This supplement contains the papers presented at a substantive conference in 'Sex Differences and Analgesics' organized by the Sex, Gender and Pain Special Interest Group of the International Association for the Study of Pain in London, UK on 11 November 2001. As the Chair and convenor of this unique event, I formulated the programme to include the many facets of sex differences from population studies of analgesic use to basic scientific mechanisms. An international group of experts, some presenting original data, was invited to review their area of interest across a spectrum of pain management from acute to chronic cancer-related pain and from non-human animal experiments to human volunteers and patients (community, hospital and hospice-based). Although there are confounding factors in any study of sex differences such as age and physical status (e.g. weight) evidence is rapidly accumulating that when patients are prescribed analgesic medication the effectiveness of a particular drug or drug combination may be related to biological differences of which sex is one obvious visible but under researched example.
For many years, pharmacological research methodologies have indirectly positively discriminated against measuring sex differences. In human studies these can be described as gender differences, being the sex with which a person identifies. For example, Phase I and early Phase II studies have excluded women based on paternalistic arguments such that women should be protected from side effects especially during their childbearing years . Thus government statutes have perpetuated a lack of data on pharmacokinetic characteristics, dose-response relationships and adverse effects of analgesics in women. The way forward has been led by the US Food and Drug Administration (FDA) that acknowledged women's autonomy and biological differences. The FDA developed new guidelines in 1993 for drug research in recognition of the variations in women's hormonal status: the effects of menstrual and menopausal status on pharmacokinetics and the influence of exogenous sex hormone administration (e.g. oral contraceptives) on drug pharmacokinetics and effectiveness . The effect of such policies will reverse some of the long-standing barriers to investigating sex differences and provide a political sounding board for similar changes in other international regulatory authorities' guidelines; for example, gender issues are now being investigated in mainstream European Union policies including those on drug regulation.
Clinical trials in postoperative pain have often been designed to include similar numbers of men and women into each group rather than dividing the comparative groups separately into men and women. Thus it is only in the last year that we have the results of an evaluation of sex differences in patient controlled analgesia (PCA) morphine requirements in acute postoperative pain . This review demonstrates the paucity of studies where sex differences have been researched despite the extensive literature on postoperative pain relief. Of the studies that demonstrated sex differences, even when weight related changes were excluded, the striking findings were that males demanded and consumed more opioid analgesics than females. Interestingly these studies did not measure analgesic effectiveness, only analgesic consumption. In human volunteer studies, as described by Fillingim  it is the type of opioid that determines sex differences in analgesic effectiveness such that κ-opioids are more effective in women than men. In contrast animal studies demonstrate significantly greater analgesia when μ- and κ-opioids are administered to males than to females [5,6]. The results for PCA use would suggest that factors for opioid use in humans might relate not only to effectiveness but also to other biological, psychological and environmental factors that require investigation in order to improve patient satisfaction. One explanation for the differing analgesic use of PCA opioids is that women experience more adverse effects and it is these adverse effects which limit their analgesic consumption.
Dr Tim Lovell described the research evidence for sex differences in adverse drug events relating to analgesics. Data presented at the conference included examples of analgesic drugs from the US FDA Spontaneous Reporting System website (www.fda.gov/cder/aers) that has in total over a million reports since 1969. In the use of population statistics to determine gender differences in analgesic use and their side effects in the community the article by two pharmacoepidemiologists, Isacson and Bingefors  is timely. It is often epidemiological studies that highlight the serious and significant nature of sex differences in pain. The initial alert came from seminal studies of self-report health insurance data  and now the use of more structured questionnaires by Isacson and colleagues in the general population is proving a tool for evaluation of sex differences in analgesic use for both hospital and community based studies. The methods to exclude confounding factors (such as psychological and economic differences) are explained leaving significant differences between males and females to be explored in future studies.
My thanks to the contributors to this supplement include not only the speaker's scientific contributions but also an unconditional educational grant.
1. Ciccone GK, Holdcroft A. Drugs and sex differences: a review of drugs relating to anaesthesia. Br J Anaesthesia
2. Merkatz RB, Temple R, Subel S, Feiden K, Kessler DA. Women in clinical trials of new drugs - a change in food and drug administration policy. Working group on women in clinical trials. N Engl J Med
3. Miaskowski C, Gear RW, Levine JD. Sex-related differences in analgesic responses. In: Fillingim RB, ed. Sex, Gender and Pain, Progress in Pain Research and Management: Vol. 17.
Seattle, USA: IASP Press, 2000: 209-230.
4. Fillingim RB. Sex differences in analgesic responses: evidence from experimental pain models. Eur J Anaesthesiol
(Suppl 26): 16-24.
5. Isacson D, Bingefors K. Epidemiology of analgesic use - a gender perspective. Eur J Anaesthesiol
(Suppl 26): 5-15.
6. LeResche L. Gender differences in pain: epidemiologic perspectives. Pain Forum