DISULFIRAM AND ITS ENEMIES

Colin BrewerThe Stapleford Centre

London

Conflict of Interest Statement.

No conflict of interest. My presentation does not advocate the

off-label use of disulfiram. I have no links with any manufacturer or

marketer of disulfiram.

As well as RCTs and Cochrane-type reviews, here’s the killer fact in any argument about DSF.

Alcohol abuse is almost completely unknown among Japanese who are homozygous for ‘inefficient’ ALDH and thus, in effect, have life-long, built-in DSF.

DSF simply turns alcoholic patients, for as long as required, into good imitations of Japanese homozygotes.

In the (very small) handful of ALDH2*/2* homozygous alcohol abusers reported in the literature, the pattern of drinking is unique. They sip rather than drink, typically consume fewer than 5-6 units/day, spread out over the day and drink beer rather than spirits .

Dependence is psychological rather than physical. (Chen et al. 1999)

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Distribution of prevalence of inactive ALDH2

Li et al. Ann Hum Genet 73: 335-45, 2009

Slides showing mild (L) and severe (R) disulfiram-alcohol reaction causing

flushing and hypotension

Good DSF supervision (and instant feedback of defaulting) means good compliance. Result:

Compliant patients are unlikely to drink, even when strongly tempted. If they do drink and get no DSF/ethanol reaction, you increase DSF dose until they stop drinking, get side-effects, or leave treatment because they don’t actually want to stop.

By consistently not drinking when tempted, they learn – by necessity – how to resist temptation and what to do instead of drinking. Eventually, not drinking and alternative behaviour become habitual. This can take up to two years on DSF.

It’s called ‘exposure and response prevention’ in other contexts and it is how DSF works. It uses pharmacology but it’s a psychological treatment.

THIS IS NOT, BASICALLY, A NEW IDEA

‘We become temperate by abstaining from indulgence and we are the better able to abstain from indulgence after we have become temperate.’

ARISTOTLE. (384 – 322 BC) Nichomachean Ethics,

II. (Transl: Thomson, J.A.) Sect. 2. p.95. Penguin edition.

Many first-time alcoholic patients do well whatever treatment they have and even

without treatment. (Edwards et al 1977 ‘Treatment vs Advice’)

However, if ‘treatment’ is needed, there is now Cochrane-standard evidence that supervised DSF plus appropriate psychosocial input is effective - and more effective than similar psychosocial programmes using oral NTX or ACP.

Supervised DSF is therefore indicated for: 1. Patients for whom previous treatment has

failed, especially if it included NTX or ACP. 2. Patients who will be in serious trouble (medical,

legal, domestic, work) if they have an early relapse.

3. Less challenging patients who nevertheless like the idea of DSF treatment.

What the supervisor does. The supervisor is not an ‘enforcer’ but an agent of the physician.

The patient agrees to this arrangement as part of the therapeutic contract since it is simpler than alternatives. Supervisors should encourage compliance but should also immediately inform the physician/therapist about non-compliance etc.

The physician/therapist can then use the therapeutic relationship to try to persuade the patient – directly or by telephone - to adhere to the therapeutic contract.

Since ALDH inhibition usually lasts for several days after the last dose, this allows several days for persuasion, during which the patient cannot escape involvement by getting drunk.

There should be no argument about this but DSF has several enemies, including (1)

The ‘12-step’ movement – not invariably but pretty generally. In Germany, they say: ‘nichts über die zunge’ (‘nothing [ie no medication] over the tongue’).

This is illogical because they also insist that addiction is a ‘disease’, in which case it is appropriate for doctors to be involved and to offer the evidence-based tools of our trade – including medication.

Even if addiction isn’t seen as a disease, medication can still be appropriate. Unwanted pregnancy isn’t a ‘disease’ but most people don’t mind using pharmacology to avoid it.

In any case, Cochrane gives no support to 12-step treatment.

Historical 12-step note The two founders of AA were not anti-doctor.

One of them reportedly relied on barbiturates for sleep and needed doctors to treat his emphysema (caused by smoking - the addiction that eventually killed him).

The ‘Big Book’ of AA specifically states that ‘To take DSF, to go into therapy, to change your job – these are your decisions and we respect them’. Unfortunately, not many people in AA seem to have read that bit.

‘Recovering addicts’ are widely used as cheap labour by 12-step clinics, despite (or because of) their ignorance of other approaches and even of their own ideological history.

Enemies (contd). No 2. Psychologists.

After about 1970, psychologists, counsellors and other un-medical people obtained a significant toe-hold in the world of addiction treatment.

Such people naturally resist surrendering any of their hard-won territory to doctors, of whose prestige (and income) they are often already rather envious or resentful.

They may also resist suggesting treatments that involve some loss of professional autonomy (and, in private practice, of consultation fees as well).

(‘If your only tool is a hammer, all your problems start to look like nails’.)

Enemies: No 3. Influential members of the addiction treatment community. Prof Griffith Edwards claims DSF is “a

unique example of treatment that involves poisoning the patient”. (Alcohol: the ambiguous molecule. Penguin 2000)

Edwards also tried to have probation-linked DSF declared unethical in Britain. (He failed.)

Actually, most medical treatments involve ‘poisoning the patient’: the trick is to achieve an adequate therapeutic effect while minimising the toxicity of the drug in question.

No. 4. Many psychoanalysts, social workers, counsellors and other evidence-phobic mental health professionals.

An ideological tendency to regard all problems as having important childhood origins leads them to see alcohol abuse as merely a ‘symptom’ of an underlying disorder that must be exposed and vanquished (or at least ‘worked through’).

This may sometimes be the case but many psychological and social problems are caused or exacerbated by alcohol abuse. If drinking stops, the problems commonly disappear or become fairly ordinary, manageable aspects of existence.

In any case, their proper assessment and treatment are much easier when patients have been sober for two or three months.

GOOD AND BAD COUNSELLORS. In the Vanderbilt study (Strupp & Hadley

1979) anxious students responded equally well overall, whether they were counselled by interested but untrained faculty members or by trained therapists. This result is consistently found in comparative psychotherapy studies. Furthermore, four-fold differences in outcome and dropout rates between the most effective and the least effective addiction therapists and counsellors were common. (Najavitz and Weiss 1994)

Whereas….

DSF (like NTX for opiates) is always the same molecule and never gets headaches, hangovers, PMT, depression or ‘flu.

Neither does it get burn-out or suffer from rapid staff turnover, or get angry because a colleague doesn’t turn up, leaving it with twice the work and half the time for therapy.

Reduction in counselling time and drinking time when DSF is supervised –

because sober patients have fewer problems.

No. 5. Clinics more interested in making money than in effectiveness or cost-

effectiveness. Private residential clinics make most money by

admitting patients and keeping them in for as long as they can get away with. Their morality is often that of a hotel-owner.

DSF is quintessentially an out-patient treatment. Indeed, the ‘exposure and response-prevention’ component means that residential treatment, away from alcohol cues, would be counter-productive.

Many patients don’t even need admitting for withdrawal.

None of this is welcome news to clinic owners, their full-time employees or regular visiting consultants.

(Contd.) No 6. Big Pharma

DSF is long out of patent and mostly made or marketed by ‘generic’ companies, historically not much interested or involved in funding research.

DSF - cheap and under-prescribed – is comparatively unprofitable.

Funding for ambitious ‘publish or perish’ researchers much more likely from the makers of newer, more profitable products.

Comparatively little advertising and promotion of DSF. In an evidence-based world, this shouldn’t matter much but it all helps to keep DSF below the radar for many practitioners.

7. Ignorance and Fear. Ignorance - many textbooks and reviews

still don’t stress importance of supervision and strong evidence-base.

Fear - of side-effects, especially fulminating hepatitis. Very rare in alcoholism treatment (1:25,000 patient-years) but common (c10%) when DSF used by dermatologists. Incidence F>M, though far fewer female patients.

Reason?

NICKEL SENSITIVITY!

DSF chelates Ni and other heavy metals.

Common cause of dermatitis. Women wear more Ni-plated jewellery

than men (as a rule). Ni is very toxic. Alcoholic fulminant patients sometimes

die, dermatological ones hardly ever. ?Because dermatologists usually

examine their patients and psychiatrists usually don’t.

No. 8. The special case of Dr Zullino Arguments published mainly in Forum Med Suisse/Schweitz

Med Forum. Zullino et al. and Thorens et al. In summary:

1. DSF has no theoretical justification.

2. Its apparent effectiveness compared with purely psychosocial interventions or other drugs such as acamprosate (ACP) and naltrexone (NTX) is an artefact that can be explained without invoking any true pharmacological effects of DSF.

Zullino contd.

3. Because DSF treatment involves the threat of punishment, it is morally unacceptable.

Therefore, the use and marketing of DSF should end – at least in Switzerland but by implication, in the rest of the world as well.

1. “It’s the treatment package including DSF that makes for effectiveness...It’s the ritual of tablet-taking that matters, not the nature of the tablet...To demonstrate the real effect of DSF, one would have to compare a total package including DSF with a similar package not including DSF. So far, this has not been done.” (Zullino et al. Forum Med Suisse, 2010)

But it has been done (Chick et al c.1993) and found to be significantly superior, even when the DSF dose is sub-optimal.

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“The therapeutic object of treatment with DSF is abstinence”

No. It is usually abstinence for a period long enough to change their drinking habits. What they do after that is a matter of discussion and experience but it could be either abstinence or moderation.

Some patients use DSF to achieve controlled or occasional drinking from the start. Control is almost certainly easier to achieve after a period of abstinence, compared with straight after heavy drinking. Some patients take DSF sporadically to help them deal with high-risk situations.

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“‘DSF is a form of deterrence by [the threat of] reprisals. It supposes a rational patient, someone who can make a cost-benefit analysis of his choices, but the inability to behave according to such an analysis is the central element in addiction. If he were able to make a rational choice, he wouldn’t be an addict!”

This is both wrong and patronizing. By the time an alcoholic asks for help, then by definition he accepts that his cost-benefit analysis has been incorrect and that he needs help to change it in a way that involves no (or less) drinking.

 

“Addicts aren’t rational. Deterrence doesn’t work with them”.

Zullino is happy to prescribe NTX for alcohol abuse (because it works on a putative brain mechanism) but not for opiate abuse (because it works through a psychological mechanism – deterrence – of which he disapproves on quasi-moral or philosophical grounds.)

In this respect, his arguments are dangerously close to those used by (some) Catholic gynaecologists who will claim to be prescribing the constituents of oral contraceptives to prevent irregular periods and not to prevent pregnancy.

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DSF deters drinking as speed cameras deter speeding. (NTX deters heroin use not by causing an unpleasant reaction but by preventing a pleasant one.)

The fact that ‘placebo’ speed-cameras can also work is not an argument for abolishing cameras: it’s an argument for optimising their deployment. But they would be ineffective if everyone believed that all speed cameras were ‘placebos’.

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While low-dose ‘quasi placebo’ DSF - or other patients’ reports of an alcohol-DSF reaction - effectively deter many prudent or fearful alcoholic patients, only personal experience of the reaction will persuade some people. Thus, low-dose DSF (as advised by Krampe et al) is not always adequate.

Alcohol challenges – obsolete and unethical or still sometimes indicated?

Maybe Germans are different but in several studies, >20% of patients tested-out the reaction and may need a higher DSF dose for adequate deterrence.

There is still a case for alcohol challenge doses in cases where early relapse would be particularly disastrous.

CONCLUSION

These conceptual, pharmacological, financial, medical, ideological and psychological complexities may explain why DSF is underused and misunderstood but they do not excuse it. Health professionals should be accustomed to complexity.