Data available prior to this study
Data collected in this study
Discussions and conclusions
Pages: 45 to 54
Creation Date: 1980/01/01
This study was initiated by WHO when concern was expressed by the UN Commission on Narcotic Drugs about the intention to utilize, instead of Papaver somniferum, the poppy species Papaver bracteatum with its main constituent thebaine as raw material for the manufacture of opioid agonists, especially codeine and antagonists (1). The subject had temporarily aroused considerable concern. The increasing world-wide legitimate demand for codeine would have had to be met by either the increased production of alkaloids from Papaver somniferum with the ensuing increased risk of its diversion into illicit channels or, preferably, the cultivation of the species bracteaturn, instead of somniferurn, provided that thebaine had no, or at least appreciable lower, dependence and abuse potential than the opium alkaloids, morphine and codeine.
The present report addresses itself to the question of the pharmacological profile of thebaine with particular reference to its dependence potential. No documented information was available on the occurrence of abuse of thebaine or Papaver bracteatum.
With financial support from the United Nations Fund for Drug Abuse Control (project No. ACB-90117) a literature review and a study of the dependence potential of thebaine was carried out by WHO, Division of Mental Health, with the assistance of a Group of Advisors, several of whom contributed ad hoc experimental work.
* This paper has been prepared by a WHO Advisory Group comprised of:
Dr H. Halbach, Honorary Professor of Pharmacology, University of Munich, Munich, Federal Republic of Germany;
Dr Louis S. Harris, Chairman, Department of Pharmacology, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA;
Dr J. Knoll, Professor and Head, Department of Pharmacology, University of Semmelweis, Medical School, Budapest, Hungary;
Dr O. O. Ogunremi, Chairman, Department of Psychiatry, University of Ifc, Ifc, Nigeria;
Dr Omal ElGarem, Professor and Head of the Psychiatric Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt;
Dr C. R. Schuster, Director, Research Centre Studying Drug Dependence and Abuse, The University of Chicago, Department of Psychiatry, Chicago, Illinois, USA (Chairman);
Dr R. Willette, Chief, Research Technology Branch, Division of Research, National Institute on Drug Abuse, 5600 Fishers Lane, Rockville, USA, and
Dr T. Yanagita, Director, Preclinical Research Laboratories, Central Institute for Experimental Animals, 1433 Nogawa, Kawasaki, Japan (Rapporteur).
Representatives of the United Nations:
Dr George M. Ling, Director, UN Division of Narcotic Drugs, United Nations, Vienna International Centre, A-1400 Vienna, Austria, and
Dr O. Braenden, Chief, UN Narcotics Laboratory, United Nations, Vienna International Centre, A-1400 Vienna, Austria.
Representative of the International Narcotics Control Board:
Dr T. L. Chrusciel, Professor of Pharmacology, Deputy Director, Institute for Drugs, Research and Control, 30/34 Chemska Street, 00-725 Warsaw, Poland.
Dr Inayat Khan, Senior Medical Officer, Division of Mental Health, World Health Organization,Geneva, Switzerland (Secretary).
Dr D. R. Jasinski, Director, National Institute on Drug Abuse, Addiction Research Centre, Lexington, Kentucky, USA, who did not participate also contributed to this report.
Thebaine is one of the phenanthrene alkaloids contained in the opium poppy and constitutes usually about 0.3 to 1.5 per cent of opium, but figures up to 6 per cent have been reported. Thebaine is the major alkaloid in Papaver bracteatum and can readily be extracted from the capsules and roots of that plant.
Thebaine is dehydromorphine 3,6-dimethyl ether.
Its hydrochloride salt is sparingly soluble in water up to about 8 w/v%.
Thebaine can be converted into drugs of abuse, such as oxycodone and hydrocodone. Furthermore, a series of thebaine derivatives with very high analgesic potency, such as acetorphine and etorphine (known as "Bentley compounds") has been developed. However, there are considerable problems in connexion with the conversion of thebaine into these substances, especially into the Bentley compounds.
An Expert Group was convened by the United Nations Narcotics Laboratory in January 1976 to consider the feasibility of the conversion of thebaine into drugs of abuse and the potential of abuse (2). Having evaluated the problems associated with the possible use of thebaine in the production of such drugs, the Expert Group considered that these are not such that they should prejudice the manufacture of thebaine and its use as a commercial source of therapeutically useful substances.
Most of the facts were obtained from two extensive reviews (3, 4) Unless otherwise indicated.
Central nervous system. The predominant effect of thebaine is central nervous system stimulation. In the mouse, rabbit, cat and dog, hyper-irritability and increase in motor activity as well as reflex excitability were observed at doses around 2-10 mg/kg s.c. or i.m. The Straub-tail reaction was noted only occasionally. In rabbits, thebaine antagonized the effects of phenobarbital and potentiated those of caffeine.
Convulsions were observed in almost all species of animals including the skate, frog, sparrow, pigeon, mouse, guinea pig, rabbit, cat and dog. In the rhesus monkey, transient tremors, restlessness, hyper-irritability and convulsions were observed (5). The convulsive doses were around 20 mg/kg s.c. in mice, rabbits, cats, dogs and rhesus monkeys.
Naloxone, a known morphine-antagonist', antagonized the convulsions induced by thebaine in mice (convulsive dose 7.4 mg/kg i.v.). However, it was 10 times less effective against thebaine than it was against heroin. In mice, treated with 30 mg/kg of thebaine s.c., neither sotalol nor propanolol changed the survival rate; propanolol (25 mg/kg s.c.) prevented the tonic phase of the convulsions, but did not prevent death.
The respiratory effect of the drug was usually observed to be stimulatory in mice, rabbits, cats and dogs.
In rabbits, thebaine in doses of 2 mg/kg antagonized the respiratory inhibition caused by 5 mg/kg of morphine. Mixtures of narcotine (15 mg/kg i.v.)and thebaine (1 mg/kg i.v.) strongly stimulated respiration.
The analgesic effect varied, depending on the investigator, method applied and animal species. While positive effects were reported for mice and cats, some reports were negative for mice and dogs. A "narcotic" effect, as judged by the over-all depressive manifestation including drowsiness was not observed in the mouse, guinea pig, rabbit, cat or dog.
Electrophysiologically, the spasmolytic effect of thebaine was different from that of morphine and codeine, but similar to that of strychnine.
Cardiovascular system. Decreased blood pressure and heart rate in the dog were reported in several studies. In one study with anaesthetized dogs, a fall in blood pressure, continuing for 1-3 hours was reported.
Gastro-intestinal system. Many studies indicated an increase in the tone and activity of the intestine in situ by thebaine. In the isolated intestine of the guinea pig, however, the tone diminished and peristalsis was inhibited.
In anaesthetized rats, thebaine had no effect on the central vagal stimulation of pancreatic secretion induced by 2-deoxy-D-glucose in doses up to 17 mg/kg s.c. Inhibition of this stimulation has been suggested to be specific for morphine agonists.
Thebaine caused a slight decrease in heart and brain catecholamine levels. It had an inhibitory effect on human, guinea pig and horse cholinesterase, as well as on human procain-esterase; neither lactic and citric acid, nor glucose dehydrogenases were inhibited.
Thebaine is far more toxic than morphine. The LD 50 in mice is 31 mg/kg s.c. and 20 mg/kg i.p.; other authors have reported an intraperitoneal LD 50 of 42 mg/kg in mice (7). In rabbits, the intravenous LD 50 is 3-4 mg/kg and is dependent on the age of the animals (7). In the dog the lethal doses are reported to be 10-30 mg/kg s.c. and 5-7 mg/kg i.v. (3). In chicken embryo, thebaine has been reported to induce pseudohyperfeminization.
The only documented indication for tolerance was the report that in anaesthetized dogs, a single dose of thebaine decreased the blood pressure for 1-3 hours; after that, it did not change significantly with additional doses of thebaine, nor with morphine (3). However, this may be more indicative of tachyphylaxis than of tolerance.
The physical dependence potential of thebaine had not been systematically investigated, but was believed to be non-existent until it was first reported at the 5th International Congress of Pharmacology in San Francisco in 1972. Rhesus monkeys manifest severe withdrawal signs upon abrupt withdrawal following intravenous self-administration of thebaine at a daily dose level of 10-30 mg/kg for one month. However, thebaine not only failed to suppress the morphine withdrawal signs in monkeys physically dependent on morphine, but served to precipitate the signs as well (5). Such seemingly contradictory effects are known with many of the partial antagonists.
The reinforcing effect of thebaine was not evident in the cross self-administration experiments, but was clearly demonstrated in a continuous intravenous self-administration experiment (5). The average daily doses ingested were 20-35 mg/kg at a unit dose of 1 mg/kg/injection. During the active self-administration period, no marked drug effects were observed.
The metabolism of thebaine in rats has been studied by Misra et al. (8, 9). In the urine from rats treated with thebaine at a single subcutaneous dose of 5 mg/kg, several metabolites, though only in residual amounts, were found by thin-layer chromatography. The possibility that these metabolites were codeinone, codeine, morphine and 14-hydroxycodeinone was suggested. The investigators discussed the possible cause of the difference in the dependence potential of thebaine between the rat and the rhesus monkey and attributed it to different metabolic pathways of thebaine.
Studies on isolated organ preparations. The morphine-like character of the guinea pig ileum and the mouse vas deferens by Kosterlitz (10). In the former preparation the maximum inhibiting potency of thebaine was 0.32 ± 0.07 per cent of that of morphine, was much slower in onset, and only partially reversed by naloxone. A similar profile was obtained with the mouse vas deferens preparation. The very weak morphine-like action of thebaine and its incomplete reversal by naloxone as shown in these tests permit the interpretation that these are not specific morphine-like effects.
Analgesic tests in mice. Aceto et al. (11) reported that thebaine was inactive as an analgesic in the tail-flick and phenylquinone abdominal stretching tests. It was also inactive as an antagonist of morphine in the tail-flick test. Thebaine was active in the hot place (ED 50 = 8.2 mg/kg s.c.) and Nilsen (ED 50 =4.4 mg/kg s.c.) tests. However, doses in the higher range of the dose responses curves produced convulsions.
Gross behavioural observation of acute effects of thebaine in rhesus monkeys. In a preliminary test for a tolerance study, Yanagita and Miyasato (12) studied the effects of single intravenous injections of thebaine to rhesus monkeys. The results were: no effect at 1.0 mg/kg; tremor at 2.0 mg/kg; and convulsions and drowsiness at 4.0 mg/kg. The convulsions occurred a few minutes after the injection, but drowsiness followed much later, becoming prominent about 2 hours after administration and continuing for another 2 hours. This delayed onset of the depressant effect may be attributed to the metabolic breakdown of thebaine.
Operant behavioural effects of thebaine in rats. Takada et al. (13) studied the operant behavioural effects of thebaine, pentazocine and codeine in rats using FR 30 and DRL 20 seconds schedules with food reinforcement. At subcutaneous doses of up to 16 mg/kg, thebaine did not exert much influence on responding generating by the FR 30 schedule, but did depress the responding at 64 mg/kg. In the DRL experiment, thebaine increased the number of responses at 16 mg/kg and shortened the modal inter-response time at 4 mg/kg but not at 16 mg/kg. Since 64 mg/kg is a near-lethal dose, the effect observed in the FR experiment may be unspecific. In contrast, a mild stimulatory effect by the drug was observed in the DRL experiment. In these experiments the order of potencies was pentazocine-codeine-thebaine.
Effect of thebaine on food-reinforced responding in rhesus monkeys. Hartel et al. (14) studied the effects of thebaine on food-reinforced responding rhesus monkeys, and their modification by nalaxone. A chain DRO 30 seconds FR 30 schedule was used. Saline as well as 0.32 and 1.0 mg/kg thebaine had no effect on the response rates during the FR component of the schedule while 3.2 mg/kg of thebaine reduced them. Naloxone had no influence on the above results. It was concluded that naloxone does not antagonize the effects of thebaine on operant responding for food.
In an attempt to produce tolerance to the convulsant effect of thebaine in rhesus monkeys, Yanagita and Miyasato (12) repeatedly administered 2 mg/kg of thebaine 6 to 24 times daily for 6 weeks or longer to 4 monkeys by programmed injection through intravenous in-swelling catheters. Every two weeks the monkeys were challenged with 4 mg/kg of thebaine which is the convulsant dose. No evidence for the development of tolerance to the convulsant effect of thebaine was obtained.
Physical dependence studies in rats. Thebaine was tested by Harris and his colleagues(15) for physical dependence potential in the rat using continuous intraperitoneal infusion. A seven-day dose schedule was used and the animals were observed periodically for weight changes and behavioural signs of abstinence for 96 hours after abrupt withdrawal. Using doses up to 360 mg/kg/day (lethal to 4/6 animals), no evidence of physical dependence was obtained.
Physical dependence studies in dogs. Gilbert and Martin (16) studied the physical dependence potential of thebaine in chronic spinal dogs. In the first experiment, thebaine or naloxone were given to morphine dependent and non-dependent dogs. Thebaine did not precipitate morphine withdrawal signs. In the second experiment, dogs were chronically treated with thebaine or morphine, and challenged with naloxone or naltrexone. Thebaine was administered intravenously, initially at 1 mg/kg/day and finally at 22.5 mg/kg/day divided over 24 injections.
Naltrexone produced very mild withdrawal signs in the thebaine-treated animals. Thus, unlike the findings reported for the rhesus monkey, in the dog the physical dependence potential of thebaine was found to be very low and its antagonistic action lacking.
Substitution studies in morphine dependent monkeys. Aceto et al. (11) and Swaine et al. (17) investigated the ability of thebaine to substitute for morphine in physically dependent rhesus monkeys. Subcutaneous doses up to 9.6 mg/kg failed to support physical dependence on morphine. This confirms the previous report by Yanagita (5).
Development of physical dependence on thebaine by subcutaneous administration in rhesus monkeys. Yanagita et al. (18) studied the physical dependence potential of thebaine in rhesus monkeys by subcutaneous injections of the drug at doses of 3 mg/kg every six hours for 31 days. In confirmation of a previous study (5) with intravenous self-administration, definite withdrawal signs were observed in the monkeys upon abrupt withdrawal of thebaine and also following the administration of naloxone.
Development of physical dependence on thebaine by intravenous self-administration in rhesus monkeys. In the course of a continued intravenous self-administration experiment with thebaine, Hartel et al. (14) attempted to precipitate withdrawal signs by administering naloxone at 1.0 mg/kg to three monkeys. The monkey which ingested thebaine at the highest daily close level (about 30 mg/kg/day) manifested severe withdrawal signs including retching, acute sensitivity to abdominal pressure and violent thrashing about in her cage. The animal was found dead the next morning, clearly not due to convulsions or thebaine overdose. However, the two remaining monkeys did not manifest any withdrawal signs following naloxone injection.
Experiment of cross and continuous self-administration of thebaine in rhesus monkeys. Hartel et al. (14) conducted experiments with both cross and continuous intravenous self-administration of thebaine in rhesus monkeys. In the cross self-administration experiments saline or thebaine in unit doses ranging from 0.0003 to 1.0 mg/kg/infusion were substituted for codeine, but little, if any, reinforcing effect was demonstrated with thebaine. In the continuous self-administration experiment, an increase in the injection rate was observed in three out of four monkeys when they were allowed to take thebaine instead of saline. When each response was followed by the injection of 1.0 mg/kg of thebaine, the animals self-administered an average of 15-32 mg/kg/day. When the number of responses required for each injection was increased to 10 the number of injections earned decreased in two of the animals but increased in the third. In all instances, however, the lever-press responding generated by thebaine was higher than that obtained with saline. This definitely demonstrates that thebaine can serve as a reinforcer in the rhesus monkey.
Progressive ratio experiment in rhesus monkeys. Yanagita and Miyasato (19) assessed the reinforcing intensity of thebaine by the progressive ratio technique in rhesus monkeys. In this experiment, the ratio of lever-presses to injections gradually increased by a factor of 4/2 after each injection. When the number of lever-presses for the last 48 hours diminished to less than 50 per cent of the number required for the next injection, the monkeys were considered to have reached the breaking point. Using these procedures two monkeys were tested with low and high unit doses of thebaine (0.25 and 1.0 mg/kg/inj) and of pentazocine (0.06 and 0.25 mg/kg). The final ratios obtained with the high unit doses of thebaine and pentazocine were respectively 1,900 and 1,900 in one monkey and 2,260 and 2,610 in the other. Thus it was found that the reinforcing intensity of thebaine in rhesus monkeys is high and comparable to that of pentazocine.
Yanagita et al. (20) studied the metabolism of thebaine using urine obtained from rhesus monkeys treated with thebaine at single subcutaneous doses of 8 mg/kg. Thebaine and its metabolites were extracted from the urine and separated by thin-layer chromatography. Five spots including thebaine itself were detected, and their RF values were 0.39 (M 1),0.23 (M 2) and 0.1-0.2 (M 3 and M 4). M 1 has been identified as oripavine by gas chromatographic-mass spectrographic analysis. Later, a supply of authentic oripavine (provided through the courtesy of Mr. K. C. Reid of MacFarlan Smith Limited, United Kingdom) was compared with and found to be identical to M 1 in mass spectra, GC-retention time and TLC-Rf values. M 2 appeared to be a codeine-like substance, but has not yet been identified because of its very limited availability. M 3 was positive in the colour reaction with phosphomolybdic acid-ammonium hydroxide and nitroprusside, indicating the existence of a phenolic functional group and a secondary amine group. The chemical structure of M 3 has since been identified as nororipavine by GC-mass spectrographic analysis, M 4 has not yet been identified.
Thebaine was long believed to have no morphine-like agonistic properties and many studies, old and recent, are supportive of this view. However, it is now evident that it has a meaningful dependence potential, both physical and psychological, when large doses are ingested over a certain period in the rhesus monkey. As one of the causes of these discrepancies, contamination by morphine-like substances of thebaine used for the monkey studies was suspected. Since, however, in the analysis by Dr. Jacobson (National Institutes of Health, USA), the sample was found to be free from significant impurity, the species differences in metabolism of thebaine might well explain the discrepancy as already postulated by some investigators. There are some findings which tend to support the idea that the agonistic property of thebaine in rhesus monkeys may be attributable to its metabolites:
Thebaine is devoid of opiate agonistic effects as shown in the guinea pig ileum longitudinal muscle and the mouse vas deferens.
The depressant effect on the gross behaviour of rhesus monkeys appears after a time delay in contrast to the immediate onset of the stimulating and convulsant effects.
The reinforcing effect, which has been found to be equally strong as that of pentazocine, could not be demonstrated in cross self-administration experiments, probably because of the delayed onset of the agonistic effects.
The initiation of self-administration requires a longer time period with thebaine than with other opioids.
Some metabolites Of thebaine, such as oripavine, nororipavine and probably codeine, are detectable in the urine of the rhesus monkey. The question arises as to whether these metabolites have a dependence potential and are biosynthesized in sufficient quantities to produce dependence.
In this connexion the pharmacological profile and dependence potential of oripavine deserve particular attention because:
Oripavine may be the pharmacologically most active metabolite of thebaine;
it may be biosynthesized by ingestion of other opium alkaloids as well; and
it may become available in the future as a therapeutic agent or a substance of abuse.
For these reasons, the Group concluded:
that thebaine has a meaningful dependence potential, both physical and psychological, when large doses are ingested over a certain period in the rhesus monkey;
it is desirable to investigate the dependence potential of oripavine in view of its being a most active metabolite of thebaine; and
the findings in this study apply to animals; whether or not they would apply to humans requires further study. From the monkey studies it would appear that large doses of thebaine are necessary to produce dependence. It is unlikely that comparable doses could be given to humans experimentally or would be self-administered in an abuse situation.
The Dependence Potential of Thebaine; Report of a WHO Advisory Group, Consolidated report of the Consultations held in Geneva, 11-22 October 1976, 3-4 October 1977, 25-26 September 1978 and 24-25 September 1979.002
The Feasibility of the Conversion of Thebaine into Drugs of Abuse and of Potential Abuse . Report of an Expert Group, MNAR/4/1976 (Geneva, United Nations Narcotics Laboratory, Division of Narcotic Drugs, 1976).003
H. Kruger, N. B. Eddy and M. Sumwalt, eds., The Pharmacology of the Opium Alkaloids , U.S. Public Health Service, Public Health Report, Supplement No. 165 (Washington, DC, Government Printing Office, 1941).004
J. Kettenes-Van Den Bosch, C.A. Salemink and I. Khan, The Biological Activity of the Alkaloids of Papaver Bracteatum Lindl, MNH/79.31 (Geneva, World Health Organization, 1979).005
T. Yanagita, "An experimental framework for evaluation of dependence liability of various types of drugs in monkeys", Bulletin on Narcotics , vol. 25, No. 2 (1973), pp. 57-64.006
V. Preininger, "The pharmacology and toxicology of the alkaloids from the plants of the family Papaveraceae", Acta Universitatis Palackianae Olomucensis, Facultatis Medicae , vol. 61, 1972, pp. 213-254 and references cited therein.007
A. P. Corrado and V. G. Long, "An electrophysical analysis of the convulsant action of morphine, codeine and thebaine", Archives internationales de pharmacodynamie et de therapie , vol. 132, 1961, pp. 255-269.008
A. L. Misra, R. B. Pontani and S. J. Mule, "Pharmacokinetics and metabolism of (3H) thebaine", Xenobiotica, vol. 4, 1974, p. 17.009
A. L. Misra, R. B. Pontani and S. J. Mule, "Relationship of pharmacokinetic and metabolic parameters to the absence of physical dependence liability with thebaine (3H)", Experientia, vol. 29, 1973, p. 1108.010
H. W. Kosterlitz, personal communication.011
M. D. Aceto and others, "Dependence studies of new compounds in the rhesus monkey", Proceedings 39th Annual Scientific Meeting, Committee on Problems of Drug Dependence (Cambridge, Mass., 1977), p. 586.012
T. Yanagita and K. Miyasato, "An attempt to produce tolerance to convulsant effect of thebaine in rhesus monkeys", Annual Report of Preclinical Research Laboratories (Central Institute for Experimental Animals, 1977).013
K. Takada and K. Ando, "Behavioural effects of thebaine in rats", Annual Report of Preclinical Research Laboratories (Central Institute for Experimental Animals, 1977).014
C. R. Hartel, J. H. Woods and C. R. Schuster, "Behavioural effects of thebaine in the rhesus monkey", submitted to Psychopharmacology.015
L. S. Harris and others, personal communication.016
P. E. Gilbert and W. C. Martin, "The pharmacology of thebaine in the chronic spinal dog", Drug and Alcohol Dependence , vol. 3, 1978, pp. 139-142.017
H. H. Swain, C. L. Fly and M. H. Seevers, "Evaluation of new compounds for morphine-like physical dependence in the rhesus monkey", Proceedings of the 39th Annual Scientific Meeting, Committee on Problems of Drug Dependence (Cambridge, Mass., 1977), pp. 614.018
T. Yanagita and others, "Dependence potential of brotebanol, codeine and thebaine tested in rhesus monkeys", Bulletin on Narcotics, vol. 29, 1977, pp. 1 and 33.019
T. Yanagita and K. Miyasato, "Progressive ratio test in intravenous self administration of thebaine and pentazocine in rhesus monkeys", Annual Report of Preclinical Research Laboratories (Central Institute for Experimental Animals, 1977), Proceedings 40th Annual Meeting, Committee on Problems of Drug Dependence.020
T. Yanagita, Y. Yamazoe and H. Numata, "Thebaine metabolites in the urine of rhesus monkeys (Part 1)", Annual Report of Preclinical Research Laboratories (Central Institute for Experimental Animals, 1977), Proceedings 40th Annual Scientific Meeting, Committee on Problems of Drug Dependence.