For example, marked upregulation of opioid receptors and hyper-sensitivity to opioids have been observed with naltrexone in preclinical studies. Another possibility is that the central opioid system may have low endogenous functionality in most individuals, becoming active only in the presence of exogenously administered opioid receptor agonists or with stimulation by endogenous opioids induced by pain or stress. A third possibility is that normal individuals may experience different side effects with naltrexone than people with addictive disease such as alcohol or opioid dependence, who may have altered opioid tone or responsiveness. It is notable in this regard that most studies of naltrexone have been in people with substance dependence.Naltrexone may also initially produce opioid withdrawal-like symptoms in a small subset of people not dependent on opioids:
The side-effect profile [of naltrexone], at least on the recommended dose of 50 mg per day, is generally benign, although 5 to 10 percent of detoxified opioid addicts experience immediate, intolerable levels of withdrawal-like effects including agitation, anxiety, insomnia, light-headedness, sweating, dysphoria, and nausea. Most patients on naltrexone experience few or no symptoms after the first 1 to 2 weeks of treatment; for a substantial minority (20 to 30 percent) protracted discomfort is experienced.Persisting affective distress related to naltrexone may account for individuals taking the drug who drop out of treatment.Naltrexone has been reported to reduce feelings of social connection. Studies on whether naltrexone can decrease the pleasurable effects of listening to music are conflicting.
In accordance with its partial agonism, although naltrexone is described as a pure opioid receptor antagonist, it has shown some evidence of weak opioid effects in clinical and preclinical studies.By itself, naltrexone acts as an antagonist or weak partial agonist of the opioid receptors. In combination with agonists of the MOR such as morphine however, naltrexone appears to become an inverse agonist of the MOR. Conversely, naltrexone remains a neutral antagonist (or weak partial agonist) of the KOR and DOR. In contrast to naltrexone, 6β-naltrexol is purely a neutral antagonist of the opioid receptors. The MOR inverse agonism of naltrexone when it is co-present with MOR agonists may in part underlie its ability to precipitate withdrawal in opioid-dependent individuals. This may be due to suppression of basal MOR signaling via inverse agonism.Occupancy of the opioid receptors in the brain by naltrexone has been studied using positron emission tomography (PET). Naltrexone at a dose of 50 mg/day has been found to occupy approximately 90 to 95% of brain MORs and 20 to 35% of brain DORs. Naltrexone at a dose of 100 mg/day has been found to achieve 87% and 92% brain occupancy of the KOR in different studies. Per simulation, a lower dose of naltrexone of 25 mg/day might be expected to achieve around 60% brain occupancy of the KOR but still close to 90% occupancy of the MOR.