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Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone.

ABSTRACT: Prescription opioid abuse has risen dramatically in the United States as clinicians have increased opioid prescribing for alleviation of both acute and chronic pain. Opioid analgesics with decreased risk for abuse are needed.Preclinical and clinical studies have shown that opioids combined with ultra-low-dose naltrexone (NTX) may have increased analgesic potency and have suggested reduced abuse or dependence liability. This study addressed whether addition of ultra-low-dose naltrexone might decrease the abuse liability of oxycodone (OXY) in humans.This double-blind, placebo-controlled study systematically examined the subjective and physiological effects of combining oral OXY and ultra-low NTX doses in 14 experienced opioid abusers. Seven acute drug conditions given at least 5 days apart were compared in a within-subject crossover design: placebo, OXY 20 mg, OXY 40 mg, plus each of the active OXY doses combined with 0.0001 and 0.001 mg NTX.The methods were sensitive to detecting opioid effects on abuse liability indices, with significant differences between all OXY conditions and placebo as well as between 20 and 40 mg OXY doses on positive subjective ratings (e.g., "I feel a good drug effect" or "I like the drug"), on observer- and participant-rated opioid agonist effects, and on a drug-versus-money value rating. There were no significant differences or evident trends associated with the addition of either NTX dose on any abuse liability indices.The addition of ultra-low-dose NTX to OXY did not decrease abuse liability of acutely administered OXY in experienced opioid abusers.

SUBMITTER: Tompkins DA

PROVIDER: S-EPMC2878387 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone.

Tompkins David Andrew DA Lanier Ryan K RK Harrison Joseph A JA Strain Eric C EC Bigelow George E GE

Psychopharmacology 20100413 4

<h4>Rationale</h4>Prescription opioid abuse has risen dramatically in the United States as clinicians have increased opioid prescribing for alleviation of both acute and chronic pain. Opioid analgesics with decreased risk for abuse are needed.<h4>Objective</h4>Preclinical and clinical studies have shown that opioids combined with ultra-low-dose naltrexone (NTX) may have increased analgesic potency and have suggested reduced abuse or dependence liability. This study addressed whether addition of ...[more]

PMID: 20386884

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Project description:It is estimated that nearly a third of people who abuse drugs started with prescription opioid medicines. Approximately, 11.5 million Americans used prescription drugs recreationally in 2016, and in 2018, 46,802 Americans died as the result of an opioid overdose, including prescription opioids, heroin, and illicitly manufactured fentanyl (National Institutes on Drug Abuse (2020) Opioid Overdose Crisis. https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis . Accessed 06 June 2020). Yet physicians will continue to prescribe oral opioids for moderate-to-severe pain in the absence of alternative therapeutics, underscoring the importance in understanding how drug choice can influence detrimental outcomes. One of the opioid prescription medications that led to this crisis is oxycodone, where misuse of this drug has been rampant. Being one of the most highly prescribed opioid medications for treating moderate-to-severe pain as reflected in the skyrocketed increase in retail sales of 866% between 1997 and 2007, oxycodone was initially suggested to be less addictive than morphine. The false-claimed non-addictive formulation of oxycodone, OxyContin, further contributed to the opioid crisis. Abuse was often carried out by crushing the pills for immediate burst release, typically by nasal insufflation, or by liquefying the pills for intravenous injection. Here, we review oxycodone pharmacology and abuse liability as well as present the hypothesis that oxycodone may exhibit a unique pharmacology that contributes to its high likability and abuse susceptibility. We will discuss various mechanisms that likely contribute to the high abuse rate of oxycodone including clinical drug likability, pharmacokinetics, pharmacodynamics, differences in its actions within mesolimbic reward circuity compared to other opioids, and the possibility of differential molecular and cellular receptor interactions that contribute to its selective effects. We will also discuss marketing strategies and drug difference that likely contributes to the oxycodone opioid use disorders and addiction.

Project description:BackgroundAttempts 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.MethodsNon-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).ResultsOxycodone 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.DiscussionThe 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.

Project description:RATIONALE:Subanesthetic ketamine (KET) elicits rapid, robust, but transient antidepressant effects. KET's antidepressant actions can be augmented and maintained for a longer duration when repeatedly delivered. However, KET is recreationally abused, raising long-term treatment safety concerns. Women are more likely than men to seek treatment for depression, escalate from casual to compulsive drug use, and are more sensitive to antidepressants. Similarly, female rodents are more sensitive than males to KET's rapid antidepressant-like behavioral effects; dose-response thresholds in these assays equal 2.5 and 5.0mg/kg (i.p.), respectively. This suggests the utility of preclinical rodent models in optimizing sex-differential KET therapy protocols and minimizing adverse drug reactions. OBJECTIVES:Here, we assessed behavioral and biochemical correlates of abuse liability following six serial KET treatments on alternating days at three subanesthetic, antidepressant-like doses (2.5, 5.0, or 10mg/kg, i.p.) in adult male and female rats. A potential role for ?FosB-mediated transcription in the nucleus accumbens is outlined in the context of KET-mediated locomotor sensitization. RESULTS:Antidepressant-like threshold doses (2.5, 5.0mg/kg KET) failed to evoke a conditioned place preference in all animals, but only males positively responded to a higher dose (10mg/kg). Behavioral sensitization to 5.0 or 10mg/kg KET's locomotor-activating effects was established in both sexes, and females' sensitized response to 5.0mg/kg was greater than males'. KET-induced hyperlocomotion positively correlated with ?FosB protein expression in the nucleus accumbens. rAAV-?JunD inhibition of ?FosB-mediated transcription in the accumbens failed to block locomotor sensitization to 10mg/kg KET. CONCLUSIONS:These data suggest that in rats, six alternating-day treatments with 2.5mg/kg KET do not induce apparent behavioral signatures of abuse liability despite accumulation of ?FosB protein in the accumbens. Additionally, females are more sensitive than males to KET's locomotor-stimulant properties, both acutely and after repeated treatments. More studies are needed to determine brain regions and neural mechanisms responsible for KET-induced behavioral adaptations and to extrapolate these data to inform sex-dependent strategies for long-term KET therapy protocols for depression.

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Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone.

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Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone.

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