patients in each group stayed in treatment through the 16-week flexible dosing period.
An earlier study conducted by Drs. Rolley E. Johnson, Jerome H. Jaffe, and Paul J. Fudala in NIDA's intramural research program in Baltimore also found that buprenorphine was as effective as methadone in maintaining patient participation in an opiate addiction treatment program. In the randomized study, 162 patients were given fixed daily doses of 8 mg of buprenorphine or 60 or 20 mg of methadone over a 17-week treatment period. Treatment retention rates for the three groups of patients were 42 percent, 32 percent, and 20 percent, respectively.
However, NIDA officials are quick to caution that approval of buprenorphine would not diminish the importance of methadone in the treatment of heroin addiction. "It's certainly not our intent to supplant methadone," Segal says. "Rather, NIDA wants to expand the drug treatment armamentarium and the overall number of patients in treatment."
The findings of the recently completed clinical trial soon will be submitted to the FDA for review, Segal says. However, NIDA will not submit a formal new drug application (NDA) to the FDA until late 1995 or early 1996, she says. An NDA initiates the FDA review process for all new medications. An NDA also is required by the FDA to begin the process for approving existing medications, such as buprenorphine, for uses other than those for which they were originally approved.
Segal says that NIDA will seek approval for a buprenorphine-naloxone combination tablet rather than for buprenorphine alone. The combination product is being developed by NIDA and Reckitt and Colman Pharmaceuticals, Inc., buprenorphine's manufacturer.
As a partial mu agonist, buprenorphine has some potential for misuse, making it subject to diversion--being sold by patients to other addicts. This characteristic makes it unsuitable to use as a take-home medication. Segal says the combination product is designed to address this problem. If a heroin addict attempted to abuse the combination tablet by dissolving it and injecting it intravenously, he or she would experience unpleasant withdrawal symptoms brought on by the naloxone component. However, naloxone, an opiate antagonist, does not produce these unpleasant effects when taken sublingually, beneath the tongue, in tablet form. "We would like to market a product that could benefit various segments of the untreated opiate-dependent population," says Segal.
Gaining FDA approval of a buprenorphine-naloxone combination product, says Segal, will require submission of additional clinical data for the combination product. This will push the date for NDA submission to late 1995 at the earliest. Officials at NIDA, Reckitt and Colman, and the FDA currently are discussing the kinds of studies that will be necessary to include in the NDA, she says. However, once an NDA is filed, a quick decision from the FDA is expected, notes Segal.
The FDA has agreed to an expedited review of the buprenorphine compound. After an expedited review in 1993, the FDA approved LAAM, the newest medication available for treating opiate addiction, only 18 days after the NDA was submitted. A similar turnaround time would be likely with buprenorphine, says Segal.
Sources
- Johnson, R.E.; Jaffe, J.H.; and Fudala, P.J. A controlled trial of buprenorphine treatment for opioid dependence. JAMA 267(20):2750-2755, 1992.
- Strain, E.C.; Stitzer, M.L.; Liebson, I.A.; and Bigelow, G.E. Comparison of buprenorphine and methadone in the treatment of opioid dependence. American Journal of Psychiatry 151(7):1025-1030, 1994.