Question No. 1.
Is buprenorphine (alone and in combination) a safe and effective treatment for drug addiction?
While the ultimate decision concerning safety and efficacy rests with the Food and Drug Administration (FDA), NIDA has funded many studies that support the safety and efficacy of buprenorphine and the buprenorphine/naloxone combination for the treatment of opiate dependence. During the time NIDA has studied this medication, we have been impressed with its safety and efficacy as a treatment for opiate dependence. Over the last five years NIDA has worked with Reckitt & Colman Pharmaceuticals, Inc., under a Cooperative Research and Development Agreement in an attempt to bring buprenorphine (which the FDA has designated as an orphan product), to a marketable status in the United States. These studies have been submitted by Reckitt & Colman to the FDA in support of a New Drug Application for buprenorphine products in the treatment of opiate dependence. The major studies of relevance have shown that buprenorphine is more effective than a low dose of methadone (Johnson et al, J.A.M.A., 1992), and that an orderly dose effect of buprenorphine on reduction of opiate use occurred (Ling et al, Addiction, 1998).
Most recently, buprenorphine tablets (either buprenorphine alone or the combination with naxolone) were shown in a large clinical trial to be superior to placebo treatment in reducing opiate use (Fudala et al, CPDD, 1998). Additional clinical studies have shown that the addition of naxolone to the buprenorphine tablet decreased the response to buprenorphine when the combination is injected under controlled conditions. This means that when persons attempt to dissolve the tablets and inject them, they will either experience withdrawal or a diminished buprenorphine effect. These properties will make buprenorphine combined with naxolone undesirable for diversion to illicit use, especially when compared with other existing illegal and legal opiate products.
Pharmacologically, buprenorphine is related to morphine but is a partial agonist (possesses both agonist and antagonist properties). Partial agonists exhibit ceiling effects (i.e., increasing the dose only has effects to a certain level). Therefore, partial agonists usually have greater safety profiles than full agonists (such as heroin or morphine and certain analgesic products chemically related to morphine). This means that buprenorphine is less likely to cause respiratory depression, the major toxic effect of opiate drugs, in comparison to full agonists such as morphine or heroin. We believe this will translate into a greatly reduced chance of accidental or intentional overdose. Another benefit of buprenorphine is that the withdrawal syndrome seen upon discontinuation with buprenorphine is, at worst, mild to moderate and can often be managed without administration of narcotics.
Question No. 2.
Do current regulations properly set forth the rules for administration, delivery, and use of these drugs?
There are no current regulations which address the use of buprenorphine or buprenorphine/naloxone for the treatment of opiate dependence because these products are not yet approved for this purpose by the FDA. The current regulations (21 CFR 291) for administration and delivery of narcotic medications in the treatment of narcotic dependent persons were written for the use of full agonist medications such as methadone with demonstrated abuse potential and do not take into account the unique pharmacological properties of these drugs. Therefore, these regulations would need to be re-examined and substantially rewritten in order to recognize the unique possibilities
posed by buprenorphine/naloxone. Among these are the potential to administer buprenorphine and buprenorphine/naloxone in settings and situations other than the formal Narcotic Treatment Programs (NTPs) which have existed to date under existing regulations. NTPs are the most highly regulated form of medicine practiced in the U.S., as they are subject to Federal, State, and local regulation. Under this regulatory burden, expansion of this system has been static for many years. This has resulted in a "treatment gap", which is defined as the difference between the number of opiate dependent persons and those in treatment. The gap currently is over 600,000 persons and represents 75-80% of all addicts.
It may be useful to note the status of the last new product introduced to the opiate dependence treatment market (levoacetyl methadol, tradename ORLAAM). ORLAAM was an orphan product developed by NIDA and a U.S. small business in the early 1990s for narcotic dependence. ORLAAM was approved by the FDA as a treatment medication for opiate dependence in July 1993. In the five years since its approval and dispensing under the more restrictive rules relating to the use of full agonist medications (21 CFR 291), ORLAAM has been poorly utilized to increase treatment for narcotic dependence. It is estimated that 2,000 of the estimated 120,000 patients in narcotic treatment programs are receiving ORLAAM. The failure of ORLAAM to make an appreciable impact under the more restrictive rules suggests that if buprenorphine is to make an appreciable impact on the "treatment gap" it must be delivered under different rules and regulations.
The issue then becomes why should buprenorphine products be delivered differently from ORLAAM and methadone. First, buprenorphine's different pharmacology should be kept in mind when rules and regulations are promulgated. The regulatory burden should be determined based on a review of the risks to individuals and society of this medication being dispensed by prescription and commensurate with its safety profile, as is the case with evaluation of all controlled substances. It is our understanding that the Drug Enforcement Administration has recognized the difference between buprenorphine treatment products and those currently subject to 21 CFR 291. Second, there are many narcotic addicts who refuse treatment under the current system. In a recent NIDA funded study (NIDA/VA1008), approximately 50% of the subjects had never been in treatment before. Of that group, fully half maintained that they did not want treatment in the current narcotic treatment program system. The opportunity to participate in a new treatment regimen (buprenorphine) was a motivating factor. Fear of stigmatization is a very real factor holding back narcotic dependent individuals from entering treatment. Third, narcotic addiction is spreading from urban to suburban areas. The current system, which tends to be concentrated in urban areas, is a poor fit for the suburban spread of narcotic addiction. There are many communities whose zoning will not permit the establishment of narcotic treatment facilities, which has in part been responsible for the treatment gap described above. While narcotic treatment capacity has been static, there has been an increase in the amount of heroin of high purity. The high purity of this heroin has made it possible to nasally ingest (snort) or smoke heroin. This change in the route of heroin administration removes a major taboo, injection and its attendant use of needles, from initiation and experimentation with heroin use. The result of these new routes of administration is an increase in the number of younger Americans experimenting with, and becoming addicted to, heroin. The incidence of first-time use of heroin in the 12 to 17 year old group has increased fourfold from the 1980s to 1995. Treatment for adolescents should be accessible, and graduated to the level of dependence exhibited in the patient. Buprenorphine products will likely be the initial medication(s) for most of the heroin-dependent adolescents.
Question No. 3.
Should more physicians be permitted to dispense these drugs under controlled circumstances?
More treatment should be made more widely available for the reasons stated above. The safety and effectiveness profiles for buprenorphine and buprenorphine/naloxone suggest they could be dispensed under controlled circumstances that would be delineated in the product labeling and associated rules and regulations. As currently envisioned, buprenorphine and buprenorphine/naloxone would be prescription,
Schedule V controlled substances. The treatment of patients by physicians or group practice would allow office-based treatment to augment the current system, while placing an adequate level of control on the dispensing of these medications. Given the increased need for treatment, the relative safety and efficacy of the treatment product, and the development of a regulatory scheme satisfactory to the Department of Health and Human Services, these goals could be accomplished in a timely and effective manner.