Buprenorphine is chemically 21-cyclopropyl-7-α-[(S)-1-hydroxy-1,2, 2-trimethylpropyl]-6,14-endo-ethano-6,7,8,14-tetrahydrooripavine (CAS 53152-21-9 for hydrochloride; 52485-79-7 for free base). It is marketed under at least 26 trade names.
In 1983, a WHO Review Group did not recommend international control of buprenorphine, although it recommended the inclusion of pentazocine (a pharmacologically related substance) in Schedule III of the 1971 Convention (6). A critical review of buprenorphine was again undertaken at the twenty-fifth meeting of the Committee (7), which recommended its placement in Schedule III of the 1971 Convention. However, other than the difference between the partial μ-opioid agonist buprenorphine and such prototypic μ-opioid agonists as heroin, morphine and methadone, the Committee did not provide any additional explanation for the choice of the 1971 Convention over the 1961 Convention. In its report for 1995, INCB requested a revision of the control system of buprenorphine by WHO. In consideration of these issues and evidence of significant abuse and illicit trafficking despite international control in Schedule III of the 1971 Convention, the Committee recommended critical review of buprenorphine at its thirty-second meeting (4).
Similarity to known substances and effects on the central nervous system
Buprenorphine is a partial μ-opioid agonist and k-opioid receptor antagonist. It has been widely marketed as an analgesic and more recently has been used in the treatment of opioid dependence. As a partial μ-opioid agonist it produces pharmacological effects similar to those of low-to-moderate doses of morphine and other full μ-opioid agonists, but has a significantly lower maximal effect. Because of its low intrinsic activity, high affinity for, and slow dissociation from, the μ-opioid receptor it precipitates withdrawal syndrome in morphine-dependent animals and humans. Furthermore, pretreatment with buprenorphine attenuates the effects of morphine and other full μ-opioid agonists. For these reasons buprenorphine is both an opioid agonist and an antagonist.
Buprenorphine has reinforcing effects in animal studies, produces euphoria and other positive mood changes in opioid abusers and produces mild physical dependence. No studies published after the twenty-fifth meeting of the Committee (7) have suggested the need for revising their earlier conclusion that buprenorphine does have significant dependence potential.
Actual abuse and/or evidence of likelihood of abuse
Although buprenorphine is widely marketed, France and the United Kingdom consume far more of the drug on a per capita basis than the other countries. In France, where buprenorphine is the main maintenance treatment for patients with opioid dependence that general practitioners are allowed to prescribe, there have been reports of diversion and abuse by polydrug abusers. Information from other countries and INCB on diversion and abuse indicates that buprenorphine is liable to be abused so as to constitute a substantial risk to public health and society. Despite the diversion and abuse of buprenorphine in France the number of deaths from opioid overdosage has decreased significantly following the introduction of buprenorphine substitution therapy. Overall, the risk-benefit ratio for the use of buprenorphine in the treatment of opioid dependence was judged by the Committee to be favourable.
Buprenorphine is currently used in about 60 countries as an analgesic and in about 30 countries for substitution treatment of opioid dependence. However, its use as a treatment for opioid dependence is rapidly increasing.
Application of the Guidelines
The majority of the Members of the Committee considered that, on the basis of the similarity criterion, buprenorphine should be reclassified under the 1961 Convention. The Committee considered that buprenorphine has greater similarity to morphine than to lefetamine, the only analgesic drug controlled as a psychotropic substance at the time the 1971 Convention was adopted. Although lefetamine is an analgesic that binds to brain opioid receptors it was abused during the 1950s in Japan for its stimulant effects on the central nervous system.
The Committee also noted that the scheduling criterion for psychotropic substances would apply to almost all drugs controlled under the 1961 Convention. Morphine and cocaine are clearly psychoactive substances capable of producing stimulation or depression of the central nervous system, “resulting in hallucinations or disturbances in motor function, thinking, behaviour, perception or mood”. They are also dependence-producing. Therefore, morphine and cocaine meet the first-level requirement for being scheduled as psychotropic substances. There is no authoritative guidance, in either the 1971 Convention or in the Guidelines, as to which of the two optional criteria the Committee should apply. The Committee was also informed that the Guidelines require stronger justification for recommending a change in the control status of a substance from one convention to another.
For the reasons stated above, the Committee considered that the final decision on buprenorphine should be taken at a future meeting of the Committee. The Committee also recommended that WHO, in consultation with the United Nations, develop guiding principles for making the choice between the two optional scheduling criteria for psychotropic substances and elaborate the Guidelines with regard to the choice of the more appropriate convention when a substance under review has some similarity to both a psychotropic substance and a narcotic drug. This issue is of particular relevance to the consideration of changing the control of a substance from one convention to the other.