Reduced dosing and liability in methadone maintenance treatment by targeting oestrogen signal for morphine addiction

Abstract

Methadone maintenance treatment (MMT) is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. This study discovered that the estrogen‐response element single nucleotide polymorphism (ERE‐SNP; rs16974799, C/T) of cytochrome 2B6 gene (cyp2b6; methadone catabolic enzyme) responded differently to MMT dosing. Oestradiol was associated with high MMT dosing, high enantiomer (R‐ or S‐) of 2‐ethylidene‐1,5‐dimethyl‐3,3‐dipheny‐pyrrolidine (EDDP; methadone metabolite) to methadone ratio and increased drug‐seeking behaviour, implicating oestradiol‐CYP‐EDDP/methadone axis decreasing MMT efficacy. In mouse model, oestrogen mitigates methadone antinociceptive response, facilitates methadone catabolism and up‐regulates methadone‐associated metabolizing enzymes. Oestrogen also ablates chronic methadone administration‐induced rewarding response. Mechanism dissection revealed the CC genotype of CYP2B6‐ERE‐SNP exerts higher ERE sequence alignment score, higher estrogenic response as compared to TT genotype. At last, preclinical study via targeting estrogen signal that tamoxifen (TMX; selective estrogen receptor modulator, SERM) could facilitate the tolerance phase rewarding response of methadone. Strikingly, TMX also reduces tapering/abstinence phases methadone liability in mice. In conclusion, this study demonstrates altering methadone metabolism through targeting estrogen signals might be able to free morphine addictive patients from the addiction of opioid replacement therapy. Therefore, the add‐on therapy clinical trial introducing SERM in MMT regimen is suggested.

Can neuroimaging help combat the opioid epidemic? A systematic review of clinical and pharmacological challenge fMRI studies with recommendations for future research

“…Furthermore, endogenous gonadal hormones impact opioid effects. For example, estrogens can diminish opioids' antinociceptive effects [132], there is evidence of interactions and crosstalk between opioid and estrogen receptors [133], and estrogens may impact the antinociceptive and rewarding effects of methadone through effects on methadone metabolism [134]. In addition, recent preclinical work suggests sex-specific effects of acute opioid withdrawal and subsequent opioid replacement (with methadone or buprenorphine) on regional brain metabolism within regions including the anterior cingulate, amygdala and striatum [135,136].…”

Review: Sex‐Based Differences in Treatment Outcomes for Persons With Opioid Use Disorder

“…An additional multi-site trial in Canada (N=231) reported that men receiving MMT had lower levels of testosterone than healthy non-MMT males, and that testosterone levels were negatively correlated with methadone dose; there were no significant findings regarding testosterone levels in females in this study 31 . A study in Taiwan (N=411) found that higher methadone doses in women was positively correlated with higher levels of estradiol 32 . Finally, a retrospective chart review of medical records from a publicly-funded treatment center (N=465) reported that women experienced more total adverse events, and specifically headaches, than men following treatment with the opioid antagonist/relapse prevention medication extended-release naltrexone 33 .…”

LDLR-mediated lipidome–transcriptome reprogramming in cisplatin insensitivity

“…The protocol for detecting mRNA expression followed that detailed in a previous publication (Chiang et al 2017) with some modifications. Total RNA was isolated from the tissue using the Trizol™ reagent (Invitrogen) according to the manufacturer's protocol.…”