Naloxone-Induced Withdrawal in Individuals With and Without Fentanyl-Positive Urine Samples.

BACKGROUND AND OBJECTIVE: This retrospective analysis of data from heroin users screening for clinical research, sought to determine if more naloxone is needed to precipitate opioid withdrawal among those who regularly use heroin with fentanyl, as opposed to those who use heroin without fentanyl. METHODS: Over the course of three to five screening visits, participants completed assessments of drug use, along with urine toxicology tests at each visit. To test for opioid dependence, 29 participants completed a modified Wang test (score: 0-150) during which an intramuscular dose of naloxone (0.2-0.4 mg) was administered and the severity of withdrawal was quantified. RESULTS: The severity of opioid withdrawal was compared between individuals whose urine toxicology regularly tested positive for fentanyl (N = 15), and those only positive for other opioids (N = 14). No significant differences were found in demographic or drug use between the fentanyl-positive (mean: age 41.1 years, 9.1 bags heroin/d) and fentanyl-negative (42.0 years, 10.0 bags heroin/d) groups. Intramuscular naloxone-precipitated robust withdrawal in both samples (P < .01) with no significant difference (P = .8) in the severity (fentanyl positive [100.6 ± 13.4]; fentanyl negative [82.7 ± 9.6]). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These data suggest that a standard naloxone dose can be equally effective at precipitating withdrawal in individuals using heroin with fentanyl compared to heroin without fentanyl. These data contribute to our understanding of how naloxone antagonizes the effects of fentanyl and may have significant implications for the clinical laboratory and opioid overdose. A prospective clinical laboratory study with the proper opioid maintenance controls is needed to provide a more definitive finding. (Am J Addict 2019;00:00-00).

Assessing the contribution of opioid- and dopamine-related genetic polymorphisms to the abuse liability of oxycodone.

BACKGROUND: Attempts to identify opioid users at increased risk of escalating to opioid use disorder have had limited success. Data from a variety of sources suggest that genetic variation may mediate the subjective response to opioid drugs, and therefore contribute to their abuse potential. The goal of the current study was to observe the relationship between select genetic polymorphisms and the subjective effects of oxycodone under controlled clinical laboratory conditions. METHODS: Non-dependent, volunteers with some history of prescription opioid exposure (N = 36) provided a blood sample for analyses of variations in the genes that encode for the µ-, κ- and δ-opioid receptors, and the dopamine metabolizing enzyme, catechol-O-methyltransferase (COMT). Participants then completed a single laboratory test session to evaluate the subjective and analgesic effects of oral oxycodone (0, 10, and 20 mg, cumulative dose = 30 mg). RESULTS: Oxycodone produced typical µ-opioid receptor agonist effects, such as miosis, and decreased pain perception. Oxycodone also produced dose-dependent increases in positive subjective responses such as: drug "Liking" and "Good Effect." Genetic variants in the µ- (rs6848893) and δ-opioid receptor (rs581111) influenced the responses to oxycodone administration. Additionally, self-reported "Stimulated" effects of oxycodone varied significantly as a function of COMT rs4680 genotype. DISCUSSION: The current study shows that the euphoric and stimulating effects of oxycodone can vary as a function of genetic variation. Though the relationship between the stimulating effects of opioids and their abuse liability is not well established, we know that the ability of opioids to provide intense feelings of pleasure is a significant motivator for continued use. If replicated, specific genetic variants may be useful in predicting who is at increased risk of developing maladaptive patterns of use following medical exposure to opioid analgesics.