Sex-Related Differences in Pharmacological Response to Opioids: Comparison
Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Mirabela Romanescu.

Clinical experience proves that pharmacological response may vary between the two sexes since pathophysiological dissimilarities between men and women significantly influence the pharmacokinetics and pharmacodynamics of drugs. Opioids seem to produce better analgesia in women especially when they are administered for a prolonged period of time.

  • sex-related differences
  • pharmacological response
  • adverse drug reactions

1. Introduction

Differences between the two sexes exist, and, from a medical point of view, they have a significant impact on prevalence, incidence, and severity of a wide range of diseases and conditions. Accordingly, physiologic differences between the two sexes affect drug activity with dissimilarities within pharmacokinetics, pharmacodynamics, and pharmacotoxicity. However, most drugs are prescribed to women and men at the same dose, although therapeutic effectiveness varies [1]. In research, women and non-human female mammals have often been underrepresented, especially in previous decades. The reasoning behind it is the assumption that results from males readily apply to females, or the concern that hormonal cycles negatively influence the homogeneity of study populations and complicate experimental designs [2]. Moreover, the risk of ADRs such as teratogenicity or toxicity may outweigh other considerations, and, thus, females of child-bearing potential, pregnant, or breastfeeding are sometimes advised by healthcare professionals against enrolling in such studies [3].
Pharmacokinetics in women is influenced by several factors, such as: lower body weight, higher percentage of body fat, slower gastrointestinal motility, higher gastric pH, decreased intestinal enzymatic activity, and slower glomerular filtration rate [4]. With regard to medication, drugs in women usually have a larger volume of distribution, and the free fraction is also increased. Female sex hormones alter hepatic enzyme activity, which can result in decreased elimination and accumulation for some drugs. However, the way estrogen and progesterone affect pharmacokinetics of drugs is hard to predict and assess, with studies yielding conflicting results [5]. Differences in pharmacodynamics occur when the same plasma concentration of a drug does not cause the same pharmacological response between the sexes. Unlike pharmacokinetic differences, pharmacodynamic disparities are more difficult to assess, as pharmacological effects are not easily measurable [6]. However, there are certain examples in the literature where such differences are obvious. To name a few, women are more likely to experience QT interval prolongation following therapy, while males show a greater sensitivity to propofol’s anesthetic effect [7]. Another example would be that verapamil has a lower bioavailability and increased clearance in male patients compared to females [8]. Regarding pharmacotoxicology, women are significantly more likely to be hospitalized secondary to an ADR, as they have a nearly two-fold greater risk than men for exhibiting side effects across many drug classes [9]. For instance, women appear to be at a higher risk for ADRs following treatment with thyroid hormones, phychoanaleptics, and TNF-α inhibitors [10]. Additionally, women are more at risk of admission using thiazide diuretics causing hypokalemia and anticoagulants causing rectal bleeding, whereas males have higher rates of hematuria and subdural hemorrhage following treatment with anticoagulants [11].

2. Opioids

It is well known that pain sensitivity varies among individuals; therefore, assessing and treating postoperative pain requires a personalized approach, making it difficult to follow protocols strictly. An effective analgesia needs to take into account various factors, such as weight, height, age, body mass index, sex, type of surgery, surgery site, preoperative pain, and medication [12]. It is established that the majority of chronic pain syndromes occur more often in women (chronic fatigue syndrome, fibromyalgia, interstitial cystitis, temporomandibular disorder, headache, migraine, low back pain, neck pain, and osteoarthritis) [13]. Likewise, studies indicate a greater pain prevalence among women and determined that women seem to show greater sensitivity to the majority of experimentally induced pain methods [14,15,16][14][15][16]. However, the differences in pain perception observed within most studies may not be statistically significant and are not always consistent, as suggested by a series of review papers [17,18,19,20][17][18][19][20]. Pain perception seems to be linked to sex hormones, since testosterone was found to decrease pain sensitivity; thus, a low testosterone state is incriminated in a wide range of chronic pain conditions. Nevertheless, female hormones have both pro- and antinociceptive properties, making the effects of estrogen and progesterone on pain more difficult to evaluate [21]. Regarding opioid addiction, it is established that the desire for opioids is considerably higher among women, and they are at an increased risk of abusing opioids through initial prescription painkiller use [22]. Most pain-related animal studies only include male subjects; few are focused on females, and just a small number are explicitly designed to test for sex differences [23]. Animal studies reveal that, generally, opioid analgesia is more effective in males compared with females. It is known that adult female rodents have a lower percentage of body fat than males, whereas the situation is opposite in humans. These sex-related differences may affect the distribution of highly lipophilic drugs, having a substantial impact on drugs’ potency, efficacy, and duration of action [23,24,25][23][24][25]. However, results in human subjects are not as consistent as those in rodents. Although recent years were marked with significantly increased research regarding sex differences in pain, studies on gender differences in opioids concluded a mixture of different results. Most papers focus on μ agonists, especially morphine, as a main treatment for pain alleviation, since it is perhaps the most clinically significant opioid [26]. Existing data regarding sex differences in response to morphine are highly inconsistent, and a general assumption is difficult to make. It appears that discrepancies in the sex-related response to morphine analgesia might virtually depend on the pain model and/or drug dose/regimen used. To begin with, some clinical studies investigating the difference in the postoperative morphine requirements determined that male opioid consumption was higher than the one observed in females through patient-controlled analgesia (PCA) [12,27,28][12][27][28]. This means that women self-administer significantly less morphine than men [29]. In addition, further research showed that women experience greater morphine potency, as well as a slower speed of onset and offset of the analgesic effect. However, no sex differences in plasma concentrations of morphine and its major metabolites (morphine-3 and 6-glucuronide) were observed. Those findings suggest that gender differences in opioid analgesia are not related to morphine’s pharmacokinetics [25,30][25][30]. On the other hand, when analyzing the immediate postoperative analgesia, following intravenous titration of morphine, it appears that women require a higher dosage than men [31,32][31][32]. This might be explained by the slower onset of morphine in women, who experience later analgesia. Contrarywise, other research papers reported similar analgesic effects of morphine in both sexes. These studies used experimental pain models and evaluated the response to intramuscular morphine by measuring its plasma levels as well as subjective experience, performance, and physiological effects [33,34][33][34]. However, the results on elderly patients appear steadier, with no significant differences in the analgesic effect of morphine being observed in most studies [31,35][31][35]. Regarding ADRs, there is considerable, as well as consistent, evidence that sex influences the intensity and frequency of morphine’s side effects. Findings indicate that females have a substantially higher risk of developing nausea and vomiting than men following opioid analgesia [36]. These observations might be related to the higher frequency of post-operative nausea and vomiting among women than men [37,38][37][38]. However, the same results were also obtained in a study of narcotic-induced emesis in the emergency department, which strengthens the initial conjecture [39]. Furthermore, additional studies reported greater morphine-induced respiratory depression in females than in males [40,41][40][41] as well as an increased feeling of disorientation and sluggishness [42]. In addition, preliminary results suggest some cardiovascular differences between the two sexes following IV morphine administration: women experienced a lower heart rate, but only men developed hypertension and had an attenuated cardiovascular response to ischemic pain. However, the observed differences were small, and only one low morphine dose was tested; therefore, further investigations are needed [34]. Leaving morphine aside and analyzing opioids as a whole, the same conclusion can be drawn—distinct investigations reveal various results. It appears that earlier studies tend to deduce that opioids are better analgesics for females [43,44,45][43][44][45]. However, it is hypothesized that this may happen because older studies did not correct for the body weight differences between the two sexes [46]. For instance, the mixed µ-k-opioid agonist-antagonist nalbuphine, butorphanol, and pentazocine produced significantly better postoperative analgesia in women than in men [47]. In contrast, other studies using experimental pain models showed that pentazocine produced analgesia of similar magnitude in men and women [48,49][48][49]. Regarding µ-opioids, a similar analgesic response in the two sexes is achieved after the administration of alfentanil, as well as morphine’s active metabolite, morphine-6-glucuronide [50,51][50][51]. Considering PCA studies on µ-opioids, it generally appears that opioid consumption is higher in men than in women. However, most studies actually assess opioid consumption rather than pain relief. Therefore, PCA poses problems in terms of reliability, as it can be influenced by other factors than just postoperative pain, such as: expectations, baseline pain sensitivity, fear of addiction, and the occurrence of unpleasant ARDs, such as nausea and vomiting [52]. The general verdict regarding the diverse outcomes of studies is that results may be influenced by procedural and subject variables. Broadly, opioids seem to produce better analgesia in women, especially when they are administered for a few days, as the onset of action is delayed in this category of patients. However, the various responses to pharmacological pain interventions appear inconsistent and dependent on treatment type, genotype, gonadal steroid hormone state of subjects, and characteristics of the pain and the provider [14,16,26,53][14][16][26][53].

References

  1. Whitley, H.P.; Lindsey, W. Sex-Based Differences in Drug Activity. Am. Fam. Physician 2009, 80, 1254–1258.
  2. Beery, A.K.; Zucker, I. Sex Bias in Neuroscience and Biomedical Research. Neurosci. Biobehav. Rev. 2011, 35, 565–572.
  3. Parekh, A.; Fadiran, E.O.; Uhl, K.; Throckmorton, D.C. Adverse Effects in Women: Implications for Drug Development and Regulatory Policies. Expert Rev. Clin. Pharmacol. 2011, 4, 453–466.
  4. Fadiran, E.; Zhang, L. Effects of Sex Differences in the Pharmacokinetics of Drugs and Their Impact on the Safety of Medicines in Women. Med. Women 2015, 41–68.
  5. Soldin, O.P.; Mattison, D.R. Sex Differences in Pharmacokinetics and Pharmacodynamics. Clin. Pharmacokinet. 2009, 48, 143–157.
  6. Gandhi, M.; Aweeka, F.; Greenblatt, R.M.; Blaschke, T.F. Sex Differences in Pharmacokinetics and Pharmacodynamics. Annu. Rev. Pharmacol. Toxicol. 2004, 44, 499–523.
  7. Madla, C.M.; Gavins, F.K.H.; Merchant, H.A.; Orlu, M.; Murdan, S.; Basit, A.W. Let’s Talk about Sex: Differences in Drug Therapy in Males and Females. Adv. Drug Deliv. Rev. 2021, 175, 113804.
  8. Krecic-Shepard, M.E.; Barnas, C.R.; Slimko, J.; Jones, M.P.; Schwartz, J.B. Gender-Specific Effects on Verapamil Pharmacokinetics and Pharmacodynamics in Humans. J. Clin. Pharmacol. 2000, 40, 219–230.
  9. Zucker, I.; Prendergast, B.J. Sex Differences in Pharmacokinetics Predict Adverse Drug Reactions in Women. Biol. Sex Differ. 2020, 11, 32.
  10. De Vries, S.T.; Denig, P.; Ekhart, C.; Burgers, J.S.; Kleefstra, N.; Mol, P.G.M.; van Puijenbroek, E.P. Sex Differences in Adverse Drug Reactions Reported to the National Pharmacovigilance Centre in the Netherlands: An Explorative Observational Study. Br. J. Clin. Pharmacol. 2019, 85, 1507–1515.
  11. Hendriksen, L.C.; van der Linden, P.D.; Lagro-Janssen, A.L.M.; van den Bemt, P.M.L.A.; Siiskonen, S.J.; Teichert, M.; Kuiper, J.G.; Herings, R.M.C.; Stricker, B.H.; Visser, L.E. Sex Differences Associated with Adverse Drug Reactions Resulting in Hospital Admissions. Biol. Sex Differ. 2021, 12, 34.
  12. Periasamy, S.; Poovathai, R.; Pondiyadanar, S. Influences of Gender on Postoperative Morphine Consumption. J. Clin. Diagn. Res. JCDR 2014, 8, GC04–GC07.
  13. Mogil, J.S. Sex Differences in Pain and Pain Inhibition: Multiple Explanations of a Controversial Phenomenon. Nat. Rev. Neurosci. 2012, 13, 859–866.
  14. Fillingim, R.B.; King, C.D.; Ribeiro-dasilva, M.C.; Rahim-williams, B.; Riley, J.L.; Dentistry, C. Sex, Gender, and Pain: A Review of Recent Clinical and Experimental Findings. J. Pain 2009, 10, 447–485.
  15. Riley, J.L.; Robinson, M.E.; Wise, E.A.; Myers, C.D.; Fillingim, R.B. Sex Differences in the Perception of Noxious Experimental Stimuli: A Meta-Analysis. Pain 1998, 74, 181–187.
  16. Bartley, E.J.; Fillingim, R.B. Sex Differences in Pain: A Brief Review of Clinical and Experimental Findings. Br. J. Anaesth. 2013, 111, 52–58.
  17. Racine, M.; Tousignant-Laflamme, Y.; Kloda, L.A.; Dion, D.; Dupuis, G.; Choinire, M. A Systematic Literature Review of 10 Years of Research on Sex/Gender and Experimental Pain Perception—Part 1: Are There Really Differences between Women and Men? Pain 2012, 153, 602–618.
  18. Unruh, A.M. Gender Variations in Clinical Pain Experience. Pain 1996, 65, 123–167.
  19. Berkley, K. Sex Differences in Pain. J. Am. Dent. Assoc. 1997, 143, 764–765.
  20. Fillingim, R.B.; Maixner, W. Gender Differences in the Responses to Noxious Stimuli. Pain Forum 1995, 4, 209–221.
  21. Packiasabapathy, S.; Sadhasivam, S. Gender, Genetics, and Analgesia: Understanding the Differences in Response to Pain Relief. J. Pain Res. 2018, 11, 2729–2739.
  22. Back, S.E.; Payne, R.L.; Wahlquist, A.H.; Carter, R.E.; Stroud, Z.; Haynes, L.; Hillhouse, M.; Brady, K.T.; Ling, W. Comparative Profiles of Men and Women with Opioid Dependence: Results from a National Multisite Effectiveness Trial. Am. J. Drug Alcohol Abuse 2011, 37, 313–323.
  23. Greenspan, J.D.; Craft, R.M.; LeResche, L.; Arendt-Nielsen, L.; Berkley, K.J.; Fillingim, R.B.; Gold, M.S.; Holdcroft, A.; Lautenbacher, S.; Mayer, E.A.; et al. Studying Sex and Gender Differences in Pain and Analgesia: A Consensus Report. Pain 2007, 132, 26–45.
  24. Kest, B.; Sarton, E.; Dahan, A. Gender differences in opioid-mediated analgesia: Animal and human studies. Anesthesiology 2000, 93, 539–547.
  25. Cicero, T.J.; Ennis, T.; Ogden, J.; Meyer, E.R. Gender Differences in the Reinforcing Properties of Morphine. Pharmacol. Biochem. Behav. 2000, 65, 91–96.
  26. Craft, R.M. Sex Differences in Opioid Analgesia: “From Mouse to Man”. Clin. J. Pain 2003, 19, 175–186.
  27. Chia, Y.Y.; Chow, L.H.; Hung, C.C.; Liu, K.; Ger, L.P.; Wang, P.N. Gender and Pain upon Movement Are Associated with the Requirements for Postoperative Patient-Controlled Iv Analgesia: A Prospective Survey of 2298 Chinese Patients. Can. J. Anesth. 2002, 49, 249–255.
  28. Tsui, S.L.; Tong, W.N.; Irwin, M.; Ng, K.F.J.; Lo, J.R.; Chan, W.S.; Yang, J. The Efficacy, Applicability and Side-Effects of Postoperative Intravenous Patient-Controlled Morphine Analgesia: An Audit of 1233 Chinese Patients. Anaesth. Intensive Care 1996, 24, 658–664.
  29. Burns, J.W.; Hodsman, N.B.A.; McLintock, T.T.C.; Gillies, G.W.A.; Kenny, G.N.C.; McArdle, C.S. The Influence of Patient Characteristics on the Requirements for Postoperative Analgesia. Anaesthesia 1989, 44, 2–6.
  30. Sarton, E.; Olofsen, E.; Romberg, R.; Den Hartigh, J.; Kest, B.; Nieuwenhuijs, D.; Burm, A.; Teppema, L.; Dahan, A. Sex Differences in Morphine Analgesia: An Experimental Study in Healthy Volunteers. Anesthesiology 2000, 93, 1245–1254.
  31. Aubrun, F.; Salvi, N.; Coriat, P.; Riou, B. Sex- and Age-Related Differences in Morphine Requirements for Postoperative Pain Relief. Anesthesiology 2005, 103, 156–160.
  32. Cepeda, M.S.; Carr, D.B. Women Experience More Pain and Require More Morphine Than Men to Achieve a Similar Degree of Analgesia. Anesth. Analg. 2003, 97, 1464–1468.
  33. Comer, S.D.; Cooper, Z.D.; Kowalczyk, W.J.; Sullivan, M.A.; Evans, S.M.; Bisaga, A.M.; Vosburg, S.K. Evaluation of Potential Sex Differences in the Subjective and Analgesic Effects of Morphine in Normal, Healthy Volunteers. Psychopharmacology 2010, 208, 45–55.
  34. Fillingim, R.B.; Ness, T.J.; Glover, T.L.; Campbell, C.M.; Hastie, B.A.; Price, D.D.; Staud, R. Morphine Responses and Experimental Pain: Sex Differences in Side Effects and Cardiovascular Responses but Not Analgesia. J. Pain 2005, 6, 116–124.
  35. Macintyre, P.E.; Jarvis, D.A. Age Is the Best Predictor of Postoperative Morphine Requirements. Pain 1996, 64, 357–364.
  36. Cepeda, M.S.; Farrar, J.T.; Baumgarten, M.; Boston, R.; Carr, D.B.; Strom, B.L. Side Effects of Opioids during Short-Term Administration: Effect of Age, Gender, and Race. Clin. Pharmacol. Ther. 2003, 74, 102–112.
  37. Stadler, M.; Bardiau, F.; Seidel, L.; Albert, A. Difference in Risk Factors for Postoperative Nausea and Vomiting. J. Am. Soc. Anesthesiol. 2003, 98, 46–52.
  38. Myles, P.S.; McLeod, A.D.M.; Hunt, J.O.; Fletcher, H. Sex Differences in Speed of Emergence and Quality of Recovery after Anaesthesia: Cohort Study. Br. Med. J. 2001, 322, 710–711.
  39. Zun, L.S.; Downey, L.V.A.; Gossman, W.; Rosenbaum, J.; Sussman, G. Gender Differences in Narcotic-Induced Emesis in the ED. Am. J. Emerg. Med. 2002, 20, 151–154.
  40. Sarton, E.; Teppema, L.; Dahan, A. Sex Differences in Morphine-Induced Ventilatory Depression Reside within the Peripheral Chemoreflex Loop. J. Am. Soc. Anesthesiol. 1999, 90, 1329–1338.
  41. Dahan, A.; Sarton, E.; Teppema, L.; Olievier, G. Sex-Related Differences in the Influence of Morphine on Ventilatory Control in Humans. Anesthesiology 1998, 88, 903–913.
  42. Zacny, J.P. Morphine Responses in Humans: A Retrospective Analysis of Sex Differences. Drug Alcohol Depend. 2001, 63, 23–28.
  43. Fillingim, R.B.; Gear, R.W. Sex Differences in Opioid Analgesia: Clinical and Experimental Findings. Eur. J. Pain 2004, 8, 413–425.
  44. Niesters, M.; Dahan, A.; Kest, B.; Zacny, J.; Stijnen, T.; Aarts, L.; Sarton, E. Do Sex Differences Exist in Opioid Analgesia ? A Systematic Review and Meta-Analysis of Human Experimental and Clinical Studies. Pain 2010, 151, 61–68.
  45. Averitt, D.L.; Eidson, L.N.; Doyle, H.H.; Murphy, A.Z. Neuronal and Glial Factors Contributing to Sex Differences in Opioid Modulation of Pain. Neuropsychopharmacology 2019, 44, 155–165.
  46. Lee, C.W.; Ho, I. Sex Differences in Opioid Analgesia and Addiction: Interactions among Opioid Receptors and Estrogen Receptors. Mol. Pain 2013, 9, 45.
  47. Gear, R.; Miaskowski, C.; Gordon, N. Kappa-Opioids Produce Significantly Greater Analgesia in Women than in Men. Nat. Med. 1996, 2, 1248–1250.
  48. Fillingim, R.B.; Ness, T.J.; Glover, T.L.; Campbell, C.M.; Price, D.D.; Staud, R. Experimental Pain Models Reveal No Sex Differences in Pentazocine Analgesia in Humans. Anesthesiology 2004, 100, 1263–1270.
  49. Mogil, J.S.; Wilson, S.G.; Chesler, E.J.; Rankin, A.L.; Nemmani, K.V.S.; Lariviere, W.R.; Groce, M.K.; Wallace, M.R.; Kaplan, L.; Staud, R.; et al. The Melanocortin-1 Receptor Gene Mediates Female-Specific Mechanisms of Analgesia in Mice and Humans. Proc. Natl. Acad. Sci. USA 2003, 100, 4867–4872.
  50. Olofsen, E.; Romberg, R.; Bijl, H.; Mooren, R.; Engbers, F.; Kest, B.; Dahan, A. Alfentanil and Placebo Analgesia. Anesthesiology 2005, 103, 130–139.
  51. Romberg, R.; Olofsen, E.; Sarton, E.; Den Hartigh, J.; Taschner, P.E.M.; Dahan, A. Pharmacokinetic-Pharmacodynamic Modeling of Morphine-6-Glucuronide-Induced Analgesia in Healthy Volunteers: Absence of Sex Differences. Anesthesiology 2004, 100, 120–133.
  52. Dahan, A.; Kest, B.; Waxman, A.R.; Sarton, E. Sex-Specific Responses to Opiates: Animal and Human Studies. Anesth. Analg. 2008, 107, 83–95.
  53. Koons, A.L.; Greenberg, M.R.; Cannon, R.D.; Beauchamp, G.A. Women and the Experience of Pain and Opioid Use Disorder: A Literature-Based Commentary. Clin. Ther. 2018, 40, 190–196.
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