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Repurposing Apomorphine

Apomorphine as a non-aversive treatment for alcoholism

Luke Ridley, MSc
Andrew J. Lees, FRCP, MD
Principal Clinical Research Associate, UCL
Reta Lila Weston Institute of Neurological Studies, 1 Wakefield Street, London, WC1N 1PJ
Conflicts of Interest: None.

Abstract

Background and Aims: Apomorphine has a chequered history as a treatment for alcoholism. This paper reviews the history of its clinical use and its relation to the role of dopamine in the neurobiology of addiction.

Methods: Search of archival material and Pubmed.

Results: Apomorphine was widely used as a non-aversive treatment for alcoholism, seemingly successfully.

Conclusion: Apomorphine has clinical and theoretical evidence for its use as a treatment for alcoholism, although much of it is old or methodologically flawed. It is a viable target for drug re-purposing.

Early Use in Alcoholism

The medical history of apomorphine in alcoholism begins in 1899 when two American doctors, James Tompkins and Charles Douglas, independently published their observations on its use in the treatment of alcoholics (1). Tompkins injected ‘one tenth of a grain’ [6.5mg] of apomorphine and reported:

‘In four minutes free emesis followed, rigidity gave way to relaxation, excitement to somnolence, and without further medication the patient, who before had been wild and delirious, went off into a quiet sleep.’

Douglas identified two indications for apomorphine (2). Not only did he note its use to treat ‘a paroxysm of dipsomania [an episode of intense alcoholic craving]’, but also:

‘in minute doses it is much more rapidly efficient in stilling the dipsomaniac craving than strychnine or atropine… Four or even 3m [minim – roughly 60 microlitres] of the solution usually checks for some hours the incessant demands of the patient… when he awakes from the apomorphine sleep he may still be demanding alcohol, though he is never then so insistent as before. Accordingly it may be necessary to repeat the dose, and even to continue to give it twice or three times a day. Such repeated doses, however, do not require to be so large: 4 or even 3m is usually sufficient.’

This example, which was published before Pavlov’s discovery of the ‘conditioned reflex’ in 1903, shows the early awareness of the effects of low doses (non-emetic – 1/30 of a grain, 2.16mg, about ‘one-third of the usual emetic dose’) of apomorphine to control craving.

In a short article in the New York Medical Journal Douglas presciently commented (3)

‘In treating the pathology of this disease it is customary to enumerate the abnormalities found in the stomach, liver, bowels, kidneys, etc. But the disease of alcoholism stands quite apart from these ailments. The patient may or may not have gastritis or enteritis or nephritis, but in all cases he will have an abnormal condition of the nervous system that produces either a perpetual or a periodic demand for the drug action of alcohol. Hence alcoholism per se is a disease of the nervous system’.

His final paper in 1910 provides a possible explanation as to why apomorphine had not caught on in the clinic; (4)

‘apomorphine… has always been known as a vigorous emetic, but its remarkable hypnotic properties were unknown to the profession until I published my first paper on the subject in 1899. The year before the publication of this paper a standard materia medica said: “It (apomorphine) is neither hypnotic nor narcotic in any degree. The peculiarities of this drug have led to the publication of many inaccurate statements in standard medical works. The hypnotic action of apomorphine is unlike that of any other hypnotic.”’

The use of apomorphine as a hypnotic in alcoholics was taken up by a few other practitioners, including a Dr Rosebrugh in Canada (5), and was used widely for some years at the Bellevue Hospital in New York, although the same doctors noted that its use had remained ‘almost unknown’. 

In 1905 Francis Hare, an Irish doctor, opened a sanatorium outside London. He described apomorphine as ‘the most useful single drug in the therapeutics of inebriety’ (6), describing his use of it in his 1912 book ‘On Alcoholism’;

‘In (the) sanatorium it is used in three different sets of circumstances: 1, in maniacal or hysterical drunkenness: 2, during the paroxysm of dipsomania, in order to still the craving for alcohol; and 3, in essential insomnia of a special variety.’

He was explicit in his view that it affected the mental state of the patient;

‘The outstanding advantage of apomorphine is the exceeding promptness of its action, whether given in large emetic, or merely small and perhaps barely hypnotic, doses. To alter completely the whole mental aspect of the case by means of apomorphine injections is only a matter of minutes, and this whether emesis or sleep are induced or not.’

Of 390 treated patients, 253 (62.3%) were no longer drinking when reassessed after intervals of 6 months to 2 years. In ‘The Practitioners Guide to Medical Treatment’ he wrote (7):

‘[after giving apomorphine] the patient’s mental condition is entirely altered. He may be sober: he is free from the time being from any craving from alcohol. The craving may return, however, and then it is necessary to repeat the injection, it may be several times at intervals of a few hours. These succeeding injections should be quite small, 3 to 6 min. being sufficient. Doses of this size are rarely emetic. There is little facial pallor, a sensation as of the commencement of sea-sickness, perhaps a slight malaise with a sudden subsidence of the craving for alcohol, followed by a light and short doze.’

Hare also reaffirmed the hypnotic effects of apomorphine:

‘This case well illustrates the value of apomorphine in dipsomania… On his last admission he [the patient] merely had 1/55 gr. [1.18mg] and 1/46 gr. [1.4mg] respectively at bedtime on the first two days. Before entering he had had very little sleep, and that broken up into ‘snatches’. After the first dose of apomorphine he slept for 7 hours continuously, and expressed himself as very much better next day… After the second dose he slept for eight hours continuously, and expressed himself as absolutely well next day. All his symptoms had then ceased; in fact the paroxysm had been aborted.’

Hare also emphasised that the effects of apomorphine were short-lived and repeated injections at short intervals were necessary.  

‘Although in some cases six or even eight hours’ sleep follows an injection, yet, as I have said, I do not believe that the hypnotic effect endures for more than two to three hours… And the freedom from the dipsomaniac craving conferred is equally fleeting. Hence the necessity for frequent repetition.’

The 1914 Harrison Narcotics Tax Act, an attempt to control the burgeoning narcotics trade, stifled the use of apomorphine in the United States. All opium derivatives, including apomorphine, were heavily taxed. Doctors were also banned from writing prescriptions for morphine.

Some enthusiasts continued to use the drug in Europe, and in 1930 Dr Francois Arnaud in Marseilles confirmed that apomorphine was an emetic ‘that works directly on the brain, rather than causing a reflex action in the stomach’ (8). This coincided with the use of apomorphine as an aversion therapy and a flurry of papers (9), mainly from Russia, discussing its value in ‘conditioned reflex therapy’.

Dent (1888-1962)

John Yerbury Dent, arguably the best-known proponent of  apomorphine as a therapy for addiction, first published his results in alcoholics (10) in the British Journal of Inebriety in 1934. While working at St Pancras Infirmary as a junior doctor (11), he had noticed that alcoholics brought in from the street for sobering up who were injected on admission with apomorphine ‘were in far better fettle and much less ashamed of themselves than whose that had been stomach pumped’ (12). This prompted his 40-year investigation into the therapeutic benefits of apomorphine in chronic alcoholics, seen through the prism of his interest in anxiety.

The then-novel method of aversion therapy influenced his earliest protocol:

‘He is given his favourite drink, and his favourite brand of that drink… The small dose of apomorphine, one-twentieth of a grain [3.24mg], is now given subcutaneously into his thigh, and he is told that he will be sick in a quarter of an hour. A glass of whisky and water and a bottle of whisky are left by his bedside. At six o’clock (four hours later) he is again visited and the same treatment is again administered… The nurse is told in confidence that if he does not drink, one-fortieth [1.62mg] of a grain of apomorphine should be injected during the night at nine o’clock, one o’clock, and five o’clock, but that if he drinks the injection should be given soon after the drink and may be increased to two hourly intervals. In the morning at about ten he is again given one or two glasses of whisky and water… and again one-twentieth of a grain [3.24mg] of apomorphine is injected… The next day he is allowed to eat what he likes, he may drink as much tea as he likes… He will be strong enough to get up and two days later he leaves the home.’

The simultaneous administration of alcohol and apomorphine remained a standard component of his inpatient treatment protocol for his entire career. As he became more experienced with the use of the drug he placed more emphasis on the use of lower doses (1.6mg). By 1941 he had published a paper describing non-emetic low-dose apomorphine eliminating craving in both alcoholics and morphine addicts – ‘The latter (apomorphine) I can also support, as I have found even small quantities – sub-vomiting doses of one-eightieth [0.8mg] to one-fortieth [1.6mg] of a grain – to remove not only alcoholic craving, but the much more serious deprivation symptoms of heroin and morphine’. 

In 1944 Dent (13) described an outpatient method of treatment using crushed apomorphine tablets nasally:

‘The procedure is briefly this: On going to bed the patient puts a bowl and a glass of water within reach and puts a quarter of a tablet up his nose and waits events. If nothing happens he increases the dose every night by a quarter. This he should do until he has produced a vomit. He then knows his minimal vomiting dose. After this he can take half this dose any night he likes, and it does produce a more restful sleep with hardly any feeling of nausea before it, and a quarter of the vomiting dose can be taken any time during the day.’

The intranasal method caused irritation of the nasal mucosa leading him to experiment with sublingual pellets. This version of the treatment was written up in his book and ended up being viewed as the ‘standard’ version of his method, despite his insistence that treatment by injection obtained better results.

Dent changed his mind over his life about how apomorphine worked. In his 1934 paper he wrote both ‘Alcohol has had vomiting associated with it… He has received a conditioned reflex such that when he drinks alcohol he is sick’ and ‘though vomiting is one of the ways that apomorphine relives the patient, I do not believe it to be its main therapeutic effect.’ In 1948 he concluded in a paper presented to the British Society of Addiction that:

‘I said in my paper [the 1934 paper], that the virtue of the treatment lay in the conditioned reflex of aversion produced in the patient. This statement is not even a half truth… I have been forced to the conclusion that apomorphine has some further action than the production of a vomit.’ (14)

This paper also contained his updated protocol, in which apomorphine was given round the clock for 2-3 days in high doses, followed by 2 days of lower doses (exact quantities unspecified). He claimed a 60-70% one-year abstinence rate, with only 10% of those treated being classified as ‘total failures’. He also reported success in treating morphine and barbiturate addicts with a similar protocol (and would publish another paper in 1953 specifically on the subject) (15) with subemetic doses of apomorphine, leading to the later successful treatment of the writer William S. Burroughs.

In the appendix to the 1962 edition of Naked Lunch (16) Burroughs wrote ‘I feel that I was never completely cured of the craving for morphine until I took apomorphine treatment.’

Dent died in 1962, by which time his treatment methods were considered antiquated and much inferior to disulfiram (Antabuse) and psychotherapy. 

Feldmann (1919-1984)

In 1945, after a visit to the Society for Inebriety in London, Dr Harry Feldmann carried out a trial of apomorphine in Geneva (17). He reported that of the 150 treated alcoholics, 46% were totally abstinent for 2 years – and that vomiting was not a prerequisite for remission, ‘We adopted the apomorphine method… we thought that apomorphine, by provoking vomiting, acted on the patients by means of a conditioned reflex… But we realised that apomorphine had an infinitely “deeper” action’18. His protocol was similar to that used by Dent:

‘The patient is given one or two glasses of the alcoholic drinks which he habitually takes and then we inject at the very moment when the alcohol starts to produce a sensation of well-being in the patient 1/10 of a grain [6.4mg] of apomorphine subcutaneously, which after 3 to 7 minutes provokes nausea and vomiting. Two to four hours later he is given a second injection of 6mg. of apomorphine, accompanied by a glass of the usual drink. If the patient continues to drink a third injection of apomorphine is made two hours later. If he does not drink much, or not at all, the third injection of apomorphine will only be 1/12 [5.4mg] of a grain of apomorphine. We keep on injecting 1/12  then 1/16 [4mg] of a grain every two hours, day and night, as long as the patient continues to drink… When the patient can no longer drink, the doses of apomorphine are reduced and only 1/16, then 1/20 [3.2mg] then 1/30 [2.2mg] of a grain are injected every hour… The treatment usually lasts from 6 to 10 days’.

Feldmann went on to report his clinical experience with 500 patients (19), comparing the results of apomorphine monotherapy to apomorphine combined with psychotherapy, and declared a 45% success rate in the apomorphine patients versus 49% for apomorphine plus psychotherapy (albeit counting those who return to social, but managed drinking, as successes). Of the 500 patients given apomorphine, 75 had no emesis.

Finally, in 1959 he (20) described some success with a Dent-style oral treatment in 250 patients, with a 42% 6-month abstinence rate.

1960–80

In spite of the discovery that apomorphine was a powerful dopamine receptor agonist by Ernst in 1965, (21) and the implication of catecholamine dysfunction in both anxiety and depression, interest in apomorphine as a psychotropic drug waned.

Dr Noel Moynihan (22) (1965) tested Dent’s ‘comparatively gentle oral regime for outpatients’ (literally, in this case; it included the simultaneous administration of sublingual apomorphine and alcoholic drinks) on 87 alcoholic patients, achieving an over 70% rate of one-year abstinence. Despite being the co-founder of the Medical Council on Alcoholism, his enthusiasm for apomorphine did not seem to have much effect on the treatment of alcoholism in the UK. Most of the activity relating to alcoholism and apomorphine the 1970s was the result of the interest of Oluf Martensen-Larsen (1912-2000), a psychiatrist in Denmark. He switched from aversion therapy to testing Antabuse (disulfuram) at the behest of Erik Jacobsen, its discoverer, in 1947, publishing his Antabuse results in the Lancet (23) on 83 patients in 1948, finding it to be efficacious in observational studies. By 1957, after communication with Dent and greater experience with Antabuse, he switched to apomorphine as his preferred treatment.

From 1968 onwards Martensen-Larsen offered apomorphine therapy via injection at Dr. Carl Carlsson’s alcoholism clinic [Personal Communication with Carl Carlsson, 2016]. This resulted in revived interest in apomorphine therapy for addiction, especially in Scandinavia, culminating in a conference on the subject and the consequent publication in 1976 of The Treatment of Multiple Drug Dependence and Alcoholism with Apomorphine.

In a chapter of the proceedings entitled Apomorphine Revived (24), Martensen-Larsen discussed what they saw as the difficulties of using apomorphine – expensive, short half-life in the body, hard to store and low availability by mouth – before discussing what they called the ‘intensive’ treatment.

The patient would be given 30mg of the anti-emetic Primperan (metoclopramide) [J Scheel-Kruger, personal communication 2016] followed by 10mg of apomorphine 40 minutes later, injected subcutaneously, with the same dose given again in the evening. Patients were also given apomorphine capsules every third hour. They tested various combinations of apomorphine and L-dopa as follow-up treatment, which could last up to 3 months. They settled on 20mg apomorphine, 20mg levodopa and 5mg Benserazide, with 2mg of carbidopa. Using this formulation there was less nausea and fewer spontaneous penile erections, and better control of shaking, but two schizophrenic patients experienced a “negative influence” from the addition of levodopa.

In a separate chapter of the book Dr Arne Tallberg (25) discussed his personal experience at an outpatient alcoholic clinic in Tyreso. At first he had been reluctant to deviate from the standard approach of Antabuse, vitamins and hypnotics; however, he began to use apomorphine more and more, both via injection (2mg) and capsule (10 or 20mg).

The regime described was to inject a small dose of apomorphine – starting at 0.4mg – and adding 0.2-0.4mg at intervals of 20-45 minutes. If the patient vomited the dose was reduced, then gradually ramped up again. He noted that the dose of individual injections rarely exceeded 5mg. After 2 weeks the injections were supplemented with apomorphine capsules of 10-40mg, and finally after 2 more weeks the injections were stopped. Capsules were continued for up to 6 months, depending on the patient.

He noted;

‘The most interesting thing with Apomorphine treatment is that it does not hinder the patient’s drinking like Antabuse; it takes away the desire, the compulsion to drink. He simply does not want to drink anymore, and several of my patients have also stopped or reduced their smoking or coffee drinking.’

He estimated that 1 in 2 of his patients who received apomorphine recovered compared with 1 in 5 with Antabuse.

Review of Clinical Trials

During the 1970s several clinical trials were performed:

Schlatter and Lal. (1972) conducted a trial on 86 war veterans between the ages of 35 and 55 using ‘Dent’s oral outpatient protocol’, with 35 in the apomorphine group and 51 in the control group.

Patients were given mounting doses of apomorphine via sublingual tablet until they became nauseated, at which point they were given ¾ of that dose every 2 hours for a day. The dose was then increased again incrementally until they vomited, at which point they were given ¾ of that dose for another 72 hours (mean or standard doses not given). This protocol was carried out in hospital and lasted 4 to 7 days. Craving was assessed using a 3-point scale before and after the treatment period, with 0 being no desire and 2 being continuous desire. 20 of the treatment group and 25 of the control group reported craving at baseline. 

Of those who reported pre-treatment craving, only 2 of the apomorphine group reported craving immediately after treatment, while 18 of the control group did so (mean hospital stay duration 24 days). Only 3 of the apomorphine group and 7 of the non-apomorphine group were abstinent at the 6-month follow up mark. Spontaneous penile erections occurred in 63% of the apomorphine-treated cases and was by far the commonest side-effect.

The authors concluded ‘the significant decrease in subjective craving… suggests the difference from controls was real… poor results in terms of duration of abstinence indicate the transience of the drug’s effects and… fail to confirm Dent’s optimism… Reliance on the patient to resume self-treatment… was found to be uniformly unsuccessful.’

Carl Carlsson (26) (1977) performed a double-blind crossover study on 20 chronic alcoholics aged 27 to 54, over 14 days. They were given capsules containing either 20mg of apomorphine or lactose (control) three times a day and a questionnaire was administered 1 hour after the morning dose.

They concluded that apomorphine had a highly significant effect on craving (p = 0.012), and improved co-existing anxiety (p = 0.048). The placebo group required significantly more sleeping tablets (p = 0.029). 

Buus-Jensen, Christofferson and Noerregard (27) (1977) conducted a double-blind study comparing apomorphine to placebo in 89 alcoholics (49 control, 40 treatment). On the first day the treatment group were given apomorphine injections increasing by 0.4mg per hour until vomiting occurred (on average 4.5mg). This was followed by 14 days of tablets (6 tablets of either 6mg or 18mg strength depending on emesis, at regular intervals). There was a significant (p < 0.05) increase in sobriety in the apomorphine group, and more of them remained attendees. There was also a trend for alcoholics in the treatment group to feel better mentally and physically than the placebo group   

Jensen remains sceptical that the apomorphine itself had much effect [Personal Communication, Jensen 2016], but was struck by the speed with which apomorphine sobered people up. One patient had been brought in extremely drunk, given apomorphine and 4 hours later passed the various neurological tests (Finger/Finger, Finger/Nose, walking the line) and discharged himself. Despite medical advice the patient insisted on driving home and crashed his BMW 10 minutes later. 

The local media became interested in the case, describing apomorphine as a ‘party pill’ which could be used to instantly sober people up. Jensen commented that ‘the issue of the party pill was probably a killer for the continued use of the drug.’

Beil and Trojan (1977) described their results with parenteral apomorphine administered in two different protocols in the British Journal of Addiction (28). Of the 123 subjects 55 were alcoholics, 59 were opiate addicts or multiple drug abusers and 9 were barbiturate abusers.

The high-dose treatment consisted of patients being given 10mg of apomorphine 3 times a day for 2 weeks, increased up to a maximum of 15mg if no vomiting occurred.  After this dose frequency was reduced to twice a day for a further 2 weeks. Repeat treatments were carried out over the next 2 to 6 months if craving reoccurred.

The low-dose treatment consisted of an initial dose of 0.5mg, increasing by 0.1mg every 2 hours until vomiting occurred. Then treatment was continued by the patient injecting themselves with 0.1mg below the emetic dose (usually between 1 to 1.5mg) for between 4 and 6 weeks.

They wrote:

‘Positive effects of apomorphine treatment were impressive: Withdrawal symptoms which occur in the beginning are tolerated by the patient; the need for the drug or alcohol vanishes after 4 days, anxieties are reduced and a general tranquillity takes place. The personality of the patient tends to be reconstructed and all patients report an aversion against alcohol or drugs respectively.’

However, while their results with alcoholics were good (41 of the 55, or 75% remaining drug free at between 6 and 13 months) the results with opiate addicts and multiple drug abusers were much less so (only 29% remaining fully drug free, although another 20% were mostly drug free with temporary relapses). Of the two treatment protocols they noted that the low-dose approach tended to fail because people did not comply with the repeated small injections required, but that the high dose treatment was ineffective when dealing with opiate abusers. Finally, they recommend that ‘Future studies should lay stress on testing orally effective compounds’.

After the 1970s

Martensen-Larsen continued to give apomorphine injections to patients for alcoholism well into the 1990s and confirmed that he still believed in its efficacy [Personal Communication, Martensen-Larsen 1993].  Arvid Carlsson, who received the Nobel Prize for his work on catecholamines, and was familiar with Martensen-Larsens studies, still believes in the efficacy of the treatment [Personal Communication 2013, Arvid Carlsson].

The last reports of clinical experience with apomorphine in the treatment of alcoholism come from a summary in Addiction by IP Anokhina of the Russian experience in 1987 (29). She wrote:

‘The application of small doses of dopamine receptor stimulants… is one of such approaches. A technique of apomorphine application for the therapy of the alcohol abstinence syndrome was also developed. The clinical experience thus accumulated confirms that small doses of apomorphine were sufficiently effective to arrest abstinence states.’ 

By the end of the 1970s interest in apomorphine in Europe had waned. In John Spence Madden’s Guide to Alcohol and Drug Dependence (1984) (30) he notes, after mentioning Martensen-Larsen:

‘Although Schlatter and Lal did suggest that a maintenance dose of apomorphine might have some effect in the maintenance of sobriety, neither their report nor the other studies justify confidence in apomorphine as a treatment for alcohol dependence. The usage of apomorphine has largely been conducted by a few enthusiasts…’

Commonalities in the Clinical Observations

A consistent finding from the published observational studies is that sub-emetic doses reduces short term craving, with the suggestion that it may also reduce craving over the long-term too.

Addicts frequently commented that after the treatment they felt emotionally stable and clearheaded. Patrick Riddell, a patient of John Dent’s wrote in 1955, ‘I was thinking straight! Not only were the eyes of my head in focus, the eyes of my mind were in focus too’.

Tallberg reported ‘patients are… calm, well balanced, active, eager to work and improve their actual situation which they can now look at and discuss in an objective and creative way.’ Dent commented ‘He [the patient after being given apo] awakes with no feeling of the “morning after” with little remorse, and a much more hopeful attitude towards life’. Hare observed patients were ‘quiet and tractable’, with others reporting increased ‘lucidity’. Beil and Trojan reported “patients developed more insight and became more motivated for psychotherapeutic treatment. Martensen-Larsen: ‘One of the commonest things in a cured patient is for him to describe his condition as “freedom”. He says, now I can make plans for the future…’

As well as anxiolytic effects apomorphine also had beneficial effects on disrupted sleep patterns. After an injection of 3mg the effect could be dramatic (onset of sleep 7-15 minutes), with the sleep reported as feeling refreshing. Alcoholics undergoing withdrawal commonly experience disturbed sleep (31).

The problem of how to deliver, store and use apomorphine appears in almost every account; pills taken sublingually were bitter and caused mouth ulcers, while injections were also disliked by many patients. Hare wrote in 1912 that there was a ‘prejudice… against the use of the hypodermic needle in the case of alcoholists’, with one doctor suggesting to him that anyone ‘giving a hypodermic injection to an alcoholic inebriate should be shot!’. Spilled apomorphine also stained clothes and carpets green.

Its reputation also suffered from association with aversion therapy. Dent wrote that ‘Doctors who will cheerfully inject cobra venom or malaria into their patients refuse to inject apomorphine’.

In his papers (32):

‘There is a special antagonism, I can only call it, that against administering apomorphine in the USA and in Canada’. 

Potential Mechanisms for the therapeutic effects of Apomorphine

Apomorphine is a synthetic aporphine which activates both D2-like dopamine and, to an order of magnitude less, D1-like dopamine receptors. It has activity at all 5 subtypes of dopamine receptor (33)(34), with its strongest occupancy at D3 (82% Emax) (35). At D2, it shows stronger activity at the D2s autoreceptor (79% max occupancy) than the D2l post-synaptic receptor (53%). It is a powerful partial agonist at D4 receptors. It also acts as an antagonist of 5-HT2 and α-adrenergic receptors with high affinity.

Dysfunction of dopaminergic signalling (36), in the nucleus accumbens (Nac) has been implicated in the neurobiology of addiction. Substance dependence can be divided into a three-stage cycle; binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation, with the binging phase involving spikes of dopamine release and withdrawal being associated with low basal dopamine.

Spikes of dopamine cause reinforcing effects (37), while long-term psychostimulant drug use is commonly associated with a reduction in D2 receptors and DA release in the striatum. This results in a baseline surfeit of stress and deficiency in rewarding feelings associated with non-drug activity (38)(39)(40).

Addiction to alcohol has also been found to be associated with reduced D2 receptor availability in PET studies (41), and higher striatal dopamine receptor availability may be protective against alcohol addiction. Apomorphine challenge testing has provided indirect evidence for reduced dopaminergic receptor sensitivity in alcoholics and increased yawning occurs after apomorphine in heroin addicts compared with controls (42).

A partial dopamine agonist might be the ideal candidate for treating addiction (43). Terguride reversed amphetamine withdrawal in rats (44), while a dopaminergic stabiliser (OSU6162) was found to reduce priming-induced craving in alcoholics (45). 

Apomorphine treatment can restore basal dopamine levels allowing the disrupted dopaminergic system to return to normal levels of function. When used with continuous infusion in Parkinson’s it may correct impulse control disorders caused by other dopaminergic drugs (46). This would also be associated with a short-term reduction in craving for the drug and could possibly lead to lasting changes even after apomorphine treatment has been stopped.

Apomorphine’s stronger effect at D2 receptors might also be beneficial; D2 receptors have been hypothesised to be more sensitive to tonic dopamine, while D1 receptors are more sensitive to dopamine spikes (47).

There are other potential mechanisms by which apomorphine might cause long-term changes in dopamine signalling. Traditionally this has been viewed as the ‘aversive’ part of the older treatment protocols; in reality apomorphine was not that effective in inducing aversion (as can be seen by Voegtlin rapidly turning to emetine). In rats it eliminates conditioned place aversion to morphine withdrawal and ameliorates withdrawal-potentiated startle in rats undergoing nicotine withdrawal. This effect was not observed using other dopamine agonists (quinpirole and SKF82958) unless they were given together; one hypothesis is that the NAc shell effects are mediated by a D1-D2 heterodimeric signalling complex (48), and that apomorphine is able to bind to it.

Apomorphine has been found to have transcriptional effects; in human astrocytes (49)(50) it increases production of GDNF by 1.8, and NGF 122-fold. It has been shown (51) that there is a GDNF-dependent mechanism affecting rat alcohol seeking behaviour, with cabergoline used as the dopaminergic agonist to induce GDNF upregulation (52). Cabergoline decreases both ethanol self-administration and ethanol-seeking in rats, and does nothing in heterozygous GDNF knockout rats, demonstrating a GDNF-dependent mechanism.

In rats treated with 6 months of ethanol administration followed by a 2-month withdrawal period, there was a 64% reduction in the density of cholinergic variscosities (53). This was reversed by NGF; the number and density of NPY-reactive neurons and the size of cholinergic neurons increased. This might also explain why other dopaminergic agents have been ineffective in treating alcoholism; if part of the effect is NGF dependent, ostensibly similar dopamine agonists have heterogeneous effects on it (122x for apo versus 6.3x for ropinirole, bromocriptine at 6.8 and SKF-38393 at 20). Changes in NGF levels are also observed in the male offspring of ethanol-exposed mice, with concomitant changes in ethanol-elicited preference (54).

It seems possible that one of the effects of apomorphine was that it treated the negative affect of withdrawal, as well as abolishing craving directly by restoring basal level of dopaminergic function. It also suggests a reason why opiate addicts like William Burroughs obtained symptomatic relief from apomorphine.

Alcoholics display impairments in the maintenance of spatial information, decision making and behavioural inhibition; and apomorphine has the propensity to reduce these disturbances55. Healthy people performing target/nontarget continuous discrimination tests displayed poorer performance after being given a low dose of apomorphine, while alcoholics showed improved performance after the same dose.

Conclusion

A review of the early literature of apomorphine in the treatment of alcoholism and opiate dependence provides support for the notion that continuous stimulation with low dose apomorphine can reduce craving and potentially also restore normal dopaminergic function for periods exceeding the duration of treatment.

Given the low risks of apomorphine, its current use as an anti-parkinsonian agent, its cheap cost and its negligible potential for addiction, a randomised controlled trial with continuous subcutaneous delivery delivered by ambulatory pump for 7-10 days in a small number of carefully studied patients with alcohol dependence and /or opioid addiction should be considered.

References

  1. Tompkins, J Apomorphine In Acute Alcoholic Delirium, Medical Record 1899
  2. APOMORPHINE AS A HYPNOTIC. The Lancet. 1900;155(3998):1083.
  3. Douglas, J. The New York Medical Journal, p.626. 1899
  4. Douglas, J. The Medical Times, p.172. 1910
  5. APOMORPHINE AS A HYPNOTIC IN ALCOHOLISM. The Lancet. 1908;172(4444):1316
  6. Hare F. On alcoholism; its clinical aspects and treatment. 1st ed. London: Churchill; 1912.
  7. Langdon B. The Practitioners Encyclopedia of Medical Treatment. 1st ed. Oxford University Press; 1915.
  8. Arnaud F. Therapeutique pharmcaologie matière médicale. 1st ed. Masson et Cie; 1930.
  9. LEMERE F. Aversion Treatment of Alcoholism: some reminiscences. Addiction. 1987;82(3):257-258.
  10. Dent J. Autobiographical notes. Rubinstein Private Collection
  11. DENT, J. (1934). APOMORPHINE IN THE TREATMENT OF ANXIETY STATES, WITH ESPECIAL REFERENCE TO ALCOHOLISM. Addiction, 32(2), pp.65-88.
  12. Dent J. Anxiety and its treatment. 1st ed. London: J. Murray; 1941.
  13. DENT, J. (1944). SELF-TREATMENT OF ANXIETY AND CRAVING, BY APOMORPHINE, THROUGH THE NOSE. Addiction, 41(2), pp.78-83.
  14. DENT, J. (1949). APOMORPHINE TREATMENT OF ADDICTION. Addiction, 46(1), pp.15-28.
  15. DENT J. APOMORPHINE IN THE TREATMENT OF ADDICTION TO “OTHER DRUGS”. Addiction. 1953;50(1):43-45.
  16. Burroughs W. LETTER FROM A MASTER ADDICT TO DANGEROUS DRUGS. Addiction. 1957;53(2):119-132.
  17. MORSIER GFELDMANN H. THE BIOLOGICAL TREATMENT OF CHRONIC ALCOHOLISM BY APOMORPHINE. STUDY OF 150 CASES. Addiction. 1950;47(2):50-61.
  18. FELDMAN H. HUMORAL EQUILIBRIUM IN THE TREATMENT OF CHRONIC ALCOHOLISM BY APOMORPHINE. Addiction. 1953;50(1):59-66.
  19. FELDMANN H., [Treatment of chronic alcoholism with apomorphine; study of 500 cases]. Sem Hop. 1953 May 2;29(29):1481-91
  20. FELDMANN, H. (1959). THE AMBULATORY TREATMENT OF ALCOHOLIC ADDICTS. Addiction, 55(2), pp.121-128.
  21. Ernst AM., Relation between the action of dopamine and apomorphine and their O-methylated derivatives upon the CNS. Psychopharmacologia. 1965 May 21;7(6):391-9.
  22. MOYNIHAN NH. THE TREATMENT OF ALCOHOLISM IN GENERAL PRACTICE. Practitioner. 1965 Aug;195:223-7.
  23. Schlatter EK, Lal S., Treatment of alcoholism with Dent’s oral apomorphine method. Q J Stud Alcohol. 1972 Jun;33(2):430-6.
  24. Halvorsen K, Martensen-Larsen O. Apomorphine Revived: Fortified, Prolonged, and Improved Therapeutical Effect. International Journal of the Addictions. 1978;13(3):475-484.
  25. Tallberg, A, Work and results in a minor alcohol clinic outside Stockholm. The Treatment of Multiple Drug Dependence and Alcoholism with Apomorphine, 1976
  26. Carlsson C, Johansson PR, Gullberg B. A double-blind cross-over study: apomorphine/placebo in chronic alcoholics. Int J Clin Pharmacol Biopharm. 1977 May;15(5):211-3.
  27. Jensen SB, Christoffersen CB, Noerregaard A. Apomorphine in outpatient treatment of alcohol intoxication and abstinence: a double-blind study.  Br J Addict Alcohol Other Drugs. 1977 Dec;72(4):325-30.
  28. Beil H, Trojan A. . The use of apomorphine in the treatment of alcoholism and other addictions: results of a general practitioner. Br J Addict Alcohol Other Drugs. 1977 Jun;72(2):129-34
  29. Anokhina IP, Ivanets NN, Burov YuV, Kogan BM. Alcohol and alcohol problems research 13. U.S.S.R. Br J Addict. 1987 Jan;82(1):23-30.
  30. Madden J. A guide to alcohol and drug dependence. 1st ed. Bristol: J. Wright; 1984.
  31. Arnedt, J., Conroy, D. and Brower, K. (2007). Treatment Options for Sleep Disturbances During Alcohol Recovery. Journal of Addictive Diseases, 26(4), pp.41-54.
  32. Dent J. Autobiographical notes. Rubinstein Private Collection
  33. Newman-Tancredi A. Differential Actions of Antiparkinson Agents at Multiple Classes of Monoaminergic Receptor. II. Agonist and Antagonist Properties at Subtypes of Dopamine D2-Like Receptor and alpha 1/alpha 2-Adrenoceptor. Journal of Pharmacology and Experimental Therapeutics. 2002;303(2):805-814.
  34. Newman-Tancredi A. Differential Actions of Antiparkinson Agents at Multiple Classes of Monoaminergic Receptor. III. Agonist and Antagonist Properties at Serotonin, 5-HT1 and 5-HT2, Receptor Subtypes. Journal of Pharmacology and Experimental Therapeutics. 2002;303(2):815-822.
  35. Subramony J. Apomorphine in Dopaminergic Therapy. Mol Pharmaceutics. 2006;3(4):380-385.
  36. Nutt D, Lingford-Hughes A, Erritzoe D, Stokes P. The dopamine theory of addiction: 40 years of highs and lows. Nature Reviews Neuroscience. 2015;16(5):305-312.
  37. Volkow, N., Wang, G., Telang, F., Fowler, J., Logan, J., Childress, A., Jayne, M., Ma, Y. and Wong, C. (2006). Cocaine Cues and Dopamine in Dorsal Striatum: Mechanism of Craving in Cocaine Addiction. Journal of Neuroscience, 26(24), pp.6583-6588.
  38. Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F., Dopamine in drug abuse and addiction: results of imaging studies and treatment implications.  Arch Neurol. 2007 Nov;64(11):1575-9.
  39. Gilpin N, Koob G. Neurobiology of Alcohol Dependence: Focus on Motivational Mechanisms. Alcohol Res Health. 2008; 31(3): 185–195.
  40. Koob G, Volkow N. Neurobiology of addiction: a neurocircuitry analysis. The Lancet Psychiatry. 2016;3(8):760-773.
  41. Volkow ND, Fowler JS, Wang GJ, Goldstein RZ. Role of dopamine, the frontal cortex and memory circuits in drug addiction: insight from imaging studies. Neurobiol Learn Mem. 2002 Nov;78(3):610-24.
  42. CASAS, M., GUARDIA, J., PRAT, G. and TRUJOLS, J. (1995). The apomorphine test in heroin addicts. Addiction, 90(6), pp.831-835.
  43. Pulvirenti L, Koob G. Dopamine receptor agonists, partial agonists and psychostimulant addiction. Trends in Pharmacological Sciences. 1994;15(10):374-379.
  44. Orsini C, Koob GF, Pulvirenti L. Dopamine partial agonist reverses amphetamine withdrawal in rats. Neuropsychopharmacology. 2001 Nov;25(5):789-92.
  45. Khemiri L, Steensland P, Guterstam J, Beck O, Carlsson A, Franck J et al. The effects of the monoamine stabilizer (-)-OSU6162 on craving in alcohol dependent individuals: A human laboratory study. European Neuropsychopharmacology. 2015;25(12):2240-2251.
  46. Barbosa P, Lees A, Magee C, Djamshidian A, Warner T. A Retrospective Evaluation of the Frequency of Impulsive Compulsive Behaviors in Parkinson’s Disease Patients Treated with Continuous Waking Day Apomorphine Pumps. Movement Disorders Clinical Practice. 2016;4(3):323-328.
  47. Radke A, Gewirtz J. Increased Dopamine Receptor Activity in the Nucleus Accumbens Shell Ameliorates Anxiety during Drug Withdrawal. Neuropsychopharmacology. 2012;37(11):2405-2415.
  48. Rashid, A., So, C., Kong, M., Furtak, T., El-Ghundi, M., Cheng, R., O’Dowd, B. and George, S. (2006). D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proceedings of the National Academy of Sciences, 104(2), pp.654-659.
  49. Ohta M, Mizuta I, Ohta K, Nishimura M, Mizuta E, Hayashi K et al. Apomorphine Up-Regulates NGF and GDNF Synthesis in Cultured Mouse Astrocytes. Biochemical and Biophysical Research Communications. 2000;272(1):18-22.
  50. Ohta K, Kuno S, Inoue S, Ikeda E, Fujinami A, Ohta M. The effect of dopamine agonists: The expression of GDNF, NGF, and BDNF in cultured mouse astrocytes. Journal of the Neurological Sciences. 2010;291(1-2):12-16.
  51. Carnicella SRon D. GDNF — A potential target to treat addiction. Pharmacology & Therapeutics. 2009;122(1):9-18.
  52. Barak S, Wang J, Ahmadiantehrani S, Ben Hamida S, Kells A, Forsayeth J et al. Glial cell line-derived neurotrophic factor (GDNF) is an endogenous protector in the mesolimbic system against excessive alcohol consumption and relapse. Addiction Biology. 2014;20(4):629-642.
  53. Pereira, P., Neves, J., Vilela, M., Sousa, S., Cruz, C. and Madeira, M. (2014). Chronic alcohol consumption leads to neurochemical changes in the nucleus accumbens that are not fully reversed by withdrawal. Neurotoxicology and Teratology, 44, pp.53-61.
  54. Ceccanti M, Coccurello R, Carito V, Ciafrè S, Ferraguti G, Giacovazzo G et al. Paternal alcohol exposure in mice alters brain NGF and BDNF and increases ethanol-elicited preference in male offspring. Addiction Biology. 2015;21(4):776-787.
  55. Schellekens A, Grootens K, Neef C, Movig K, Buitelaar J, Ellenbroek B et al. Effect of apomorphine on cognitive performance and sensorimotor gating in humans. Psychopharmacology. 2009;207(4):559-569.
  56.