Gender Differences and Pain Medication

Abstract

Subtle genetic and psychological variations are Increasingly recognized to contribute to pain and analgesic efficacy and safety. The influence of sex on this relationship remains poorly understood, particularly in humans. The issue is complicated by the overlay of gender onto physical sex, and its associated stereotypes and expectations. Women appear to use more pain-relieving medications than men; however, it remains unclear whether these observations represent true differences in analgesic usage patterns, or reporting bias. Differences in analgesic efficacy relating to body composition, metabolism and hormonal profiles have been demonstrated. Psychological and social elements of gender have also been associated with altered pain experiences and analgesic use profiles, albeit with significant individual variations. Intra-group differences may ultimately prove more important than sex differences. Further research may unravel the various threads linking gender and sex effects on analgesia with the aim of individualizing analgesia to optimize pain relief.

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Learning objectives

Upon completion of this activity, participants should be able to:

• Compare the use of analgesics among men and women

• Identify sex-based differences in the response to analgesics

• Identify gender-based differences in pain reporting and the use of analgesics

• Compare adverse events related to analgesic use among men and women

Financial & competing interests disclosure

CME Author

Charles P Vega, MD, FAAFP, Associate Professor; Residency Director, Department of Family Medicine, University of California, CA, USA, has disclosed that he has served as an advisor or consultant to Novartis, Inc.

Author Disclosures

Jen Richardson, MA, Department of Anaesthesia, Intensive Care & Pain Medicine, Imperial College London, London, UK has disclosed no relevant financial relationships.

Anita Holdcroft, MB, ChB, MD, FRCA, Department of Anaesthesia, Intensive Care & Pain Medicine, Imperial College London, London, UK has disclosed no relevant financial relationships.

No writing assistance was utilized in the production of this manuscript.

Editor

Elisa Manzotti, Editorial Director, Future Science Group, London, UK. Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

Pain and its relief are common problems in medicine. Single analgesics may lack clinical efficacy but, in the laboratory, studies demonstrate sex differences and in practice multiple therapeutic interventions are used without rigorous studies [1]. In the context of orthodox science and evidence-based medicine, the greatest regard is given to symptoms and therapies that can be tested and validated. This requires variables that lend themselves to reproducible, objective and quantitative measurements. These demands are necessarily in direct conflict with the internationally accepted, subjective definition of pain ( Box 1 ). The study of experimental pain in human subjects is restricted by the specific ethical constraints on intentional infliction of such an experience. Furthermore, biological, psychological and social confounders interfere with attempts to objectify and quantify pain. Individual' experiences of pain, like any other emotional experience, are hugely diverse and 10/11-point scales and surveys do as little justice to the variations of pain as they do to those of anger, fear or love [2,3]. Rat and mouse models are the most common animal models in use, and attempt to circumvent some of these issues by minimizing social influences. However, as rodents cannot articulate ‘pain’ experiences, its presence, intensity and quality are inferred from observation of physical and behavioral response to presumed noxious stimuli. Clearly, such inferences have questionable accuracy. In addition, pharmacokinetics of antinociceptive drugs in rodents can significantly differ from humans (e.g., the hepatic metabolism of morphine) [4].

International professional groups have championed the importance of identifying and managing pain as a basic human right, in recognition of the physical and emotional suffering it causes [5]. Furthermore, pain is often the limiting factor in other activities, with financial and social implications. Pain may cause health problems; for example, poorly controlled postoperative pain predisposes to morbidity as a result of reduced lung function [6]. Increasingly, evidence also suggests that poor control of acute pain is a risk factor for the development of chronic pain, with its attendant psychosocial issues [7]. For all these reasons, aggressive pain management is a key healthcare aim, including consideration of pain assessment as the fifth vital sign, medication and adjuvant therapies [8]. Both men and women may experience suboptimal management of pain disorders, albeit at different frequencies and for different reasons ( Box 2 ). A recent in-hospital survey recorded a 91% incidence of pain, yet only 29% received analgesics, with women having a significantly higher probability of receiving pain-relieving drugs [9].

A female preponderance is found in many conditions that can cause chronic pain in the head and neck, limbs and nonreproductive internal organs. The incidence of such pain can change across a lifespan, often in response to sex hormone alterations ( Box 3 ) [10], and some disorders co-occur with increased morbidity, for example irritable bowel syndrome, interstitial cystitis, migraine and fibromyalgia [1,11]. Despite this, beliefs that women have a higher pain threshold than men and are better able to tolerate pain pervade both lay and medical communities. The origins of these beliefs are unclear, although it appears that men and women conceptualize pain differently [12], which may influence their presentation, for example, with acute coronary syndromes [13,14]. Observation of the specific and powerful phenomenon of pregnancy-induced analgesia [15] may inform popular opinion. In addition, women have been observed to use significantly less opioid drugs (i.e., opioid receptor agonists) than men to achieve equivalent analgesia after the immediate postoperative period [16]. Repeated anecdotal reports of similar observations could contribute to an unproven doctrine of superior female pain tolerance. However, increasing evidence suggests that such beliefs may be partly, if not fully, erroneous. In addition to a lower pain threshold, women may derive fewer benefits from analgesic medication owing to higher baseline pain measures as well as pharmacological differences and observer bias [17]. By contrast, men may be less aware of unwanted effects associated with analgesics as well as being differently susceptible to them. Both sexes may also deny or minimize pain in attempts to avoid unwanted effects of analgesics, and sex-specific effects (e.g., erectile dysfunction) have been recently noted in patients receiving opioids and NSAIDs [18–20]. This may prevent men from receiving appropriate analgesia. A multimodal therapeutic approach may provide more benefit to women because they are self-motivated to effect this [21,22] and, in the context of comorbidity, women anecdotally report that analgesia for one disorder provides pain relief for another.

Box 1.

Definitions

• Pain: ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’ [81].

• Sex: the ‘classification of living things, generally as male and female according to their reproductive organs and functions assigned by chromosome complement’ [82].

• Gender: ‘a person's self-representation as male or female, or how that person is responded to by social institutions on the basis of the individual's gender presentation’ [82].

Several recent excellent reviews explore the genetic, hormonal and social basis for sex and gender differences in pain responses and the animal basis for querying similar differences in analgesic responses [23–26]. In this report, we build on this recent work, examining human work and its clinical implications while proposing areas for future development.

Analgesic use

It has been observed that women are dispensed more analgesic prescriptions (and indeed, more medications overall) than men [27]. In response to a health-related quality-of-life questionnaire for adults aged over 65 years with osteoarthritis, women were significantly more likely to be prescribed NSAIDs than men, even when controlled for demographics and gastrointestinal risk factors [28]. Women also report more over-the-counter analgesic use than men [29] demonstrated from evidence including a large telephone interview study, in which a significantly higher proportion of women than men self-medicated for pain (28.2 vs 23.6%; p < 0.05) [30]. In this study, the type of non-prescribed analgesic used was also related to sex. Women used aspirin and acetaminophen (paracetamol) similarly, whereas men showed a clear preference for aspirin.

The potential for self-selection and reporting bias in such studies is significant. Nevertheless, the pattern of analgesic use does not reflect that expected if assumptions of superior pain tolerance in women compared with men were justified; rather, it appears that women use more analgesia than men, whether obtained via healthcare professionals or independently.

There are several possible explanations for these observations, which encompass elements of ‘sex’ and ‘gender’ concepts ( Box 1 ), and the gender-role constructs of ‘masculinity and femininity’ [25]. In general, sex differences relate to genetic and physiological factors such as hormone levels and neurological processing. Psychological, cognitive, social factors and beliefs may also contribute to pain sensations and their relief, and these are more appropriately associated with ‘gender’. While these terms may appear dichotomous, and certainly studies are often described in relation to one of the two, elements relating to both may impact on outcomes – for example, experiments to measure sex differences in rodents may lack full disclosure of social handling of the animals [31]. Similarly, in humans, subject' genetic characteristics have been assumed rather than measured – for example, when resistance to the effects of subcutaneous lidocaine was measured in women with red hair they were assumed to have the mutated MCR1 gene [32]. Sex and gender distinctions are to some extent academic, but the mechanisms underlying observed differences in analgesic use probably include complex interactions between the two. In medicine, the ability to consider sex and gender as part of a single system in which social elements interact to produce the final outcome has important consequences in therapeutics. For example, in irritable bowel syndrome where pain sensations from the GI tract and bowel control are altered, the more frequent use of opioid medication may predispose women to their constipating effects and change the presentation of the disorder [1]. A more profound consequence is that of the physiological, physical and social environment on a person's genetic characteristics producing phenotypic differences that can alter the drug's effects. Phenotypic biomarkers for analgesic effects may therefore be more appropriate than genetic ones for individual analgesic prescribing [33,34].

Box 2.

Gender barriers to optimal analgesic management

Patient

• Adverse effects

• Anxiety

• Fears of addiction

• Cognition and beliefs

• Gender role expectancies

Physician

• Beliefs

• Gender role expectancies

• Cognition for example, lack of recognition of reproductive age/hormonal effects/biological rhythms

Healthcare system: research

• Regulatory scrutiny

• Lack of clinical trial data in women/lack of comparable reproductive groups/lack of meta-analysis because of poor subgroup definitions

• Differences in baseline pain measures between males and females

Box 3.

Age-related factors influencing sex differences

Fetus

• Organizational/phenotype effects on developing drug metabolic systems, for example, decreased aspirin absorption in adult females.

Childhood

• Neonatal pain responses differ in males and females.

Adolescence

• Patterns similar to adulthood.

Reproductive age

• Effects on opioid binding:

• Contraception:

• Stage of menstrual cycle:

• Pregnancy:

Menopause & postmenopause

• Hormone-replacement therapy:

• Drug-receptor bindings change:

Taken from [1,57,58,60,83–85].

Biological factors

An increasing body of evidence suggests that healthy women experience greater pain than men in response to various laboratory-based noxious somatic and visceral stimuli [35–40]. This evidence has not been uncontested and the findings in rodents of absent or opposite sex differences in different species have led to important studies of the genetic basis for sex differences [41,42].

For analgesics such as NSAIDs, research history passes from humans back to genetic studies in the laboratory. In volunteer studies using an electrical stimulus, men demonstrated a significantly larger analgesic effect from ibuprofen than women [43]; contrasting results were reported with ketorolac for cold pressor pain [44]. The small sample sizes, possible observer bias and different placebo effects led to clinical translation because such findings have important implications; NSAIDS are often used to treat conditions with a higher female prevalence, such as arthritis. Retrospective analyses of trial data found no clinical differences [45,46], however, another review of 25 trials recommended that side effects in men should be studied because they were under-represented in the studies [47]. Irrespective of acute analgesic effects, however, reduced joint destruction is observed in knockout cyclooxygenase (COX)-deficient female mice in comparison with wild-type. Such a difference was not observed in male COX-knockouts, suggesting a sex difference in NSAID effects on healing and, therefore, in their ability to relieve chronic pain [48].

Rodent and human studies have demonstrated sex differences in the modulation of pain behaviors in response to opioid and other analgesics ( Box 4 ) [49]. In rodents, findings of sexually dimporphic recruitment of opioid and N-methyl-d-aspartate (NMDA) systems by estrogen during stress-induced analgesia led to investigation of the MCR1 gene. This gene is expressed in functional brain areas for pain modulation [50] and is homozygous in a proportion of red-haired women. Further studies have confirmed greater efficacy of pentazocine, a κ opioid, in women homozygous for the gene [51]. In a dental pain model, women have demonstrated greater analgesic responses than men to administration of the κ opioid nalbuphine [52]. Furthermore, an increase in pain intensity (i.e., an antianalgesic response) has been repeatedly reported in men receiving nalbuphine for postoperative dental pain when compared with a placebo group [52]. Studies investigating various combinations of an opioid antagonist (naloxone) [53], neuroleptics (haloperidol and chlorpromazine) [54] and a subanalgesic dose morphine with nalbuphine [55], have demonstrated elimination of this sexual dimorphism. Although the mechanisms for these observations remain unclear, it is plausible that they arise from pharmacodynamic differences between the sexes [56]. A multimodal approach to analgesia has potential for exploitation to improve sex-specific analgesic development.

The literature remains divided as to how to investigate sex hormone effects [57] and the effects of female hormonal changes on pain perception [36,58], and clearly pain perception may influence analgesic requirements. Age-related changes remain a confounding factor ( Box 3 ) [59,60]. For example, in elderly subjects, sex differences in responsiveness to postoperative opioids were not observed, unlike those seen in younger participants in the same study [61]. Hormonal modulation of analgesic efficacy seems plausible, with the menopause representing a significant equalizing point. For future studies, it is important to recognize that different groups of women may exhibit different analgesic use profiles.

A sex difference in the onset of opioid analgesia after drug administration has been observed in different contexts. In volunteers and in the postoperative setting, intravenous morphine can take longer to reduce pain in females than in males [62,63]. Females tend to recover from anesthesia faster than men; and therefore, earlier administration of drugs for postoperative analgesia may be required to ensure they obtain maximal benefit [64]. Similarly, optimal dosing intervals may differ between sexes [62]. These decisions, however, need to be considered in light of the risk of unwanted effects and possible influence of body composition on opioid pharmacokinetics.

A common pitfall in analgesic efficacy studies is the difficulty in obtaining reliable estimates of the brain concentration of a particular drug. While plasma concentration of analgesic drugs may be considered a surrogate, there is often a poor correlation with brain concentration. Furthermore, plasma concentrations may reflect physical and pharmacokinetic differences between the sexes. Although well recognized, such variations may not be effectively used to maximize analgesic efficacy or reduce adverse effects from a relative overdose (Boxes 2 & 3). Sex hormones cause alterations in protein levels affecting the binding of many analgesic drugs (e.g., NSAIDs, morphine and local anesthetic drugs). The introduction of new routes of administration of drugs has led to a reappraisal of fentanyl pharmacokinetics for transdermal drug delivery. In rats, subcutaneous administration demonstrated a delayed distribution in females [65]. While body composition may vary more within a same-sex group than between sexes, different analgesic doses or routes of administration may be appropriate to male or female subjects.

Box 4.

Examples of sex hormone modulations in peripheral and central nociception and the analgesic or potential analgesic target

Peripheral nerves

• NGF binds to TrkA and sensitizes primary afferent nerve. Estrogen alters response.

• Bradykinin B2 receptor is modulated by estrogen. Plasma extravasation exhibits sex differences

Spinal cord processing

• GABA and glutamate, dopamine, serotonin and norepinephrine levels are all modulated by sex steroids.

• Cholinergic systems and gonadal hormones.

• G-protein coupled inwardly rectifying potassium channels (GIRK2).

Brain processing

• Opioid-receptor binding and estrogens.

Taken from [1,41,49,59,60,86].

It seems most probable that a complex interplay of genetic and hormonal modulatory effects determine sex differences in analgesic efficacy, but, as the evidence summarized here ( Box 5 ) suggests, the relative contributions of each factor remain to be determined through rigorously designed studies.

Effect of gender

In hospital or community healthcare settings, obtaining analgesia is usually contingent on patients reporting pain to nursing or medical staff. In an experimental setting, men were less likely to report pain from a noxious stimulus to female testers than to other men, and their reluctance increased in proportion to the perceived attractiveness of the tester; while women appeared keener to report pain to a male than to a female [66,67]. It is unclear whether such behavior represents the subject' conscious attempts to encourage the tester to view them as particularly stoic or vulnerable, unconscious attempts to do the same, or is simply coincidental. The findings have not been reproduced in every similar study [68]. However, by extrapolation, gender-dependant reporting bias may affect patient' tendency to request analgesia. Patient-controlled analgesia might be expected to minimize the effects of reporting bias on analgesic use; indeed, a large prospective study of postoperative patients found that males consumed more morphine/kg than females during the 1–3-day postoperative period [16].

It has not been established whether a comparable gender bias affects the professional' responses to reports of pain. However, a retrospective study of paramedic records in the USA found women were significantly less likely than men to receive prehospital opioids for isolated extremity injury [69]. This difference persisted when controlled for pain intensity. This may result from an observer bias on the part of the paramedics that women have greater capacity to tolerate pain than men. However, the study failed to subclassify injuries or record paramedic' sexes. Knowledge of the type of injury, the distributions of injury subtypes between sexes and the sexes of attending paramedics may have yielded important insights into analgesic use.

The suggestion from these studies is that patient-controlled analgesia may be important to enable both male and female patients to access adequate analgesia, reducing effects arising from their differing inclinations to report pain and professional' responses to such report.

From an anthropological perspective, it is interesting to consider whether patient and observer perspectives on pain reporting are consistent across cultures. The gender roles and expectations may differ substantially between ethnic groups, as do attitudes to pain; evidence from parturients suggests that a significant difference can be observed in pain management when different ethnic groups present in acute pain [70].

Adverse effects

As with any drug, the benefits of analgesics in terms of pain relief can only be considered prudently, together with the risks of unwanted effects. Women appear to be more vulnerable than men to some adverse effects of analgesic drugs. For example, in healthy volunteers [71] and in emergency department patients [72,73], women have been found to experience more nausea and vomiting than men following opioid administration. Of life-threatening concern, reduced responsiveness to CO₂ and resultant respiratory depression has been demonstrated in female compared with male volunteers administered morphine [74]. In clinical practice, voluntary reports of adverse effects associated with analgesic drugs commonly used in anesthesia were more frequent from women than men, but this may have been the result of reporting bias, use of multiple drugs or more frequent surgery [75].

Box 5.

Summary of published strategies for future research

Sherman and LeResche (2006) [58]

• Use biologically relevant windows (e.g., highest and lowest sex hormone levels).

• Measure time of ovulation.

• Measure sex hormones directly (e.g., noninvasive salivary levels).

• Direct manipulation of hormone levels using a patch.

• Include hormonal contraception group recording type and dose.

• Use site-specific investigations, for example, abdomen, lower limbs, head and neck. Becker et al. (2005) [57]

• Limit extraneous sensory stimuli in animal holding rooms or experimental environments.

• If handling or restraint is necessary, subjects should be well habituated to the procedure before the actual testing session to obviate possible effects of an acute stress response.

• Test at a constant point in the day to minimize confounding effects of glucocorticoid effects on the hypothalamic–pituitary–gonadal axis.

Greenspan et al. (2007) [25]

• Identify results for each sex subgroup in clinical trial methods, analysis and reporting.

• Include both sexes in medication trials in sufficient numbers to detect sex or gender effects.

• Mandate reporting of outcomes in each sex for pharmaceutical trials.

In relation to body composition differences in humans and susceptibility to toxicity ( Box 3 ), significant sex differences in acetaminophen (paracetamol) metabolism have been observed with increased sulphate and reduced glucuronide conjugation [76]. Findings in mice have demonstrated that males are significantly more vulnerable than females to hepatotoxicity [77,78]. CD1 strain males and females pretreated with testosterone also are more vulnerable to nephrotoxicity compared with untreated females [79], suggesting that hormonal influences may be critically important in determining adverse effects to analgesics as well as genetic variants.

It is also possible that women may be protected from some adverse effects of analgesics by greater awareness of risks than men ( Box 2 ), for example, in relation to postoperative patient-controlled analgesia opioid administration and of gastrointestinal side effects from over-the-counter analgesics [80].

Future perspective

The possibility of genuine sex and gender discrepancies in seeking of pain relief medication, as well as its efficacy, has significant implications for the conduct of research in this area. The EU GenderBasic project has had success in improving awareness of the general area of sex differences and directing basic research interest towards them [101]. The International Association for the Study of Pain (IASP) has also advanced a consensus statement recommending sex-specific adverse drug reaction reporting and study design to accommodate sex and gender differences [25]. Crossover studies may be useful in reducing the effect of individual variations on results, although these have their limitations, including the washout periods needed, and the neuroplasticity involved in nociceptive processing and subsequent pain perception. Coupling of analgesics with other classes of drug, such as neuroleptics, may enable sex differences to be minimized, if not eliminated. Furthermore, the current consensuses do not fully address the logistical and financial problems associated with drug development. These issues are not confined to analgesics but arise across drug classes in relation to gender, ethnicity and other variables as pharmacogenomics permits development of increasingly targeted and personalized therapies. It is possible that pharmaceutical companies will tend to develop drugs suitable for the most lucrative markets, and a comprehensive debate is required regarding if and how this should be regulated. One possibility might be that medications targeting particular genes or gene products known to vary between sexes would have to be developed in tandem to promote equity of efficacious drug availability. Furthermore, continued efforts need to be made by healthcare professionals to ensure that gender perceptions of both patients and professionals do not prevent access to effective and safe analgesia.

Executive summary

Background

• Both men and women may experience suboptimal management of pain disorders, albeit at different frequencies and for different reasons.

• A multimodal therapeutic approach may particularly benefit women.

• Men may fail to receive appropriate analgesia because of inhibitions about reporting pain.

Analgesic use

• Women appear to use more analgesia than men, whether obtained via healthcare professionals or independently.

• Women have been shown to be significantly more likely to be prescribed NSAIDs than men.

• Women report more over-the-counter analgesic use than men.

• Phenotypic biomarkers for analgesic effects may be more appropriate than genetic ones for individual analgesic prescribing.

Biological factors

• Pharmacodynamic differences between men and women may be exploited in analgesic development.

• Different hormonal groups of women may show different effects.

• The onset of opioid analgesia after drug administration is slower in women.

• While body composition may vary within sexes, different analgesic doses or routes of administration may be appropriate to males or females.

Effect of gender

• Gender-dependant reporting bias may affect analgesic requests.

• Patient-controlled analgesia may be an important method to enable male patients to access adequate analgesia.

Adverse effects

• Hormonal influences may be critically important in determining adverse effects to analgesics as well as genetic variants.

• Women may be protected from some adverse effects of analgesics by greater awareness of risks than men.

Conclusion

• The current consensuses do not fully address the logistical and financial problems associated with drug development for individuals as males or females.