Invited Review

Sex differences in the response to opioids for pain relief: A systematic review and meta-analysis

Opioids are the most frequently prescribed drugs for severe, acute [1] or chronic cancer, and non-cancer pain [2]. Their widespread use for chronic pain has contributed to the recent opioid epidemic [3,4].

Differences in both sex (related to biological effects) and gender (related to psycho-socio-cultural effects) have been described in pain sensitivity, tolerance to painful stimuli, prevalence of some chronic pain conditions [5,6] and in the safety, tolerability, efficacy and abuse liability of opioids [7,10]. For instance, certain chronic pain conditions, such as fibromyalgia, migraine, and osteoarthritis, are more frequent in women than men, and women seem to perceive certain painful stimuli as more intense than men [11]. Women also seem to be at higher risk of developing severe postoperative pain than men [12]. The neurobiological basis of these differences is not completely understood, but they seem to be the result of complex interactions between sex and gender effects, together with previous pain experiences [12].

While women receive opioid prescriptions twice as frequently as men [10], it is unclear whether women need less opioid to achieve pain relief. Some studies suggest that women require lower doses of opioids, or higher doses, and other studies did not find sex differences in the dose of opioids to achieve pain relief [13]. Several factors may have influenced these conflicting findings, including differences in the perception of pain at baseline, the type of opioid administered, the dose and the route of administration [e.g., fixed doses or patient-controlled analgesia (PCA)], age-related hormonal status, and comorbid psychiatric disorders [6,9]. For example, men and women metabolize opioids differently [14]. The effects of opioids primarily metabolized by the enzyme CYP3A4 (e.g., fentanyl) may be lower in women than in men, given that the hepatic expression of CYP3A4 is higher in women than men. On the other hand, the effects of opioids like codeine, primarily metabolized by the enzyme CYP2D6, whose hepatic expression is higher in men than women, may be lower in men than in women. Opioid metabolism may be further influenced by exogenous and endogenous sex hormones that are substrates of CYP3A4 and CYP2D6 [15]. Since opioids are lipophilic and men and women differ in body composition (women have more body fat than men) and body weight (BW, on average, women weigh less than men), administration of fixed doses of opioids, not adjusted according to BW, may result in higher blood concentrations in women [8,14,16]. Additionally, the menstrual cycle influences pain thresholds [14], pharmacokinetics [8], analgesic effect [6,17,18], and susceptibility to the side effects of opioids [18]. Furthermore, addictive and mental disorders are common among patients using opioid analgesia [19], and there are large sex/gender differences in their prevalence [17].

In summary, these factors may account for the variability on the interaction between sex/gender and exposure to opioids. To our knowledge, the role of these potential influencing factors has not been systematically investigated in sex variability to the response to opioids. In this meta-analysis, we aimed to investigate the role of potential influencing factors like baseline pain intensity, BW, comorbid mental disorders, type of administration (e.g., fixed doses, dose adjusted according to BW, or PCA), mean age, phase of the menstrual cycle, typology of participants, and use of alcohol, tobacco, or cannabis in sex differences in the response to opioids for pain control. We hypothesized that these factors may be able to influence sex similarities and/or differences in the response to opioids for pain control. To achieve this aim, we first conducted a systematic review and a meta-analysis to evaluate the presence of similarities and differences between men and women in the response to opioids for pain control. Then, we investigated whether the results of the meta-analysis were modified by the potential influencing factors mentioned above.