Systematic review of sex-based differences in opioid-based effects

Abstract

Background: There are several biological factors that might play a role in physiological response to opioids and/or the onset of problematic opioid use; however, sex-based differences in non-analgesic opioid-based effects are poorly understood. The goal of this review is to provide a current analysis of the preclinical literature on sex-based differences in response to endogenous and exogenous opioids, including the interplay between sex hormones and opioid receptor-mediated neuronal activity and associated behaviors. Methods: A systematic search was performed on the following terms within PubMed between March and April of 2018: “opioid estrogen” “opioid progesterone” “opioid estradiol” “opioid testosterone”. Results: Preclinical research on the non-analgesic, sex-based effects of opioids is disparate, both in terms of methodology and outcomes, which prohibits a cohesive summary of the results. Themes from the preclinical literature suggest that opioid receptor binding, coupling, and density vary as a function of hormone exposure. Findings also suggest that interactions between endogenous opioid and stress systems may differ between males and females as a function of ovarian hormones. Conclusions: Given the current opioid-related public health crisis, there is a pressing need to increase systematic preclinical and clinical research on sex-based differences in opioid-effects and opioid use disorder.

Establishing Preclinical Withdrawal Syndrome Symptomatology Following Heroin Self-Administration in Male and Female Rats

“…These data 487 suggest that for females, body temperature may be an important withdrawal sign during both the 488 acute and protracted withdrawal period, though males may only show a signal on body 489 temperature during the protracted period. These findings converge with other preclinical evidence 490 that sex mediates some opioid effects (Huhn, Berry, & Dunn, 2018). Current human clinical data 491 on this topic are limited to differences in treatment presentation between men and women (Huhn,492 Berry, & Dunn, 2019), neonatal abstinence syndrome following prenatal opioid exposure (Klaman 493 et al, 2017), and menstrual cycle abnormalities and amenorrhea following chronic opioid 494 exposure (Santen et al, 1975;Schmittner et al, 2005).…”

Non-Opioid Neurotransmitter Systems that Contribute to the Opioid Withdrawal Syndrome: A Review of Preclinical and Human Evidence

“…Thus, this paper should be conceptualized as a narrative summary to stimulate future investigations. Finally, despite evidence that many opioid effects may be mediated by gonadal hormones (Huhn et al, 2018) the majority of preclinical and human studies reviewed herein evaluated predominately (and often exclusively) male samples. More research is needed to determine whether medications are equally effective for both sexes, particularly in light of data suggesting hormones impact craving and relapse vulnerability for other drugs of abuse (e.g., Carpenter et al, 2006;Franklin et al, 2008).…”

“…1; Table 1) that vary across individuals with regard to incidence and severity; no demographic or drug use characteristics have been identified that reliably predict the severity of human opioid withdrawal symptoms. An exception to this is gender, for which there is substantial preclinical evidence to support causal associations between gonadal hormones and opioid effects (Huhn et al, 2018), and some limited human empirical evidence that gender may moderate withdrawal severity (Dunn et al, 2018b).…”

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

“…Manuscripts were included in this review if they (1) included a study abstract, (2) were published in English, (3) were a peer reviewed, original research article, (4) were published between the years of 1990 -March, 2018, (5) focused on outcome measures relevant to OUD treatment (e.g., continued drug use, comorbidities), (6) reported data that statistically compared outcomes as a function of sex, and (7) were conducted in human subjects. Manuscripts were excluded if (1) the primary outcome measures were pain, analgesia, and/or antinociception, or (2) only described results for one sex.…”

“…Sex may be one of the most obvious potential biological predictors of disease, and there is growing recognition that men and women respond to drugs in a way that is qualitatively different and clinically meaningful. There is evidence from preclinical literature that sex hormones confer sex-based differences in opioid-based effects 6 , and animal studies suggest females are more vulnerable to the positive reinforcing effects of opioids that underlie acquisition of OUD and the negative reinforcing effects of opioids that promote dysregulation, escalation, and relapse that might also exacerbate the pace of OUD progression 7 . In the clinical literature, sex-based differences has been well characterized for stimulants, for which there is clear evidence that women's subjective experience to stimulants such as cocaine varies as a function of the menstrual cycle phase 8 .…”