Sex Differences in Pharmacology

The subject of the last annual meeting of BARA (Belgian Association of Regional Anesthesia) was “Wom-an-esthesia”. Anesthesia for breast surgery and obstetrics, chronic pelvic pain and the role of the female anaesthetist were a few obvious topics. But what about the role of sex during the regular daily practice, for surgeries equally performed in men and women? Does it matter if the patient in front of you is male or female?

When deciding on the dosing of our drugs, we consider several factors. Should sex be one of them? In fact, little is known about sex differences in pharmacology as historically females were always excluded from research. Only starting from 2000 Health Research institutes started to change their policy and stated that the biological sex of the subjects studied is an important variable that should be included in research. [1]

Individual variability in drug-effect can be attributed to pharmacokinetic or pharmacodynamic reasons. We know that sex influences body composition. Females have a higher percentage of body fat (5-10%) and a lower percentage of total body water (15-20%). This has its effect on the distribution volume of drugs, with females having a higher volume of distribution for lipid soluble drugs and a lower volume of distribution for water soluble drugs. Furthermore, females also have a lower level of protein binding capacity and the CYP450 system is prone to hormonal influence.

Female sex hormones, like progesterone and estrogen, also have an influence on sleep pattern and pain experience. Progesterone and its derivatives have sedative effects by their interaction with GABA_A receptors. When injected in rodents, progesterone induces EEG-changes similar to sleep or to benzodiazepines.[2] This may explain sex-related and cyclic variations in sensitivity to hypnotic drugs.

Multiple studies have shown females are less sensitive to propofol. During EEG-monitored anesthesia, females use up to 18% more (weight-corrected) propofol than males and have shorter emergence times. [3] Plasma levels of propofol decline faster at the end of infusion. These differences are partially caused by the greater volume of distribution and an increased metabolism, but there is also a real pharmacodynamic difference as BIS scores in women tend to be higher at similar plasma levels of propofol. [4] We know women are at higher risk of awareness and of course this lower sensitivity to propofol could be a contributing factor. And we could question why sex is not included as a parameter in the most frequently used TCI protocols?

For volatile anesthetics it is widely recognised that MAC values tend to be lower during pregnancy, when progesterone levels are higher. For non-pregnant women there is no strong evidence to support any clinical important sex difference, although it is sometimes suggested that there is a slight variability in sensitivity during menstrual cycle, with a lower requirement during the luteal phase. [5, 6] One study even investigated the weak correlation between emergence times and the waist:hip ratio of female patients as an argument for the hormonal influence in recovery from general anesthesia.[7] Although females woke up faster, Buchanan found longer recovery stays and lower QoR-40 scores during the first three postoperative days.

Muscle relaxants are water-soluble drugs and after a single weight-based dose the plasma concentrations in females tend to be higher.[8, 9] It is clearly demonstrated that rocuronium and vecuronium have a faster onset and a longer duration in females. Dosing can be reduced 20-30% in females to achieve a same neuromuscular block. [10, 11]

Pregnant patients have a higher neuronal sensitivity to local anesthetics. This is thought to be caused by a progesterone-induced facilitation of diffusion through the nerve sheath. Plasma protein binding is less which puts them at a higher risk for systemic toxicity. For non-pregnant patients no strong evidence for sex-related differences in sensitivity to local anesthetics could be found, although smaller reports suggest e.g. a higher sensitivity to spinal bupivacaine or a longer lasting sciatic sensory block in diabetic females. [12-14]

Pain is a complex experience influenced by sociocultural, emotional and cognitive factors. As a consequence, sex-related variability in opioid effect is difficult to study. Experimental pain studies try to exclude those more ‘subjective’ influences and show a lower pain threshold in females. [15] Chronic pain conditions also have a higher prevalence in women.

Sex hormone receptors are distributed in areas of the peripheral and central nervous system involved in nociception and considerable literature indicates an influence of sex hormones on pain experience. [16] As such chronic pain conditions happen to have a cyclic variability and pain perception seems to be more pronounced during intervals of the menstrual cycle associated with rapid hormonal changes (ovulation and early menstruation).[6]

Experimental pain models have shown that morphine has a higher potency in females, with a slower onset and a longer duration. A meta-analysis by Niesters also concluded females have a higher sensitivity to opioids, especially to PCA administered morphine, for the analgesic effect as well the side effects.[17] Data on other -opioids and mixed-receptor opioids are less clear. The mechanism for this sex-related variability in opioid effect appears to be a combination of pharmacokinetic and pharmacodynamic factors.

We can conclude that sex is to be taken into account when deciding on the dose of the drug you use, but it is only one of many variables and the influence of sex may be overshadowed by other factors. It emphasizes the importance of tailoring your anesthesia to the unique patient in front of you, with all its characteristics. Anesthesia depth and neuromuscular block should be measured, and pain therapy should be adapted to your patient’s needs. Protocols and standardisation are necessary tools but that doesn’t exclude we need to continue finetuning case by case.

References

1. Olivia A. Moody, K.F.V.a.K.S., Sex, drugs, and anaesthesia research. British Journal of Anaesthesia, 2021. in press.
2. Lancel, M., et al., Progesterone induces changes in sleep comparable to those of agonistic GABAA receptor modulators. American Journal of Physiology-Endocrinology and Metabolism, 1996. 271(4): p. E763-E772.
3. Haensch, K., et al., Women need more propofol than men during EEG-monitored total intravenous anaesthesia / Frauen benötigen mehr Propofol als Männer während EEG-überwachter total-intravenöser Anästhesie. Biomed Tech (Berl), 2009. 54(2): p. 76-82.
4. Hoymork, S.C. and J. Raeder, Why do women wake up faster than men from propofol anaesthesia? Br J Anaesth, 2005. 95(5): p. 627-33.
5. Erden, V., et al., Increased progesterone production during the luteal phase of menstruation may decrease anesthetic requirement. Anesth Analg, 2005. 101(4): p. 1007-1011.
6. Kurdi, M. and A. Ramaswamy, Does the phase of the menstrual cycle really matter to anaesthesia? Indian Journal of Anaesthesia, 2018. 62(5): p. 330-336.
7. Buchanan, F.F., P.S. Myles, and F. Cicuttini, Effect of patient sex on general anaesthesia and recovery. British Journal of Anaesthesia, 2011. 106(6): p. 832-839.
8. Pleym, H., et al., Gender differences in drug effects: implications for anesthesiologists. Acta Anaesthesiol Scand, 2003. 47(3): p. 241-59.
9. Filipescu, D. and M. Ştefan, Sex and gender differences in anesthesia: Relevant also for perioperative safety? Best Practice & Research Clinical Anaesthesiology, 2021. 35(1): p. 141-153.
10. Adamus, M., T. Gabrhelik, and O. Marek, Influence of gender on the course of neuromuscular block following a single bolus dose of cisatracurium or rocuronium. Eur J Anaesthesiol, 2008. 25(7): p. 589-95.
11. Xue, F.S., et al., Dose-response curve and time-course of effect of vecuronium in male and female patients. Br J Anaesth, 1998. 80(6): p. 720-4.
12. Benhamou, D., Sex-based differences in local anaesthetic-induced motor block. Eur J Anaesthesiol, 2011. 28(4): p. 235-6.
13. Camorcia, M., G. Capogna, and M.O. Columb, Effect of sex and pregnancy on the potency of intrathecal bupivacaine: determination of ED₅₀ for motor block with the up-down sequential allocation method. Eur J Anaesthesiol, 2011. 28(4): p. 240-4.
14. Tang, S., et al., Sex-dependent prolongation of sciatic nerve blockade in diabetes patients: a prospective cohort study. Regional Anesthesia & Pain Medicine, 2019. 44(9): p. 860-865.
15. Kwon, A.H. and P. Flood, Genetics and Gender in Acute Pain and Perioperative Opioid Analgesia. Anesthesiol Clin, 2020. 38(2): p. 341-355.
16. Bartley, E.J. and R.B. Fillingim, Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth, 2013. 111(1): p. 52-8.
17. Niesters, M., et al., Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies. Pain, 2010. 151(1): p. 61-68.