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FDA Approves Two Forms of Buprenorphine for Opiate Treatment

FDA Approves Two Forms of Buprenorphine for Opiate Treatment

Feature Article
By Bob Curley

The U.S. Food and Drug Administration (FDA) has approved two versions of the drug buprenorphine for treating opiate dependence, clearing the way for heroin and other opiate users to receive treatment in doctors’ offices in addition to methadone clinics.

Like methadone, buprenorphine can be used to treat dependence on opioid-based prescription drugs, such as OxyContin and various pain medications, as well as illicit drugs like heroin. But buprenorphine is subject to less-stringent government regulation than methadone, meaning doctors may be more willing to prescribe it to patients.

“It will still be a while before addiction medicine is truly mainstream, but this is the first step in moving towards that, and also in people understanding that addiction should be treated medically,” said Joycelyn Woods, president of the National Alliance of Methadone Advocates (NAMA) . “For 30 years, doctors have not able to treat addiction, so in that respect it’s really a step forward.”

Currently, almost all treatment for opioid dependence in the U.S. is delivered through methadone clinics, typically located in urban areas and often out of reach for addicted individuals living in suburban and rural communities, where opiate addiction has grown rampant in recent years.

The FDA announced on Oct. 8 that it has approved Subutex (buprenorphine hydrochloride) and Suboxone (buprenorphine combined with naloxone) for prescription and sale in the U.S. Buprenorphine is the third anti-opiate medication approved for use in the U.S., joining methadone and LAAM (Levo-Alpha-Acetyl-Methadol). Buprenorphine is less powerful than methadone but is considered to be somewhat safer and causes fewer side-effects, making it especially attractive for patients who are mildly or moderately addicted.

Buprenorphine is a partial opiate agonist: it blocks withdrawal and craving without producing a strong narcotic high. Naltrexone is an opiate antagonist that causes unpleasant side-effects for opiate users; it is added to prevent diversion and abuse because its effects are felt most acutely when the pills are crushed in order to be injected intraveneously.

The FDA said Subutex should be used at the beginning of treatment, while Suboxone should be used for maintenance.

Both Subutex and Suboxone are manufactured by Reckitt Benckiser Pharmaceuticals , which expects buprenorphine to be available to pharmacies by the end of 2002. The FDA approved 2 mg and 8 mg tablets of both formularies for treatment of addiction.

Both Drugs Listed Under Schedule III

The FDA concurred with the U.S. Drug Enforcement Administration’s (DEA’s) Oct. 7 decision to list both forms of buprenorphine under Schedule III of the Controlled Substances Act , placing them on par with drugs like Tylenol with Codeine in terms of potential for abuse and illegal diversion. “Buprenorphine is considered to have less risk for causing psychological and or physical dependence than the drugs in Schedule II, such as morphine, OxyContin, or methadone,” the FDA noted.

Woods said that listing buprenorphine in Schedule III will encourage doctors to prescribe the medication. “If it was in Schedule II it would be useless, because nobody would use it,” she said.

However, some advocates had wanted to see Suboxone included under the more lenient Schedule IV (similar to benzodiazapines like Valium, Xanax, and Halcion), even if Subutex was listed in Schedule III.

Lawrence S. Brown, Jr., M.D., president of the American Society of Addiction Medicine (ASAM) , said that putting the bupro/naloxone combination in the same schedule as plain buprenorphine would deter physicians from prescribing the combined drug.

“We believe the differential scheduling will play an important role in the safe and effective introduction of this treatment modality,” Brown told the DEA. “We strongly urge you to implement a differential scheduling to distinguish the mono product from the buprenorphine/naloxone preparation.”

Charles O’Keefe, president of Reckitt Pharmaceuticals, predicted that placing both versions of the drug in Schedule III would result in more use of the mono version of buprenorphine, leading to more — not less — potential for diversion and abuse.

“Placing all buprenorphine products in Schedule III is not only unjustified, but also contrary to both congressional intent and existing government policy of safely bringing more patients into treatment for opiate dependence,” O’Keefe wrote in an April 2002 letter to the DEA.

Woods said that, given a choice, most opiate addicts would prefer Subutex over Suboxone because of the side-effects associated with naloxone, such as headache, withdrawal symptoms, pain, and nausea.

However, the American Association for the Treatment of Opioid Dependence (AATOD, formerly the American Methadone Treatment Association) wrote to DEA in support of placing all forms of buprenorphine in Schedule III.

“We found the DEA’s reasoning to be on solid ground,” AATOD President Mark A. Parrino, MPA, wrote to the agency in April. “While buprenorphine is an effective medication in treating chronic opioid dependence, we know that patients can overdose on the medication when it is combined with other drugs … Our association believes that the DEA has considered wisely, especially in view of the recent experiences in the United States with OxyContin.”

H. Wesley Clark, director of the federal Center for Substance Abuse Treatment (CSAT), contends that placing buprenorphine under Schedule III will have no impact on physicians’ decision to prescribe the drug. “The difference between Schedules III, IV and V are nominal,” he said, noting that the restrictions on Schedule III drugs including a 30-day limit on prescriptions, with no more than five refills.

“Who wants to write prescriptions for scheduled drugs for more than five months in the first place?” Clark asked. “DEA’s logic is that Schedule III might remind doctors that this is an addictive drug and they need to exercise caution. That’s probably a good thing.”

Congress Cleared the Way

Buprenorphine advocates have been restlessly awaiting FDA approval almost from the moment that Congress passed the Drug Abuse Treatment Act of 2000 (DATA), which cleared the way for doctors to prescribe anti-opiate medications in their offices, rather than limiting treatment to methadone clinics.

Buprenorphine received ringing endorsements from the U.S. medical community and researchers, including CSAT, the National Institute on Drug Abuse (NIDA), and ASAM. But the extended FDA review process, coupled with active opposition from some methadone treatment providers, led many in the field to question whether buprenorphine would ever be approved.

“It’s almost like I can’t believe it’s true, because this is the second year since the law was passed,” said Woods.

Some blamed the delay on methadone providers who petitioned the FDA to subject buprenorphine to further review. One unnamed opiate treatment provider asked the DEA in May to list buprenorphine as a Schedule II substance, citing the drug’s potential for abuse.

But the petition filed with DEA also reveals what critics say is the true reason for resistance by some methadone clinics: money.

“Methadone clinics treat both new patients and patients who have been stabilized to methadone,” a legal brief filed on behalf of the anonymous treatment program stated. “As a general matter, the latter group provides economic stability to the program. The former group exacts a disproportionate economic toll on the program. However, it is the stabilized patient group that is most likely to be eligible for buprenorphine treatment and, therefore, is the most likely to leave the program in favor of office-based treatment.”

“The intentional placement of buprenorphine in Schedule III ‘to expand narcotic treatment’ to physicians offices will have a significant impact on opioid treatment programs,” the brief concluded.

Parrino said that methadone programs that oppose buprenorphine because they think it will steal away their best customers are “extremely misinformed.” He said that the dosage ceiling inherent in buprenorphine means the drug will be effective for only a certain segment of opiate addicts, including many who never would have shown up at a methadone clinic in the first place.

“There are a number of people who would be very reluctant to go to a methadone clinic but who would go to a private physician,” agreed Charles Schuster, M.D., former NIDA director and currently director of the research department at Wayne State University’s Department of Psychiatry and Behavioral Neurosciences.

“There are programs that see buprenorphine as a threat,” acknowledged Parrino. “However, as far as our organization goes, we’re not opposing it. We think it should be handled carefully.”

Schuster, who also runs the Jefferson Avenue Research Clinic in Detroit, said methadone programs should look at buprenorphine as a business opportunity. “The better programs could very well hook up with local physicians to provide non-medical services like counseling and support programs, even if they’re not providing the medication. That’s what I’m planning to do.”

Training Seen as Critical

Immediately after FDA announced its approval of buprenorphine, NIDA and the Substance Abuse and Mental Health Services Administration (SAMHSA) officially unveiled the certification and training program for physicians who want to prescribe buprenorphine — a project that actually has been going on quietly for months.

Under the DATA law, physicians are required to have a minimum of eight hours of training to prescribe buprenorphine, and must obtain a waiver from the DEA. Physicians who are already certified as addiction specialists are exempt from the training requirements.

Still, concerns about physician training linger. Parrino, for instance, faults the DATA law for failing to require counseling along with the medication (the law simply requires doctors to have the “capacity to refer” patients to counseling).

“I argued very strongly for counseling and lost,” said Parrino. “I don’t know if [the planned system] will work. We’ll find out … What could destabilize the opiate-treatment community is giving doctors the OK to prescribe methadone at Schedule II without counseling. If that’s the logical next step, inevitably we will see problems.”

Office-based prescription of buprenorphine could be a stepping stone to wider availability of methadone, advocates say. But Parrino and Woods worry about unintended consequences. “We want to make sure that as buprenorphine is wildly promoted, methadone does not get denigrated,” said Parrino. And Woods said that methadone must also remain available, especially for long-term opiate users.

“I don’t think buprenorphine works half as good as methadone,” she said. “It works about as good as low-dose methadone, so it’s really for people who haven’t been using drugs for very long.”

Will Doctors Buy In?

About 2,000 physicians have already received training through CSAT, each of whom can treat up to 30 patients under the law. That creates the potential for 66,000 opiate users to receive office-based addiction treatment. (CSAT plans to establish a national registry of buprenorphine-certified physicians.)

However, there are almost a million chronic heroin users in the U.S., according to the federal Office of National Drug Control Policy, and fewer than one-third are receiving treatment.

So far, doctors who already specialize in some form of addiction medicine, such as members of ASAM and the American Academy of Addiction Psychiatry , have been the ones most interested in buprenorphine. To spread the word more widely, SAMHSA will hold a series of informational meetings for physicians, and has set up a website and toll-free number for doctors to find out more about buprenorphine (866-BUP-CSAT).

For buprenorphine to make a real dent in opiate addiction, general practitioners need to buy in. For now, that remains one of the biggest question marks about the drug’s long-term impact on opiate addiction.

“Even with the new regulations allowing doctors to prescribe, they’re not going to run out and do it,” predicts Woods. “Most don’t want addicts as patients … and addicts won’t present to doctors as long as we have this drug war directed at the victims and blaming them for their problems.”

“Wouldn’t it be ironic if buprenorphine patients ended up in the clinics?” asked Woods. “If the doctors don’t want to prescribe, then who is there?”

David Fiellin, M.D., an associate professor of medicine at Yale University’s School of Medicine and chairman of ASAM’s buprenorphine training subcommittee, said the initial response from physicians has been encouraging. “ASAM has trained 1,000 physicians, and the majority have been people who have identified themselves as having experience treating opioid-dependent people in the past, either through methadone clinics or detoxification programs,” said Fiellin. However, he added, “Among those are a high proportion of family physicians and internal-medicine specialists.”

To date, most of the training offered by CSAT has focused on addiction-specialty organizations. “But the next efforts are going to join with [mainstream] groups like the American College of Physicians to train their members,” said Fiellin. “My sense is that as pubic interest and knowledge grows, physicians will likely become more aware of this option and be called upon by their patients to provide it.”

Ironically, increasing abuse of prescribed opiates like OxyContin — which carries less stigma than heroin — could make general practitioners more open to an anti-opiate medication like buprenorphine, said CSAT’s Clark. “We’re sending out notifications to 75,000 primary-care doctors,” he noted. “If that gets even 7,500 more providers interested, then we’ve increased our capacity pretty dramatically.”

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