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. Author manuscript; available in PMC: 2019 Oct 1.
Published in final edited form as: Curr Opin Behav Sci. 2018 Sep 3;23:183–190. doi: 10.1016/j.cobeha.2018.08.001

Impact of sex on pain and opioid analgesia: a review

Evan F Fullerton 1, Hillary H Doyle 1, Anne Z Murphy 1
PMCID: PMC6428208  NIHMSID: NIHMS1503105  PMID: 30906823

Abstract

Chronic pain is a debilitating condition that impacts tens of millions each year, resulting in lost wages for workers and exacting considerable costs in health care and rehabilitation. A thorough understanding of the neural mechanisms underlying pain and analgesia is critical to facilitate the development of therapeutic strategies and personalized medicine. Clinical and epidemiological studies report that women experience greater levels of pain than men and have higher rates of pain-related disorders. Studies in both rodents and humans report sex differences in the anatomical and physiologic properties of the descending antinociceptive circuit, mu opioid receptor (MOR) expression and binding, morphine metabolism, and immune system activation, all of which likely contribute to the observed sex differences in pain and opioid analgesia. Although more research is needed to elucidate the underlying mechanisms, these sex differences present potential therapeutic targets to optimize pain management strategies for both sexes.

Sex differences in pain and pain sensitivity

Pain is one of the most commonly reported health problems in the United States (Elzahaf et al., 2012; Kennedy et al., 2014). An NIH survey found that roughly 55% of American adults experienced acute pain within the previous three months, while more than 10% reported experiencing chronic pain, clinically defined as pain lasting longer than three months (Nahin, 2015). As both acute and chronic pain affect a significant portion of the population, the treatment of pain is of large-scale economic concern. Indeed, the United States annual cost of pain treatment is estimated at $600 billion (Medicine, 2011).

Epidemiological studies report that women suffer from chronic pain more frequently than men (LeResche, 2011; Greenspan et al., 2007). Women also experience higher rates of chronic pain conditions such as fibromyalgia, migraine, and osteoarthritis (Unruh, 1996; Fillingim et al., 2009; Mogil, 2012; Ruau et al., 2012; Kennedy et al., 2014). Although it is not clear if the increased incidence of chronic pain conditions observed in females results from greater susceptibility to such conditions or is due to women being more likely than men to report pain (for review see Berkley et al., 2006), women are more likely than men to use health care services for both painful and non-painful conditions (Bertakis et al., 2000; Prevention, 2014). Women are also more likely to experience significantly higher pain levels than men with the same diagnosis (Ruau et al., 2012).

Importantly, not all studies in humans report a sex difference in pain sensitivity (Fillingim et al., 2009). However, when results do suggest a sex difference, women are found to be more sensitive to pain than men and experience greater adverse effects of pain than men (Fillingim et al., 2009; Mogil, 2012).

Opioid Analgesia

Opioids are the most effective and common treatment for pain management (Trescot et al., 2008), with over 65 prescriptions written per 100 Americans in 2016 (CDC, 2017). Sex differences in the prescription of opioids have been reported, with women more likely than men to be prescribed opioids. Women are also prescribed higher doses than men (Campbell et al., 2010). Opioids (such as morphine and fentanyl) act by binding to neuronal mu-opioid receptors (MORs) to inhibit pain. However, opioids also induce respiratory depression, gut immotility, nausea, dysphoria, headache, and vomiting, with women more likely than men to experience many of these negative side effects (Myles et al., 1997; Cepeda et al., 2003; Fillingim et al., 2005; Comer et al., 2010). Long-term opiate use also results in the development of tolerance, leading to a reduction in opioid potency that is typically countered with dose escalation (Trescot et al., 2006; Trescot et al., 2008). The development of opioid tolerance and the resulting dose increase leads to a higher risk of addiction and overdose (Trescot et al., 2006). Clinically, men are two times more likely to have used opiates, including heroin, within the past month, year, and across the lifespan (NSDUH, 2016; see Riley et al. 2018 for review), and preclinical studies in rodents report that males experience longer and more severe withdrawal symptoms from opiates than females (Cicero et al., 2002; Diaz et al., 2005).

The existence of sex differences in opioid analgesia remains controversial. Although some studies report no sex difference in the analgesic efficacy of opioids in humans (Sarton et al., 2000; Fillingim et al., 2005; Bijur et al., 2008), other studies report that opioids exhibit decreased analgesic efficacy in women (Cepeda and Carr, 2003; Miller and Ernst, 2004). Importantly, these results are dependent on the setting (clinic versus laboratory), duration of pain (acute versus chronic) and type of pain (visceral, inflammatory or orofacial) for which opioids are prescribed. Preclinical studies using rodent models are more consistent, with the majority of studies reporting that morphine is more efficacious in modulating persistent pain in males than females. Indeed, using a variety of acute and chronic pain assays, researchers have shown that morphine’s median effective dose in female rodents is approximately twice the concentration of the dose needed for males to achieve comparable levels of pain relief (Kepler et al., 1989; Cicero et al., 2002; Ji et al., 2006; Loyd and Murphy, 2006; Loyd et al., 2008; Posillico et al., 2015). Researchers using other opioids have reported similar results (Barrett et al., 2002; Bai et al., 2015). Studies investigating the side-effects of opioids suggest that in rodents, females suffer from higher rates of opioid-induced hyperalgesia than males (Holtman and Wala, 2005; Juni et al., 2008). It is important to note that the origin of these sexually dimorphic properties may result from biological differences between sexes, environmental factors, or some interaction between the two. Researchers investigating the source of phenotypic differences between the sexes take into account multiple developmental elements that impact neurobiology and behavior such as genetic, hormonal, and epigenetic factors (for a thorough review, see Becker and Chartoff, 2018).

Mechanisms of analgesia: Endogenous

The CNS utilizes an endogenous descending neural pathway to reduce pain in a process called antinociception. Essential to this descending antinociceptive pathway is the midbrain periaqueductal gray (PAG) and its downstream targets, the rostral ventromedial medulla (RVM), and the spinal cord (Behbehani and Fields, 1979; Fields and Heinricher, 1985; see Figure 1). Indeed, electrical stimulation of the PAG induces a robust, opioid-dependent analgesia (Reynolds, 1969) that is attenuated by intra-PAG injection of the opioid receptor antagonist (−)-naloxone (Akil et al., 1976). Sex differences in pain sensitivity have been suggested to occur, in part, due to differences in endogenous opioid neurotransmission and in the circulation of steroid hormones (Micevych et al., 2003; LeResche et al., 2003; Smith et al., 2006; Pluchino et al. 2009). Specifically, studies in rodents indicate significant sex differences in the anatomical and physiological characteristics of the PAG-RVM-spinal cord circuit. Further, persistent inflammatory pain results in a greater activation of this descending circuit in males than in females. Similarly, systemic administration of morphine results in a significantly greater activation of this circuit in males than in females (Loyd and Murphy, 2006; Loyd et al., 2007).

Figure 1.

Figure 1.

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Noxious stimuli activate nociceptors located on primary afferents, which then relay nocispecific information to the dorsal horn of the spinal cord via the dorsal root ganglia (DRG). From here, nociceptive-specific information is relayed supraspinally to the PAG, thalamus and higher cortical regions. Both endogenous and exogenous opioids activate the PAG and its descending projections to the RVM and spinal cord to ultimately inhibit incoming pain signals (adapted from Guo et al., 2006).

Mechanisms of analgesia: Exogenous

Morphine and other exogenous opioids bind to MORs in the central nervous system to further modulate pain (Jensen and Yaksh, 1986; Loyd et al., 2008). MORs are G-protein coupled receptors whose activation inhibits neuronal activity (i.e. hyperpolarization) (Millan, 2002). The midbrain PAG, a critical structure in the descending modulation of pain, contains a high density of MOR+ neurons (Wang and Wessendorf, 2002; Commons et al., 2000), and we have previously reported that male rats show higher levels of PAG MOR expression and binding than females (Loyd et al., 2008). The binding of PAG MORs disinhibits tonically active GABAergic interneurons, resulting in the net activation of the PAG-RVM-spinal cord circuit and the inhibition of pain transmission (Al-Hasani and Bruchas, 2011; Lau and Vaughan, 2014). Intra-PAG administration of morphine or MOR selective agonists results in sex-dependent analgesia. For example, Krzanowska and Bodnar (Krzanowska and Bodnar, 1999) reported intra-PAG morphine ED50 values of 1.2 μg for male rats in comparison to 50 μg in estrus female rats. In a model of persistent inflammatory pain, we reported intra-PAG morphine ED50 values for males of 7.5 μg versus 15 μg for females (Loyd et al., 2008). Ablation of MOR+ neurons in the ventrolateral PAG reduces the analgesic efficacy of morphine in males but not in females, suggesting that PAG MOR expression is correlated with the degree of opioid analgesia in males (Loyd et al., 2008). Although sex differences in PAG MOR levels contribute to the dimorphic effects of morphine, several other factors have also been implicated, including neuroimmune signaling and opioid metabolism.

Opioids and Inflammation

Neuroinflammation has been implicated in increased pain sensitivity and decreased opioid analgesia via the activity of glial cells, particularly microglia. Microglia survey the central nervous system for signals of cellular distress such as tissue injury and react to the presence of pathogens, including nitric oxide, substance P, and prostaglandins (Watkins et al., 2009). These molecules bind to receptors called toll-like receptors (TLRs), located primarily on the surface of microglia. Binding to microglial toll-like receptor 4 (TLR4) results in the transition of microglia from a resting state to an activated state, a process called reactive gliosis (Watkins and Maier, 2003; Hutchinson et al., 2008a; Watkins et al., 2009). In their activated state, microglia release pro-inflammatory molecules including cytokines (e.g. interleukins 1 and 6, (IL-1, IL-6), and tumor necrosis factor (TNF)), chemokines (e.g. IL-8, CCL2, and CCL5), cyclooxygenase-2 (COX-2), prostaglandins, and reactive oxygen species (ROS) (Bonizzi and Karin, 2004). Together these molecules down-regulate inhibitory GABAA receptors, up-regulate excitatory neuronal AMPA and NMDA receptors, and decrease glutamate transporter activity, effectively increasing neural excitability and opposing morphine action (Watkins et al., 2005; Yan et al., 2014; Eidson et al., 2016). Activated microglia are observed in virtually every known animal model of clinical pain, and the activation of microglia via complete Freund’s adjuvant (CFA) or the TLR4 agonist lipopolysaccharide (LPS), causes robust allodynia and hyperalgesia (Watkins et al., 1994; Sorge et al., 2011). Both the inhibition of microglial function and the blockade of pro-inflammatory molecule release prevent the development of hyperalgesia (Maier and Watkins, 1998; Ledeboer et al., 2005; Hutchinson et al., 2008).

Morphine and other opioids bind not only to neuronal MOR but also to microglial TLR4 and its co-receptor myeloid differentiation factor 2 (MD-2), which together with the recruitment of the adaptor protein MyD88, initiate a neuroinflammatory response that contributes to many of the negative side effects associated with opioid consumption, including hyperalgesia, respiratory depression, and tolerance (Hutchinson et al., 2007; Hutchinson et al., 2010; Eidson and Murphy, 2013; Thomas et al., 2015; see Figure 2). Recently, our lab has shown that morphine activates TLR4 within the midbrain PAG to induce cytokine release, resulting in the attenuation of morphine analgesia and the induction of tolerance (Eidson and Murphy, 2013; Eidson et al., 2016). Blockade of PAG TLR4 signaling, and the ensuing cytokine production, augments morphine-induced analgesia and attenuates the development of tolerance (Eidson and Murphy, 2013; Eidson et al., 2017; Doyle et al., 2017).

Figure 2.

Figure 2.

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TLR4 binding leads to the transcription and release of pro-inflammatory products.

Microglia and Sex Differences

Our recent studies suggest that sex differences in microglia phenotype within the PAG also contribute to the sexually dimorphic effects of morphine (Doyle et al., 2017; Doyle and Murphy, 2018). Specifically, we showed that although no sex differences in basal microglia expression (density) was observed within the PAG, the percentage of microglia showing an ‘activated’ phenotype at baseline was significantly higher in females than males. We further showed a significant relationship between morphine potency (i.e. ED50) and the percentage of activated microglia in the PAG of females, but not males.

As stated above, in addition to binding to neuronal MOR, most opioids, including morphine, bind to the the MD-2 co-receptor of TLR4 on microglia. Although the classical MOR binds only the (−)-stereoisomer of opioids, TLR4 binds opioids in a non-stereoselective manner, such that both the (−) and (+) isomers of opioid ligands modulate glial signaling. This unique feature has allowed researchers to investigate TLR4-mediated activity without affecting opioid receptor signaling (Wu et al. 2006). Our lab has recently reported that inhibition of PAG microglia with the selective TLR4 antagonist (+)-naloxone significantly potentiated morphine analgesia in females, but not males, abolishing the sex difference in opiate response. Indeed, morphine ED50 values for females co-administered (+)-naloxone decreased from 7.9 mg/kg to 3.16 mg/kg, a 2.5-fold reduction in ED50. These results suggest that PAG microglia are innately different in males and females in terms of their morphological state and implicate TLR4 in the attenuated response to morphine observed in females.

Morphine Metabolism

Morphine is metabolized by both the liver and the brain to produce two metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) (Coffman et al., 1997; Togna et al., 2013). The metabolism of morphine results from the addition of a glucuronic acid component to the morphine substrate, a process called glucuronidation (Christrup, 1997). Multiple enzymes act to metabolize morphine, including 1A1, 1A6, 2B1, and importantly the family of uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes.

Morphine’s two primary metabolites have opposing effects on pain modulation. M3G binds to microglial TLR4 to produce hyperalgesia and allodynia (pain response from non-noxious stimuli) (Due et al., 2012), whereas M6G binds to MOR to produce potent pain inhibition (Wittwer and Kern, 2006; see Figure 3). Pharmacological studies show that administration of M3G correlates with nociception (Smith and Smith, 1995) and that M3G actively opposes opioid analgesia, as well as the analgesic effects of M6G (Ekblom et al., 1993; Roeckel et al., 2017;Doyle and Murphy, 2018).

Figure 3.

Figure 3.

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Morphine is metabolized via glucuronidation to produce M3G and M6G which bind to TLR4 and MOR, respectively (adapted from Doyle and Murphy 2018).

A number of studies point to a sex difference in the metabolism of morphine. For example, gene expression of UGT1 and UGT2 enzymes is significantly higher in females (Iwano et al., 2012), likely due to higher levels of estradiol. Studies on glucuronide concentrations in humans are inconclusive, as some report a sex difference (Murthy et al., 2002), while others do not (Sarton et al., 2000). However, animal studies consistently report that females have higher serum and plasma concentrations of M3G than males (South et al., 2001; South et al., 2009). Recent studies by our lab suggest that the increased production of M3G in females contributes to the attenuated response to morphine, implicating morphine metabolism as a vital factor in the sexually dimorphic effects of morphine (Doyle and Murphy, 2018).

Conclusions

The neural pathways mediating pain and analgesia show sexual dimorphism at many points, notably in the PAG and its descending output, in the engagement of the immune system, and in the metabolism of morphine (see Figure 4). Although opioids are among the most efficacious and frequently prescribed medications for chronic pain, the sexually dimorphic mechanisms of analgesia are not yet fully elucidated. Future experiments on possible sex differences in the binding affinities of morphine, M6G, and M3G at MOR and MD-2, as well as dimorphisms in the internalization and downstream activity of MOR, will provide a more detailed model of the mechanisms underlying sex differences in opioid analgesia. Moreover, continued study of the origins of these sex differences (be they hormonal, autosomal, or epigenetic) will provide novel information on the developmental processes underlying the phenotypical differences between males and females.

Figure 4.

Figure 4.

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Summary of sex differences in pain and opioid analgesia.

To ensure effective management of chronic pain and its related conditions for both sexes, a research agenda focused on sex differences in opioid treatment is critical. The sex-specific differences presented in this review represent potential targets of future treatment strategies in the pursuit of developing effective analgesics for both sexes. Importantly, sex differences in the impact of opioids on mood, reward, and addiction are paramount to the development of personalized medicine and therefore integral components in the comprehensive study of opiates.

Highlights.

  • Research on pain and analgesia must include the role of sex

  • Discussion of several factors contributing to pain and analgesia

  • Sex differences in pain sensitivity and opioid efficacy

  • Sex-specific effects of morphine metabolism

  • Sexual dimorphism in inflammatory processes and immune signaling

Acknowledgements.

This work has been supported by NIH grants DA16272 and DA041529 awarded to AZM. Hillary Doyle was supported by a Honeycutt Fellowship.

Footnotes

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