History of Buprenorphine

 Buprenorphine has been in active use for 10 years as a treatment medication for opioid addiction.

As explained by Nicholas Reuter, MPH, senior public health analyst with SAMHSA’s Center for Substance Abuse Treatment (CSAT), the development of buprenorphine was preceded by the development and approval by the Food and Drug Administration (FDA) of levo-alpha-acetyl-methadol (LAAM). The government supported the development of LAAM, but the medication “couldn’t generate enough income from patient use to be sustainable,” he said.

“At the time, there was a lot of discussion about the treatment gap,” he told AT Forum. There were at least 2 to 3 million people who needed treatment for opioid addiction, and only 150,000 or fewer could get into Opioid Treatment Programs (OTPs). “The thinking was that we needed to develop an office-based model,” said Mr. Reuter.

Buprenorphine had been approved for addiction treatment in other countries, Mr. Reuter said, and the molecule is interesting because it is a partial agonist, which gives it a ceiling effect. This means that the risk of overdose is attenuated. “Taken in increasing amounts, it causes dysphoria [anxiety, depression, unease],” noted Mr. Reuter.

People on Capitol Hill were working to see how buprenorphine could be developed as an office-based treatment for opioid addiction, and this led to the development of DATA 2000, said Mr. Reuter. “It was set up as an experiment.” Safeguards were built into the law, so that if treating patients in the physician’s office with narcotic drugs did not turn out to be a good idea, the law could be rescinded. “We were required to do a formal analysis.”

The “experiment” worked, and in 2002 the FDA approved buprenorphine for the treatment of opioid addiction.

Why Not More OTPs?

Why didn’t SAMHSA just increase methadone slots in OTPs, if there was a need for more treatment? First of all, it’s not that easy to increase the number of OTPs, said Mr. Reuter, noting that almost everyplace a program tries to open up, there is a NIMBY battle from the local community. But perhaps more important, there were concerns about methadone overdoses. It turned out that the overdoses were mainly related to pain prescribing, but that was not known at the time. That’s because the increase in pain prescribing coincided with the rule allowing more flexible methadone take-home doses.

But SAMHSA was in a difficult position, nevertheless. “Here you have people saying methadone is a dangerous drug, too many people are dying from it, and we have to look at how it’s used,” said Mr. Reuter. “Methadone mortality was such a significant concern. We would hear it every day.”

While there has been an increase in the number of OTPs in the past decade, there is still a treatment gap, said Mr. Reuter. There were 900 OTPs ten years ago, and now there are 1,260. The number of patients treated in OTPs has gone from 170,000 In 1998 to about 300,000.

Instead of expanding some office-based models for methadone, the government decided to look at buprenorphine—in large part because of problems with methadone mortality, which peaked in 2001, said Mr. Reuter.

Buprenorphine in Practice

Something similar has happened with buprenorphine’s early years—in spite of all of the agency collaboration. “What’s interesting is that as physicians got more experience in treating opioid addiction, they realized that there is a high relapse rate, and maintaining the patient is better than withdrawing the patient,” said Mr. Parrino. This doesn’t mean that every patient will need to be on medication for life.

But by increasing access to buprenorphine, DATA 2000 did not necessarily provide access to counseling and other comprehensive treatment services, said Mr. Parrino. “As far as we know, many patients did not receive counseling in addition to the medication prescribed, did not receive routine toxicology tests to guide clinical decision making, and appeared to divert buprenorphine take-home medication,” he told AT Forum. “Without question, treatment access was increased significantly because patients who never would have sought treatment in the OTP, or simply felt more comfortable receiving such care in a physician office setting, did get access to treatment. But what kind of treatment did they receive?”

Buprenorphine Prescribing Trends

It’s easy to find the number of physicians who are certified through the DATA waiver process to prescribe buprenorphine, but much more difficult to find out how many of them are actually prescribing, or how many patients they have, or whether they are providing counseling or drug testing.

According to the Drug Enforcement Administration’s ARCOS data, over 190 million dosage units of buprenorphine were distributed to pharmacies in 2010, said Mr. Reuter. That’s almost five times the 40 million distributed in 2006. Only 1.1 million dosage units were distributed to OTPs during 2010. Almost 800,000 individuals got prescriptions for buprenorphine from office-based physicians in 2010—five times the 140,000 estimated in 2006.

SAMHSA measures the number of prescribing physicians by how many submit applications to get certified to prescribe buprenorphine. Currently, that’s about 23,000, according to Mr. Reuter. But that doesn’t mean that they are all prescribing—far from it. In fact, the number of physicians prescribing buprenorphine has gone down; fewer physicians are prescribing to more patients, and there is a clear need for more access to buprenorphine.

In 2005, there were 22,000 physicians certified to prescribe buprenorphine under DATA 2000. Of these, almost 5,200 requested to treat up to 100 patients, according to the final rule. In 2009, when the DEA stepped up its investigations of buprenorphine-prescribing physicians, to make sure they were adhering to 100-patient caps, some physicians objected, and surrendered their certificates. Mr. Reuter noted that some of these doctors (about 2,000) had obtained the certification but not gotten any patients, and didn’t want to be bothered with the inspections.

As of September 2012, about 3.9 million patients had been treated with Suboxone, said Tim Baxter, MD, global clinical director of Reckitt Benckiser, which makes the Suboxone brand of buprenorphine.  Of the 23,000 physicians who are waivered to prescribe buprenorphine, 12,000 have actually prescribed it—“many have written only one prescription,” said Dr. Baxter. In fact, there aren’t enough physicians prescribing it. “Initially the number of prescribers went up, and then it flattened out,” he said. Many active prescribers are now fully booked. “With the 100-patient limit, it’s harder for patients to find a prescriber.”

Buprenorphine Diversion

Abuse and diversion of buprenorphine are a concern to us and the FDA, said Mr. Reuter. The 2010 DAWN national data showed an increase in buprenorphine reports in the emergency department.

There are concerns about increases in buprenorphine abuse and diversion, which has paralleled the prescribing increase in the buprenorphine mono formulation, the one without naloxone. The naloxone is what prevents people from being able to get high from melting down and injecting the medication.

One problem is that the mono formulation has been available in generic versions for three years. Generic versions are less expensive than Suboxone, and prescribing of mono buprenorphine has increased steadily.

According to the final rule, HHS “is not aware of compelling evidence to support the assertion that more OTPs than office-based physicians will dispense mono buprenorphine.” But controls already in place regarding OTPs—much more intense controls than those regarding office-based physicians—“will mitigate diversion issues in OTPs with either buprenorphine formulation,” the final rule states. In addition, “the risk for buprenorphine diversion from buprenorphine dispensed by OTPs in accordance with this final rule will be less than the risk of diversion associated with office-based settings.”

If an OTP patient gets a 30-day supply of methadone, or, under the new rule, buprenorphine, that patient is “still subject to drug-testing requirements, still subject to counseling, and still has a treatment plan,” said Mr. Reuter. “On the other end of the spectrum are the buprenorphine prescribers who could prescribe a 30-day supply of Suboxone or buprenorphine, with no requirements for drug testing or counseling,” he said. “That may explain why there is an escalating abuse and diversion of buprenorphine.”

Buprenorphine Not a Miracle Cure

Treatment with buprenorphine is effective, said Mr. Reuter. Medication-assisted treatment has expanded, even in parts of the country where it wasn’t available, such  as Wyoming and North Dakota. Those states don’t permit OTPs. “But the success has to be looked at in terms of the real world, in which people relapse,” he said. “It’s not a miracle cure, and I never thought it would be. To my mind, it’s expanded treatment capacity, but it’s not a cure. And now we see increasing abuse and diversion.”

Mr. Parrino thinks the reason buprenorphine has been successful is that it is not “stigmatized,” the way methadone is. Interestingly, the earliest prescribers of buprenorphine were using it primarily as a withdrawal agent, rather than a maintenance agent, he said. Many of these patients undoubtedly relapsed; as a huge NIDA clinical trial showed, more than 9 out of 10 patients who were tapered off buprenorphine, relapsed.

See comment from Robert Newman, MD in comment section. 

Reference

Center for Substance Abuse Treatment. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS Publication No. (SMA) 04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004.