A number of studies have documented that the dosage requirements for targeted effects of CNS drugs can vary widely . For example, in a study of over 3,000 patients experiencing pain following postoperative hip replacement, the therapeutic morphine dosage requirements varied almost 40-fold . Wide inter-patient variability in response to, and therefore in the dosage requirement for morphine have been demonstrated in cancer patients receiving morphine for pain control .
It appears that a number of genetic and environmental factors can lead to significant variation in the doses of a drug necessary to produce therapeutic, hedonic and/or adverse effects. However, there is increasing evidence that gene polymorphisms may be an important factor in determining a person's sensitivity and tolerance to a drug. The mu opioid receptor (OPRM1) is the primary site of action for opiates; about 20 variants in the mu opioid receptor gene (OPRM1) have been identified with amino acid substitutions that have polymorphic frequencies over 1% [4–11]. The most common single nucleotide polymorphism (SNP) reported on is A118G (rs1799971), which encoded the Asp40Asn codon change with most data suggesting that it is a functional variant [4, 12].
There have been a series of studies in both healthy volunteers and in clinical patients suggesting that, the A118G variant may alter response to opioid drugs (see  for review). Lotsch and colleagues reported the 118G allele conferred smaller analgesic effects and produced less pupillary constriction during morphine and morphine-6-glucuronide (MG6) infusion [13–15]. In an experiment using a measure of pain tolerance to electrical stimulation, higher MG6 concentrations were associated with a 25% increase in current (C25) participants with the 118G allele [16, 17]. Similar findings have been found for alfentanil  and levomethdone . In clinical studies, data from patients with the 118G polymorphism tend to confirm data from experimental pain studies where those patients with the variant required higher alfentanil doses for analgesia or more morphine during colorectal surgery  or for pain/toxicity associated with morphine use in renal failure [13, 14]. However, it appears that the effects may be drug or disease specific owing to presumed variation in environmental and/or other uncontrolled variables [1, 21, 22].
Several studies have suggested that the mu receptor may also mediate some of the hedonic and/or addictive effects of non-opioid drugs, such as alcohol [23, 24]. Indirect support for this hypothesis is provided by studies demonstrating the efficacy of naltrexone for the treatment of alcohol dependence [25–31]. Further support is provided by studies evaluating associations between response to naltrexone pharmacotherapy for alcohol dependence and the presence of the A118G variant. In a study that combined data from three different clinical trials, Oslin and colleagues  demonstrated that carriers of the 118G allele had a significantly lower rate of relapse and a longer time to a return to heavy drinking when compared to those individuals who were homozygous for the 118A allele. This finding was not supported in the Veterans Affairs (VA) Cooperative Study where no significant interactions were found between naltrexone treatment response and any polymorphic variants at each of the three opioid receptor genes . More recently, data from the Study for the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study demonstrated that treatment with naltrexone produced a significantly improved clinical global outcome in alcohol dependent participants with the 118G allele, as compared to those with the 118A allele . The A118G polymorphism has also been associated with an individual's response to a naloxone challenge with subjects with the 118G allele showing higher plasma cortisol concentrations [35, 36].
There has been a plethora of studies that have investigated the relationship between a diagnosis of drug and/or alcohol dependence and the A118G polymorphism. The results have been conflicting and inconsistent. In a recent meta-analysis of 28 different studies, including over 8000 subjects, the conclusion was that the OPRM1 A118G variant did not appear to affect risk for substance dependence. However, the authors further speculated that additional research would be needed to determine whether another polymorphism in the gene might influence receptor function and thus risk for substance dependence . An additional feature of these studies, that may have weakened the results, is the use of a dichotomous phenotype, drug dependence, a diagnosis that is made based on both heritable and non-heritable factors . Town and colleagues  suggested that genetic studies on the influence of mu opioid receptors polymorphisms be viewed within the broader context of alcoholism where the opioid receptor genes are taken to be partial, rather than complete, risk factors for the disorder. Thus, it may be that polymorphisms in OPRM1 encode for a variant that influences a more narrowly defined risk factor for alcoholism. This risk factor is envisioned to partially influence the development of the disorder, but may or may not ultimately be associated with the diagnosis depending on the age of the participant, presence of other risk factors and environmental variables.
Individual sensitivity to alcohol represents such an inherited factor that affects the likelihood of drinking and mediates the disposition for developing alcoholism , and has a strong genetic basis . In general, people at higher genetic risk for alcoholism are less sensitive to the effects of alcohol and people at lower genetic risk for alcoholism are more sensitive. Support for this theory is provided by many, but not all, studies examining the reaction to alcohol among children of alcoholics, who are at greatly elevated risk for developing alcoholism . Results have indicated that at moderate doses of alcohol, subjects who are family history positive for alcoholism and subjects who are family history negative for alcoholism attain equivalent blood alcohol concentrations, but most studies have found that subjects with a positive family history rate themselves as significantly less intoxicated than control subjects with a negative family history [43–46]. Although not all studies agree , a meta-analysis focusing on subjective level of intoxication confirmed a diminished response to alcohol as a characteristic more frequently seen in subjects with a positive family history than in those with a negative family history . In addition, an 8-year follow-up of previously studied men with positive and negative family histories found that both a family history of alcoholism and a low response to alcohol were related to the development of alcohol-related problems .
Studies using similar methodologies among groups at lower risk for alcoholism have provided additional support for the idea that individual sensitivity to alcohol might also mediate protection from developing alcoholism. Individuals of Asian heritage, who have mutations in the aldehyde dehydrogenase gene (ALDH2) [50–53], and individuals of Jewish decent , two groups with low rates of alcoholism, were found to have more intense, although not necessarily more negative, responses to alcohol than matched control subjects of average alcoholism risk.
Genetic studies of complex phenotypes, such as sensitivity to alcohol, often have advantages when they are conducted in well-defined populations such as Native American tribes living on reservations . A once popular notion, called the firewater myth, proposed that Native American Indians are constitutionally predisposed to an altered response to drinking alcohol . In one empirical study, Native American Indians, like Caucasian sons of alcoholics, were found to have less intense objective and subjective effects of alcohol in an alcohol challenge paradigm. Additionally, participants with at least 50% Native American heritage reported less intense effects of alcohol than did those with less than 50% Native American heritage, despite equivalent blood alcohol concentrations [57–59].
The present report is part of a larger study exploring risk factors for substance dependence among Native American Indians [57–68]. The lifetime prevalence of substance dependence in this Indian population is high and evidence for heritability and linkage to specific chromosome locations has been demonstrated [65, 69–72]. The purpose of the present set of analyses was to determine if a significant association could be detected between 13 SNPs in the OPRM1 receptor gene and self-report of subjective response to alcohol in this population.