Introduction

Chronic pain affects 1 in 5 adults in the United States, with significantly higher rates of chronic pain and high-impact chronic pain (that which limits activities related to work or daily living) reported in women compared to men.¹ Recent research has supported these findings and shown that several key physiologic and psychosocial differences exist between men and women that affect chronic pain disorders and their management.² However, these disparities are not unique to patients with chronic pain; sex- and gender-based differences are apparent causes of differences in rates of death and disability across a wide range of diseases including cancers, infectious diseases, cardiovascular diseases, diabetes, and hypertension, to name a few.³ Gender medicine refers to the study of these differences between men and women and how they affect disease symptoms, presentation, prevention, and pharmacotherapeutic effects.

Historically, preclinical and clinical research was conducted almost solely on males, and much of what we know today in medicine is based on those studies.³ However, beginning in 2014, the United States National Institutes of Health announced new requirements for inclusion of both sexes in preclinical studies of cells and animals.⁴ In 2016, a separate policy was created to require sex to be considered as a biological variable in animal and human studies, to ensure that both sexes be included in the design, analysis, and reporting of research studies. While some progress has already been made in defining some of the important differences between men and women and how those differences impact disease management, there is still much to learn from ongoing and future studies.

Sex versus gender

Although the terms are often used interchangeably, sex and gender represent distinct classifications.⁵ Sex and gender can each affect patients differently, including the way that their medical problems (e.g., pain) are managed. Sex is assigned based on biological characteristics present at or prior to birth, such as gonads, sex chromosomes and hormones, internal reproductive organs, and the appearance of external genitalia. Individuals with biological features that do not consistently align with either a male or female sex are classified as intersex. Differences in sex hormones between male and female patients can lead to variable treatment responses. For example, higher levels of testosterone in males have been associated with an increased clearance of certain antihypertensives (e.g., propranolol), higher selectivity of insulin, and better overall health among patients with diabetes.⁶ In females, elevated levels of the sex hormones estradiol and progesterone can alter drug metabolism. Estrogen is thought to increase sensitivity to opioids in females and proposed to be associated with development of a prolonged QT interval.

Differences in gene expression between males and females can also lead to variation in how drugs are metabolized.⁶ The cytochrome P450 (CYP) 3A4, 2B6, and 2A6 enzyme families are more frequently expressed and active in females, whereas the CYP1A2 and 2E1 enzymes are expressed with higher frequency in males; these differences can potentially lead to alterations in drug metabolism and exposure between men and women. There are many other sex-specific factors that can influence drug disposition; some examples of these factors and how they differ in women compared to men are provided in Table 1 below.^6,7 Pharmacodynamics are also believed to be impacted by sex, based on the fact that men and women sometimes respond differently to medication therapy despite similar exposure to a given drug; however, this effect has not been well studied to date.⁶ All of these factors can also contribute to the risk of adverse effects from a given drug. Females are approximately twice as likely to experience adverse events from drugs than men, which is thought to be due to a combination of pharmacokinetic, pharmacodynamic, and other factors related to the frequency of reporting adverse events.

Gender is a complex construct that is influenced by psychological, cultural, social, and behavioral factors.⁵ Society applies certain gender roles, or societal “norms” or stereotypes, to the sexes which can influence how a person lives out their life; examples include expectations related to diet, stress level, exercise, and smoking.⁸ Individuals may conduct themselves in a certain way based on the societal expectations of their gender, which can directly impact their health and likelihood for various diseases, including pain conditions. Gender is a fluid concept; many men and women exhibit traits that may typically be attributed to the opposite sex. Further, an individual’s gender identity (the gender that one identifies themself with) may be the same (cisgender) or different (transgender) from their assigned sex at birth.

Sex and gender are interconnected; however, each can also independently affect health outcomes.⁸ As an example, sex and gender-based differences in cardiovascular care have been well-defined in the literature. Traditionally, it has been thought that women develop ischemic heart disease later in life due to protective effects from estrogens. Although it has since been found that this is not always true, studies have shown that women with ischemic heart disease often seek care later than their male counterparts, are frequently underdiagnosed, and inappropriately managed. Ischemic heart disease develops differently in men and women; women are more likely to develop ischemic heart disease as a result of small vessel damage whereas men are more traditionally affected by large vessel disease. Myocardial infarctions also present differently in men and women, with women being more likely to experience non-classic symptoms such as pain occurring between the shoulder blades. Interestingly, one study found that men and women with ischemic heart disease who were found to have feminine gender characteristics were more likely to experience recurrent myocardial ischemia, regardless of their biological sex; these findings further support a bias in the management of women with ischemic heart disease based on gender. As research continues to be conducted, similar disparities in patient management based on sex and gender are being discovered across the spectrum of chronic diseases, including pain.

Pregnancy and lactation

Pregnancy causes multiple physiologic changes in a female that can affect therapeutic management of various conditions, including pain.⁶ Pregnant women are considered a special population due to the potential risk of medication exposure to the fetus, which often leads to their exclusion in clinical trials. However, pregnant women also undergo significant physiologic alterations that affect drug disposition; some of the major alterations affecting pharmacokinetics and pharmacodynamics are summarized below in Table 2. Increases in total body water, cardiac output, and body fat composition can increase the volume of distribution of certain drugs, thus lowering their effective concentration in the blood and leading to potential decreases in efficacy. Plasma protein concentrations are also altered in pregnancy; increased concentrations of albumin can lead to elevated plasma concentrations drugs that are normally highly bound to albumin, which can lead to adverse effects. Altered expression of hormones, including estrogen and progesterone, can increase activity of certain CYP enzymes while decreasing activity of others, leading to variable effects on the serum concentration of drugs used to treat pain that are metabolized via those mechanisms. For example, increased CYP3A4 enzyme activity in pregnant women increases the clearance of methadone.⁹ Finally, increases in glomerular filtration rate cause increased renal clearance of drugs that are eliminated via the kidneys, such as morphine.^6,9

Women who choose to breastfeed after birth have also traditionally been considered a special population and excluded from clinical trials.¹⁰ Drug pharmacokinetic characteristics such as low plasma protein binding, slightly basic pKa, low molecular weight, and high lipophilicity are associated with an increased likelihood for a medication to pass into the breast milk. However, there is a paucity of data evaluating the risk of transmission of medications via breast milk and their potential effects on the breastfed infant. Some medications, such as decongestants, may also reduce milk supply and affect a woman’s ability to effectively breastfeed.¹¹ Healthcare providers may be hesitant to prescribe appropriate treatment to a breastfeeding woman for a variety of acute and chronic conditions due to the unknown effect on the lactating mother or unknown risk to the infant.¹⁰

Differences in pain based on sex

Many conditions that are associated with chronic pain are more prevalent in women compared to men.^12,13 Examples include fibromyalgia, migraine headaches, osteoarthritis, low back pain, irritable bowel syndrome, and inflammatory arthropathies. Women are also more likely to have a variety of comorbid conditions, such as depression, which may further affect their perception of pain.¹² It has also been reported that women are more sensitive to pain, have heightened pain perception, and are more likely to report severe pain compared to men. However, historically, preclinical studies involving pain and its management only included male animals. More recent research incorporating women has shed light on several biologic variations between men and women that alter pain mechanisms and signaling.¹⁴ These differences are thought to be due, at least in part, to variations in genes, receptors, and sex hormones between males and females.

Several genes have been found to be implicated in the development of acute and chronic pain in one sex, but not the other.¹⁵ A few examples include the OPRM1 and OPRK1 genes, which respectively encode for the mu and kappa opioid receptors, and the HTR2A gene, which encodes for the serotonin 2A receptor. Multiple studies have demonstrated that gene expression related to chronic pain varies substantially based on sex. Similarly, animal studies have shown that a multitude of endogenous receptors involved in processing of pain may have variable expression based on sex. For example, studies in healthy adults have shown that women have a higher expression, binding affinity, and binding potential of the mu opioid receptor compared to men, although this difference is lessened after menopause.¹² Opioids that exhibit their effects via the kappa opioid receptor have also been found to produce greater analgesic effects in women compared to men. Many other receptors are similarly expressed more in one sex versus the other; these receptors have varying effects on hypersensitivity to pain. Additionally, animal studies have shown that there are key differences between men and women in expression and activity of immune cells, such as toll-like receptor 4 cells, microglia, and T-cells, which are involved in inflammation and hypersensitivity to pain.^14,15

Sex hormones also play a role in sex-based variations in pain.¹⁴ Testosterone has been found to have a protective effect against pain, and it reduces the amount of proinflammatory cytokines including tumor necrosis factor alpha (TNFα), interleukin (IL) 1β, and IL-6. Animal studies have shown that increased levels of testosterone can reduce pain in both sexes. However, the effects of estrogens on pain are complex and have not been fully elucidated; research has shown that estrogen increases pain sensitivity for certain types of pain, decreases sensitivity to other types of pain, and in some cases, has no effect on pain.¹² Reduced levels of estradiol are associated with increases in TNFα, IL1β, and IL-6, but higher levels appear to have a protective effect. The relationship between estrogens and pain is further demonstrated by the fact that some patients experience migraine attacks following withdrawal of estrogen.¹⁴ Animal studies also point to a potential relationship between elevated prolactin levels and development of chronic pain; however, this relationship has not been fully explored.¹⁴

Interaction of sex and gender and their effect on pain management

Gender-based differences in pain perception and response to therapy also exist.¹⁶ Societal influence often paints a picture of men who are “brave” and “manly”, do not talk about their pain, and have a high tolerance for pain. Male patients have also been found to be less adherent to opioid therapy compared to women.¹⁷ Gendered norms of women include that they are more sensitive to pain, more likely to report pain, and more emotional or dramatic in doing so. It is thought that these stereotypes can potentially impact how a health care provider might treat pain in men compared to women²; however, the existing evidence base is limited and shows conflicting results as to whether this occurs in practice.¹⁸

Some available evidence has suggested that there are sex- and gender-based differences in response to opioids between men and women.⁶ Women are generally prescribed opioids more frequently than men, and at higher dosages; in 2018, approximately 17% of women in the United States received at least 1 prescription for an opioid compared to less than 13% of men.^19,20 Women also experience a higher rate of adverse effects from opioids compared to men.¹⁹ However, the existing literature is conflicting as to whether there are sex-based differences in the effectiveness of opioids for the treatment of pain. Some studies have found that women are less likely to experience analgesia from opioids (although these findings vary greatly based on a number of patient-specific factors such as the duration and location of origin of pain) whereas others have not found this difference. One study found that women are more sensitive to the analgesic effects of morphine, but also more likely to develop adverse effects such as gastrointestinal symptoms (i.e., nausea and vomiting) and respiratory depression.⁶ These differences are believed to be due to a combination of sex- and gender-based differences between men and women, including variations in body size, opioid receptor expression, concentration of sex hormones that mediate analgesic effects (i.e., testosterone and estrogen), and perceived sensitivity to analgesic medications.

Sex- and gender-based differences in migraine development and management provide a helpful example of how some of the factors discussed thus far can affect men and women differently.¹⁷ For example, migraines occur much more commonly in women compared to men, with an estimated incidence of 43% in women compared to 18% in men.^17,21 Development of migraine is believed to be related to large fluctuations in estrogen concentrations in some women, thus, it commonly fluctuates with the menstrual cycle. Gender also plays a role, as migraines occur more frequently in transgender women compared to cisgender men; this difference is believed to be related to the presence of increased estrogen from supplementation and suppression of androgens. The onset of migraine and its symptoms also vary by sex, with women being more likely to experience nausea and vomiting than men. Since migraine is linked to hormone fluctuations, treatment in cisgender women and transgender women may involve hormone alteration. Traditional migraine treatment options are also commonly used. While limited, there is evidence that suggests that responses to both preventive and acute abortive treatment agents are different based on sex. A systematic review and meta-analysis evaluating these differences in men and women prescribed triptans for migraines found that women treated with triptans had similar response rates, but also had more adverse events, higher drug exposure, and higher recurrence of migraine, when compared with men.²¹

Pregnancy/lactation and pain management

Pain occurs frequently during pregnancy and is associated with both pregnancy-related and unrelated causes.⁹ Although analgesics are the most commonly used class of medications in pregnant women, with some studies estimating a prevalence of up to 70%, some pregnant women may still be hesitant to take analgesics out of concern for the effects on the fetus. To further compound this issue, data on the efficacy and safety of analgesic agents are lacking, as are evidence-based guidelines to aid clinicians in proper management of pain during pregnancy. However, ineffective pain management can lead to depression, stress, sleep disruption, and hypertension in pregnant women and contribute to adverse fetal outcomes.

Use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs is common since they are readily available without the need for a prescription.⁹ Over time, it has been noted that pregnant women are also using opioid prescription medications more frequently to treat pain.⁹ When treating acute or chronic pain in pregnant women, providers should initially consider nonpharmacologic measures including physical therapy and behavioral/psychological treatment modalities. Prescribed analgesics should be administered at the lowest effective dose; if initial treatment does not provide suitable pain relief, the dose of that medication should be titrated up instead of starting a second medication.

Acetaminophen is generally considered to be a safer analgesic option for use in pregnancy due to a lack of consistent data supporting a risk to the fetus.⁹ However, recent reports have called this into question, suggesting cautious use of acetaminophen at the lowest effective dose to reduce the potential risk for certain urogenital, reproductive, and neurodevelopmental abnormalities.²² Low doses of aspirin, less than 150 mg per day, are also generally considered to be safe; however, doses used for pain and inflammation (above 650 mg per day) administered late in pregnancy are associated with a variety of bleeding-related risks in both the mother and the neonate.⁹ There is a proposed risk of miscarriage when nonsteroidal anti-inflammatory drugs are used in the first trimester of pregnancy due to their negative effects on synthesis of prostaglandin; however, existing studies have found conflicting information regarding this risk. Nonsteroidal anti-inflammatory drugs should not be administered after 20 weeks’ gestation since they can cause premature closure of the ductus arteriosus, oligohydramnios, and bleeding abnormalities in the mother and fetus.^9,23 Although data are limited, acetaminophen and nonsteroidal anti-inflammatory drugs are also thought to be relatively safe when used in breastfeeding women; however, aspirin is generally not recommended first-line due to limited reports of potential complications (e.g., metabolic acidosis and thrombocytopenia) in infants exposed to aspirin via breast milk.¹⁰

Acute pain that is more severe may be treated with short courses of opioids.⁹ Short courses of codeine, fentanyl, morphine, and oxycodone have not been found to increase risk for negative outcomes in the mother or fetus.⁹ Tramadol and tapentadol are opioid agonists with a lower affinity for the mu opioid receptor compared to other opioid agents; tramadol and tapentadol may effectively manage acute pain with a reduced risk for misuse and addiction compared to opioid agents with a stronger affinity for the mu receptor.⁹ All opioids come with a potential risk for neonatal withdrawal syndrome which is defined as a withdrawal syndrome in the neonate which can cause issues with sleeping, feeding, and regulation of temperature and can lead to more serious effects including respiratory distress, delays in development, and failure to thrive. This risk is highest when opioids are prescribed for longer courses with extended-release preparations.⁹ Opioid medications such as tramadol and morphine are also considered relatively safe when administered to breastfeeding women in short courses.¹⁰ Codeine should be avoided since it can produce unexpectedly high levels of morphine in ultrarapid metabolizers and has been associated with adverse outcomes in some infants.

Certain antiepileptic medications and antidepressants may also be relatively safer options for the management of chronic pain; anticonvulsants are particularly helpful for chronic pain associated with neuropathic conditions such as diabetic neuropathy and fibromyalgia.⁹ Anticonvulsants, including gabapentin, levetiracetam, lamotrigine, pregabalin, and topiramate have been used in pregnancy, mainly for the treatment of non-pain conditions such as epilepsy and various mood disorders. Most of these agents have been found to be relatively safe in pregnancy, although long-term safety data for pregabalin and gabapentin are lacking. Further, use of topiramate may be associated with an increased risk for congenital malformations. Administration of at least 5 mg of folic acid is recommended both 1 month prior to and during use with these agents in pregnant women to aid in the prevention of neural tube defects in the fetus. Use of older generation anticonvulsants, including phenytoin, valproate, and carbamazepine, is associated with known fetal malformations, and generally should be avoided. However, guidance on use of these agents for treatment of epilepsy in pregnant patients suggests that carbamazepine is associated with a lower risk for fetal malformations compared to valproate.²⁴ Although the evidence is limited, selective norepinephrine reuptake inhibitors and tricyclic antidepressants have generally been found to be safe and effective for management of chronic pain in pregnant women, although there is still a small risk for fetal malformations. Women who are exposed to antidepressants or anticonvulsants during pregnancy are encouraged to report outcomes to pregnancy registries; additional information on existing pregnancy registries can be found at https://www.fda.gov/science-research/womens-health-research/list-pregnancy-exposure-registries.²⁵ The data on use of second-generation anticonvulsants and antidepressants in breastfeeding women are extremely limited.²⁶ While many of these agents have been shown to pass into the breast milk to some extent, the existing evidence base suggests that use of these agents is generally safe. In 2017, the Academy of Breastfeeding Women published guidance on providing analgesia to breastfeeding women.²⁷ These guidelines can be consulted for additional resources on medication use in breastfeeding women, including specific recommendations on the use of various opioids, NSAIDs, and other analgesics (i.e., acetaminophen, gabapentin, and pregabalin).

In general, the recommended approach for treatment of pain in pregnant women should start with nonpharmacologic management followed by pain relief with simple agents such as acetaminophen.¹⁹ If this initial management strategy is not effective, a second generation anticonvulsant (e.g., gabapentin) or antidepressant can be trialed. Opioids may be considered as a third-line option at the lowest effective dose and with close monitoring. Multimodal analgesia should be implemented if opioids are used, to limit the overall dose of opioid needed. Women who are pregnant or breastfeeding should be counseled about the risks and benefits of use of any analgesic agent before starting therapy.²⁶

Sex- and gender-based differences and opioid use disorder

Differences also exist between the sexes regarding the risk for substance use disorder and addiction.¹² Risk factors for development of opioid use disorder also vary between the sexes.²⁸ Risk factors for opioid use disorder in men include age younger than 34 years, currently living with their children, recent history of depression, and use of hallucinogens.²⁸ On the other hand, women who are younger than 54 years of age, and women who have a history of alcohol or inhalant use or drug overdose are at the highest risk for developing opioid use disorder.²⁸ Other factors that are associated with development of opioid use disorder in women include personal or family history of psychiatric illness, initial use of opioids as a prescription, history of tobacco use, low income, and childcare duties.

A 2016 publication from the National Institute on Drug Abuse, which discusses sex and gender differences in substance use mentions that men are more likely than women to use illicit drugs; men are also more likely to present to the emergency department and die from overdose due to illicit drug use.²⁹ However, men and women have similar rates of addiction, and women with substance use disorder have a higher risk for cravings and relapse compared to men. Women with substance use disorders are also more likely to have comorbid conditions affecting their physical or mental health (e.g., psychiatric conditions such as depression and anxiety, history of physical violence or other trauma), which may contribute to their risk for substance use.^12,30 These differences may also impact the effectiveness of medications for opioid use disorder, as sex-based alterations in pharmacokinetics and pharmacodynamics can potentially lead to variable exposure to available treatment options.³⁰ For example, when buprenorphine is dosed the same in men and women, women generally have higher plasma concentrations, although it is currently unknown whether these differences are clinically significant.

Issues such as unemployment and other financial struggles, perceived stigma, and family or childcare obligations may disproportionately impact women and prevent them from seeking appropriate care for substance use disorders.³⁰ However, only a small proportion of available substance use disorder treatment centers provide services that enhance availability for women, including providing service to only women, sex-specific care, pregnancy programming or prenatal care, and childcare.

Pregnancy/lactation and management of opioid use disorder

Opioid use disorder has become a significant concern among pregnant women, with reported increases of more than 300% seen since the start of the opioid epidemic in 1999.³¹ Opioid use disorder can negatively impact outcomes in both the mother and fetus, and death from overdose is a leading cause of death among pregnant women in the United States. Further, rates of neonatal withdrawal syndrome have increased by four-fold over time due to the rise in use of opioids in pregnant women.³² The American College of Obstetricians and Gynecologists provide the following pain management recommendations for health care providers to attempt to limit opioid use disorder among pregnant women:

• Verify that use of opioids is appropriate; leverage nonpharmacologic and nonopioid pharmacologic treatment strategies as appropriate.
• Review treatment goals and risks and benefits of opioid use with the patient from the start of therapy.
• Review the patient’s history of substance use and leverage the Prescription Drug Monitoring Program to assess prior use of opioids and other high-risk medications (e.g., benzodiazepines).
• Discuss future family planning goals and the impact of long-term opioids.
• Consider the balance between the need for pain control and the risk of opioids and prescribe with caution; pregnancy and concern for misuse of opioids or neonatal withdrawal syndrome is not an appropriate reason to avoid treating acute pain.

All pregnant women should be screened for substance use early in pregnancy.³² Validated screening questionnaires can facilitate this process. Examples include the 4P’s (history of problematic alcohol or drug use in the patient’s parents, partner, past, or present), National Institute on Drug Abuse (NIDA) quick screen, or CRAFFT. These tools are quick questionnaires with a few questions that can be asked to assess for risk of problematic substance use. 

For pregnant women with opioid use disorder, recommendations from both the American College of Obstetricians and Gynecologists and the Substance Abuse and Mental Health Services Administration state that opioid agonist medications (i.e., methadone and buprenorphine) should be used for treatment in combination with a comprehensive addiction management program.^32,33 Treatment with these medications has been shown to reduce the risk of relapse, improve the likelihood that the mother receives appropriate prenatal care and addiction treatment, and reduce the risk of other pregnancy-related complications.³² Both methadone and buprenorphine have evidence supporting their safe and effective use in pregnant women with opioid use disorder. Selection of medication should be individualized based on patient-specific factors. Buprenorphine is recommended to be administered as a single agent for treatment of opioid use disorder in pregnant women.^32,33 Limited existing evidence suggests that combination buprenorphine products have similar safety outcomes to single agent buprenorphine. Methadone must be dispensed through a certified opioid treatment facility, while buprenorphine can also be prescribed by a healthcare provider in an office setting less frequently. Healthcare providers who intend to prescribe buprenorphine in an office setting for the treatment of opioid use disorder must apply for a waiver from the Substance Abuse and Mental Health Services Administration to do so; approved applicants receive a unique Drug Enforcement Administration registration number for prescribing buprenorphine.³³

Some studies have suggested that treatment retention may be improved with use of methadone over buprenorphine.³³ However, methadone interacts with many other prescription medications since it is hepatically metabolized by both the CYP3A4 and CYP2B6 enzymes. Although buprenorphine is metabolized via similar mechanisms, it is generally associated with fewer clinically significant drug interactions compared to methadone.^32,33 Use of either agent with combined opioid agonist/antagonist or full antagonists can precipitate withdrawal.³³ Both agents have a similar risk for development of neonatal withdrawal syndrome; however, neonatal withdrawal syndrome typically lasts longer in infants born to women who took methadone while pregnant. Pharmacokinetics of both methadone and buprenorphine can be impacted by the physiologic alterations that occur during pregnancy (see Table 2).^31,32 Split dosing or increased dosing may be necessary, especially during the third trimester, to account for these changes. Other treatment options discussed in guidelines for management of opioid use disorder in pregnancy include medically supervised withdrawal and naltrexone; however, these options are currently not recommended in pregnant women. Medically supervised withdrawal is not recommended since it is associated with relapse rates as high as 90%, which can lead to adverse outcomes in both the mother and baby.^32,33 Long-acting injectable naltrexone is another therapy that has demonstrated efficacy for management of opioid use disorder in patients who are not pregnant; however, it has not been well studied in pregnancy and is currently not recommended due to concerns related to the unknown risk to the fetus. Methadone and buprenorphine are transferred to breast milk in very low levels, and there is limited data suggesting that use of other opioid use disorder treatments (i.e., buprenorphine/naloxone combination and naltrexone) may be safe when administered to breastfeeding women who are stable on these medications.³³ Healthcare providers should involve patients in the decision-making process and discuss the risk and benefits of opioid use disorder and its treatment with women who plan to breastfeed.

Considerations for pharmacists

To provide an inclusive environment for all patients, information on gender identity should be obtained from all patients in order to ensure that they are referred to by their preferred names and pronouns.³⁴ Knowledge of a patient’s gender identity will also enhance their overall care by allowing for appropriate management and screening based on both their biological sex and gender. The United States Preventive Services Task Force recently published plans for incorporating sex- and gender-specific considerations into their future guidance documents, and other organizations are likely to follow suit as future research further elucidates the impact of sex and gender on patient management and outcomes.³⁵

Patient-centered care in patients with chronic pain incorporates patient values and preferences into all clinical decisions that are made related to the treatment of their pain.³⁵ Research has shown that teaching patients about the background physiology and biology of pain is associated with improvements in pain and function in the patient. This education can also help to set expectations related to expected improvements in pain. Open-ended communication is key; communicating with the patient using a motivational approach helps to keep them engaged in their own care.^35,36 Pharmacists should also incorporate discussion about tolerance and addiction in patients who are prescribed opioids.³⁶ Avoidance of these sensitive topics has been identified as a major barrier to open communication from both the pharmacist and patient perspective. Finally, pharmacists should learn to identify their own implicit biases, and can encourage inclusive care for all patients by incorporating the following principles:³⁵

• Provide culturally safe care for all patients by identifying and avoiding implicit bias, discrimination, and stereotypes.
• Make management plans that are individualized for each patient.
• Ask patients about their families and consider family support in the care process.
• Employ appropriate screening and monitoring in long-term opioid users and remove barriers to accessible care (e.g., provide naloxone to patients with substance use disorders).
• Provide trauma-informed care.

Conclusion

Sex and gender are two separate but interconnected concepts that can have variable effects on all aspects of care in patients with chronic pain. Women are known to have a higher rate of chronic pain conditions compared to men; however, historically they have not been included in sufficient numbers in preclinical and clinical studies to inform the true impact of these differences on patient management. There are a number of physiologic differences between men and women that can alter pharmacokinetics and pharmacodynamics, ultimately impacting drug efficacy. Gender also plays an important role, as both patient and provider actions may, in part, take place because of gendered norms in society. Pregnant women have also historically been excluded from clinical trials; however, pregnancy alters the female physiology and can have significant impacts on drug disposition. Men and women (including pregnant women) have variable risk factors for the development of opioid use disorder, and sex- and gender-based differences may further impact the most appropriate care of these patients. Future research on the effects of sex and gender on outcomes in clinical trials will be paramount to better understand the implications of these differences in healthcare.

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