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The opioid receptor triple agonist DPI-125 produces analgesia with less respiratory depression and reduced abuse liability.

ABSTRACT: Opioid analgesics remain the first choice for the treatment of moderate to severe pain, but they are also notorious for their respiratory depression and addictive effects. This study focused on the pharmacology of a novel opioid receptor mixed agonist DPI-125 and attempted to elucidate the relationship between the ?-, ?- and ?-receptor potency ratio and respiratory depression and abuse liability. Five diarylmethylpiperazine compounds (DPI-125, DPI-3290, DPI-130, KUST202 and KUST13T02) were selected for this study. PKA fluorescence redistribution assays in CHO cells individually expressing ?-, ?- or ?-receptors were used to measure the agonist potency. The respiratory safety profiles were estimated in rats by the ratio of ED50 (pCO2 increase)/ED50 (antinociception). The abuse liability of DPI-125 was evaluated with a self-administration model in rhesus monkeys. The observed agonist potencies of DPI-125 for ?-, ?- and ?-opioid receptors were 4.29±0.36, 11.10±3.04, and 16.57±4.14 nmol/L, respectively. The other four compounds were also mixed agonists with varying potencies. DPI-125 exhibited a high respiratory safety profile, clearly related to its high ?-receptor potency. The ratio of the EC50 potencies for the ?- and ?-receptors was found to be positively correlated with the respiratory safety ratio. DPI-125 has similar potencies for ?- and ?-receptors, which is likely the reason for its reduced abuse potential. Our results demonstrate that the opioid receptor mixed agonist DPI-125 is safer and less addictive than traditional ?-agonist analgesics. These findings suggest that the development of ?>??? opioid receptor mixed agonists is feasible, and such compounds could represent a promising class of potent analgesics with wider therapeutic windows.

SUBMITTER: Yi SP

PROVIDER: S-EPMC5519248 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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The opioid receptor triple agonist DPI-125 produces analgesia with less respiratory depression and reduced abuse liability.

Yi Shou-Pu SP Kong Qing-Hong QH Li Yu-Lei YL Pan Chen-Ling CL Yu Jie J Cui Ben-Qiang BQ Wang Ying-Fei YF Wang Guan-Lin GL Zhou Pei-Lan PL Wang Li-Li LL Gong Ze-Hui ZH Su Rui-Bin RB Shen Yue-Hai YH Yu Gang G Chang Kwen-Jen KJ

Acta pharmacologica Sinica 20170515 7

Opioid analgesics remain the first choice for the treatment of moderate to severe pain, but they are also notorious for their respiratory depression and addictive effects. This study focused on the pharmacology of a novel opioid receptor mixed agonist DPI-125 and attempted to elucidate the relationship between the δ-, μ- and κ-receptor potency ratio and respiratory depression and abuse liability. Five diarylmethylpiperazine compounds (DPI-125, DPI-3290, DPI-130, KUST202 and KUST13T02) were selec ...[more]

PMID: 28502978

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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:BACKGROUND:This is an updated version of the original Cochrane review published in Issue 4, 2006. Patients may control postoperative pain by self administration of intravenous opioids using devices designed for this purpose (patient controlled analgesia or PCA). A 1992 meta-analysis by Ballantyne et al found a strong patient preference for PCA over non-patient controlled analgesia, but disclosed no differences in analgesic consumption or length of postoperative hospital stay. Although Ballantyne's meta-analysis found that PCA did have a small but statistically significant benefit upon pain intensity, a 2001 review by Walder et al did not find statistically significant differences in pain intensity or pain relief between PCA and groups treated with non-patient controlled analgesia. OBJECTIVES:To evaluate the efficacy and safety of patient controlled intravenous opioid analgesia (termed PCA in this review) versus non-patient controlled opioid analgesia of as-needed opioid analgesia for postoperative pain relief. SEARCH METHODS:We ran the search for the previous review in November 2004. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 12), MEDLINE (1966 to 28 January 2015), and EMBASE (1980 to 28 January 2015) for randomized controlled trials (RCTs) in any language, and reference lists of reviews and retrieved articles. SELECTION CRITERIA:We selected RCTs that assessed pain intensity as a primary or secondary outcome. These studies compared PCA without a continuous background infusion with non-patient controlled opioid analgesic regimens. We excluded studies that explicitly stated they involved patients with chronic pain. DATA COLLECTION AND ANALYSIS:Two review authors independently extracted data, which included demographic variables, type of surgery, interventions, efficacy, and adverse events. We graded each included study for methodological quality by assessing risk of bias and employed the GRADE approach to assess the overall quality of the evidence. We performed meta-analysis of outcomes that included pain intensity assessed by a 0 to 100 visual analog scale (VAS), opioid consumption, patient satisfaction, length of stay, and adverse events. MAIN RESULTS:Forty-nine studies with 1725 participants receiving PCA and 1687 participants assigned to a control group met the inclusion criteria. The original review included 55 studies with 2023 patients receiving PCA and 1838 patients assigned to a control group. There were fewer included studies in our updated review due to the revised exclusion criteria. For the primary outcome, participants receiving PCA had lower VAS pain intensity scores versus non-patient controlled analgesia over most time intervals, e.g., scores over 0 to 24 hours were nine points lower (95% confidence interval (CI) -13 to -5, moderate quality evidence) and over 0 to 48 hours were 10 points lower (95% CI -12 to -7, low quality evidence). Among the secondary outcomes, participants were more satisfied with PCA (81% versus 61%, P value = 0.002) and consumed higher amounts of opioids than controls (0 to 24 hours, 7 mg more of intravenous morphine equivalents, 95% CI 1 mg to 13 mg). Those receiving PCA had a higher incidence of pruritus (15% versus 8%, P value = 0.01) but had a similar incidence of other adverse events. There was no difference in the length of hospital stay. AUTHORS' CONCLUSIONS:Since the last version of this review, we have found new studies providing additional information. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides moderate to low quality evidence that PCA is an efficacious alternative to non-patient controlled systemic analgesia for postoperative pain control.

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The opioid receptor triple agonist DPI-125 produces analgesia with less respiratory depression and reduced abuse liability.

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The opioid receptor triple agonist DPI-125 produces analgesia with less respiratory depression and reduced abuse liability.

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