The misuse of benzodiazepines.
- Epidemiology and patterns of use
- The potential of different benzodiazepines for misuse and dependence
- The potential for misuse by injecting
- Benzodiazepine dependence and alcohol dependence: the overlap
- Guidelines for management of misuse of non-prescribed benzodiazepines
Epidemiology and patterns of use
The rise in benzodiazepine prescribing in the United Kingdom in the 1960s and 1970s was a development that followed the previous period of prescribing of barbiturates and other sedatives. Concerns about the obvious toxicity of barbiturates, and previously other sedatives, in overdose, together with knowledge of their dependence-inducing characteristics, led to their replacement with the safer benzodiazepines as the commonly prescribed anxiolytic and hypnotic drugs. Case reports of patients who escalated their dose of benzodiazepines above the recommended dose, and who experienced convulsions and confusional states on stopping them, began to appear in the 1970s. (1,2) In the mid-1970s and onward, regulatory bodies in the United Kingdom and United States began to recognize the abuse potential of benzodiazepines even in therapeutic doses. Dependence on benzodiazepines was well described in the early literature on the development of these drugs but surprisingly clinical dependence was not reported in the medical literature until the early 1980s. (3,4)
Dependence on therapeutic doses of prescribed benzodiazepines is covered in this article: anxiolytics and hypnotics. In this article we are concerned with abuse of and dependence on high doses of benzodiazepines.
The upsurge in the drug epidemic in the 1980s was associated with an increase in misuse of hypnosedatives, and in the late 1980s there was a series of reports on the intravenous use of benzodiazepines, in particular temazepam. (5,6) Because benzodiazepines are the most commonly prescribed anxiolytics and hypnotics it is not surprising to find that they are also reported to be commonly misused. However, patterns of misuse vary, from episodic use of non-prescribed medication with up to 15 per cent of young people reporting some experience with benzodiazepines, to continuous high-dose use. Since the mid-1980s there has been a substantial drop in the prescription of benzodiazepines as anxiolytic agents but use as hypnotics has remained relatively steady with the concentration of long-term use being in the elderly population. Changes in prescribing practices are likely to influence diversion of benzodiazepines to the illicit market.
Reports indicate that supra-therapeutic dose misuse and dependence is strongly associated with polydrug and alcohol abuse and dependence. (7,8) This pattern of benzodiazepine misuse and dependence is probably much less common than iatrogenic benzodiazepine dependence. However, it presents a substantial problem to many clinicians in primary care and specialist settings. In particular, high-dose misuse is likely to be associated with ‘doctor shopping' and efforts to extract additional medication on top of that already prescribed. The high doses used present a particular risk because they are often used in combination with other substances such as alcohol, opiates, and stimulants. High doses use may be intermittent in nature (in a ‘binge' pattern), and not associated with dependence (in which case the initiation of a prescription may change a pattern of intermittent binge use to daily dependent use in a manner that entrenches polydrug use; see the section below on guidelines for management.
Drug misusers use benzodiazepines in a non-dependent fashion for a variety of reasons. For example, benzodiazepines may be used to enhance the effects of other drugs (such as boosting the euphoria with heroin), or to alleviate unwanted effects from other drugs (to ‘cushion' the ‘come-down' from cocaine), or to help alleviate withdrawal symptoms when drugs such as heroin are unobtainable, or in attempts at self-detoxification from other drugs. Misuse of benzodiazepines may also arise from injudicious patterns of prescribing for the treatment of alcohol dependence, or from attempts at self-treatment for alcohol dependence. Some drug misusers will also develop a dependent pattern of use of benzodiazepines in their own right. Benzodiazepine dependence may be a factor contributing to poor outcome for patients who are attempting opiate detoxification.
High-dose use is associated with substantial tolerance to the sedating effects of the medication but some of the other effects may not be equivalently protected by tolerance. Thus, some individuals may consume extraordinary high doses, and not appear sedated, but experience profound amnesia for their actions. Such effects of amnesia may also be associated with the reported high rates of risk-taking behaviour, and amnesia may be more pronounced in injecting benzodiazepine users, although there are no good data to confirm this.
The potential of different benzodiazepines for misuse and dependence
In view of the frequency of prescribing of benzodiazepine drugs, it is an important question as to whether some benzodiazepines are more likely to be misused, or to lead to dependence, than others. The similarities between different benzodiazepines are much greater than the differences. Patients may maintain that they need a specific named benzodiazepine, but there is marked cross-tolerance, and patients changed to an equivalent dose of a different benzodiazepine under double-blind conditions show almost complete cross-dependence (i.e. no difference in withdrawal symptoms from those whose medication has been unchanged). (9) However, this cross-dependence was shown for patients who were already benzodiazepine dependent. It is possible that the properties of certain benzodiazepines lead to a stronger motivation for people to desire their effects, to escalate the dose, and to persist with their use.
Factors that have been considered to influence the liability to misuse and development of dependence include the relative potency of the drug, and its elimination half-life. (10) Triazolam, a very short-acting benzodiazepine prescribed for insomnia, was withdrawn from the British market following concerns about the severity of rebound anxiety experienced even after a single dose. Triazolam is a very potent benzodiazepine that binds very readily to benzodiazepine receptors, and experience with its use suggested that it had a more euphoriant effect than other benzodiazepines, resulting in greater potential for misuse and for the development of dependence.
Other benzodiazepines that have high potency and have caused concern include flunitrazepam and lorazepam. Flunitrazepam is relatively rarely prescribed in the United Kingdom, but frequently reported as one of the most common benzodiazepines misused in many European countries and in Australia. It is not marketed in the United States. Concerns about its availability on the illicit market continue. (11,12) It has attracted media attention as a drug used to facilitate ‘date rape'; it is unclear why this particular benzodiazepine should have this image, although it is a potent drug. Lorazepam, also a potent benzodiazepine, is much more widely prescribed in the United Kingdom, and alprazolam is used in the United States.
Some studies suggest that lorazepam and alprazolam may be associated with an earlier and more difficult withdrawal process than diazepam. (9,13) In one European study, triazolam and lorazepam were found to feature more highly among individuals dependent on high doses of benzodiazepine drugs than among those dependent on low or ‘therapeutic' doses. (14) In summary, it appears that potency is a contributory factor in the abuse and dependence-inducing potential of benzodiazepine drugs. However, this picture is somewhat complicated by the fact that drugs such as lorazepam tend to have been marketed at higher equivalent doses than some other benzodiazepines. The elimination half-life influences the nature of withdrawal; if it is short, withdrawal symptoms appear more rapidly and may appear more severe, although withdrawal of more insidious onset in longer-acting benzodiazepines may be just as problematic.
As well as properties of the drugs themselves, the abuse potential of different benzodiazepines is also associated with broader prescribing patterns which affect the potential for diversion to illicit market. Diazepam and temazepam have been the most widely prescribed benzodiazepines in the United Kingdom, and are therefore the most likely to be encountered by drug misusers and problem drinkers. Drugs such as clonazepam which tend to be prescribed much less widely, and generally for epilepsy rather than for anxiety or insomnia, seem infrequently to raise concerns about misuse. (10) In other parts of Europe where flunitrazepam is more commonly prescribed, there are reports of its high levels of abuse among the illicit drug-using population.
The potential for misuse by injecting
Drugs such as temazepam and flunitrazepam are more frequently reported to be injected. (7) There are a number of factors that may influence this. These include the availability of the drug, its short-acting nature, and also the formulation of the drug. In the 1980s temazepam was marketed as a liquid-filled capsule, which enabled easy extraction of the contents to put into a syringe for injecting. The later gel formulation was also injected, by heating to liquidize the gel, resulting in very damaging injecting complications. Some medications that come in easily soluble form can also be converted into a form for injecting, such as liquid diazepam.
The injection of benzodiazepine drugs is associated with substantially more harmful drug misuse in a number of respects, (15) with increased rates of reported sharing of injecting equipment,(9,16) increased risks of overdose, and poorer general health. (8)
Benzodiazepine dependence and alcohol dependence: the overlap
There are high reported rates of alcohol dependence among the homeless, and there are substantial reports of benzodiazepine abuse and dependence in this population also. Cross-tolerance between benzodiazepines and alcohol permits individuals who are alcohol dependent to tolerate high doses of benzodiazepines. Patients may be prescribed benzodiazepines to manage alcohol withdrawal, but injudicious prescribing that is not targeted towards the management of alcohol withdrawal symptoms may result in iatrogenic benzodiazepine dependence.
The extensive research on pharmacological interventions for management of alcohol withdrawal in alcohol-dependent patients has been examined in a meta-analysis by Mayo-Smith, who subsequently produced a systematic review with treatment guidelines. (17) This review supports the use of benzodiazepines as the treatment of choice for managing withdrawal symptoms for patients whose symptoms are of sufficient severity to warrant medication. Alternative agents used in withdrawal, such as chlormethiazole and the barbiturate phenobarbital, are less well-supported by controlled trials than benzodiazepines, and carry higher risks of adverse effects.
The potential for misuse of benzodiazepines must be considered in alcohol-dependent patients. However, this is not an adequate reason for avoiding the use of benzodiazepines in the management of withdrawal in view of their superiority in effectiveness, and possibly in potential for harmful misuse, over other treatments. Benzodiazepines with a slower onset of action, such as chlordiazepoxide, appear to have less potential for misuse. The prolonged use of benzodiazepines in withdrawal is rarely necessary or helpful, and evidence for benefits of ‘substitute prescribing' of benzodiazepines for alcohol users in the longer term is lacking. Use of benzodiazepines to manage phobic and anxiety disorders associated with alcohol dependence should be strenuously avoided.
Guidelines for management of misuse of non-prescribed benzodiazepines
So far, no clear guidelines have been produced for management of this problem. These are a complex group of patients to manage and in general such patients should be referred for specialist assessment.
Assessment should attempt to confirm evidence for benzodiazepine dependence. Assessment over a number of visits should involve obtaining urine specimens to determine objectively the regularity (or intermittent nature) of benzodiazepine consumption. Part of the initial assessment process should identify underlying psychiatric disorders that may have been the trigger for a doctor initiating a prescription or for the patient obtaining drugs for the purpose of self-medication. High levels of psychiatric morbidity have been found among samples of patients with severe benzodiazepine dependence. (18) The commonest conditions are probably anxiety disorders for which anxiolytics have been prescribed injudiciously; however, in some instances major depressive disorders may be treated or self-medicated with benzodiazepines. Thorough assessment should explore for evidence of major depression and if identified, consideration should be given to the use of antidepressant medication combined with cognitive-behavioural therapy.
In the presence of polydrug abuse or dependence, caution needs to be exercised about initiating a prescription for benzodiazepines. Where dependence is established, dose titration should aim to ameliorate withdrawal symptoms rather than to match the large doses of medication that the patient reports consuming. Long-acting benzodiazepines such as diazepam are preferred (see: anxiolytics and hypnotics), and doses should rarely exceed 40 to 60 mg daily. Where large doses are prescribed these should ideally be dispensed on a daily pick-up basis from the community pharmacist. The prescribing doctor should avoid succumbing to pressure from the patient to increase the dose without a thorough dose assessment and evidence of withdrawal symptoms.
Prescriptions issued on a routine ‘repeat' basis should be avoided, and the patient should be informed that lost medication will not be replaced. Requests for replacement medication or additional medication should encourage the doctor to review the overall care plan and to consider stopping the benzodiazepine prescription. Virtually all benzodiazepine prescriptions should be time limited and part of a detoxification plan with gradual reduction over a clearly stated and negotiated time period. Alternatively, inpatient detoxification, perhaps with longer admissions, may be the best course of action where reduction regimens fail in the community setting. Reduction regimens with benzodiazepines are very variable and many clinicians opt for a very gradual withdrawal with small dose reduction at wide intervals. There is no evidence to indicate that such a gradual approach is any more effective than 20 to 25 per cent reductions over a shorter more clearly defined time (such as 6 weeks).
Currently there is no evidence base for long maintenance prescribing of benzodiazepines for those who are high-dose injecting polydrug abusers. However, this intervention has not been subject to any structured evaluation and merits further study in the face of the difficulties of managing such patients.
There is a valuable role for benzodiazepines, and a need for vigilance and care in their use, as well as active recognition and management of those who are dependent. However, there is a need for greater awareness of the risks of polydrug dependence with misuse of high doses of benzodiazepines in conjunction with both alcohol dependence and opiate dependence. Caution needs to be used in assessing patients, and benzodiazepine prescribing should be restricted to those where there is clear evidence of dependence. The risk of synergistic effects with other drugs and consequent overdose should be explained to all patients who are identified as being involved in such behaviour. Community detoxification or inpatient detoxification is the best option based on the evidence of available research and evaluation of current interventions.
1. Woody, G.E., O'sBrien, C.P., and Greenstein, R. (1975). Misuse and abuse of diazepam: an increasingly common medical problem. International Journal of Addiction, 10, 843–8.
2. Bliding, A. (1978). The abuse potential of benzodiazepines with special reference to oxazepam. Acta Psychiatrica Scandinavia Supplementum, 274, 111–16.
3. Petursson, H. and Lader, M.H. (1981). Benzodiazepine dependence. British Journal of Addiction, 76, 133–45.
4. Hallstrom, C. and Lader, M. (1981). Benzodiazepine withdrawal phenomena. International Pharmacopsychiatry, 16, 235–44.
5. Farrell, M. and Strang, J. (1988). Misuse of temazepam. British Medical Journal, 297, 1402.
6. Ruben, S.M. and Morrison, C.L. (1992). Temazepam misuse in a group of injecting drug users. British Journal of Addiction, 87, 1387–92.
7. Strang, J., Seivewright, N., and Farrell, M. (1992). Intravenous and other novel abuses of benzodiazepines: the opening of Pandora's box? British Journal of Addiction, 87, 1373–5.
8. Ross, J., Darke, S., and Hall, W. (1997). Transitions between routes of benzodiazepine administration among heroin users in Sydney. Addiction, 92, 697–705.
9. Murphy, S.M. and Tyrer, P. (1991). A double-blind comparison of the effects of gradual withdrawal of lorazepam, diazepam and bromazepam in benzodiazepine dependence. British Journal of Psychiatry, 158, 511–16.
10. Tyrer, P. (1993). Pharmacological differences in the dependence potential of benzodiazepines. In Benzodiazepine dependence (ed. C. Hallstrom), pp. 77–90. Oxford University Press.
11. Simmons, M.M. and Cupp, M.J. (1998). Use and abuse of flunitrazepam. Annals of Pharmacotherapy, 32, 117–19.
12. Woods, J.H. and Winger, G. (1997). Abuse liability of flunitrazepam. Journal of Clinical Psychopharmacology, 17 (Supplement 2), 1S–57S.
13. Rickels, K., Case, W.G., Schweizer, E.E., et al. (1986). Low dose dependence in chronic benzodiazepine users; a preliminary report on 119 patients. Psychopharmacology Bulletin, 22, 415–17.
14. Martinez-Cano, H., Vela-Bueno, A., De Iceta, M. et al. (1996). Benzodiazepine types in high versus therapeutic dose dependence. Addiction, 91, 1179–86.
15. Darke, S., Hall, W., Ross, M., and Wodak, A. (1992). Benzodiazepine use and HIV risk-taking behaviour among injecting drug users. Drug and Alcohol Dependence, 31, 31–6.
16. Klee, H., Faugier, J., Hayes, C., Boulton, T., and Morris, J. (1990). AIDS-related risk behaviour, polydrug use and temazepam. British Journal of Addiction, 85, 1125–32.
17. Mayo-Smith, M.F. (1997). Pharmacological management of alcohol withdrawal: a meta-analysis and evidence-based practice guideline. Journal of the American Medical Association, 278, 144–50.
18. Busto, U.E., Romach, M.K., and Sellers, E.M. (1996). Multiple drug use and psychiatric comorbidity in patients admitted to the hospital with severe benzodiazepine dependence. Journal of Clinical Psychopharmacology, 16, 51–7.