Sex variations in pain control

5 Dec 2014  |  Print

Sex variations in pain control

In 1959, Lipsitt and Levy did an experiment to analyse the sensitivity of newborn babies to electrical pain.[1] It seems unlikely that such a study would be approved in the 21st century, although the electric shocks administered were – of course – small. However, this work did produce an important finding; across the first 4 days of life, baby girls had a significantly lower threshold for pain than baby boys.

Experimental methods have come a long way since then, but the issue of gender differences in pain perception remains an important scientific question.

Many decades of research have shown quite clearly that pain prevalence differs between the sexes.[2] But does the response to pain treatment – and in particular to opioid-based therapy – differ between males and females?

Opioid potency

As long ago as 1980, an early study compared the potency of the opioid buprenorphine in men and women. A clear difference was shown; women required a significantly lower amount of buprenorphine than men to manage post-operative pain following hip replacement surgery.[3] This suggested that opioids may be more potent in females than males.

A more recent study, this time examining the effect of remifentanil on the prevention of cough during emergence from anesthesia, reached a similar conclusion. The opioid was about twofold more potent in women than in men.[4]

Opioid analgesia

Does the increased potency of opioids in women translate into greater efficacy? The answer appears to be yes – and no.

Many clinical studies have examined differences in the analgesic effect of mu-opioids in males and females, typically in the acute rather than the chronic pain setting. A recent systematic review and meta-analysis of 25 such studies found no significant overall sex–analgesia association.[5] However, further interrogation of these data revealed some important caveats.

First, restriction of the analysis to the 15 studies examining patient-controlled analgesia (PCA) revealed that women experienced significantly greater analgesic efficacy in that setting.[5] Second, further restriction to the 11 studies examining morphine PCA yielded an even greater differential effect in women.[5]

Furthermore, in the same meta-analysis, study duration mattered. In the PCA studies that examined analgesia over several days, there was a difference in analgesic efficacy in favor of women; in contrast, in studies examining effects over just a few hours, analgesia appeared to be slightly greater in men.[5]

How can we explain this time dependency in opioid effect between genders? A pharmacokinetic/pharmacodynamic analysis in healthy volunteers may hold the answer.[6] In this study, morphine had greater potency but slower speed of onset and offset in women than in men.[6] Hence, in men there was a rapid spike in analgesic effect that also tailed off rapidly; in women, there was a higher but more slowly reached peak that also tailed off less quickly than in men. The crossover point was at around 1-2 hours. Before that time, opioids appeared to be more efficacious in men, but after that they were more efficacious in women.[6]

Opioid side effects

In addition to efficacy, gender also appears to be linked with differences in opioid side effects

For example, fracture risk is increased in users of opioid analgesics, possibly due to a greater risk of falls, caused by the central nervous system (CNS) effects of opioids, such as sedation and dizziness.[7]

In a study examining the correlation between fracture risk and cumulative opioid use (based on the number of prescriptions received) in patients aged 18-60 years, those currently using one opioid prescription had a greatly increased fracture risk, irrespective of gender. However, in patients receiving two or more such prescriptions, only women were at elevated fracture risk.[7] This suggests that men were better able to tolerate the CNS side effects of the opioid.

Opioids also affect ventilatory control.[8] However, in a randomized controlled trial, there were important differences between men and women in the ways that opioids affected ventilator responses.[8] As a result, women seemed to have a higher probability of respiratory depression than men.

Gender differences with non-opioid analgesia

There may also be sex-specific differences in response to non-opioid analgesics. For example, in a randomized controlled study in patients with Complex Regional Pain Syndrome, ketamine produced greater pain relief in men than in women – largely the reverse of what was observed with opioids.[9]

Meanwhile, a meta-analysis of studies of ibuprofen for the relief of moderate to severe dental pain found no gender differences.[10]

Pain treatment – a gender mismatch?

As we have seen, current data suggest that there are differences between men and women in their response to opioid analgesics – in terms of potency, efficacy and side effects. Data with non-opioids are somewhat lacking, but suggest that there could also be gender differences with some other classes of analgesics.

In addition to these differences in response, it is possible that physicians use analgesics differently depending on a patient’s gender. For example, there is evidence that physicians are more likely to prescribe opioid analgesics to patients of the same sex.[11] Furthermore, females may be more likely to be recommended by nurses for opioid-based treatments.[12]

These very important gender differences should be considered when prescribing analgesics to our patients.


1. Lipsitt LP, Levy N. Electrotactual threshold in the neonate. Child Dev1959;30:547-554.

2. Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth2013;111:52-58.

3. McQuay HJ, Bullingham RE, Paterson GM, Moore RA. Clinical effects of buprenorphine during and after operation. Br J Anaesth1980;52:1013-1019.

4. Soh S, Park WK, Kang SW, Lee BR, Lee JR. Sex differences in remifentanil requirements for preventing cough during anesthetic emergence. Yonsei Med J2014;55:807-814.

5. Niesters M, Dahan A, Kest B, et al. Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies. Pain2010;151:61-68.

6. Sarton E, Olofsen E, Romberg R, et al. Sex differences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology2000;93:1245-1254.

7. Li L, Setoguchi S, Cabral H, Jick S. Opioid use for noncancer pain and risk of fracture in adults: a nested case-control study using the general practice research database. Am J Epidemiol2013;178:559-569.

8. Dahan A, Sarton E, Teppema L, Olievier C. Sex-related differences in the influence of morphine on ventilatory control in humans. Anesthesiology1998;88:903-913.

9. Sigtermans MJ, van Hilten JJ, Bauer MC, et al. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain 2009;145:304-311.

10. Averbuch M, Katzper M. A search for sex differences in response to analgesia. Arch Intern Med2000;160:3424-3428.

11. Weisse CS, Sorum PC, Sanders KN, Syat BL. Do gender and race affect decisions about pain management? J General Inter Med2001;16:211-217.

12. Hirsh AT, George SZ, Robinson ME. Pain assessment and treatment disparities: a virtual human technology investigation. Pain2009;143:106-113.