The above mentioned paper appeared a couple of years ago, but well summarizes a clinically significant problem that has been discussed also in more recent papers (see below). Many painful conditions occur more frequently in women: e.g. fibromyalgia, interstitial cystitis, irritable bowel syndrome, migraine, temporomandibular disorders and so on.

It is not totally fully understood why women experience pain differently from men. Even if there are many researches and clinical studies that demonstrated that women have a lower threshold and tolerance for pain, actually women’s pain is generally under treated. Some of the differences are outlined in the following few lines.

Sex differences in the opioid receptor system. In the last few years pain research has focused on significant sex differences in the opioid receptor system: many authors showed that in women there is a better pain relief with k-receptor agonist than in men (who have a better response with morphine). Otherwise other studies showed that women taking the same morphine dose as men, experienced more respiratory depression, while men require 30-40% more morphine to achieve the same pain relief. It is interesting the Gears’ finding who found 2 separate opioid k receptors, one with analgesic effect and another that produce antianalgesic effect (RW Gear 2008); he postulated that men may have more of antianalgesic receptors than woman, explaining in this way their better response to morphine than to Nalbuphine.

Sex specific pain pathway. Mogil and colleagues found that Mc1r gene plays a role in modulating a k specific pain pathway that exists only in woman (Mogil 2003). With these study the author stated “not only there are sex differences in the output of pain systems, but I believe that males and females actually have separate and distinct pain processing pathways with different neurotransmitters and genes”.

Sex differences in how pain is processed. Studies with Positron Emission Tomography (PET) detected sex differences in the regional cerebral activation of the µ-opioid system in response to sustained pain with difference in the magnitude and direction of the µ-opioid system in distinct brain nuclei.

The role of sex hormones. It has to be mentioned the role of sex hormones, which appears to be also a major factor in pain modulation. Zubieta and colleagues correlated estrogens levels and pain perception by showing that high levels of estrogens cause a greater µ receptor expression (Zubieta 2002). Otherwise, it is largely accepted that sex hormones influence inflammation and also neural processing of pain. On the other hand, studies involving female rodents that could not be performed on humans indicated that high levels of estrogens are associated with decreased opioid analgesia.

All the above observations suggest that since sex differences in pain perception/processing are so important, it is mandatory to include and evaluate separately male and females in clinical studies, in addition it has not yet been explored how these differences may be modified by the aging process.

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References

Gear RW, Gordon NC, Hossaini-Zadeh M, Lee JS, Miaskowski C, Paul SM, Levine JD. A subanalgesic dose of morphine eliminates nalbuphine anti-analgesia in postoperative pain. J Pain. 2008 Apr;9(4):337-41. Epub 2008 Jan 16.

Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KV, Lariviere WR, Groce MK, Wallace MR, Kaplan L, Staud R, Ness TJ, Glover TL, Stankova M, Mayorov A, Hruby VJ, Grisel JE, Fillingim RB. The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4867-72. Epub 2003 Mar 27.

Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, Meyer CR, Koeppe RA, Stohler CS. mu-opioid receptor-mediated antinociceptive responses differ in men and women. J Neurosci. 2002 Jun 15;22(12):5100-7.