Buprenorphine, Heroin, and Methadone: Comparison of Relative’ Reinforcing Properties

2015

Buprenorphine is a partial agonist of the morphine type. It is both a long-acting opiate antagonist, like naltrexone, and a potent opiate agonist with respect to analgesia, physiological and subjective reactions in man (). However, buprenorphine does not induce physical dependence in several species and appears to produce only minimal physical dependence in man ().

Buprenorphine’s positive morphine-like agonist effects combined with its antagonist potency, low toxicity, and minimal capacity for producing physical dependence, suggested that it should be valuable for the treatment of opiate addiction (). Clinical studies have shown that buprenorphine maintenance (8 mg/ day s.c.) significantly suppressed self-administration of heroin (21 to 40.5 mg/day) by male heroin addicts over 10 days of heroin availability in comparison to buprenorphine placebo (). Buprenorphine (0.282 to 0.789 mg/kg/day i.v.) also significantly suppressed opiate self-administration in the rhesus monkey drug self-administration model (). Recent clinical studies have shown that sublingual administration of buprenorphine (1-2 mg) should be suitable for daily maintenance for the treatment of narcotic addiction ().

The opiate agonist effects of buprenorphine resemble those of methadone and morphine in terms of reported subjective responses (). The degree of euphoria and other positive subjective effects of 8 mg/day of buprenorphine were equivalent to those produced by 120 mg/day of morphine (30 mg q.i.d.) or 40 to 60 mg of methadone (). There is usually a high concordance between subjective reports of opiate effects and animal drug self-administration data (), and buprenorphine has also been shown to be a positive reinforcer in rhesus monkeys and baboon ().

The abuse potential of buprenorphine relative to the abuse potential of the opiate agonist methadone is unknown, and the relative efficacy of buprenorphine and methadone in attenuating opiate self-administration has not been compared in inpatient or outpatient clinical studies. The accumulated clinical experience with methadone abuse () argues for the importance of systematic evaluation of the potential abuse liability of new pharmacotherapies. One approach to evaluating relative reinforcing efficacy of various drugs, and inferring potential abuse liability, is the progressive ratio procedure. This procedure provides a quantitative index of the number of responses that a monkey will emit for a single drug injection, a measure sometimes described as “response cost.” Different doses of a single drug or different drugs can be ranked according to the maximum number of responses emitted to acquire a single drug injection (). This report describes preliminary data obtained on the relative reinforcing properties of buprenorphine, methadone, and heroin using progressive ratio procedures.

Methods

Six male Macaque monkeys (1 Macaca mulatta and 5 Macaca nemestrina) weighing 6.0 to 8.4 kg were studied. Five monkeys had a history of opiate agonist and mixed agonist-antagonist self-administration and one monkey was drug-naive at the beginning of these studies. Monkeys were surgically implanted with chronic indwelling catheters to permit intravenous drug self-administration. All surgical procedures were performed under aseptic conditions. Monkeys were anesthetized with either pentobarbital (30 mg/kg/i.v.) or ketamine (25 mg/kg/i.m.) and a double lumen silicon rubber catheter (I.D. 0.028”; O.D. 0.088”) was placed in a vein. Following surgery, animals were given 1 ml of combiotic every other day for a total of five injections.

Animal maintenance and research was conducted in accordance with the guidelines provided by the Committee on laboratory Animals Facility and Care, the National Research Council Institute of laboratory Animals Resources. The facility is licensed by the U.S. Department of Agriculture. The health of the monkeys was periodically monitored by a consultant veterinarian from the New England Regional Primate Center.

Monkeys worked at an operant task for food (1 gm banana pellet) and for buprenorphine (.01,.03,.05,.10 mg/kg/inj), heroin (.01,.05,.10 mg/kg/inj), methadone (.03,.10,.25 mg/kg/inj) and saline. Food and baseline drug self-administration were maintained under a second-order schedule of reinforcement [FR 4 (VR 16:S)]. An average of 16 responses on a variable ratio schedule (VR 16) produced a brief colored stimulus light (S+). However, a drug injection or a food pellet was delivered only after a fixed ratio of 4 (FR 4) of the VR 16 response requirements had been completed; i.e., each food pellet or drug injection required an average of 64 responses. Details of the apparatus have been published (). Monkeys were maintained at ad lib weight and given multiple vitamins, fresh fruit and vegetables daily to supplement a banana pellet diet.

Food sessions began at 11 a.m., 3 p.m., 7 p.m. and 11 p.m. each day, and drug sessions began one hour later at 12 noon, 4 p.m., 8 p.m. and midnight. Each food or drug session lasted either one hour or until 20 drug injections or 65 food pellets were delivered. The chamber was dark between 1 a.m. and 9 a.m.

Each dose of buprenorphine, heroin, and methadone was available for a minimum of 40 sessions over 10 days or until baseline drug self-administration was stable. Subsequently, the second order schedule response requirement was systematically increased by increasing the number of responses required in the Fixed Ratio (FR) component of the second order schedule in increments of two. The resulting progressive ratio response requirements per drug injection are summarized below.

Each increase in the FR schedule component was run for eight sessions over two days. Progressive increases in the response requirement were continued until drug self-administration decreased significantly below baseline levels. The usual ‘breakpoint” criterion is two consecutive days of no drug self-administration, The inmediately preceding response requirement for a single drug injection indicates the maximum number of responses that the monkey will emit for that dose of the drug.

Once the “breakpoint” at a single drug dose was reached, the monkey was returned to the baseline schedule requirement (FR 4 VR 16:S) at the same drug dose until drug self-administration resumed. This procedure was useful to reduce the extinction-like effects of the progressive increases in response requirements for drug. Monkeys were then given access to the next dose of drug and run at the basic second order schedule response requirement until drug self-administration was stable over 40 consecutive sessions or 10 days. Response requirements were then increased progressively as before and continued until the monkey reached the “breakpoint” at that dose. All monkeys were not run at every dose of each drug.

Results

These studies are still in progress and all 10 drug doses and saline have not yet been evaluated in all monkeys. The group average breakpoints for buprenorphine (.01-.10 mg/kg/inj), heroin (.01-.10 mg/kg/inj) and methadone (.03-.25 mg/kg/inj) are shown in Figure “Group average maximum number of responses per injection emitted for ascending doses of buprenorphine (.01-.10 mg/kg/inj), heroin (.01-.10 mg/kg/inj) and methadone (.03-.25 mg/kg/inj) on a progressive ratio schedule”.

The reinforcing efficacy of buprenorphine appears to be greatest at low doses. Buprenorphine at doses of.01 and.03 mg/kg/inj maintained responding on progressively increasing values of second order schedules for longer than higher doses of buprenorphine (.05 and.10 mg/kg/inj). Yanagita and co-workers () also reported that rhesus monkeys worked longer for a low (.015 mg/kg/inj) than for a high (.06 mg/kg/inj) dose of buprenorphine on a progressive ratio schedule. This pattern is consistent with the notion that the antagonist component of this mixed agonist-antagonist drug attenuates its agonist effect at higher doses. Several agonist effects of buprenorphine such as euphoria (), “stupor” (), antinociception and respiratory depression in rats () each are maximal at relatively low doses and are significantly reduced or fail to increase at higher doses.

These data are also concordant with observations in baboons that self-administered buprenorphine on an FR 160 schedule (). Buprenorphine self-administration tended to plateau over a dose range of 0.1 to 1.0 mg/kg/inj (). Changes in buprenorphine injections per day as a function of dose were less consistent in rhesus monkey when responding was maintained on a second order FR 3 (VR 16) schedule. Only 2 of the 5 monkeys showed a consistent decline in buprenorphine injections as the dose per injection was increased over a range of.005 to.10 mg/kg/inj ().

Monkeys consistently emitted more responses for heroin than for bu-prenorphine across the range of doses studied. These data suggest that the abuse potential of buprenorphine relative to heroin is low. Moreover, in contrast to buprenorphine, the progressive ratio breakpoint for heroin increased as a function of increased heroin dose. These data are consistent with previous progressive ratio studies of heroin (.001 to 0.5 mg/kg/inj) and codeine (.01 to 16 mg/kg/inj) self-administration in rhesus monkey (), but a number of procedural differences limit further comparisons between these studies.

The lowest dose of methadone (.03 mg/kg/inj) maintained less responding in a progressive ratio paradigm than either buprenorphine or heroin. At an intermediate methadone dose (.10 mg/kg/inj) progressive ratio breakpoints were almost twice as high as those for buprenorphine. However, the abuse potential of methadone relative to heroin and buprenorphine cannot be estimated with confidence until additional progressive ratio data for methadone self-administration are available.

 

Selections from the book: “Problems of Drug Dependence, 1983. Proceedings of the 45th Annual Scientific Meeting, the Committee on Problems of Drug Dependence, Inc.” Louis S. Harris, Ph.D., ed. A collection of papers which together record a year’s advances in drug abuse research; also includes reports on tests of new compounds for efficacy and dependence liability. National Institute on Drug Abuse Research Monograph 49, March 1984.