Washington Agonizes Over a Partial-Agonist
by Geoff Mumford, PhD, Public Policy Office

Developing pharmacotherapies for the treatment of drug dependence has been a challenge to say the least. And although several compounds continue to demonstrate promise in the laboratory, few have made it to market.

Unfortunately, even medications that appear to be pharmacologically ideal are hard to get patients to take. For example the opiate antagonists, naltrexone and naloxone would appear to be perfect treatment agents for opiate dependence. With the right dose of antagonist on-board, it would be difficult or impossible for patients taking these medications to overcome the blockade with an affordable dose of an opiate drug. But although antagonist therapy has become a mainstay for reviving patients who have overdosed on opiates, patients are reluctant to take them as a maintenance therapy.

So, at least for opiate dependent patients, the pharmacotherapeutic approach of choice has been substitution or replacement therapy with a synthetic, longer-acting opiate--methadone. Methadone maintenance has allowed thousands of opiate-dependent individuals to return to productivity and has stemmed the tide of blood-borne infections related to sharing of paraphernalia used to inject heroin. With a 30-year history of demonstrated efficacy, methadone clinics have become part of the urban landscape in many, but not all, U.S. cities where heroin-dependence is a problem. But methadone has not penetrated every heroin “market,” and the reason why says more about the ideological bias of policymakers than the efficacious management of opiate dependence. Still progress is being made and another domino fell recently, when the state of Vermont reversed its long-standing opposition to methadone.

But the pharmacotherapy of drug dependence produces some challenges to formulation scientists not posed in other medical subspecialties. The worst case scenario for most healthcare professionals is that their patients won’t take their medication as prescribed, but few have to be concerned that medication might be diverted for illicit use. However, because methadone is a full agonist at opiate receptors and is associated with a high abuse liability, patients generally drink their dose under observation. In some programs, patients can earn methadone take-home privileges after long periods of sustained abstinence from illicit opiate use (confirmed with random urine screens) and regular participation in clinic activities. But the potential abuse liability of methadone, and its close cousin LAAM, has limited the expansion of pharmacotherapeutic treatment services beyond these structured narcotic treatment programs.

But over the past several years, the guile of opiate-dependent patients has been matched by the creativity of pharmacologists, who have tested the efficacy of another opiate medication called buprenorphine. Unlike methadone, which is classified as a full-agonist, buprenorphine is a partial-agonist and, as such, there is a ceiling on its effects, unlike that of the full-agonist. The practical advantage of that is twofold: decreased abuse liability and increased safety. The drug produces a limited “high,” and the likelihood of lethal respiratory depression associated with a full-agonist overdose is reduced (conferring yet another benefit, less then daily dosing). A second formulation combining both buprenorphine and naloxone is even more ingenious: taken sublingually (under the tongue), the buprenorphine is absorbed, but the naloxone is not. Should these pills be diverted for illicit use, ground up and injected, the naloxone would precipitate an immediate withdrawal reaction. Both the single and combination forms of buprenorphine have reached the “approvable” stage as treatment medications for opiate dependence, and the Food and Drug Administration (FDA) requires a fairly minimal response from the manufacturer in order to grant final approval.

That's the good news. The bad news is that there are several political and legal issues that are delaying the introduction of this new treatment option. While FDA approval (still pending) is important, federal and state laws currently prohibit physicians from prescribing opiates to opiate dependent individuals. Thus, while the drug may soon be "FDA approved," it will be illegal to prescribe it unless the relevant federal agencies adopt new regulations, or unless new federal legislation is passed allowing doctors to prescribe it.

If new laws are not in place at or near the time of FDA approval, the drug companies developing and marketing the product may conclude that the new drug is not commercially viable. Although the drug has been under development by Reckitt & Coleman through a Cooperative Research and Development Agreement with NIDA, once the FDA gives final approval, the patent clock starts ticking down.

Within the Department of Health and Human Services (DHHS), the Substance Abuse and Mental Health Services Administration (SAMHSA) and specifically the Center for Substance Abuse Treatment (CSAT) have traditionally worked with FDA to oversee and administer the nation’s narcotic treatment programs. Last fall, the CSAT Advisory Council approved a set of recommended guidelines for the administration of buprenorphine by physicians in office-based settings that would alleviate some of the market pressures and increase treatment access. But, because this approach represents such a radical change to the way opiate-dependent patients are treated, it has triggered a painfully long review. In May, DHHS released a Notice of Intent to issue new regulations based on the CSAT recommendations, and the first real step in that effort--a Notice of Proposed Rule Making--is expected to be released this fall for public comment.

Fortunately, this information is also filtering down to our lawmakers, and recognizing the unique pharmacological profile of the medication, legislation has been introduced to facilitate buprenorphine prescription privileges for physicians. As such, buprenorphine would help close the “treatment gap”--a term used to describe the difference between the available opiate-dependence treatment slots (about 120,000) and the number of additional individuals needing treatment (about 600,000). Further, it may potentially address the changing demographic client base--white-collar suburbanites put off by the stigma of methadone clinics and the emerging population of teen heroin users.

However, such privileges are unprecedented in the treatment of opiate-dependence and have set off a number of alarms, particularly within the DEA and members of the treatment community who run methadone clinics as a business enterprise. The key element of the new legislation is a waiver that circumvents the dense web of regulatory restrictions, imposed by the long-standing Narcotic Addiction Treatment Act (NATA). The laudable intent of NATA has failed to keep pace with the changing abuse liability profile of medications like buprenorphine. Legislative action has been further complicated as several different congressional committees have jockeyed for jurisdiction over broader issues of drug control policy.

So the promise of this new pharmacotherapy lies in limbo, as congressional champions argue the merits of demand reduction versus interdiction initiatives. The waiver provisions have passed the House in a stand-alone bill (H.R. 2634) and similar language is included in two broader bills in the House (H.R 2987) and Senate (S. 486) that focus on the proliferation of methamphetamine and other “club drugs.” And although those bills would provide for more NIDA supported research and funds to search out and dismantle illicit drug labs, they contain controversial elements that divide Congress along partisan lines.

Given the uncertainties of the federal regulatory process, we have spent most of our effort working with the House Commerce and Judiciary Committee staffs to advance the waiver language.  Specifically, we’ve asked Committee staff to add wording strongly encouraging referral to psychosocial services rather than leaving it optional.  Such a recommendation follows a well worn principle of addiction treatment research that pharmacotherapy works best when provided in the context of other behavioral and psychosocial services.  Further, we recommended an increase in the minimum training required for physicians to obtain the addiction treatment certification necessary to dispense the new medication.

With only 25 work days left in this session of congress, it’s hard to be imagine that this sort of bill will take priority after the August recess.  If that’s the case, we’ll hope the next congress will find buprenorphine legislation a less bitter pill to swallow.

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