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Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder.

ABSTRACT: Background and Purpose: Mitragyna speciosa extract and kratom alkaloids decrease alcohol consumption in mice at least in part through actions at the δ-opioid receptor (δOR). However, the most potent opioidergic kratom alkaloid, 7-hydroxymitragynine, exhibits rewarding properties and hyperlocomotion presumably due to preferred affinity for the mu opioid receptor (µOR). We hypothesized that opioidergic kratom alkaloids like paynantheine and speciogynine with reduced µOR potency could provide a starting point for developing opioids with an improved therapeutic window to treat alcohol use disorder. Experimental Approach: We characterized paynantheine, speciociliatine, and four novel kratom-derived analogs for their ability to bind and activate δOR, µOR, and κOR. Select opioids were assessed in behavioral assays in male C57BL/6N WT and δOR knockout mice. Key Results: Paynantheine (10 mg∙kg^-1, i.p.) produced aversion in a limited conditioned place preference (CPP) paradigm but did not produce CPP with additional conditioning sessions. Paynantheine did not produce robust antinociception but did block morphine-induced antinociception and hyperlocomotion. Yet, at 10 and 30 mg∙kg^-1 doses (i.p.), paynantheine did not counteract morphine CPP. 7-hydroxypaynantheine and 7-hydroxyspeciogynine displayed potency at δOR but limited µOR potency relative to 7-hydroxymitragynine in vitro, and dose-dependently decreased voluntary alcohol consumption in WT but not δOR in KO mice. 7-hydroxyspeciogynine has a maximally tolerated dose of at least 10 mg∙kg^-1 (s.c.) at which it did not produce significant CPP neither alter general locomotion nor induce noticeable seizures. Conclusion and Implications: Derivatizing kratom alkaloids with the goal of enhancing δOR potency and reducing off-target effects could provide a pathway to develop novel lead compounds to treat alcohol use disorder with an improved therapeutic window.

SUBMITTER: Gutridge AM

PROVIDER: S-EPMC8596301 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportancePersons with opioid use disorder (OUD) and co-occurring alcohol use disorder (AUD) are understudied and undertreated. It is unknown whether the use of medications to treat OUD is associated with reduced risk of alcohol-related morbidity.ObjectiveTo determine whether the use of OUD medications is associated with decreased risk for alcohol-related falls, injuries, and poisonings in persons with OUD with and without co-occurring AUD.Design, setting, and participantsThis recurrent-event, case-control, cohort study used prescription claims from IBM MarketScan insurance databases from January 1, 2006, to December 31, 2016. The sample included persons aged 12 to 64 years in the US with an OUD diagnosis and taking OUD medication who had at least 1 alcohol-related admission. The unit of observation was person-day. Data analysis was performed from June 26 through September 28, 2020.ExposuresDays of active OUD medication prescriptions, with either agonist (ie, buprenorphine or methadone) or antagonist (ie, oral or extended-release naltrexone) treatments compared with days without OUD prescriptions.Main outcomes and measuresThe primary outcome was admission for any acute alcohol-related event defined by International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. Conditional logistic regression was used to compare OUD medication use between days with and without an alcohol-related event. Stratified analyses were conducted between patients with OUD with and without a recent AUD diagnostic code.ResultsThere were 8 424 214 person-days of observation time among 13 335 participants who received OUD medications and experienced an alcohol-related admission (mean [SD] age, 33.1 [13.1] years; 5884 female participants [44.1%]). Agonist treatments (buprenorphine and methadone) were associated with reductions in the odds of any alcohol-related acute event compared with nontreatment days, with a 43% reduction for buprenorphine (odds ratio [OR], 0.57; 95% CI, 0.52-0.61) and a 66% reduction for methadone (OR, 0.34; 95% CI, 0.26-0.45). The antagonist treatment naltrexone was associated with reductions in alcohol-related acute events compared with nonmedication days, with a 37% reduction for extended-release naltrexone (OR, 0.63; 95% CI, 0.52-0.76) and a 16% reduction for oral naltrexone (OR, 0.84; 95% CI, 0.76-0.93). Naltrexone use was more prevalent among patients with OUD with recent AUD claims than their peers without AUD claims.Conclusions and relevanceThese findings suggest that OUD medication is associated with fewer admissions for alcohol-related acute events in patients with OUD with co-occurring AUD.

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Evaluation of Kratom Opioid Derivatives as Potential Treatment Option for Alcohol Use Disorder.

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