The effect of sex on pain perception and on analgesic response has received increasing attention. Women have a lower pain threshold and less tolerance to experimental pain than men (1,2). Women also experience higher levels of pain intensity after surgery (3) and have a higher overall prevalence of pain than men (4,5).
Sex differences are not limited to pain perception but may extend to the response to analgesics. In animals, male rats exhibit greater analgesia than female rats to equal doses of opioids (6,7). In humans, sex differences in response to opioids have been described, but the findings are difficult to consolidate. Results range from women having less pain relief than men after surgery (3) to women having more pain relief than men in response to butorphanol or pentazocine, mixed opioid agonist-antagonists (8,9). Such studies have enrolled a small number of subjects (e.g., as few as 10 women). In addition, these studies evaluated opioid agonist-antagonists, which are not used as often as full agonists, such as morphine. Therefore, we sought to determine the effect of sex on pain perception, morphine consumption, and morphine analgesia after surgery.
We designed a prospective cohort study. The study was performed from February 2001 until December 2001 at San Ignacio Hospital. The study was approved by the IRB at San Ignacio Hospital, and written, informed consent was obtained from all patients. We recruited hospitalized or ambulatory patients who underwent surgical procedures under general anesthesia and who had a pain intensity of 5 or more on a 0–10 numeric rating scale (NRS) on arrival at the postanesthesia care unit (PACU). On the patients’ arrival in the PACU, we asked them to rate their baseline pain on the NRS (from 0 = no pain to 10 = worst pain imaginable). Every 10 min, we asked patients not only to rate their pain intensity on the NRS, but also to indicate the degree of pain improvement on a 5-point Likert scale (none, minimal, much improvement, very much, or complete pain relief). At the same 10-min intervals, patients received 2.5 mg of morphine IV (if younger than 65 yr) or 1.5 mg of morphine IV (if ≥65 yr) until their pain intensity was ≤4 of 10. After incremental doses of morphine were successfully titrated to achieve an NRS pain intensity of ≤4, subsequent analgesic care was taken over by each patient’s physician. This is the standard of care in the hospital.
We also recorded demographic characteristics, site of operation (head and neck, thoracic, abdominal, orthopedic, or spinal), the ASA physical status (10), and the intraoperative dose of opioid given. A morphine requirement was equated with the total dose of morphine a patient required to achieve a pain intensity of ≤4 of 10.
To determine whether there was a difference in opioid requirement between men and women, we used a robust linear regression. Robust regression does not assume normality and minimizes the effect of influential observations; it produces valid and more efficient estimates than the traditional linear regression (11). It weighs less heavily observations that have larger residuals and/or observations that are very influential (i.e., Cook’s D values >1) (12). Because the total and weight-adjusted doses of morphine had outliers, in this case robust regression provides a robust estimate that is not distorted by any particular observation. The dependent variable in the regression model was the dose of morphine (mg/kg), and the independent variables were sex, type of surgery, and age. Type of surgery and age are variables that could affect opioid consumption and pain intensity; therefore, it is important that we compared women and men of similar age who underwent similar surgical procedures to obtain valid results.
To see whether pain intensity differed between sexes at baseline, we used a linear regression and controlled for the effect of type of surgery and age. To determine whether the difference persisted throughout the duration of the study, we again used a linear regression in which pain intensity was the dependent variable and the independent variables were sex, site of operation, and age. Because each patient had multiple evaluations (until the NRS pain intensity was ≤4 of 10) and these measures were not independent, we used an analysis of repeated measures with generalized estimating equations to take this lack of independence into consideration by adjusting the se values (13,14).
To measure the effect size of the related sex difference in pain intensity, we computed the standarized mean difference as the mean intensity in women subtracted from the mean intensity in men, divided by the pooled sd (1,15). To determine whether there was a difference in pain relief between sexes, we compared the proportion of women and men who achieved a specific degree of pain relief after morphine, by means of the χ2 test.
We used Stata Version 7 SE (Stata Corp., College Station, TX) for all statistical analyses. We estimated and reported 95% confidence intervals (CI). P values <0.05 were considered statistically significant.
We estimated that we needed at least 227 patients of each sex to detect a 15% difference in opioid requirements with 80% power and an α error of 5%, assuming an average requirement in the PACU of 10.75 ± 4.75 mg of morphine. This estimated requirement was based on a study we performed in a similar population (3).
We recruited more patients because the primary aim of this study was to determine the meaning to patients of various decrements in the NRS, and for that purpose more patients were needed. The results of the primary study aim are reported elsewhere (16).
We evaluated 423 women and 277 men. Women were more likely to have abdominal surgery than men. The dose of fentanyl during surgery was similar between sexes (Table 1). The unadjusted values for baseline pain intensity indicate that women had higher pain intensity at PACU arrival than men (Table 1) and had larger opioid requirements (Table 2).
After adjusting for the effect of type of surgery and age, women exhibited more pain than men. The difference in NRS pain intensity was 0.4 U (95% CI, 0.1–0.6 U). The mean difference in pain intensity between women and men in sd was 0.25.
After adjusting for type of surgery and age, women had higher levels of pain intensity throughout the study than men. Women had on average 0.2 U higher pain intensity levels than men (95% CI, 0.03–0.4 U). To achieve the desired level of analgesia in the PACU, subjects needed 42 ± 20 min. Compared with men, women required a little more time: 4 min (95% CI, 1–7 min).
After adjusting for type of surgery and age, women had larger consumption of morphine than men to achieve NRS scores of ≤4. Women required 0.03 mg/kg more morphine than men (95% CI, 0.02–0.04).
The pain intensity levels at the end of the study were 3.5 ± 0.9 in women and 3.4 ± 0.8 in men. The proportion of women and men in each category of pain relief was similar (P = 0.3) (Fig. 1).
We found that women reported higher levels of pain intensity and required more morphine to achieve a similar degree of analgesia and pain relief than men. The difference in pain intensity between women and men across the duration of this study was 0.4 U on a 0–10 NRS. Others have found that women report higher pain intensity, more frequent pain, and pain of longer duration than do men (headache, musculoskeletal, and abdominal pain) (4). Riley et al. (15) performed a metaanalysis to quantify the differences in pain intensity during experimental pain in women and men and found that the difference in pain intensity levels was 0.5 sd. This difference is of larger magnitude than the one we found after surgery. However, the standardized mean differences in the studies included in the metaanalysis ranged from 0.16 to 1.18 sd. Although the difference in pain intensity between women and men in our study was statistically significant, it is clinically small. Changes in pain intensity of 1 U over 10 have been established as the smallest change in pain intensity that patients can notice (16,17). However, the higher pain intensity in women was observed despite female patients receiving a larger dose of morphine according to body weight (see below).
Sex differences in pain perception have been attributed to a different socialization process for men and women that influences bodily experience and the willingness to communicate distress (5). Hormone variations could also in part explain sex differences in pain experience and response to morphine (1). Women in the periovulatory, luteal, and premenstrual phases have lower pain thresholds than women in the follicular phase, a difference that is similar to the differences we observed between women and men (0.3 sd) (1).
We found that women require 30% more morphine on a per-weight basis than men to achieve a similar decrease in pain intensity. We believe that a difference of this magnitude is clinically relevant. However, 1 metaanalysis that included 195 women and 119 men who received ibuprofen for dental pain found no sex differences in response to ibuprofen (18), although it did confirm that women reported higher levels of pain intensity. However, the dose of ibuprofen was fixed, so differences in analgesic requirements were not measured. The best way to quantify the effect of an analgesic is to administer the drug until a desired effect is seen, instead of administering a fixed dose. These methods are called “indirect response models”(19,20) and have been used to study drug pharmacokinetics. In our study, we administered analgesics until a desired response was observed; we believe that this method is more sensitive to detect differences in analgesic requirements. Other studies have found that men require more morphine after surgery than women. One small study (21) enrolled only 54 women and 46 men, and morphine was not administered according to weight. Because patient weight was not controlled in that analysis and because women weigh less, the results are not necessary inconsistent with ours. A recent very large study (22) (n = 2298) in the Chinese population reported that women consumed significantly less morphine by using patient-con-trolled analgesia in the first three postoperative days than did men. It is interesting to note that, in contrast to a large body of literature, the authors found that women reported less pain than men. It is possible that cultural, ethnic, or genetic factors may account for the differing findings in the Chinese study and our study. Hospital San Ignacio treats a mixed population of black, Caucasian, and Native Indian patients, but virtually no Asians.
In rat models, opioids consistently produce greater analgesia in males than in females (6,7). Although our study supports these findings, there are reports indicating that pentazocine, butorphanol, and nalbuphine—opioids that activate κ receptors—produce a greater degree of analgesia in women than in men after third-molar extraction (8,23). It is difficult to explain this conflicting evidence. The same clinical research group that reported greater analgesia in women exposed to κ agonists found no sex differences in response to morphine (23).
To place our findings into clinical perspective, one may consider a 60-kg woman in severe postoperative pain. To achieve adequate pain relief, she will likely require 46.8 mg of morphine over 24 hours (0.13 mg × 60 kg × six doses per day), whereas a man of the same weight will need 36.0 mg. This is a 10.8-mg difference. We consider this difference clinically important but nonetheless acknowledge that the emphasis one places on this difference is a subjective matter.
If women indeed require more morphine than men, the difference in opioid requirements is not likely to be secondary to pharmacokinetic differences. A small study (n = 10 of each sex) to evaluate morphine pharmacokinetics after an IV bolus of morphine reported that concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide did not differ between men and women. These authors found, as we did, that women experienced less weight-adjusted analgesia after morphine than men (24).
In summary, we found that women exhibit higher pain intensity after surgery and have larger weight-adjusted morphine requirements than men to achieve a similar degree of analgesia. Clinicians should anticipate possible sex differences in opioid requirements to avoid undertreatment of pain in women (25).
Department of Anesthesia of San Ignacio Hospital Javeriana University School of Medicine, by Colciencias, and the Saltonstall and Armington Funds for Pain Research.
1. Riley JL, Robinson ME, Wise EA, Price DD. A meta-analytic review of pain perception across the menstrual cycle. Pain 1999; 81: 225–35.
2. Kest B, Sarton E, Dahan A. Gender differences in opioid-mediated analgesia: animal and human studies. Anesthesiology 2000; 93: 539–47.
3. Cepeda MS, Africano JM, Manrique AM, et al. The combination of low dose of naloxone and morphine in PCA does not decrease opioid requirements in the postoperative period. Pain 2002; 96: 73–9.
4. Unruh AM. Gender variations in clinical pain experience. Pain 1996; 65: 123–67.
5. Barsky AJ, Peekna HM, Borus JF. Somatic symptom reporting in women and men. J Gen Intern Med 2001; 16: 266–75.
6. Kepler KL, Standifer KM, Paul D, et al. Gender effects and central opioid analgesia. Pain 1991; 45: 87–94.
7. Cicero TJ, Nock B, Meyer ER. Sex-related differences in morphine’s antinociceptive activity: relationship to serum and brain morphine concentrations. J Pharmacol Exp Ther 1997; 282: 939–44.
8. Gear RW, Miaskowski C, Gordon NC, et al. Kappa-opioids produce significantly greater analgesia in women than in men. Nat Med 1996; 2: 1248–50.
9. Gear RW, Gordon NC, Heller PH, et al. Gender difference in analgesic response to the kappa-opioid pentazocine. Neurosci Lett 1996; 205: 207–9.
10. American Society of Anesthesiologists. New classification of physical status. Anesthesiology 1963; 24: 111.
11. Fox J. Outlying and influential data. In: Lewis-Beck MS, ed. Regression diagnostics. Newbury Park, CA: Sage, 1991: 21–39.
12. Mosteller F, Tukey JW. A class of mechanisms for fitting. In: Mosteller F, Tukey JW, eds. Data analysis and regression. Reading, MA: Addison-Wesley, 1997: 333–80.
13. Zeger SL, Liang KY, Albert PS. Models for longitudinal data: a generalized estimating equation approach. Biometrics 1988; 44: 1049–60.
14. White H. Maximum likelihood estimation of misspecified models. Econometrica 1982; 50: 1–25.
15. Riley JL, Robinson ME, Wise EA, et al. Sex differences in the perception of noxious experimental stimuli: a meta-analysis. Pain 1998; 74: 181–7.
16. Cepeda MS, Africano JM, Polo R, et al. What is the change in the pain intensity levels that is meaningful to the patients? In: Dostrovsky JO, Carr DB, Koltzenburg M, eds. Proceedings of the 10th world congress on pain. Seattle: IASP Press, 2003:601–9.
17. Farrar JT, Young JP, LaMoreaux L, et al. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001; 94: 149–58.
18. Averbuch M, Katzper M. A search for sex differences in response to analgesia. Arch Intern Med 2000; 160: 3424–8.
19. Cepeda MS, Meng QC, Roa JH, et al. Ethnicity influences morphine pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2001; 70: 351–61.
20. Bouillon T, Schmidt C, Garstka G, et al. Pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of alfentanil. Anesthesiology 1999; 91: 144–55.
21. Burns JW, Hodsman NB, McLintock TT, et al. The influence of patient characteristics on the requirements for postoperative analgesia: a reassessment using patient-controlled analgesia. Anaesthesia 1989; 44: 2–6.
22. Chia YY, Chow LH, Hung CC, et al. Gender and pain upon movement are associated with the requirements for postoperative patient-controlled iv analgesia: a prospective survey of 2,298 Chinese patients. Can J Anaesth 2002; 49: 249–55.
23. Gordon NC, Gear RW, Heller PH, et al. Enhancement of morphine analgesia by the GABAB
agonist baclofen. Neuroscience 1995; 69: 345–9.
24. Sarton E, Olofsen E, Romberg R, et al. Sex differences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology 2000; 93: 1245–54.
© 2003 International Anesthesia Research Society
25. Cepeda MS, Carr DB. Overview of pain management: approaches to pain management—an essential guide for clinical leaders. Oakbrook Terrace, IL: Joint Commission Resources, 2003: 1–20.