Naltrexone, an antagonist at μ, δ and κ-opioid receptors, is thought to block alcohol-induced opioid activation of reward pathways thereby counteracting aspects of the positive response to alcohol. Subjects in clinical trials who receive naltrexone, overall, report diminished feelings of being ‘high’ after consuming alcohol (Volpicelli et al.
; O’Malley et al.
), note less craving for alcohol (Volpicelli et al.
; O’Malley et al.
), are less likely to relapse to heavy drinking (Kranzler and Van Kirk, 2001
; Srisurapanont and Jarusuraisin, 2002
) and achieve greater rates of abstinence (Kranzler and Van Kirk, 2001
). However, for groups of patients, these actions are modest with mean effect sizes in the 0.1–0.2 range (Kranzler and Van Kirk, 2001
) that has contributed to the low utilization of naltrexone in clinical practice (Mark et al.
Efforts to identify which patients respond to naltrexone have utilized two principal approaches—examination of clinical phenomenology and examination of biogenetic markers, (see the Introduction section). These predictors are not clearly established and, indeed, some have not been confirmed, e.g. Kiefer et al. (2005)
, failed to find an association between craving and naltrexone response. Nevertheless, these efforts suggest that predictors of naltrexone response can be identified and, if confirmed and refined, might have practical clinical value.
Variation in the brain's opioid system is an obvious target to identify naltrexone predictors. The hedonic response to sweet taste represents a heritable trait (Keskitalo et al.
) that likely provides information on brain opioid activity (see Pecina and Berridge, 2005
). The results of the present study indicate that variation in the hedonic response to sweet taste is associated with the ability to achieve and maintain abstinence prior to treatment as well as during naltrexone treatment plus counseling.
Prior to initiating treatment, SL patients required a longer time to achieve 3 consecutive days of abstinence before starting naltrexone compared to SDL patients. This suggests that the propensity to drink alcohol may be stronger in SL subjects such that they have greater difficulty in achieving periods of abstinence. The biological underpinnings of this finding are not clear but could relate to altered opioid function in SL individuals (see below).
All patients demonstrated a sharp reduction in the percentage of heavy drinking days during the treatment period—from ~75% to ~20%, regardless of their SL/SDL status. The robust effect of this treatment is consistent with results reported in other published clinical trials, e.g. Garbutt et al., (2005)
However, SL and SDL individuals differed significantly in their ability to abstain from alcohol (see Fig. ). The median time to achieve 2 consecutive abstinent days for SL patients was 10 times longer than for SDL patients (Fig. ). In other words, for SL patients achieving and maintaining sobriety during treatment was considerably more difficult than for SDL patients—consistent with our finding that SL patients took longer to achieve sobriety prior to starting naltrexone.
The other major post-treatment difference between SL and SDL patients was in the relationship between baseline craving for alcohol and the likelihood of achieving abstinent days. Several groups have reported that the level of severity of the baseline craving for alcohol positively correlates with response to naltrexone (Volpicelli et al.
; Jaffe et al.
; Monterosso et al.
). In our trial we failed to find such an association in the whole sample though in the absence of a placebo-control we were unable to test for a relationship between craving and naltrexone effect size as Monterosso et al. (2001)
did. However, when the SL/SDL phenotype was included in the analysis a highly significant interaction effect between craving, SL/SDL phenotype and percent abstinent days emerged. SL patients demonstrated a positive correlation
and percent abstinent days, indicating that those with higher craving had more
abstinent days when treated with naltrexone as suggested in the literature. On the other hand, SDL subjects showed a negati
ve correlation indicating that, for SDL subjects, higher craving is associated with less
The reason why the combination of the SL/SDL phenotype and craving improves predictive power is not clear. However, one hypothesis is that hedonic response to sweet taste and alcohol craving probe different components of the brain opioid system such that taken together they are more informative than taken separately. Whereas no direct studies in humans have yet been conducted to investigate the relationship of the SL/SDL phenotype to endogenous opioid function, there is extensive animal evidence demonstrating the critical role opioids play in mediating the hedonic response to sweets (see Pecina and Berridge, 2005
). Furthermore, given the evidence that the SL phenotype is associated with familial risk for alcoholism, it could be hypothesized that SL is associated with an inherent dysfunction of β-endorphin release from presynaptic
terminals as reported in individuals at high risk for alcoholism (Gianoulakis, 2004). Conversely, craving for alcohol has been linked to the availability (Heinz et al
) and binding potential (Bencherif et al
., 2004) of postsynaptic
μ-opiate receptors. Therefore, a combination of the SL/SDL phenotype and craving may provide a more integrative measure of brain opioid function.
Another question is why the combination of hedonic response to sweet taste and initial alcohol craving had a predictive value regarding percent abstinent days but not percent heavy drinking days. One potential explanation of this phenomenon is that the overall treatment effect of counseling and naltrexone caused robust suppression of percent heavy drinking days in both SL and SDL groups but for different reasons—SL individuals responded to naltrexone while SDL individuals responded to counseling. Another potential explanation of this outcome is that loss of control over drinking within a drinking episode and inability to abstain from drinking may be determined by different opioidergic mechanisms that have different sensitivity to naltrexone treatment. For example, heavy drinking is often attributed to elevated sensitivity to the rewarding effect of alcohol stemming from increased β-endorphin release from presynaptic terminals in response to ethanol (Gianoulakis, 2004). Naltrexone treatment by reducing the pleasure or the ‘high’ associated with alcohol intake (King et al
., 1997, 2002) may reduce alcohol consumption during a drinking episode. On the other hand, the effect of naltrexone treatment on the ability to abstain from alcohol may be related to its effect on alcohol craving that is associated with the availability (Heinz et al
) and binding potential (Bencherif et al
., 2004) of postsynaptic μ-opiate receptors. However, at this point these conclusions are still highly speculative.
The sample size of the study is modest at 15 SL and 25 SDL subjects. This could lead to a type 1 error though some of the statistical findings, e.g. the interaction effect between craving and SL/SDL status, revealed very robust results, which leads to greater confidence in the finding. With the limited sample size and the preliminary nature of this research, we did not adjust the alpha-level for any statistical contrast (Rothman, 1990
). This lack of adjustment could lead to an inflated type I error as well. Another important limitation is the lack of a placebo group. Without a placebo group the effects of naltrexone versus counseling in SL versus SDL patients cannot be disentangled. This is particularly problematic for the interpretation of the heavy drinking results where both SL and SDL patients showed similar outcomes. As noted earlier, this result could be because both groups respond equally well to naltrexone or it could be, as we hypothesize, that SL patients show a superior response to naltrexone compared to placebo whereas SDL patients respond primarily to counseling.
In summary, we have found preliminary evidence that the SL phenotype predicts fewer days of abstinence in alcohol-dependent patients who are treated with naltrexone and counseling. Furthermore, we also found that the SL/SDL phenotype interacts with craving for alcohol such that SL patients who have high levels of craving are more likely to achieve abstinence whereas SDL patients with high levels of craving are less likely to achieve abstinence. These findings require confirmation and extension but support the hypothesis that the SL phenotype may be useful in advancing understanding of the biological heterogeneity of alcohol dependence and its relationship to naltrexone and treatment response.