Posted by Quintal on August 4, 2007, at 1:14:57
Those of you with good memory will recall my trial of the dopamine agonist Mirapex (pramipexole) back in March this year. During that time I happened to run out of codeine and noticed the usual withdrawal symptoms were absent. I also remarked that the sensation pramipexole induced was similar to the ‘nodding’ phase of opiate intoxication. I thought little of it at the time and since pramipexole impaired my concentration and made me drowsy I stopped taking it after a few weeks and it languished in the back of my medicine cupboard, neglected, for a few months.
Early last month I ran out of codeine once again and after a few days I was feeling low and wretched. By chance I remembered my previous trial of pramipexole so on impulse I decided to give it another go. I split off 0.125mg and swallowed it with a glass of water, and the effect appeared within minutes – my withdrawal symptoms vanished and I was aglow with relief, a little euphoric in fact. This did not last, but mercifully the withdrawal symptoms did not resurface.
I find this very interesting. There’s an obvious association between dopamine agonists and drugs of abuse in their affinity for, and stimulation of, dopamine receptors in the brain (although I understand their exact modes of action at these receptors are quite different). I was surprised dopamine agonists were not in widespread use in withdrawal clinics etc and that medical texts were silent on this subject, so I decided to do some research myself.
This website was the first clue to the history of dopamine agonists in the treatment of opiate withdrawal symptoms: http://www.geocities.com/Athens/Crete/9445/apo.html Apparently the American novelist and social critic William S. Burroughs was treated in England by Dr. John Yerbury Dent using Dr. Dent’s innovative apomorphine ‘cure’ to withdraw from his long-standing morphine addiction.
As you can see, Dr. Dent was frustrated by his colleagues’ opposition to his to the apomorphine treatment protocol. According to Dr. Dent his treatment protocol was dismissed as an aversion therapy and he felt steps were taken to block its progress into mainstream withdrawal clinics from the outset. I’m told there was enmity between Dr. Dent and the now infamous Lady Frankau, who favoured, and was a liberal dispenser of maintenance prescriptions of Heroin and cocaine to the addicts attending her withdrawal clinic. Addicts would travel from as far as Canada and the United States just to get an appointment with her; such was her reputation for gullibility during the 1960s.
There was a clear conflict of ideology between the two doctors, and Lady Frankau won the popularity contest hands down. This, so I’m told, is the murky tale of how the use of how Dr. Dent’s apomorphine treatment protocol came to be buried in medical oblivion.
Unsatisfied and with a burning curiosity I decided to do some further research myself, and set about performing an amateur meta-analysis of the studies available on the use of dopamine agonists to attenuate opiate withdrawal syndrome. This was the first result I found on searching ‘apomorphine opiate withdrawal’ using the PubMed database; an experiment which seems to contradict the hypothesis that dopamine agonists attenuate opiate withdrawal symptoms, and that of my own experience.
__________________________________________________Behav Neurosci. 2003 Oct;117(5):995-1005.
Changes in dopaminergic neurotransmission do not alter somatic or motivational opiate withdrawal-induced symptoms in rats.
Caillé S, Rodriguez-Arias M, Minarro J, Espejo EF, Cador M, Stinus L.
Centre Nacional de la Recherche Scientifique, Unite Mixte de Recherche (CNRS-UMR) 5541, Lab de Neuropsychobiologie de Desadaptations, Université Bordeaux II, Bordeaux, France. scaille@scripps.eduOpiate withdrawal has been correlated with decreased extracellular dopamine (DA) levels in the nucleus accumbens (NAC) of morphine-dependent rats. The authors tested the hypothesis that DA transmission plays a critical role in the induction of motivational and somatic withdrawal symptoms. First, the authors used a 6-hydroxydopamine-induced lesion of the NAC to chronically disrupt mesolimbic DA transmission. Second, global DA neurotransmission was acutely stimulated by the nonselective DA agonist (apomorphine) or inhibited by nonselective DA antagonists (droperidol or flupentixol). Morphine-dependent rats bearing 6-hydroxydopamine-induced lesions displayed naloxone-precipitated motivational and somatic withdrawal symptoms similar to those of sham-lesioned rats. Administration of apomorphine did not reduce naloxone-induced opiate withdrawal. Moreover, in total absence of naloxone, DA antagonists did not precipitate either conditioned place aversion or somatic abstinence signs in dependent rats. Taken together, these findings suggested that DA transmission is not critical for the induction of opiate withdrawal syndrome. (c) 2003 APA, all rights reserved
PMID: 14570549 [PubMed - indexed for MEDLINE]
__________________________________________________And another that seems to contradict the findings of the first:
__________________________________________________Nature. 1994 Sep 8;371(6493):155-7.
Comment in:
Nature. 1994 Sep 8;371(6493):108-9.Involvement of D2 dopamine receptors in the nucleus accumbens in the opiate withdrawal syndrome.
Harris GC, Aston-Jones G.
Department of Mental Health Sciences, Hahnemann University, Philadelphia, Pennsylvania 19102.The nucleus accumbens is prominently implicated in the reinforcing effects of abused drugs, and is an important site for mediating aversive stimulus properties of opiate withdrawal. It is generally thought, however, that the role of the accumbens is negligible in the somatic signs of opiate withdrawal. Contrary to this assumption, we now report that D2 dopaminergic receptor activity in the accumbens area potently regulates somatic symptoms of opiate withdrawal. We find that activation of D2 receptors within the accumbens prevents somatic signs of naloxone-induced opiate withdrawal and, conversely, that blockade of accumbal D2 receptors in opiate-dependent animals elicits somatic withdrawal symptoms. These data indicate that dopamine in the accumbens not only is important in the rewarding effects of abused drugs, but also (via D2 receptors) plays a pivotal role in opiate withdrawal.
PMID: 7915401 [PubMed - indexed for MEDLINE]
__________________________________________________Alas, deep in the bowels of PubMed archives I found a further two studies that seem to support the hypothesis that dopamine agonists are effective in attenuating opiate withdrawal symptoms:
__________________________________________________1: Int J Addict. 1978 Apr;13(3):475-84.
Apomorphine revived: fortified, prolonged, and improved therapeutical effect.
Halvorsen KA, Martensen-Larsen O.An historical review is presented of the evolution of the clinical apomorphine treatment. Some of the results from the last 10 years of psychopharmacological research have led us to the hypothesis that there exists a close relationship between abstinence and craving symptoms in drug and alcohol addicts, and that anxiety, depression, and tremor symptoms in Parkinsonism (and dementia senilis), are due to disturbances of the same, mainly dopaminergic, pathways in the CNS. In such cases, by means of effective preparations for oral use, we have utilized the synergistic effect of small amounts of apomorphine, L-dopa, and decarboxylase inhibitor with considerable therapeutic effect.
PMID: 352969 [PubMed - indexed for MEDLINE]--------------------------------------------------
2: Neuropsychopharmacology. 2000 Sep;23(3):307-15.
Expression of fos-related antigens in the nucleus accumbens during opiate withdrawal and their attenuation by a D2 dopamine receptor agonist.
Walters CL, Aston-Jones G, Druhan JP.
Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania Medical Center, Philadelphia, USA.Previous studies from this laboratory indicated that D2 dopamine (DA) receptors within the nucleus accumbens (NAc) are important for regulating somatic signs of opiate withdrawal. The present study measured the expression of Fos-related antigens (FRAs) within the NAc during opiate withdrawal to determine whether decreases in somatic withdrawal signs produced by a D2 receptor agonist are accompanied by related changes in accumbens neuronal activity. In an initial experiment, quantitative analyses of FRA immunoreactivity revealed increases in the number of FRA-positive cells throughout the NAc of opiate dependent animals undergoing naltrexone-precipitated withdrawal relative to dependent or non-dependent animals that did not experience withdrawal. A second experiment showed that somatic signs and FRA expression within the NAc could each be attenuated when the D2 agonist propylnorapomorphine (NPA; 0.1 or 0.3 mg/kg, i.p.) was administered prior to naltrexone-precipitated withdrawal. These findings suggest that D2 regulation of neuronal activity within the NAc may be important for the expression of opiate withdrawal symptoms.
PMID: 10942854 [PubMed - indexed for MEDLINE]
1: Nature. 1994 Sep 8;371(6493):155-7. Links
Comment in:
Nature. 1994 Sep 8;371(6493):108-9.
__________________________________________________Probing a little deeper I found these four studies, for which no English language abstracts exist - they being authored by German and Danish scientists. This is most unfortunate, because those are the only studies that directly investigate the treatment of opiate withdrawal syndrome with dopamine agonists in human addicts. Thus it seems that by either accident or design the most pivotal studies on this subject are unavailable to English-speaking audiences at present.
__________________________________________________1: Hedri A.
[Apomorphine in opiate withdrawal treatment]
Schweiz Rundsch Med Prax. 1972 Apr 11;61(15):488-9. German. No abstract available.
PMID: 5022281 [PubMed - indexed for MEDLINE]
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2: Gulmann NC, Kaldan B, Kobbernagal F.[Apomorphine treatment of withdrawal symptoms in young opiate addicts]
Ugeskr Laeger. 1976 Oct 11;138(42):2547-50. Danish. No abstract available.
PMID: 969008 [PubMed - indexed for MEDLINE]
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3: Amitai M, Dickhaut HH, Hasenknopf P.[Therapy of withdrawal symptoms in "fixers". (Drug abuse of adolescents by intravenous injection)]
Nervenarzt. 1972 Mar;43(3):157-60. German. No abstract available.
PMID: 5023740 [PubMed - indexed for MEDLINE]
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4: Ziegler B, Schneider E.[Treatment of withdrawal syndrome with apomorphine]
Arzneimittelforschung. 1974 Aug;24(8):1117-9. German. No abstract available.
PMID: 4479363 [PubMed - indexed for MEDLINE]
__________________________________________________In addition, I found five further studies that could possibly support the ‘dopamine elevation’ hypothesis, but again some of the abstracts are unavailable and have not been translated.
__________________________________________________1: Clin Neuropharmacol. 1986;9(5):469-76.
Effect of sulpiride on chronic abstinence syndrome in addicted patients.
Patti F, Drago F, Marano P, Nicoletti F, Scapagnini U.A total of 410 patients (342 men and 68 women) addicted to heroin for at least 38 months, with or without previous methadone treatment experience, were treated with sulpiride before the appearance of withdrawal syndrome. The drug was injected intramuscularly in a single administration at a dosage of 600 mg. Successively, sulpiride was injected intramuscularly at a dosage of 200 mg 3 times per day from days 2-21 of hospitalization, and then at a dosage of 100 and 50 mg 3 times per day (days 22-25 and 26-29, respectively). All patients showed a suppression of withdrawal signs and symptoms within 6 days of treatment, as assessed by subjective and objective scores. The effect of sulpiride was compared with that of placebo administered to a control group of 10 heroin addicts. Because prolactin has been shown to reduce the dependence of rats to heroin and the naloxone-precipitated withdrawal syndrome in morphine-addicted animals, the effects of sulpiride on heroin addiction may be related to the hyperprolactinemic action of this drug.
PMID: 3021324 [PubMed - indexed for MEDLINE]
[N.B. At low doses sulpiride blocks presynaptic inhibitory dopamine receptors, leading to increased dopaminergic transmission. This effect dominates at doses of 200mg and below. At higher doses of between 600mg and 1600mg sulpiride is a selective antagonist at postsynaptic D2-receptors, having a mild sedating and antipsychotic effect. ]
__________________________________________________2: Pol J Pharmacol. 2001 Nov-Dec;53(6):577-85.
Does combined treatment with novel antidepressants and a dopamine D3 receptor agonist reproduce cocaine discrimination in rats?
Filip M, Papla I.
Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków. filip@if-pan.krakow.plIt is established that dopamine (DA) neurotransmission plays a critical role in the behavioral (e.g. discriminative stimulus) effects of cocaine in rodents. Nonetheless, research has also demonstrated that reciprocal signaling between DA and monoamine neurotransmitters, i.e. serotonin (5-HT) and norepinephrine (NE) has important implication for understanding the actions of cocaine. The present study was focussed on the ability of novel antidepressant drugs (milnacipram, reboxetine and venlafaxine), which affect either NE or both 5-HT and NE reuptake mechanism, to alter (enhance or antagonize) the discriminative stimulus effects of cocaine. Moreover, we investigated if the combined treatment with those drugs and a DA D3 receptor agonist (pramipexole) could reproduce cocaine discrimination. Male Wistar rats were trained to discriminate cocaine (10 mg/kg, ip) from saline (ip) in a two-choice, water-reinforced fixed-ratio 20 drug discrimination paradigm. Given alone, none of antidepressant drugs induced substitution for the cocaine-lever responses. Pramipexole (0.25 mg/kg) produced a partial substitution for cocaine (i.e. 43-52% cocaine-lever responding). In combination experiments, milnacipram (10 mg/kg) or reboxetine (10 mg/kg) given with submaximal doses of cocaine (1.25-5 mg/kg) did not affect the cocaine dose-response curve or its ED50 values. Venlafaxine (10 mg/kg) given in combination with submaximal doses of cocaine (0.6-5 mg/kg) produced significant enhancement of cocaine discrimination with a leftward shift in the cocaine dose-response curve and a decrease in its ED50 value. Pretreatment with either milnacipram (10 mg/kg) or reboxetine (10 mg/kg) failed to modulate the partial substitution evoked by pramipexole (0.25 mg/kg). On the other hand, venlafaxine (10 mg/kg) given in combination with a submaximal dose of pramipexole (0.25 mg/kg), which separately elicited 16 and 42% the cocaine-lever responses, produced significant enhancement of cocaine discrimination (up to 99% of the drug-lever responding). These results indicate that the discriminative stimulus effects of cocaine in rats can be enhanced by venlafaxine or mimicked by the combination with this antidepressant drug and the DA D3 receptor agonist. This finding, together with the recent data reporting the lack of rewarding properties of venlafaxine and the attenuation of morphine dependence and withdrwal signs in rats by the drug, may indicate a possible therapeutic use of this antidepressant in cocaine abuse.
PMID: 11985331 [PubMed - indexed for MEDLINE]
__________________________________________________3: De Permentier A.
Sulpiride as a demorphinization agent.
Med J Aust. 1976 Jan 24;1(4):98. No abstract available.
PMID: 1263952 [PubMed - indexed for MEDLINE]
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4: Br J Addict Alcohol Other Drugs. 1977 Jun;72(2):129-34.
The use of apomorphine in the treatment of alcoholism and other addictions: results of a general practitioner.
Beil H, Trojan A.
PMID: 266939 [PubMed - indexed for MEDLINE]
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5: Q J Stud Alcohol. 1972 Jun;33(2):430-6.
Treatment of alcoholism with Dent's oral apomorphine method.
Schlatter EK, Lal S.
PMID: 5033142 [PubMed - indexed for MEDLINE]
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poster:Quintal
thread:773860
URL: http://www.dr-bob.org/babble/20070730/msgs/773860.html