Alexander DeLuca, M.D.
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Disulfiram for alcohol abuse:
Why is such an effective drug so under-prescribed?

by Colin Brewer - Medical Director, The Stapleford Centre,  London. Primary Care in the New NHS ; Autumn 2001;  227-231. Originally posted: 11/19/.2004; [www.doctordeluca.com/Library/AddictionMeds/WhyDisulfiramIsUnderused01.htm].


Imagine the following situation.  The cardiology services in your area are run by a consultant who believes that ischaemic heart disease is not so much a medical issue as a moral or - as he prefers to call it - a "spiritual" one.  He was once famous for his love of food and - unusually for a physician - he smoked 30 cigarettes a day but when he got his first myocardial infarct, he took the hint very seriously.  As well as stopping smoking, he lost four stone, became a regular at his local gym and cycled to the hospital come rain or shine.  His new slim-line figure is as much remarked on as his new vice-like handshake.  Certainly, his cardiac risk factors are a lot lower than they used to be and he reckons that if he can do it, so can everyone else.  Consequently, he hardly ever prescribes medication, preferring exhortations about the healthy life.  He won't even prescribe Xenical for those who are seriously trying to lose their excess weight.  This endears him to a small minority of his patients who get a little thrill out of being harangued about their weaknesses by a charismatic member of the upper middle classes.

Substitute "alcoholism" for "cardiology" and you have a fairly accurate description of many NHS and most private or charitable alcoholism services.  The NHS ones may provide a few beds for detoxifying the more moribund (or in some cases, the more articulate) drinkers but their outpatient services are almost a medicine-free zone where the treatment is entirely psychological and where those who fail are clearly not trying hard enough.  The philosophy of treatment is based either on the ‘Twelve Steps’ of AA or on various sorts of counselling. (Cognitive-behavioural models are popular.)  Some of the less hidebound services are willing to use acamprosate which has to be taken three times a day and costs the NHS about £49 for a month's supply but if you suggest that they might consider using disulfiram (Antabuse) which costs about £15, out come the garlic and the mirrors.  The better informed ones may remark that since it was introduced over 50 years ago, it obviously can't be any good. 

Like many useful drugs, disulfiram was discovered by accident.  During and shortly after the war, Denmark had a scabies epidemic.  Among other things, disulfiram is an anti-helminthic and acaricide.  (Its analogue monosulfiram is still used for the latter purpose.)  Two Danish scientists were studying it for these properties and after testing it out on a few rats, took some themselves.  The next day, both of them discovered that they had had the same unpleasant reaction when they drank  their usual glass of Carlsberg with dinner.  They tested it out on an unsuspecting colleague just to make sure and the rest is history.  Except that few drugs have been so short-changed by their researchers who, with a few honourable exceptions, have managed to ignore one of the most important facts about it.

The function of disulfiram is to deter drinking by the threat - and sometimes the actuality - of an unpleasant reaction if alcohol is consumed.  It is an effective drug in the sense that it will reliably produce this effect in most patients who take it.  As with all drugs, some patients need a larger dose than others to produce the effect but there are not many in whom the intended effect does not occur at all, which is more than can be said for quite a lot of other drugs.

One myth about disulfiram is that it has something to do with aversion therapy.  Aversion therapy is not much used these days but the principle is that you repeatedly combine the rehearsal of some particular undesired thought or behaviour – drinking alcohol or sexually abusing children, for example - with an unpleasant stimulus such as an electric shock or a distressing image.  Or making people drink while taking Antabuse until they feel ill. However, although disulfiram was used in this way in its early days by a few researchers, I don’t know of anyone who has done so in the last 30 years.

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In reality, disulfiram is a deterrent and it deters drinking in just the same way, and just as effectively, as seeing a police car in your driving mirror deters speeding.  Unfortunately, many help-seeking alcoholics (a word I use here to cover all varieties of problem drinker from the mildest to the most serious) find it impossible to stop drinking in the real world even for a day or two.  They know they should stop drinking but such is the force of habit that they just keep doing what they have always done, especially if there are social or psychological pressures on them to continue drinking.  

Disulfiram is a comparatively long acting drug.  Its main action is to inhibit acetaldehyde dehyrogenase (ALDH) leading to much higher levels of acetaldehyde than are normally present during drinking.  This causes the facial flushing, throbbing headache, nausea and sometimes vomiting which characterise the disulfiram-alcohol reaction.  (Genetically determined ALDH deficiency is common in Japan and protects against alcohol abuse.  In homozygotes for the condition, alcohol abuse is apparently never seen.)  The alcohol-sensitising effect continues not just while disulfiram remains in the blood but until new ALDH is produced.  This process can take anything up to a week or more so that unlike acamprosate, disulfiram doesn't have to be taken every day.  Thrice or even twice weekly dosage may be adequate.

However, like all drugs, disulfiram doesn't work if it isn't taken.  Since it is typical of alcoholics coming for treatment that they are very ambivalent about giving up alcohol, even for a while, it follows very naturally that they are equally ambivalent about taking a drug like disulfiram which effectively prevents them from drinking.  If you simply say to an alcoholic patient: "take disulfiram regularly and it will help you to resist temptation", in most cases, the disulfiram stays in its bottle.  Quite often, the bottle is never opened even for the initial dose.  The small number of patients who take disulfiram regularly on their own initiative are usually the sort of compliant patients who do well with any kind of treatment.  Consequently, it should cause no surprise at all that when disulfiram is given in this fashion, controlled trials usually show no significant benefit over placebo medication.

But hang on a moment. Aren’t there are quite a few other conditions in which patients commonly show poor compliance with an effective pharmacological treatment? (Answer: yes, of course there are.) And we don’t usually conclude in these conditions that the answer is to abandon the treatment altogether.  What we usually do is to try to find ways of improving compliance.  In some cases, we can do this with depot injections, as with anti-psychotics and contraceptives.  In other cases, we try to find a formulation which only requires daily or weekly dosing rather than three or four times daily.  Very often, we involve some third party – a family member or a community nurse - in seeing that the medication is actually taken.  This is routine with the very young and the very old and it ought to be routine with disulfiram. 

If we examine only those studies in which disulfiram was given under supervision as part of the treatment programme, what we find is that out of 13 controlled and 5 uncontrolled studies, all but one are positive, and often very strongly positive.  These studies are displayed in Table 1   

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[Insert Table One here]

(To save space, references are largely restricted to these trials.  Full references are given in the original paper on which this article is based (Brewer et al) [20

In any other area of medicine where there were so many controlled studies giving positive results for a medication and only one controlled study giving a negative finding, it would be game, set and match.  Especially if it turned out that in the only negative study, supervision of the disulfiram didn’t actually occur because the patients were skid row alcoholics who didn’t turn up at the clinic for their medication and the sanctions which theoretically existed for non-compliance were never applied.

An interesting and ironic feature about many of these studies is that they were conducted not by physicians, who might be expected to be biased in favour of pharmacological approaches to alcoholism treatment, but by clinical psychologists.  One of them, Professor Nathan Azrin, has gone to the trouble of setting out in detail exactly how the important business of supervision should be carried out.  His most important conclusions are that the person doing the supervising should be someone that the patient has regular contact with and that disulfiram should never be given in tablet form because many patients will pretend to swallow it and then spit it out the moment the supervisor’s back is turned.  Disulfiram should always be taken dissolved or suspended in water, which is very easy because it rapidly breaks up rather like dispersible aspirin. 

The supervisor can be a family member, provided that this is agreed beforehand and that it is also agreed that the family member can report any non-compliance to whoever is in charge of treatment.  This greatly increases the incentive to comply because it’s a fortunate fact of medical life that patients will often do things for their doctor that they won’t do for themselves or their family.  However, disulfiram can also be supervised during attendance at outpatient clinics, by hostel staff in the case of alcoholics living in hostels or rehabilitation centres, or by community nurses.  In the case of the randomised controlled study by Azrin et al, we are talking about abstinence rates approaching 100% at six months compared with 50% in a traditional AA-based outpatient programme.  After six-months of disulfiram-assisted abstinence, many patients will have got used to not drinking and will continue to abstain, or will resume drinking at much lower levels, if disulfiram is discontinued.  And if they are abstinent on disulfiram, they are much more likely to turn up for counselling and other psychological interventions where indicated, and to benefit from them. Like drinking too much, not drinking can also become a habit if practised often enough in real life.

So why is there so much opposition to the use of disulfiram?  There are several reasons but simple ignorance of the literature is the main one.  Even some academics who ought to know better keep spouting the canard that controlled trials show no benefit.  As Table 1 makes clear, this doesn’t apply to supervised disulfiram, which is highly effective.  Actually, many of the real international medical heavyweights in alcoholism research – people like Jonathan Chick in Scotland, Otto Lesch in Austria, Flavio Poldrugo in Italy, Mats Berglund in Sweden and Marc Galanter in the US – use disulfiram extensively in their clinical practice.  Some clinicians accept the evidence that supervised administration is the key to success but object that supervision can cause arguments. To which the answer is that of course it can, but not half as many as further episodes of drunken loutishness.

Excessive fear of side-effects is another reason.  The disulfiram-alcohol reaction can be severe but actual fatalities seem to be very rare (none in my experience) which is more than you can say about unchecked alcohol abuse.  Many potential prescribers seem to believe that disulfiram is a hepatotoxic drug which therefore ought not to be used in alcoholics with elevated LFTs.  In reality, apart from a very rare idiosyncratic hepatitis occurring about once in 25,000 patient years (I’ve never seen a case myself in over 30 years of prescribing) disulfiram actually protects against alcoholic liver disease and isn’t contra-indicated even in cirrhosis.  Rashes are uncommon and mostly due to the activation of nickel dermatitis though paradoxically, disulfiram is used in dermatology to treat resistant cases by chelating the nickel.   Neuropathy is seen occasionally but is dose-related and nearly always reversible, especially if detected early. Patients can and should be informed of possible side-effects and warned – as with any drug – to report possible adverse reactions promptly.  I repeat: compared with the toxicity of alcohol, the toxicity of disulfiram is trivial.

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Disulfiram is a very under-advertised drug in Britain., probably because it’s so old. Indeed, I’m not sure that I’ve ever seen an Antabuse advert in any British journal, though they’re common enough in Spain and  the US. I believe there was at one time some official discouragement of disulfiram advertisements from the DoH, even though one the leaflets put out by that same DoH urged GPs not to forget supervised disulfiram as one of the treatment options. (And no: I didn’t write the leaflet myself.)

The last of the reasons is ideology. Let’s return to our imaginary – but sadly, not unimaginable - consultant, because consultants often set the tone for treatment in their area. As I pointed out in 1995, large differences continued to exist between neighbouring regions in the availability of NHS abortion nearly 30 years after the Abortion Act[21].  Similar discrepancies existed – and probably still do – in the availability of methadone maintenance, the best documented medical intervention in heroin abuse. These discrepancies occur because both sex and drugs are moral issues as well as medical ones and few of us are immune to moral considerations. They certainly apply to our favourite drug – alcohol.

Despite numerous official proclamations that alcoholism is a ‘disease’, many people feel uncomfortable with that view. Many doctors don’t like treating alcoholics, partly because they believe that there isn’t much they can do as doctors and partly because they feel that ‘they brought it on themselves’. Personally, I don’t really mind how we categorise alcoholism. What interests me much more is whether as doctors, we have any effective interventions to offer. After all, I don’t suppose many doctors regard unwanted pregnancy as a disease either, yet few refuse to offer the numerous highly effective medical interventions that exist in this field.  However, some do refuse and they have their equivalents in addiction treatment. Some doctors think that the answer to unwanted pregnancy is for girls (and of course, boys) to abjure lust and start being ‘good’. Other  doctors think that the answer to alcoholism is not drugs which can help alcoholics to drink less or abstain but some kind of existential or ‘spiritual’ renaissance which will entirely change their attitude to alcohol and to life. For these doctors, AA is not only the best but often the only treatment. The fact that on AA’s own figures, the drop-out rate is around 95% doesn’t deter them.

Private clinics like the AA approach too. It means they can staff their treatment programmes with ex-patients who don’t mind being paid peanuts because they are now ‘therapists’ and can ‘confront’ the clinic’s patients just as they themselves were ‘confronted’ when they were patients.  These AA-brainwashed therapists usually know nothing of other psychological approaches to alcoholism, let alone medical ones. Indeed, they are often hostile to disulfiram and other drugs because it means letting the doctors into their patch.  Private psychiatrists often collude with this arrangement because although they don’t have to spend much time with their patients (we mustn’t interfere with the mysteries of the counselling process) BUPA still pays them £45 a day.  Disulfiram is an out-patient treatment par excellence.  Naturally, it is rarely mentioned in clinics which make their money mainly by putting bums on beds.

Newer drugs like acamprosate and naltrexone also have a place in alcoholism treatment. I would like to believe that they are more effective as well as newer but although no RCT of disulfiram vs acamprosate has been done, the evidence favours disulfiram.  For naltrexone, the message is pretty clear: supervised disulfiram wins hands down.  Disulfiram is certainly an old drug but to paraphrase Mark Twain, reports of its death are premature.

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References

1. BOURNE PG, ALFORD JA & BOWCOCK JZ. Treatment of skid-row alcoholics with Disulfiram Quarterly Journal of Studies on Alcohol 1966;27:42-.48.

2.  GALLANT DM, BISHOP MP FAULKNER MA et al.  A comparative evaluation of compulsory (group therapy and/or antabuse) and voluntary treatment of the chronic alcoholic municipal court offender, Psychosomatics 1968;9:306-10

3.  LIEBSON I & FAILLACE LA.  The pharmacological reinforcement of disulfiram – maintenance in chronic alcoholism.  NIDA Research Monograph 1971 pp 1266-1273

4.  HAYNES SN.  Contingency management in a municipally administered Antabuse program for alcoholics. Journal of Behaviour Therapy and Experimental Psychiatry 1973;4:31-32.

5.  GERREIN JR, ROSENBERG CM & MANOHAR V.  Disulfiram maintenance in outpatient treatment of alcoholism. Archives of General Psychiatry 1973;28:798-802.

6.  AZRIN NH.  Improvements in the community reinforcement approach to alcoholism.  Behaviour Research and Therapy 1976;14:339-348.

7.  LIEBSON I, BIGELOW G & FLAME.  Alcoholism among methadone patients: a specific treatment method. American Journal of Psychiatry 1973;130:483-485

8.  ROBICHAUD C, STRICKLER D, BIGELOW G & LIEBSON I.  Disulfiram maintenance employee alcoholism treatment: a three-phase evaluation.  Behaviour Research & Therapy 1979;14:618-21.

9. AZRIN NH, SISSONS RW, MEYER RJ, & GODLEY M. Alcoholism treatment by disulfiram and community reinforcement therapy.  J Behaviour Therapy  Exp Psychiat 1982;13:105-12.

10  BREWER C, SMITH J.  Probation-linked supervised disulfiram in the treatment of habitual drunken offenders: results of a  pilot study.  British Medical Journal 1983;287:1282-83.

11. KEANE TM. FOY DW, NUNN B et al.  Spouse contracting to increase Antabuse compliance in alcoholic veterans.  J. Clinical Psychology 1984;40:340-344.

12. SERENY G, SHARMA V, HOLT J & GORDIS E.  Mandatory supervised Antabuse therapy in an out-patient alcoholism program: a study. Alcoholism: Clinical and Experimental Research 1986;10:290-292.

13.  CHICK J, GOUGH K, FALKOWSKI W et al.  Disulfiram treatment of alcoholism.  Br J Psychiat 1992;161:84-89.

14. GERBER M, JOYCE CRB, CHRISTEN A, DUDLE U, DUSS I, WIDLER P, FISCH HU.  Disulfiram Administered By a Trustee Improves Quality of Life (QoL) in Alcoholic Outpatients.  European Psychiatry. 1994;9:184

15. BREWER C.  Attitudes to abortion, methadone maintenance and humane opiate withdrawal among health professionals: a depressing analogy. Addiction Research 1995;3:i-v (Editorial)

16. BESSON J, AEBY F, KASAS A et al  Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study.  Alcoholism - Clinical and Experimental Research 1998;22:573-579.

17.  CARROLL  KM, ZIEDONIS D, O’MALLEYet al. Pharmacologic interventions for abusers of alcohol and cocaine: a pilot study of disulfiram versus naltrexone.  American Journal on the Addictions 1993;2:77-79

18.  CARROLL KM, NICH C, BALL SA, McCANCE E. & ROUNSAVILE B J.  Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram.  Addiction  1998;93 (5), 713-728.

19.  TØNNESEN H, ROSENBERG J, NIELSEN H et al  Effect of preoperative abstinence on poor postoperative outcome in alcohol misusers: randomised controlled trial.  BMJ 1999;318:1311-6.

20. BREWER C, MEYERS RJ, JOHNSEN J.  Does disulfiram help to prevent relapse in alcohol abuse?  CNS Drugs 2000;14:329-341

21. BREWER C.  Attitudes to abortion, methadone maintenance and humane opiate withdrawal among health professionals: a depressing analogy. Addiction Research 1995;3:i-v (Editorial)

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Addiction, Pain, and Public Health website

Alexander DeLuca, M.D.

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Originally posted:  11/19/2004

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