A dose ranging study of naltrexone augmentation of transdermal nicotine patch: Effects on smoking, weight gain, and heavy drinking (Yale, O'Malley).
O'Malley, S., Cooney, J., Krishnan-Sarin, S., Blakeslee, A., Dubin, J., Meandzija, B., Romano-Dahlgard, D., McKee, S., Wu, R., & Makuch, R. Yale University School of Medicine

Although the endogenous opioid system has been implicated in smoking, studies of opiate antagonists for smoking cessation have been inconsistent. Based on human laboratory work showing that opiate antagonists can exacerbate nicotine withdrawal, we devised a method for using naltrexone in combination with nicotine replacement therapy with the goal of increasing tolerability and tested the efficacy of three doses of naltrexone compared to placebo, whereas previous studies have used a single dose. Four hundred individuals who smoked at least one pack per day were enrolled in this six week double-blind study. Smoking cessation outcomes included prolonged abstinence (defined as not even a puff from the quit date) and 6-week point prevalence abstinence. An advantage of the 100 mg dose compared to placebo was found on continuous abstinence. The 25 and 50 mg doses resulted in significantly less weight gain, with this effect occurring most strongly for women. Although there was a small dose response relationship on dropout that was not significant, the drug was well tolerated overall suggesting that the method used to administer naltrexone was successful in minimizing side effects. Among the subset of subjects who drank heavily at baseline, the percentage continuing to drink heavily during treatment was significantly reduced by the 25 and 50 mg doses. Taken together, the results indicate that naltrexone at higher doses in combination with transdermal nicotine replacement can increase smoking cessation rates, particularly when compliance is controlled for, and that lower doses can reduce weight gain and reduce alcohol use among heavy drinkers during a smoking cessation attempt. Although naltrexone's effects on smoking were less pronounced at lower doses, beneficial effects on weight gain and alcohol use in the absence of significant adverse events compared to TNR alone may motivate individuals to seek treatment who might otherwise be reluctant to quit smoking. Secondary analyses suggest that weight concerned smokers may represent an important subgroup who may benefit from naltrexone augmentation of nicotine replacement. Results of an economic study of willingness to pay suggest that prevention of weight gain is a highly valued outcome.