Geneva September if.'\..[ b. -i.>/.* ...

Transcription

1 I L \4C)KLI) HFALTII OR(;. \h IZA rion "K(;ANISArIOh MONDIALE DE LA SANTE EIGHTY REVIEW OF PSYCFiOACTI VE SUB STANCES FOR 1NTERNATIONAL CONTROL MNH/ RZtTNAL; ENGL t SN Geneva September if.'\..[ b. -i.>/.* 1. LNTRODUCTION SCOPE OF THE MEETING... 3 I 3. PROCEDURES AND CRITERIA UTILIZED IN THIS REVIEW REVIEW OF INDIVIDUAL BENZODIAZEPINES Diazepam Alprazolam Bromazepam Camazepam Chlordiazepoxide... h Clobazam... 7 Clonazepam... 7 Clorazepate... 8 Clotiazepam... 8 Cloxazolam... 9 Delorazepam... 9 Estazolam... 9 Ethyl loflazepate Etifoxine Fludiazepam Flunitrazepam Flurazepam Halazepam Haloxazolam Ketazolam Loprazolam Lorazepam Lormetazepam Medazepam Nimetazepam Nitrazepam Nordiazepam 4.28 Oxazepam 4.29 Oxazolam.. Page ' L $.?b Ti5ezonium ToElsopam rr~azolam Zoplr lone.. issiir.. ;bit document does nor constitute '"'ma' P4b. ~cdtion i+ sn~~ulti not he r~vlewed. abstracto.! or cluoted wlthour the aqreement at '" Worlcl Health Orqan~zat'~~~ 4dthorc dlane arp resdr~r -IQIP for i. C~NS OX~ICS\P~ in qlqnetl articip( Ce document ne constltue pas une publication il fie doit faire i'objer d'aucun cornpre renduou recume nl d'aiicune citation San4 I'autorisation de I'Organlsat~cn mondiale de Id ~ailte. Les opiniocs crprirnees rianr lrs drt~cles :!unps ri'engagent que ;ecirs auteuts.

2 5. RECOMMENDATIONS considerations of future programmes Types of data to be reviewed for rescheduling and descheduling ACKNOWLEXEMENTS Annex 1 LIST OF PARTICIPANTS 25 Annex 2 DISCUSSIONS WITH PHARMACEUTICAL COMPANIES 28 l. INTRODUCTION Dr N. Sartorius, Director, ~ivision of Mental Health, welcomed the participants and observers on behalf of Dr H. Mahler, Director-Ge'neral of the World Health Organization. informed the group that the world Health organization was in constant search for the id procedure to implement WHO'S responsibilities as specified in the 1971 Convention on Psychotropic Substances. He pointed out that in March 1983, the World Health Organizat had reviewed the proceduresl and further, that Professor B. Rexed would be assisting in the final formulation of these procedures which would be studied by the WHO Executive B at its Seventy-third session in January He hoped that these procedures would facilitate future work in the area of drugs being evaluated for possible international control. The group's attention was drawn to the fact that this Review Group had been conve the World Health Organization to respond to Resolution 4 (XXX) of the United Nations Commission on Narcotic Drugs which, through the Secretary-General of the United Nation requested, the World Health Organization to urgently review and assess, as part of its regular function under the Convent ion on Psychotropic Substances, all benzodiazepines currently on the market, as of a specific date to be determined by the Organization. further requested that the findings and recommendations be made on a substance by sub basis. The group was briefed on historical difficulties encountered in the review process this group of substances. Dr Sartorius emphasized that any decision reached by the participants of this review must be made exclusively on the basis of scientific, medic health considerations. While the decisions reached by previous Review Groups for some these substances need not necessarily be adhered to, he urged the participants to crit review the evidence and reasoning on which they had been made. He pointed out that th decisions reached at this meeting would have considerable consequences, not only f pharmaceutical industry but more importantly, for the health of the people of the The group's attention was drawn to the recent publication of a paper entitl Abuse of the Benzodiaze ines, which was based on the Report of the 6th Review o Psychoactive Substances g. Dr Sankaran addressed the meeting and indicated the interest his Division reports of the review meetings, particularly in respect of the needs of developin countries. This is especially important in relation to this meeting because of wide spread use of the benzodiazepine S. lmnh ~ulletin of the World Health Organization, 61 (4): (1983)

3 E OF THE MEETING charge given to the group was: eview and make recommendations for international control where appropriate, for 39 epine-type substances, namely bromazepam camazepam chlordiazepoxide c lobazam c lonazepam c lotiazepam c lorazepate c loxazo lam de lorazepam estazolam ethyl lof lazepate etifoxine fludiazepam f luni trazepam haloxazolam ketazolam loprazolam lorazepam lormetazepam medazepam nimetazepam nitrazepam nord iazepam oxazepam oxazolam pinazepam pirenzepine prazepam prop izepine temazepam tetrazepam tof isopam tibenzonium triazolam zopic lone recommendations on: ure activities of WHO including the substances that need consideration for le international control. ypes of information and data that.wil1 be needed for rescheduling or descheduling stances or drugs currently under international control. DURES AND CRITERIA UTILIZED IN THIS REVIEW p was to review the 39 benzodiazepine substances which the Commission had to review in its resolution 4 (XXX), and which were on the market at the end 983. The substances were primarily benzodiazepine types of drugs, but in anxiolytic drugs. The data to be reviewed came from a number of sources. traffic was collected through Interpol, the United Nations Division of through the Ministry of State of member states as well as WHO regional e countries. Information was sought from concerned industries through the ederation of Pharmaceutical Association (IFPMA) as well as other resource to them. In a pre-review meeting held on 11 September 1983 representatives of pharmaceutical companies and the IFPMA met and presented data to the temporary ticipants who were assigned specific topics collected scientific information sources available to th'em. included on the list of substances for the review, Zopiclone was excluded from because it was established that it was not marketed at the end of February be considered for review at a future meeting.

4 ~NH/83.28 page Scheduling criteria of 1971 Convention on Psychotropic Substances Drugs were reviewed and reported on an individual basis. In order to establish a substance met the scheduling criteria of 1971 Convention on Psychotropic Substances, group reviewed the data on the following points: ( i ) chemical structure, receptor binding characteristics, sedat ive-hypnotic, anti convulsant, and anxiolytic profile of cent-ral nervous system effects. (ii) animal data on psychological and physical dependence potential. (iii) human experimental data on both dependence and abuse. potential. (iv) clinical data on dependence and public health problems. (v) epidemiological data on public health and social problems. (vi) extent of abuse or likelihood of abuse and seriousness of public health and problems resulting from such abuse. (vii) utilization and usefulness in therapy. Of the 38 remaining substances to be reviewed, 33 were recommended for scheduli five were not. The decision to reconrmend international control of these substances based on data relevant to the 7 points listed above..data was available for a numbe substances on these seven point S. However, the group found that in the case of a n the substances, no data other than on points (i) and (vii) of the above list was On these substances the group decided by a majority vote of 8 to 3, that if a sub under review fulfils point (i), the substance was adjudged to have the capacity t state of dependence and likelihood of abuse so as to constitute a public health an problem warranting the placing of the substance under international control. 4. REVIEW OF INDIVIDUAL BENZODIAZEPINES 4.1 Diazepam Diazepam has potent, well-demonstrated anxiolytic, anti-convulsive and sediative-hypnotic properties in animals and humans which are mediated by specific in the brain. In regard to the dependence and abuse liability of diazepam the gro concluded that : (a) Diazepam has the capacity to produce: 1. a state of dependence as demonstrated by experimental studies in anima humans, as well as by clinical studies showing the development of physical Further experimental studies in animals and humans have shown that diazepam limited reinforcing capacity indicative of low to moderate psychological de potential relative to the short acting barbiturates, psycho-motor stimulant opiates. Studies of subjective effects in humans also show that diazepam C euphoria. There have been clinical reports of psychological dependence; 2. central nervous system depression resulting in disturbances in behaviour and mood, as demonstrated by studies in animals and human ataxia, changes in behaviour and mood. (b) There is sufficient evidence as revealed by clinical reports and e~idemiolo studies, that diazepam is being abused so as to constitute a public health and S problem warranting the placing of the substance under international control. Bearing in mind the medical usefulness of diazepam as an anxiolytic, anti con and sedative-hypnotic agent, as well as evidence of actual abuse, the group recorn diazepam be included in Schedule IV of the Convention on ~s~chotropic Substances.

5 MNH / 8: page!? (a) hlprazolam has the capacity to produce: 1. a state of dependence as predicted by its chemical similarity to diazepam with which it shares specific receptor mediated action as an anxiolytic, anti convulsant, sedative hypnotic. In addition, experimental studies in animals have demonstrated t alprazolam can produce physical dependence. Cases of physical dependence in humans have been reported. Further experimental studies in animals have shown that alprazolam does have limited reinforcing capacity indicative of low to moderate dependence potential. 2. central nervous system depression resulting in disturbances in motor function, behaviour and 4, demonstrated by animal and human studies showing sedation, ataxi changes in behaviour and mood. E (b) There is sufficient evidence of similarity in chemical structure and pharmacological spectrum of action to diazepam to predict that alprazolam is likely to be abused so as to constitute public health and social problem warranting the placing of the substance under international control. In addit ion, evidence, as revealed by c linical report S and epidemiological studies wz presented demonstrating actual abuse of alprazolam. Bearing in mind the medical usefulness of alprazolam as an anxiolytic, anti convulsa and sedative/hypnotic agent, as well as evidence of actual abuse, the group recommended th alprazolam be included in Schedule IV of the Convention on Psychotropic Substances. i $1~ \ i 4.3 Bromazepam (a) The group reached the following conc lusions Bromazepam has the capacity to produce: 1. a state of dependence as predicted by its chemical similarity to diazepam with which it shares specific receptor mediated action as an anxiolytic, anti convulsant, sedative hypnotic. In addition, experimental studies in animals have demonstrated th; bromazepam can produce physical dependence. Cases of physical dependence in humans have been reported. Further experimental studies in animals have shown that bromazepam does have limited reinforcing capacity indicative of low to moderate dependence potential. Clinical reports of psychological dependence were presented. 2. central nervous system depression resulting in disturbances in motor function, behaviour and mood, demonstrated by animal and human studies showing sedation, ataxia, changes in behaviour and mood. (b) There is sufficient evidence of similarity in chemical structure and phamacological ; of action to diazepam to ~redict that bromazepem is likely to be abused So as to 3 Co"titute public health and social problem warranting the placing of the substance under : '"ternational control. In addition, evidence, as revealed by clinical reports and epidemiological studies, wa D"s'nt~d demonstrating actual abuse of bromazepam. Bearing in mind the medical usefulness of bromazepam as an anxiolvtic, anti convulsant and sedative/hypnotic agent, as well as evidence of actual abuse, the group recommended '"L ~r(~nnzeparn be included in Schedule IV of the Convention on Psychotropic Substances.

6 ~NH/83.28 page Camazepam The group reached the following conclusions (a) Camazepam has the capacity to produce: 1. a state of dependence as predicted by its chemical similarity to diazepa which it shares specific receptor mediated action as an anxiolytic, anti convu sedative hypnotic. In addition, experimental studies in animals have demonstrat camazepam can produce physical dependence. 2. central nervous system depression resulting in disturbances in behaviour and e, demonstrated by animal and human studies showing changes in behaviour and mood. (b) There is sufficient evidence of similarity in chemical structure and pharmacol hpectrum of action to diazepam to predict that camazepam is likely to be abused so constitute public health and social problem warranting the placing of the substance international control. No evidence of actual abuse was presented. Bearing in mind the medical usefulness of camazepam as an anxiolytic, anti c and sedative/hypnotic agent, as well as evidence predictive of abuse, the group r that camazepam be included in 8chedule IV of the Convetion on Psychotropic Substan 4.5 Chlordiazepoxide The group reached the following conc lusions (a) Chlordiazepoxide has the capacity to produce: 1. a state of dependence as predicted by its chemical similarity to diazepam which it shares specific receptor mediated action as an anxiolytic, anti convu sedative hypnotic. In addition, experimental studies in animals and humans have demonstrated that chlordiazepoxide can produce physical dependence. Cases of ph dependence in humans have been reported. Further experimental studies in animals have shown that chlordiazepoxide d limited reinforcing capacity indicative of low to moderate dependence potential Clinical reports of psychological dependence were presented. 2. central nervous system depression resulting in disturbances in behaviour and e, demonstrated by animal and human studies showing changes in behaviour and mood. (b) There is sufficient evidence of similarity in chemical structure and pharmacol spectrum of action to diazepam to predict that chlordiazepoxide is likely to be abu to constitute public health and social problem warranting the placing of the substa international control. In addition, evidence, as revealed by clinical reports and epidemiological stu presented demonstrating actual abuse of chlordiazepoxide. Bearing in mind the medical usefulness of ch10rdiazepoxi.de as an anxiolytic, ant convulsant and sedativelhypnotic agent, as well as evidence of actual abuse, the grou recommended that chlordiazepoxide be included in Schedule IV of the Convention on Psychotropic Substances.

7 MNHf83.28 page 7 hemical similarity to diazepam with n as an anxiolytic, anti convulsant, studies in animals have demonstrated that es of physical dependence in humans have have shown that clobazam does f low to moderate dependence ~otential. ere presented. g in disturbances in motor function, human studies showing sedation, ataxia, structure and pharmacological ikely to be abused so as to lacing of the substance under reports and epidemiological studies, was mind the medical usefulness of clobazam as an anxiolytic, anti pnotic agent, as well as evidence of actual abuse, the group recommended that luded in Schedule IV of the Convention on Psychotropic Substances. d the following conclusions t S the capacity to produce: as predicted by its chemical similarity to diazepam with ceptor mediated action as an anxiolytic, anti convulsant, n animals have demonstrated that have shown that clonazeparn does g capacity indicative of low to moderate dependence potential. turbances in motor function,, demonstrated by animal and human studies showing sedation, ataxia, q fficient evidence of similarity in chemical structure and pharmacological on to diazepam to prehict that clonazepam is likely to be abused so as to c health and social problem warranting the placing of the substance under on, evidence, as revealed by clinical reports and epidemiological. studies, was nstrating actual abuse of clonazepam. in mind the medical usefulness of clonazepam as an anxiolytic, anti convulsant /hypnotic agent, as well as evidence of actual abuse, the group recommended that e included in Schedule IV of the Convent ion of Psychotropic Substances.

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9 e group reached the fo.llowing conclusions oxazolam has the capacity to produce: a state of dependence as predicted by its chemical similarity to diazepam with ich it shares specific receptor mediated action as an anxiolytic, anti convulsant, dative hypnotic. In addition, experimental studies in animals have demonstrated that oxazolam can produce physical dependence. Further experimental studies in animals have shown that cloxazolam does have ted reinforcing capacity indicative of low to moderate dependence potential. entral nervous system depression resulting in disturbances in motor function, and mood, demonstrated by animal and human studies showing sedation, ataxia, n behaviour and mood. re is sufficient evidence of similarity in chemical structure and pharmacological f action to diazepam to predict that cloxazolam is likely to be abused so as to public health and social problem warranting the placing of the substance under ional control. vidence of actual abuse was presented. ring in mind the medical usefulness of cloxazolam as an anxiolytic, anti convulsant ive/hypnotic agent, as well as evidence predictive of abuse, the group recommended azolam be included in Schedule IV of the Convention on Psychotropic Substances, roup reached the following conc lusions zepam has the capacity to produce: tate of dependence as predicted by its chemical similarity to diazepam with shares specific receptor mediated action as an anxiolytic, anti convulsant, ral nervous system depression resulting in disturbances in motor function, and mood, demonstrated by animal and human studies showing-ia, in behaviour and mood. sufficient evidence of similarity in chemical structure and pharmacological action to diazepam to predict that delorazepam is likely to be abused so as to public health and social problem warranting the placing of the substance under ence of actual abuse was presented. in mind the medical usefulness of delorazepam as an anxiolytic, anti convulsant e/hypnotic agent, as well as evidence predictive of abuse, the group recommended zepam be included in Schedule IV of the Convention on Psychotropic Substances. roup reached the following conclusions

10 MNH/~~.28 page 10 (a) Estazolam has the capacity to produce: 1. a state of dependence as predicted by its chemical similarity to diaz which it shares specific receptor mediated action as an anxiolytic, anti c estazolam can produce physical dependence. Further experimental studies in animals have shown that estazolam does limited reinforcing capacity indicative of low to moderate dependence potent behaviour and mood, demonstrated by animal and h changes in behaviour and mood. udies showin (b) There is sufficient evidence of similarity in chemical structure afid phama spectrum of action to diazepam to predict that estazolam is likely to be abused %constitute public health and social problem warranting the placing of the substa international control. and sedative/hypnotic agent, as well as evidence of actual abuse, the group recomme estazolam be included in Schedule IV of the Convention on Psychotropic Substances. 4.l3 Ethyl loflazepate (a) The group reached the following conclusions + Ethyl loflazepate has the capacity to produce: No evidence of actual abuse was presented. ~earing in mind the medical usefulness of ethyl loflazepate as an anxiolytic convulsant and sedative/hypnotic agent, as well as evidence predictive of abuse, Substances Et ifoxine The group concluded that since etifoxine is structurally dissimilar to diaze there was only limited data available on its pharmacology, that it should not be for inclusion in the Convention on Psychotropic S~bstances, 1971 at this time. I reviewed at a future meeting of WHO.

11 MNHf83.28 page* 11 reached the following conc reached the following am has the capacity

12 ~NH page Flurazepam The group reached the following conclusions (a) Flurazepam has the capacity to produce: have been reported. reports of psychologica dependence were presented. D 2. central nervous system depression resulting in disturbances in behaviour and mood, demonstrated by animal and human studies showing thantqes in behaviour and mood. international cont revealed by clinical reports and epidemiologica abuse of flurazepam Halazepam sedative hypnotic. halazepam can prod internat ionaf control. No evidence of actual abuse was presented. Bearing in mind the medical usefulness of halazepam as an anxiolytic, anti CO and sedative/hypnotic agent, as well as evidence predictive of abuse, the group re that halazepam be included in Schedule IV of the Convention on Psychotropic Substa

13 up reached the following conc lusions MNtf183.28' * page 13.

14 mj83.28 page Loprazolam The group reached the following conclusions (a) Loprazolam has the capacity to produce: 1. a state of dependence as predicted by its chemical similarit which it shares specific receptor mediated action as an anxiolytic, an sedative hypnotic. 2. central nervous system depression resulting in disturbances in behaviour and e, demonstrated by animal and human studies showin changes in behaviour and mood. (b) There is sufficient evidence of similarity in chemical structure and pharma spectrum of action to diazepam to predict that loprazolam is likely to be a % to constitute public health and social problem warranting the placing of the under international control. No evidence of actual abuse was presented. Bearing in mind the medical usefulness of loprazdlam as an anxiol sedative/hypnotic agent, as well as evidence predictive of abuse, the loprazolam be included in Schedule IV of the Convention on Psychotropic 4.22 Lorazepam e following conclusions (a) Lorazepam has the capacity to prbduce: 1. a state of dependence as predicted by its chemical similarity to diazepam W which it shares specific receptor mediated action as an anxiolytic, anti convuls sedative hypnotic. In addition, experimental studies in animals~and humans have demonstrated that lorazepam can produce physical depende,nce. Cases of physical dependence in humans have been reported. Further experimental studies in animals and humans have sho have limited reinforcing capacity indicative of low to moderate d Clinical reports of psychological dependence were presented. 2. central nervous system depression resulting in disturbances in behaviour and mood, demdnsttated by animal and human studies show4 changes in behaviour and mood. (b) There is sufficient evidence of similarity in chemical struttute and pharmacolo spectrum of action to diazepam to predict that lorazepam is likely to be abused so a constitute public health and social problem warranting the placing of the substance international control. In addition, evidence, as revealed by clinical reports and epidemiblogical studi presented demonstrating actual abuse of lorazepam. Bearing in mind the medical usefulness of loarazepdm as an anxiolytic, anti convu and sedative/hypnotic agent, as well as evidence of actual abuse, the group recommeode lorazepam be included in Schedule IV of the Convention on Psychotropic Substances.

15 NNH/83.28 page 15 e capacity to produce: fulness of medazepam as an anxiolytic, anti convulsant

16 ~ / page Nimetazepam The group reached the following conclusions (a) Nimetazepam has the capacity to produce; 1. a state of dependence as predicted by its chemical similarity to diaze which it shares specific receptor mediated action as an anxiolytic, anti CO sedative hypnotic. In addition, experimental studies in animals have demon nimetazepam can produce physical dependence. Further experimental studieb in animals and humans have demonstrated dependence potential. 2. central nervous system depression resulting in disturbances 4 behaviour and mood, demonstrated by animal and humah studies showi changes in behaviour and mood. international control. In addition, evidence as revealed by clinical reports and epidemiological S presented demonstrating actual abuse of nimetazepam Ni trazepam The group reached the following conclusions (a) Nitrazepam has the capacity to produce: which it shares specific receptor mediated action as a sedative hypnotic. In addtion, experimental studies i demonstrated that nitrazepadl can produce physical depe dependence in humans have been reported. Further experimental studies in animals ha limited reinforcing capacity indicative of low constitute public health and social problem warranting the placing of the substance international control. In addition, evidence, as revealed by clinical reports and epidemiological studie presented demonstrating actual abuse of nitrazepam. Bearing in mind the medical usefulness of nitrazepam as an anxiolytic, anti convul and sedative/hypnotic agent, as well as evidence of actual abuse, the group recommended nitrazepam be included in Schedule IV of the convention on Psychotropic Substances.

17 MWHl83.28 page 17. s the capacity to produce:, evidence, as revealed trating actual abuse of ulness of oxazepam as an anxiolytic, anti convulsant as evidence. of ac tuai abuse, the group recommevded IV of the Convention on Psychotropic Substances.,,

18 ~~ page Oxazolam The group reached the following conclusions (a) Oxazolam has the capacity to produce: 1. a state of dependence as predicted by its chemical similarity to diazepam W which it shares specific receptor mediated action as an anxiol~tic, anti convuls sedative hypnotic. In addition, experimental studies in animals have demonstrate oxazolam can produce physical dependence. Cases of physical dependence in humans h been reported. Further experimental studies in animals have shown that oxazolam does have reinforcing capacity indicative of low to moderate dependence potential; 2. central nervous system depression resulting in disturbances in behaviour and mood, demonstrated by animal and human studies showi changes in behaviour and mood. (b) There is sufficient evidence of similarity in chemical structure and pharmacologi spectrum of action to diazepam to predict that oxazolam is likely to be abused so as t constitute public health and social problems warranting the placing of the substance international control. In addition, evidence, as revealed by clinical reports and epidemiological studies presented demonstrating actual abuse of oxazolam. Bearing in mind the medical usefulness of oxazolam as an anxiolytic, anti convuls and sedat ive/hypnotic agent, as well as evidence predictive/ of actual abuse, the grou recommended that oxazolam be includedtin Schedule IV of the Convention on Psychotropic Substances Pinazepam The group reached the following conclusions (a) Pinazepam has the capacity to produce: 1. a state of dependence as predicted by its chemical similarity to diazepam wit which it shares specific receptor mediated action as an anxiolytic, anti convulsan sedative hypnotic; 2. central nervous system depression resulting in disturbances in behaviour and mood, demonstrated by animal and human studies showin changes in behaviour and mood. (b) There is sufficient evidence of similarity in chemical structure and pharmacologi spectrum of action to diazepam to predict that Pinazepam is likely to be abused so as constitute public health and social problems warranting the placing of the substance un international control. No evidence of actual abuse was presented. Bearing in mind the medical usefulness of Pinazepam as an anxiolytic, anti convuls and sedative/hypnotic agent, as well as evidence predictive of abuse, the group recomme that pinazepam be included in Schedule IV of the Convention on Psychotropic Substances.

19 the following conc lus MNH/83.28 page" 19..

20 MNH/~~.28 page 20 (a) Temazepam has the capacity to produce: 1. a state of dependence as predicted by its chemical similarity to diazepam which it shares specific receptor mediated action as an anxiolytic, anti convul sedative hypnotic. In addition, experimental studies in animals have demonstra temazepam can produce physical dependence. have limited reinforcing capacity indicative of low dependence potential. (b) There is sufficient e spectrum of action to diazepam to predict that temazepam is likely to be abused constitute public health and social problem warranting the placing of the subst international control. In addiriod, evidence, as revealed by clinical reports and epidemiological S presented dervlonstrating actual abase of terhazepam. Bearing in mind the m and sedat ive/hypnot ic aged temazepattl be included in S e following conc lusions 1. a state of dependence as predicted by its chemical which it shares specific receptor mediated action as an sedative hypnotic. 2. cenrra t nezvous system depression resulti behaviour and mood, demostrated by animal and changes in behaviour and mood. (b) There is sufficient evidence of similarity in chemical spectrum of action to diazepam to predict that tetrazepam i constitute public health and social problem warranting the p international control. No evidence of actual 4.36 Tibezonium The group re.ached the following conclusions benzodiazepine. It is used as an anti-bacterial agent.

21 MNH/83.2-8,' page. 21 g cone lusions ence, as revealed by clinical reports and epid g actual abuse of triazolam.

22 MNH/83.28 page RECOMMENDATIONS 5.1 Considerations of future programmes Reference is made to the recommendations for future review contained in the the Seventh Review (March 1983 MNH/83.7). At the review meeting to be held in M amphetamine-like drugs not currently under international control, will be review subsequent reviews will consider uncontrolled barbiturates WHO'S Programme for Pain Relief in Cancer: The WHO programme for pain relief in cancer should have close collaboration the future. The current use of analgesics and the relation of therapeutic use to analgesics should be monitored Drugs to be considered for future review As stated in the report 05 the Seventh Review of Psych International Control (MM1/83.7), the following list of top future review meetings: (a) Derivatives and congeners of tetrahydrocannabinols with regard to their potential, abuse liability and therapeutic usefulness. scheduling under both the 1961 (d) Sedative, hypnotic and a including benzadiazepine-like (a) midazolam (b) zopiclone (c) etifqxine (d) propizepine (e) quazipam ( 1 to isopam Although the above drugs were not formally considered at the discussed the results of certain pre-clinical studies which sugge their dependence potential should be carried out by' WHO. Precursors and intermediates of drugs listed in S Antipsychotic and ant The group recornended develop and implement in-d on the relationship of the manufacture illicit availa international control of S

23 ta on the dependence e of the compounds one of $his group and commendat ions. n on substances considers that it and humans be made a choact ive 4rugs. onset of pharmacologic actions otency. nt ial arcing effects iminative stimulus effects oss-physical dependence potential physical dependence potential as indicated by abstinence or precipitated wal. egorieation of subjective effects relativecto prototype nforcing effects Clinical data on dependence and public health problems rawal syndrome ological dependence ity on emergency room treatment attributable to drug ingestion alence of drug-related diagnoses and admissions y data from death records, both forensic and non-f orensic traffic and other accidents specifically related to drug administration. heal rest data for drug violations izure data ta on drug-related crime or theft among drug abusers ug-related behaviour of drug abusers, e.g., use of other compounds, aggressive or violent behaviour xicity data from forensic death records

24 ~NHJ83.28 page 24 chronic abuser Utilization and usefulness (a) Representative data on the prevalence, duration and patterns of particular, shifts and trends in prevalence and patterns of U (b) Data on physician prescribing behaviour that bear on the extent, appropriateness of medical practices. (c) Data on the volume of presctibing, production and sales. Preview WflO reports have described the methods which would be useful information (WHO Technical Report Series, Nos 618 and 656). a recommendation. 6. ACKNOWLEDGEMENTS WHO acknowledges

25 List of participants tra- SA ina Departement de phanoacologie c 5010 Paris, France nam, Director, Natio earsh Centre, University Sains, on, Department of Psychiatry, Borgarspitalinn, r, Director, Drug Dependence Res Chicago, 950 East 59th Sfreet, r, Preclinical Research Laboratories, Central Xnstifute for qtal Animals, Kawasaki, Japan ( W i

26 MNHl83.28 page 26 International Narcotics Control Board Professor Bror Rexed, M.D., F.R.C.P., Thomas Heftyes Gate 14C, Oslo 2, Norway United Nations Fund for Drug Abuse Control Mr Hans Emblad, Assistant Executive Director, UN Fund for Drug Abuse Control, International Centre, Vienna, Austria - ienna International Criminal Police organization Mr H. France de Fine. International Criminal Police Oreanization..- E rue Armeneaud. ~aint-~lni~d.?>g ' International Council on Alcohol Addict ion 6. Dr P.H. Connell, Director, Drug Dependence Clinical Research and Treatment Unit, The Maudsley Hospital, Denmark Hi1 l, London, England Committee on Problems of Drug Dependence Dr C.P. O'Brien, Professor and Chief, Psychiatry Service, Veterans Administration Centre, University of Pennsylvania, Philadelphia, PA 19104, USA International Union of Phannacdlogy Dr J.M. Gaillard, Chief, Research Department, Psychiatric Clinic of the University Geneva, Geneva, Switzerland WHO COLLABORATING CENTRES National Institute of Drug Abuse ltpa t Director for MedicaI Affairs, National Institute of Drug ~bu$ ducation and Welfare, 5600 Fishers Lane, Rockville, Maryland 201 Mr Allen Duncan, Deputy Associate Commissioner for Health Affairs, Pood and Dfu ~dminis tration. Department of Health. Education and WPTF~VP 5600 Fi char- T S ~ D - Maryland 20857; USA Addiction Research Foundation Dr U. Busto, Senior Researcher, Clinical Pharmacology ddiction Research ~oundation, 33, Russell Street, Toronto, Canada Institute Mexicano de Psiquiatria, Mexico* Health Research Institute, Chulangkorn University, Bangkok, Thailand* National Drug Dependence Clioical Research Centre, University Sains, Penaq, Malaysi V. Navaratnam (Temporary Adviser) :ed but unable to attend

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28 Annex 2 MNH/~~.28 page 28

29 ~N~ page 29