Is oxazepam a suitable drug for detoxification of benzodiazepine abuse (above all flunitrazepam and

Fråga: Is oxazepam a suitable drug for detoxification of benzodiazepine abuse (above all flunitrazepam and diazepam)?

Sammanfattning: Oxazepam may be used for detoxification treatment schedules in bensodiazepine dependent patients. It may have some advantages for this application compared to other bensodiazepines with higher lipophilia and extensive oxidative metabolism but the ideal drug for this use cannot be defined.

Svar: The capacity of the benzodiazepine drugs to produce dependence and addiction is well known. It has been associated with for example the "liking" properties of the drug (1), the time for onset of effect (the shorter time the greater the risk for dependence) and with the "benzodiazepine withdrawal syndrome". The withdrawal syndrome includes a number of typical symptoms, which start when the concentration of the drug decreases in the tissues. (2). Generally, the higher the dose and the longer the benzodiazepine is taken, the greater the risk of developing withdrawal symptoms. However, withdrawal symptoms may also occur in patients receiving recommended doses and/or short-term therapy (3). There are pharmacological reasons for differences among marketed benzodiazepines in their profiles of effects, including abuse liability. Oxazepam has a number of qualities that could make it suitable to use for detoxification. Oxazepam is metabolized rapidly and has no active metabolites. It has a slower and less peaky distribution into the brain compared to other benzodiazepines (4). A case report describes how oxazepam caused dizziness rather than euphoria in a dependent patient everytime she increased her maintenance dose. Because of this experience she never increased her dose again (5). Furthermore, oxazepam has not been associated with paradoxical aggression (4). Since diazepam is metabolized by oxidative enzymes in the so-called cytochrom P450 system in the liver and oxazepam is not; oxazepam may be a better choice in treating alcohol-dependency/withdrawal, especially in patients taking disulfiram, and in patients with liver disease. It is shown that clearance of diazepam is impaired by disulfiram (6). The metabolism by this oxidative enzyme is geneticallay determined, that is, some people may achieve very high concentrations of diazepam and others very low concentrations, on the same dosage, thus making this interindividual genetic variation crucial for the drug effect as well as for the possible adverse effects. It is also interesting to note that drug utilization data (from the Swedish pharmacies) show that despite the fact that diazepam and oxazepam are used to about the same extent and for the same clinical reasons, diazepam is associated with higher rates of prescription forgeries and theft and loss reports (7).

On the other hand, some information indicates that oxazepam is not a perfect drug for detoxification and some other compounds may be suitable for detoxification. Recent data from a Swedish benzodiazepine detoxification clinic show that the most commonly abused drugs among their patients are, in order: oxazepam, diazepam and lorazepam (8). These data correspond to the purchase data of tranquillizing compounds, where diazepam (42 per cent) and oxazepam (30 per cent) dominate the market (9,10).

It appears that the greater lag time (2-3 days) of the longer-acting benzodiazepines, such as diazepam and flunitrazepam, before onset of withdrawal symptoms, diminishes withdrawal symptoms.

Consequently, it should be an advantage of more longer-acting compounds (such as diazepam) that they have a self-tapering effect which prevents withdrawal phenomena. Accordingly, too rapid a reduction in oxazepam dosage may easily precipitate withdrawal symptoms. Therefore it is strongly recommended that all benzodiazepine therapy, and particularly with short-acting compounds, should be withdrawn gradually. Diazepam is also indicated if the patient is having seizures. A Swedish clinic specialized in benzodiazepine detoxification considers a slow dose reduction of the abused drug to be the best choice. Cross tolerant compounds are not applied (10,11). 1 Griffiths RR, McLeod DR, Bigelow GE, Liebson IA, Roache JD: Relative abuse liability of diazepam and oxazepam: behavioral and subjective dose effects. Psychopharmacology 1984; 84: 147-154 2 Borg S, Blennow G, Sandberg P, Tönne U, Wikander B: Bensodiazepinberoende och andra långtidsbiverkningar - en översikt. Läkartidningen 1986; 83: 321-326 3 Mackinnon GL, Parker WA: Benzodiazepine withdrawal syndrome: a literature review and evaluation. Am J Drug Alcohol Abuse 1982; 9: 19-33 4 Lader MH: The clinical pharmacology of oxazepam. Acta Psychiatr Scand 1978; 274(suppl): 89-93 5 Bliding A: The abuse potential of bensodiazepines with special reference to oxazepam. Acta Psychiatr Scand 1978; 274(suppl): 111-116 6 Ayd FJ Jr: Oxazepam: update 1989. Int Clin Psychopharmacol 1990; 5: 1-15 7 Bergman U, Griffiths RR: Relative abuse of diazepam and oxazepam: prescription forgeries and theft/loss reports in Sweden. Drug Alcohol Depend 1986; 16: 293-301 8 Vikander B, Borg S, Leifman H, Tönne U: Läkemedelsberoende. Öppenvårdsbehandling med stödkontakt och långsam nedtrappning ger gott resultat. Läkartidningen 1993; 90: 579-5872 9 Bergman U: Epidemiologiska aspekter på bruk och missbruk av bensodiazepiner. Hearing om bensodiazepiner. Nytta och risker. Stockholm, december 1991; page 5-15, Socialstyrelsen - Läkemedelsverket 10 Vikander B, Lindroth A, Tönne U, Borg S: Avgiftning av bensodiazepinberoende patienter. Läkartidningen 1987; 84: 3276-3278 11 Personal communication with Dr Gunilla Josephson-Weinert, TUB-enheten, St Görans sjukhus