Apomorphine Versus Addiction

Literature Review

Apomorphine as a Treatment for Alcoholism:

A Review of the Available Evidence

27.03. 2012

Luke Ridley MSc

 

Introduction

Apomorphine was discovered in 1869 by A. Mattiessen and Charles Alder Wright; morphine was heated with concentrated hydrochloric acid and resulting compound was named apomorphine. Its most immediate and obvious use was as an emetic, as it induced sustained and powerful vomiting. It was this property which led to its widespread use as an aversive agent in aversion therapy, most notably for the treatment of alcoholism, as it was believed the direct association between the act of vomiting and ingestion would be particularly effective. However, “direct” aversion therapy fell out of favour gradually from the 1930s onwards and, more significantly, many of its practitioners began to claim that apomorphine had a beneficial effect on alcoholics that was entirely independent of its effect as an aversive agent. This article pulls together what is known about apomorphine

The information was gathered from PubMed (searches using keywords “alcoholism”, “apomorphine”, “bromocriptine”, “dopamine agonist”), the Wellcome collection, various books, older offline journals, and personal correspondence. As the data was fairly sparse and often quite old and of varying quality a meta-analysis was felt to be not practical or helpful, so this document remains mostly fairly descriptive.

 

What is Apomorphine

Apomorphine is a d1 and d2-like agonist/partial agonist (Millan 2001). It is normally taken by sublingual tablet or injection, although an inhalable form has recently been developed (VR040) and it is possible to formulate effervescent swallowable tablets with moderate effect. It is an exceptionally well-studied drug and its side effects are very well understood – it has been in use since the late 19th century.

Long-term use of apomorphine, as in treatment for Parkinson’s, is associated with mild to moderate adverse effects such as nausea and vomiting, dyskinesia, dizziness, somnolence, hallucination and yawning (LeWitt et al. 2009). Although there have been reports of addiction to

apomorphine (Carlos Tellez et al. 2006), it is exceptionally rare. Short-term use of a few weeks is mostly only accompanied by nausea/vomiting if administered in high doses. 

Mechanism

One of the brain systems believed to be significantly altered in alcoholism is the dopaminergic (DA) system. Particularly implicated in most cases is the mesolimbic reward pathway (Noble 1996, Pierce 2006) for a wide variety of drugs. Alcohol addiction is no exception – particularly the ventral tegmental area (VTA).

Dopamine binds to several different receptors, ranging from d1 to d5 with various subtypes, which are normally divided into 2 main categories: the d1 (d1, d5) and d2-like (d2-4) receptors.  Both d1 and d2-like receptors are involved in mechanisms of addiction (Gonzales 2004), although it is difficult to disentangle particular elements of addictive behaviour from the receptors due to the difficulty of synthesising receptor-subtype specific agonists.

As this is a reward pathway, its long-term behaviour is tied up with the expectation of reward. PETstudies reveal that alcoholics have reduced dopamine d2 receptor availability when compared to healthy controls (Volkow et al 2002). Another way to assess this is with the use of the apomorphine Challenge Test (where apomorphine is administered and growth hormone levels monitored to check for dopaminergic function) – which consistently reports reduced dopaminergic sensitivity in alcoholics.

Therefore a logical response might be to use dopamine receptor agonists to boost dopaminergic activity in addicts in the hope of setting right the dysfunction. Given the role the system seems to play, it is reasonable to expect that this approach would have an effect on the reward-seeking element of addictive behaviour – craving. As Heidbreder et al. (2009) note:

“The role of mesolimbic DA in general reinforcement processes clearly pointed towards DA receptors as potential targets for the study of drug consumption and craving.”

However, it is likely that all of the receptor subtypes d2-4 are involved in alcoholism. Polymorphisms in DRD4 affect the craving-altering response of olanzapine (Kranzler & Edenberg 2010) and various partial d3 agonists and antagonists possibly have addiction-related effects (see discussion in Heidbreder et al. 2005).

In practice, the relationship is more complex. Both agonists and antagonists can reduce preference for alcohol in rats (Tupala & Tiihonen 2004); moreover, responses are often dose-dependent. While the exact nature of the relationship is difficult to establish, it is sufficient for the purposes of this paper to say that apomorphine is certainly a credible possibility for the treatment of addiction. It acts on areas known to be implicated and has the types of effects one would expect.

Tupala and Tiihonen note in their review:

“Although full D2 agonists have been reported to be successful in the treatment of alcoholism, they have not been proved successful enough in clinical practise, perhaps due to difficult monitoring or side effects. However, because the level of D2 receptors among alcoholics is only ~20% lower (compared to that of over 80% among Parkinsonian patients), a better way to approach the issue could be the use of partial agonists.”

Apomorphine is a partial agonist at d2-d4, making it a candidate for just such an approach.

Apomorphine also acts as a facilitator of conditioned responses. Troncoso et al. (2003) showed that apomorphine enhanced conditional responses to aversive stimulation in a dose-dependent fashion, and was inhibited by chlorpromazine. This is worth bearing in mind when looking at the treatment protocols Dent and Feldmann used (see next section).

It is also worth mentioning bromocriptine, another dopamine agonist which has been trialled (mostly successfully, (Dongier 1991, Borg 1981, 83)) on similar grounds – restoring dopaminergic activity. Indeed, the early users of bromocriptine as an addiction treatment mention it as being analogous in action to apomorphine, albeit with extra effects on noradrenaline metabolism.

 

Clinical Experience

In practice there were several medical practitioners using apomorphine before any of the controlled studies were performed. One of the earliest was the English Doctor John Yerbury Dent who started using apomorphine in an aversive capacity in the 1930s, preferring it to emetine as it helped the patients sleep, publishing his first results in the British Journal of Inebriety in 1934 (Feldmann 1955). However, he had successes in cases where aversion was unlikely to have been the full explanation; patients lacking a sense of taste or smell, or who did not vomit responded well to his treatment. He became a leading proponent of the use of apomorphine, claiming a 60-70% success rate, with success being abstinence (although it is unclear how consistently or for how long he followed his patients – see Appendix 1: Dent Case Studies).

His treatment protocol consisted of regular doses of apomorphine (starting at 1/40th of a grain, then ramping up until the patient vomits) given in conjunction with alcohol , water and vitamin B. After roughly 2 days the alcohol was phased out and replaced by soft drinks (Dent 1961).  After Vomiting was frequently, but not always, observed. Although he claimed his method was mainly non-aversive, it was still unpleasant and the simultaneous administration of apomorphine and alcohol together suggests that some aversion probably still took place.

Meanwhile a Swiss doctor in Geneva, Harry Feldmann, had performed apomorphine treatment on 2680 patients by 1955. Feldmann’s protocol, like Dent’s, involved the simultaneous administration of alcohol and apomorphine, with gradually decreasing doses given every 2 hours as long as the patient continued to drink. The first dose, 1/10th of a grain (roughly 6.5mg), normally induced vomiting, and the dose would be reduced to 1/16th until the patient refused to drink. Once the patient refused, he would be given hourly injections of 1/16th-1/30th of a grain for 8 hours.

The manner in which the initial success of this treatment was measured – “when vomiting or disgust manifest themselves immediately” (Feldmann 1955) – indicates that this treatment was definitely partially aversive. However, Feldmann also observed that the patients appeared to be more “pervious” to adjunct psychotherapy and believed that the effect of apomorphine was a lot “deeper” than aversion by other aversive agents. His long term observations reported that 42.9% of those who had gone through his program were counted as successes, although he counted those who drank moderately as successes.

He also treated “ambulatory” (outpatients) patients using apomorphine hydrochloride pills (Feldmann 1959). He did not administer alcohol this time, merely giving increasing doses of 1/20th grain apomorphine orally every 2 hours until nausea was reached. Then he would reduce this dose by 1 tablet, then continue with that dose every 2 hours until nausea was reached (due to the increased susceptibility to nausea of habituation to apomorphine), reducing the dose by one more pill, and continuing onwards until the patient was rendered nauseous by simply one pill. The patients were seen every 2 days for checkups and to check their doses. In some cases, the patients reported that they no longer desired alcohol, or it positively made them feel sick (curious given that this is not a directly aversive method).

From a group of 250 alcoholics, tracked over 2 years, 106 were cured (42.4% success), although some had to have the treatment more than once (36 needed 2 or 3 treatments).

Some time later, from 1957-1964, Moynihan claimed a 70% success rate after 1 year using a variant of the treatment. He started at 3mg of apomorphine and increased by 3mg every 2-3 hours until reaching an emetic dose, with treatment durations stretching from 3 to 19 days.

Finally, Beil & Trojan reported 47% success after 6 months on a group of 55 male German alcoholics in 1977. They tried two different variants of the protocol – one high-intensity, involving infrequent (one per 5-8 hours) high emetic doses of apomorphine, the other more frequent non-emetic doses. The former was found to be more effective.

These clinical examples provide supportive evidence but would not constitute the expectation of modern evidence-based NICE guidelines. However, the main proponents of apomorphine treatment are all dead – it seems that it simply passed into history with its practitioners.

 

Trial Results

So, while a mechanism is credible, what is the evidence from controlled trials?

Schlatter and Lal in 1972 performed a controlled (although possibly not blind) trial using 6mg sublingual tablets administered every 2 hours for 3-4 days. Although a significant number of the 35 patients reported a reduction in craving in comparison to the controls, there was no resultant overall beneficial effect on abstinence.

Jensen (1977) performed a double-blind study comparing apomorphine to placebo and control in 49 individuals (20 being treated with apomorphine). The regime was again a little different – injections on the first day, followed by 14 days of tablets (6 tablets of either 6mg or 18mg strength depending on emesis, at even intervals). There was a significant increase in sober attendance (numbers) among those in the apomorphine group, and more of them remained attendees. Jensen even remarks that it is suitable for out-patient treatment of intoxication, although suggests more research is required. The study did not investigate the possible mechanism or reasons behind its efficacy.

C Carlsson, 1977, had been using 20mg apomorphine clinically for some time to calm intoxicated alcoholics and after seeing the results from Schlatter and Jensen decided a double-blind cross-over study was justified. 20 gamma alcoholics (he was using Jellinek’s system – Gamma alcoholics have tissue tolerance, have lost control of their drinking and physical dependence) were given 20mg of apomorphine 3 times daily over 14 days. Apomorphine was shown to have significant effects on tension, craving, and he notes that there is a nearly significant effect on depression. However, there was no follow-up, as his design was to investigate if it reduced craving in the short term.

Wadstein et al. (1978) performed a randomised double-blind trial on 58 gamma-alcoholics to investigate the effect of apomorphine and L-dopa on alcohol post-intoxication symptoms. This time the mean subemetic apomorphine dose was roughly 90mg (88.5 -+13.3mg) which was administered alongside a placebo and an L-dopa version of the tablet (3 treatment groups) over the course of 3 weeks. There were no significant benefits found over placebo – in fact the apomorphine + L-dopa group were found to have slightly prolonged post-intoxication symptoms.

The most obvious observation about these 4 trials is how variable the treatment protocols were. The doses ranged from 6 to 90mg, with dramatically varying dosage frequencies. As apomorphine displays dose-dependent effects (Corwin 1995, Fornai 2001), it is possible that both too much and too little would reduce its effectiveness, and this could explain some of the variation – Schlatter and Wadstein were testing the lowest and highest doses respectively. It is also unclear how double-blindness was maintained in the case of Wadstein as sensitivity to apomorphine increases, and at least 3 of the apomorphine treated group complained of emesis taking their previously calibrated sub-emetic dose– and none in the placebo group.

It is a curious property of trials relating to treatments for alcoholism that even the “accepted” treatments (naltrexone, acamprosate, quote NICE here clinical guideline 115) have inconsistent trial records (Koob 2009) – and the trials here are no exception. These collected trials are hard to regard as conclusive. They support the craving hypothesis – in both trials where craving was tested, it was found to be significantly lowered. 

 

References

Beil H, Trojan A, The Use of Apomorphine in the Treatment of Alcoholism and other Addictions: Results of a General Practitioner, British Journal of  Addiction 1977 (72) 129-134

Borg, Bromocriptine in the prevention of alcohol abuse, 1983

Budde et al., Serotonin transporter promoter polymorphism and dopaminergic sensitivity in alcoholics, 2010

Buus Jensen S, Christofferson C B, Noerregaard A, Apomorphine in Outpatient Treatment of Alcohol Intoxication and Abstinence: A double-blind study,  British Journal of Addiction, 1977, (72) 325-330

C. Carlsson, P.R. Johansson, B. Gullbergt, A double-blind cross-over study: apomorphine/placebo in chronic alcoholics, 1977, International journal  of clinical pharmacology and biopharmacy, May;15(5):211-3

Dent J Y, Apomorphine Treatment of Addiction, some Recent Developments, The British Journal of Addiction, 1948

Dent J Y, Apomorphine in the Treatment of Anxiety States, with Especial Reference to Alcoholism, The British Journal of Inebriety, 1934 Vol 32 No 2

Dent J Y, Apomorphine in the Treatment of Addiction and Anxiety, The Medical Press, 1961

Dongier et al, Bromocriptine in the Treatment of Alcohol Dependence, 1991

Feldmann H, THE MODERN TREATMENTS OF ALCOHOLISM, with Special Reference to APOMORPHINE, BIOLOGICAL, PSYCHOLOGICAL and Social ASPECTS, British Journal of Addiction to Alcohol & Other Drugs, October 1955, Volume 52, Issue 1-2, pages 7–38

Feldmann H, The Ambulatory Treatment of Alcoholic Addicts: A Study of 250 Cases, British Journal of Addiction to Alcohol & Other Drugs. January 1959, Volume 55, Issue 2, pages 121–128

Gonzales et al, The role of mesolimbic dopamine in the development and maintenance of ethanol reinforcement, 2004

Heidbreder and Newman, Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related  disorders, 2010

Heidbreder et al., The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence, 2005

Heinz et al., Identifying the neural circuitry of alcohol craving and relapse vulnerability, 2009

Kimura &Higuchi, Genetics of alcohol dependence, 2011

Koob G F, Kenneth Lloyd G, Mason B J, Development of Pharmacotherapies for drug addiction: A Rosetta Stone approach, 2009 June Vol. 8 500-515

Kranzler & Edenberg, Pharmacogenetics of Alcohol and Alcohol Dependence Treatment, 2010

Liskow et al., Pharmacological Treatment of Alcohol Intoxication, Withdrawal and Dependence: A Critical Review, 1987

Luciano & Saunders-Pullman, Substance Abuse and Movement Disorders, 2009

Marco Diano, The dopamine hypothesis of drug addiction and its potential therapeutic value, 2011

Martensen-Larsen O., Lock Halvorsen K.A., Apomorphine Revived: Fortified, Prolonged, and Improved Therapeutical Effect, The International Journal of  the Addictions, 1978, 13(3), 475-484

Moynihan N.H   General Practioners Forum Vol. 195, 223, Aug, 1965.  Treatment of Alcoholism in General Practice

Noble, Alcoholism and the dopaminergic system: a review, 1996

Norcross J C, Koocher G P, Fala N C, Wexler H K, What Does Not Work? Expert Consensus on Discredited Treatments in the Addictions, 2010 J Addict Med  2010;4: 174-180

Pierce & Kumerasen, The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse?, 2006

Rogowski et al., Relationship between dopamine D2 receptor-associated responses and operant ethanol self-administration in the rat: a factor  analysis, 2003

Tellez C., Leonor Bustamante M., Pablo T, Pablo V, Addiction to apomorphine: a clinical case-centred discussion, Addiction, 2006 Nov;101(11):1662-5.

Troncoso et al., Apomorphine Enhances Conditioned Reponses Induced by Aversive Stimulation of the Inferior Colliculus, 2003

Tupala & Tiihonen, Dopamine and alcoholism: neurobiological basis of ethanol abuse, 2004

Volkow et al., Addiction: Beyond dopamine reward circuitry, 2010

Wadstein J., Ohlin H, Stenberg P, Effects of Apomorphine and Apomorphine-L-Dopa-carbidopa on Alcohol Post-Intoxication Symptoms, Drug and Alcohol  Dependence, 3(1978)281-287

Wiesbeck et al., Craving for alcohol and dopamine receptor sensitivity in alcohol-dependent men and control subjects, 2000

Wiesbeck et al., Sensation seeking, alcoholism and dopamine activity, 1996

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