The ^-opioid receptor antagonist Naltrexone and Acamprosate, which interacts primarily with the glutamatergic system, are the two most commonly used drugs for secondary relapse prevention in alcohol dependence in Europe. A number of double blind studies conducted during the last decade have shown that both, Naltrexone and Acamprosate prevent relapse in a relevant portion of patients - but not in all (Garbutt et al., 1999, Berglund et al., 2003). The results of recent meta-analyses suggest that the number of patients needed to treat in order to prevent one additional relapse of alcohol is about 7.5 for Acamprosate (Mann et al., 2004). This ratio points towards the need to identify predictors for response to pharmacological relapse prevention. Pharmacogenetic research may be useful in attaining this goal. Whereas for Acamprosate no pharmacogenetic analyses have been preformed, a recent study describes a dramatic improvement in treatment success for a specific genotype of a genetic variation of the ^-opioid receptor (Oslin et al., 2003.) Therefore, we will focus in this chapter on the biological effects of Naltrexone as they relate to secondary relapse prevention and to the identification of genetic predictors for treatment success.
One pharmacogenetic study analysed the impact of Naltrexone, an antagonist for the mu-opioid receptor, on the reduction of "rate of relapse" and "time to return to heavy drinking" in 82 alcohol-dependent patients who successfully completed detoxification from alcohol, compared to 59 controls. The potential impact of this pharmacogenetic approach is particularly rich according to the biological background of alcoholism, as detailed in the "neurotransmitter systems involved in alcohol central effects" section.
Indeed, many studies showed the potential interest of Naltrexone in alcohol-dependent patients. Volpicelli initially showed that Naltrexone reduced the risk of relapse (one alcohol-dependent patient out of four relapsed with Naltrexone compared to one patient out of two when treated by placebo), but also for the intensity of alcohol craving and days in which any alcohol was consumed (Volpicelli et al., 1992). As only 35 patients were treated by Naltrexone, this study could have been considered as a preliminary finding. Nevertheless, a nice replication was published in the same issue of the Archives of General Psychiatry. In a population of nearly 100 alcohol-dependent patients, Naltrexone was found superior to placebo in measures of drinking and alcohol-related problems, including abstention rates, number of drinking days, relapse, and severity of alcohol-related problems (O'Malley et al., 1992). The efficacy of
Naltrexone was assessed in other studies, the majority of them confirming the efficacy of this compound (Oslin et al., 1997; Chick et al., 2000; Anton et al., 2001; Monti et al., 2001; Morris et al., 2001), although not systematically (Kranzler et al., 2000; Krystal et al., 2001). Interestingly, some clues were proposed focusing on which clinical parameter Naltrexone could be effective. As alcohol dependence phenotype and addiction processes are particularly complex and heterogeneous, it is important to disentangle the mechanism by which a treatment may help patients to maintain their abstinence. A correct phenotype definition in pharmacogenetics is as important as looking at the appropriate polymorphism(s) of the involved gene(s).
Naltrexone blocked the euphoria produced by ethanol (Volpicelli et al., 1995; King et al., 1997). This clinical symptom of "feeling high" constitutes one of the most frequently quoted factor to explain relapse, and is presented as a way to cope against depressed mood (Strowig, 2000). As an opioid antagonist should block or reduce the effect of alcohol on opioid receptor activity, treated subjects are expected to be less reinforced by alcohol. Indeed, Voplicelli et al., (1995) found that from the reported alcohol effects during lapse from abstinence by detoxified alcoholics receiving Naltrexone, feeling "high" was the only parameter that significantly distinguished patients treated by Naltrexone compared to those treated by placebo. This was not the case for craving, but the limited size of the sample could not depict symptoms with too small effect.
The efficacy of Naltrexone in detoxified alcohol-dependent patients may alternatively be specifically involved in reducing the risk to shift from "slip" (i.e., punctual and occasional drinking) defined as less than 5 glasses on one drinking occasion, and less than 5 consecutive drinking days) to "relapse", as the primary effect of Naltrexone was seen in patients who drank any alcohol while attending outpatient treatment. (Volpicelli et al., 1992). In this view, the concepts of "binge drinking" or "losing control" may be more specifically involved regarding Naltrexone efficacy. A small dose of opiates increase alcohol drinking in rats (Hubbel et al., 1988), the opioidergic effect of the first drink may enhance alcohol craving and relapse. When opiate receptors are effectively blocked by Naltrexone, the first drink would not increase opioid activity, hence not eliciting further alcohol drinking.
An alternative mechanism could implicate the modification of stress coping capacity, as some alcohol-dependent patients sustain a relative deficiency in endogenous opioids after experiencing a stressful life event (Volpicelli, 1987; Volpicelli et al., 1990; Kreek, 1996). Fuerthermore, cortisol stimulation in early abstinent alcoholics showed a blunted response after psychosocial stress (Lovallo et al., 2000). A successful response to stress plays an important role in maintaining health and well-being. In recently detoxified alcoholics, the HPA system is indeed dysregulated with non-suppression of cortisol after dexamethasone administration. Corticotropin releasing factor (CRF) neurons, within the paraventricular nucleus of the hypothalamus, initiate activation of the hypothalamic-pituitary-adrenal (HPA) axis (Bell et al., 1998) and express mu-opioid receptors. CRF neurons are thus modulated by inhibitory tone imposed by P-endorphin neurons originating in the arcuate nucleus (Wand et al., 1998). Central nervous adaptation to the chronic action of alcohol can be observed in the functional state of hypothalamic peptides regulating HPA system function (Madeira and Paula-Barbosa 1999), and subsequent changes in pituitary and adrenal regulation that are associated with chronic alcoholism and withdrawal can be observed in the peripheral circulation.
Whatever the exact mechanism(s) involved for the treatment efficacy of Naltrexone, a large inter-subjects variability is observed. Ethanol increase, in a dose-dependent manner, the plasma level of beta-endorphin-related peptides of subjects with a history of alcoholism, but not of subjects from families without a history of alcoholism (Gianoulakis et al., 1996). The role of family history as a predictor of treatment response has led to speculation that naltrexone may function differently in genetically predisposed individuals (Oslin et al., 2003), leading to the analysis of genetic polymorphisms of the receptor antagonised by Naltrexone, i.e., the Opioid Receptor || 1 (OPRM1).
A classical "problem" in psychopharmacogenetics is that candidate genes involved in the vulnerability to the disorder (i.e., vulnerability genes) have to be distinguished from candidate genes involved in the therapeutic response to the treatment of the disorder (i.e., pharmacogenetic genes). It is possible and expected that a gene coding for a protein which is involved in one of the neurobiological pathways of the disorder (i.e., dopamine in schizophrenia, serotonin in depression, endorphin in addiction...) is also analysed in pharmacogenetics because it belongs to specific targets of the treatment which improves affected patients (i.e., antipsychotics in schizophrenia, antidepressants in mood disorders.). In this view, the OPRM1gene was initially analysed in addict patients compared to healthy controls in a large series of studies.
At least fourty-three variants were identified within the OPRM1 gene which was physically mapped to the chromosomal region 6q24-25 (Wang et al., 1993). Some mutations are potentially of specific interest. Some are located in the 5' untranslated region (T-1793A, -1699Tinsertion, A-1320G, G-172T, C-111T and C-38A), thus potentially affecting transcription rate. Three of the genetic polymorphisms (Ser4Arg; C17T [A6V] and A118G [N40D] [G24A]) may have functional consequences on the binding affinity of the receptor as they modify the amino acid sequence on the N-terminal region. Lastly, other genetic polymorphisms are located either in the third transmembrane domain (C440G [Ser147Cys] ? [N152D]) or in the third intracellular loop (G779A [R260H], [R265H], [S268P] and [D274]) (G877A [Ile Val]) (Bergen et al., 1997; Bond et al., 1998; Befort et al., 2001; Crowley et al., 2003; Wang et al., 2001). If domains in the third intra-cellular loop (R260H, R265H) have been shown to alter both G proteins coupling and calmodulin binding (Wang et al., 2001), the majority of studies were devoted to the impact of the A118G polymorphism. Indeed, the most prevalent single nucleotide substitution is at position 118 (the G118 allele being present in 10% to 15% in the Caucasian population), predicting an amino-acid change at a putative N-glycosylation site.
This A118G variant receptor binds beta-endorphin, an endogenous opioid that activates the |l opioid receptor, approximately three times more tightly than the most common allelic form of the receptor (A118), without showing altered binding affinities for other opioid peptides and alkaloids (Bond et al., 1998). Furthermore, P-endorphin is approximately three times more potent at the
A118G variant receptor than at the most common allelic form in agonist-induced activation of G protein-coupled potassium channels (Bond et al., 1998). Not all studies showed abnormalities of the OPRM1 receptor in patients with the 118G allele (compared to wild type allele), whether it concerns alteration of the glycosylation status of the receptor or binding affinities (Befort et al., 2001). Nevertheless, apart from sporadic finding about patients who had a different tolerance for morphine-6-glucuronide with versus without the G118 allele (Lötsch et al., 2002a), pupil constrictory after administration of morphine, or morphine-6-glucuronide (its active metabolite), was significantly correlated with the number of this allele (0,1 or 2), presence of the 118G allele reducing the potency of M6G in humans (Lötsch et al., 2002b). At a more clinical level, heroin-dependent patients carrying both G31A and C118G genotypes consumed relatively more drugs when compared to other addicts (Shi et al., 2002), although the latter genotype was not independently associated with higher consumption.
The role of the OPRM1 on cortisol response could also be modified in patients carrying the G118 allele. Those patients have higher cortisol concentrations at baseline and after naloxone infusion than subjects with the wild type allele (Hernandez-Avila et al., 2003). Furthermore, subjects expressing the A118G receptor variant had greater cortisol response to opiate receptor blockade (Wand et al., 2002).
If the A118G variants of the OPRM1 gene binds differentially ß-endorphin, this polymorphism offer an interesting candidate gene in addictive disorders such as opiate dependence. Indeed, the genotype distribution was found comparable in opiate dependent patients compared to healthy controls in different samples, whether in was in 180 Caucasians (Schinka et al., 2002) or 100 (Tan et al., 2003) and 200 (Szeto et al., 2001) Chinese patients. Nevertheless, negative studies were also published with samples of comparable size (Berrettini et al., 1997) or even larger (Crawley et al., 2003; Franke et al., 2001. German; Gelernter et al., 1999. European and African).
The association that was sometimes detected seemed to be unrelated to a specific type of dependence (Schinka et al., 2002). In addition, the A118G polymorphism seems to have a role on cortisol level and/or response, which may be involved in the vulnerability to other type of dependence, such as alcoholism. Just as for opiate dependence, case-control studies have failed to demonstrate a consistent association between OPRM1 sequence variation and the presence of alcohol dependence (Bergen et al., 1997; Berrettini et al., 1997; Bond et al., 1998; Sander et al., 1998; Gelernter et al., 1999; Town et al., 1999; Gscheidel et al., 2000; Franke et al., 2001; Szeto et al., 2001; Schinka et al., 2002; Crowley et al., 2003), although sometimes showing a positive association (Kranzler et al., 1998; Hoehe et al., 2000; Rommelspacher et al., 2001).
A German group tried to give sense to these discrepant results in alcohol-dependence, looking at the role of the A118G genotype on an endophenotype of alcohol-dependence, i.e., variation of central dopaminergic sensitivity during alcohol withdrawal (Smolka et al., 1999; Rommelspacher et al., 2001). In fact, the dopaminergic reward system is activated by both ethanol and opioids, and genetically determined differences in the sensitivity of the endogenous opioid system to alcohol among various individuals may be an important factor determining their risk for alcohol consumption. In two different samples, the GH response (stimulated by apomorphine) measured seven days after alcohol withdrawal was significantly increased in alcoholics with the Asn40Asp genotype compared with those carrying the Asn40Asn genotype (Smolka et al., 1999; Rommelspacher et al., 2001).
If the role of the A118G genetic polymorphism is difficult to demonstrate on the large phenotype of addictive disorders, focusing on a specific aspect, related to a precise neurobiological mechanism (i.e., an endophenotype), could be highlighting. Following the same idea, but even closer to the potential impact of this polymorphism, Oslin et al., (2003) analysed the clinical response of detoxified alcohol-dependent patients to Naltrexone, shifting from an endophenotype to a pharmacogenetic approach. This study probably represents the single psychopharmacogenetic analysis in addictive disorder that was performed until now. In this view it has many interesting aspects but also a series of pitfalls. Comparing patients treated by the active compound (Naltrexone) (1) with those treated by placebo, on the basis of a (2) follow-up analysis, taking into account rates of relapse but also (3) the time taken to return to heavy drinking, (4) assessing the percentage of patients treated by cognitive-behavioral therapy and (5) looking for the interaction between the A118G genotype and medication to explain the clinical variables of relapse constitute five important strenghts of this work. On the other hand, the sample is based on 120 alcohol-dependent patients only, and is derived from three studies which initially represented 466 patients, questioning the representativeness of the studied sample. Hence, the comparisons are mainly based on the 6 patients (out of 23) carrying the G allele who relapsed during the 12 weeks follow-up with the 25 others (out of 48) who did not relapse but who carried the AA genotype. Furthermore, because of this sample of limited size, it was not possible to focus on which core clinical features or group of patients this genotype might have a significant impact in predicting efficacy. For example, and in accordance with the three points developed before, it will be important to assess the clinical parameter for which Naltrexone could be effective knowing the genotype for the OPRM1 gene, such as possible euphoria during alcohol-consumption, occasional drinking during the follow-up, and importance of the stress that the patients faced during this same period. Knowing these three parameters will help to depict by which mechanisms the OPRM1 gene might be involved in the Naltrexeone efficacy. In another point of view, a pharmacokinetic approach should also be addressed, controlling for the inter-subjects variability of the correct dosage, even if the recent development of a depot Naltrexone may reduce the importance of this parameter (Kranzler et al., 2004). Clearly, taking into account these aspects when testing the role of a gene in order to detect which patient would benefit more clearly of such a product would mean a much larger sample of patients than the first published one.
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Alcoholism is something that can't be formed in easy terms. Alcoholism as a whole refers to the circumstance whereby there's an obsession in man to keep ingesting beverages with alcohol content which is injurious to health. The circumstance of alcoholism doesn't let the person addicted have any command over ingestion despite being cognizant of the damaging consequences ensuing from it.