Pain 112 (2004) 248253 www.elsevier.

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Gender is a confounding factor in pain trials: women report more pain than men after arthroscopic surgery
Leiv Arne Rosseland*, Audun Stubhaug
Department of Anaesthesia, Rikshospitalet University Hospital, N-0027, Oslo, Norway Received 15 April 2004; received in revised form 21 June 2004; accepted 30 August 2004

Abstract A gender difference in the incidence of acute pain may be a confounder in analgesic trials. We have tested the hypothesis that the incidence of acute pain after knee arthroscopic procedures is greater in women than men. We performed three RCTs on intra-articular analgesics in which no postoperative analgesia was given until the need for such treatment was documented by scoring moderate-to-severe pain on a verbal rating scale (VRS 04; nZ219), and a 0100 mm visual analogue pain scale (VAS) within 2 h postoperatively. All trials were performed with an intra-articular catheter technique. The design allowed us to study the natural course of pain after arthroscopic surgery until analgesia was required. Women reported more pain of at least moderate intensity than men (84 vs 57%; P!0.0001), indicating that being female is a risk factor for early postoperative pain (RR 1.47, 95% condence interval from 1.23 to 1.74). The VAS score corresponding to moderate and severe pain is similar in men and women. Only short acting anaesthetics were given in order to minimise carry-over effects. Since previous trials on arthroscopic analgesics neither measured baseline pain nor stratied for gender, a difference between treatment groups could result from an uneven distribution regarding these factors. Our ndings have major implications for the interpretation of previously published trials on intra-articular analgesia. q 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Keywords: Gender; Sex; Postoperative; Pain; Acute pain service; Visual analogue scale

1. Introduction The inuence of sex and gender on pain and the efcacy of pain relief has recently attracted interest (Fillingim, 2000). We refer to sex as indicative of the biological differences between male and female, whereas gender is a sociological construct referring to the psychological and sociological differences. Studies on chronic pain and experimental pain show a greater prevalence of pain in females than males (LeResche, 2000; Rollman et al., 2000; Unruh, 1996), but there is little documentation of gender differences in clinical acute pain trials (Unruh, 1996). A few randomised clinical trials have documented a higher female incidence and severity of acute postoperative pain (Cepeda and Carr, 2003; Taenzer et al., 2000). Such differences,
* Corresponding author. Tel.:C47 23 07 37 00; faxC47 23 07 36 90. E-mail address: l.a.rosseland@klinmed.uio.no (L.A. Rosseland).

if present, may be a major confounding factor in randomised clinical trials (RCT), if not adequately taken into account in study design. Evidence from clinical trials suggests a sex difference in response to opioids (Cepeda and Carr, 2003; Gear et al., 1999; Pleym et al., 2003). A recent review on sex differences concludes that considerably more research will be needed to determine whether the initial ndings of sex differences are reliable (Craft, 2003). An experimental human study identied the variant of the melanocortin-1 receptor gene, which is associated with red hair, fair skin and increased sensitivity to the k-opioid agonist pentazocine in women (Mogil et al., 2003). This nding, may be an example of the increasing insight into sex specic biological aspects. However, the external validity has to be tested in sufciently powered clinical trials. A sex difference in response to non-opioid analgesics such as ibuprofen has also been reported (Walker and Carmody, 1998). The authors

0304-3959/$20.00 q 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2004.08.028

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conducted an experimental trial in 10 women and 10 men. Primary outcome measure was sex specic change in tolerance-threshold of electrically induced pain. The authors regarded the difference as clinically important. However, a meta analysis on ibuprofen including 37 RCTs with 3.755 patients tears down this view since men and women showed equal analgesic response (Barden et al., 2002). The analgesic effect of peripheral opioids is documented in animals (Ferreira and Nakamura, 1979; Joris et al., 1987). The results coming from human RCTs designed to compare the analgesic effect of intra-articular morphine with placebo are conicting, and the research quality has been criticised in two systematic reviews (Kalso et al., 1997, 2002). We have performed three RCTs on intra-articular analgesics in which no postoperative analgesia was given until the need for such treatment was documented by a score of at least moderate pain on a categorical verbal rating scale (Rosseland et al., 2003a,b, 2004). Only short acting anaesthetics were given in order to minimise carry-over effects. Based on data from these trials we wanted to test the hypothesis that women experience a greater intensity of acute pain after knee arthroscopic procedures than men.

Also in the third study (Fig. 1C), the patients were not pre-medicated. General anaesthesia was induced with propofol 1.52 mg/kg and remifentanil 0.3 mg/kg per min and maintained with the same drugs supplemented with N2O in O2 3050%. A laryngeal mask was inserted. No further analgesia was given during arthroscopy. 2.3. Assessment of postoperative pain Participating patients were informed before surgery about the scoring of postoperative pain intensity on both the 5 point verbal rating scale (VRS) (0, no pain; 1, mild pain; 2, moderate pain; 3, severe pain and 4, intolerable pain) and the 0100 mm visual analogue scale (VAS; 0, no pain; 100, worst pain imaginable). They were informed that postoperative pain might develop, and were told to report if they needed an analgesic. The patients were asked to score early postoperative pain on the VRS with approximately 10 min intervals. If moderate or severe pain was reported they also scored pain intensity on the 0 100 mm VAS under identical conditions and were included in the RCT of intra-articular analgesics. Intra-articular test drug or placebo was given through an indwelling intraarticular catheter. The intra-articular catheter technique (Rosseland et al., 2003b) and the results of the RCTs are described elsewhere (Rosseland et al., 2003a,b, 2004). Participants not reporting any need for analgesia during the rst hour postoperatively (2 h in study 1), scored a nal pain intensity 1 h (2 h in study 1) after surgery. Time to inclusion, i.e. time to moderate or severe pain, was registered in all trials. Patients with no more than mild pain during the early postoperative observation period registered VAS before they left the hospital: after 2 h in trial 1, after 1 h in trials 2 and 3. Patients with intolerable pain were also not included in any RCT, and received immediate pain relief with morphine iv (nZ3, one male, two female). Patients with no or mild pain were subjects to follow-up with registration of pain intensity and rescue drug consumption for 32 h in trial 1 (Rosseland et al., 2003b) (Fig. 1). Two male investigators (LAR in trial 1 and 3, LAR and FG in trial 2) informed the patients and collected pain outcome measures scored by the patients.

2. Methods 2.1. Materials Three randomised placebo-controlled trials (RCT) on intra-articular analgesics were performed (Total nZ219) (Rosseland et al., 2003a,b, 2004). The Regional Medical Research Ethics Committee for Southern Norway and The Norwegian Medicines Control Agency approved the study protocols. Written informed consent was obtained before surgery. The patients were ASA groups 1 and 2, age over18 years, scheduled for day case knee arthroscopic procedures. Patients undergoing arthroscopic anterior cruciate ligament reconstruction were not included. 2.2. Anaesthetic procedure In the rst study (Fig. 1A) the patients were premedicated with oral diazepam 0.100.15 mg/kg (Valiumw, Roche, Basel, Switzerland). General anaesthesia was induced with alfentanil 0.01 mg/kg (Rapifenw, JanssenCilag, Beerse, Belgium), propofol 2 mg/kg (Diprivanw, Astra-Zeneca, Caponago, Italy) and maintained with sevourane (Sevoranew, Abbott, North Chicago, IL, USA) in 70% N2O/O2 mixture and a laryngeal mask was inserted. No further analgesia was given during arthroscopy. In the second study (Fig. 1B) the patients were not premedicated. General anaesthesia was induced with propofol target controlled infusion and maintained with remifentanil 0.3 mg/kg per min (Ultivaw, Glaxo, Durham, and UK) and propofol. A laryngeal mask was inserted. No further analgesia was given during arthroscopy.

3. Statistics The severity of postoperative pain intensity (VRS 04) and types of surgical interventions in male and female patients were compared statistically by Pearson chi square analysis. The difference in incidence of at least moderate pain between genders is also expressed as relative risk with a 95% condence interval. VAS scores and corresponding VRS-scores, with gender as independent variable, were analysed by the independent sample t-test. Equality of variance was tested by the Levene test. Non-normally distributed data is presented as median and range and was

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analysed by the MannWhitney U test. The calculations were performed using SPSSw version 12 (Statistical Packages for the Social Sciences, Chicago, IL, and USA) and Condence Interval Analysis version 2.0.0 (T. Bryant, University of Southampton, UK, In BMJ Books 2000).

4. Results 4.1. Incidence Women reported an 84% incidence of at least moderate (VRS 24) postoperative pain, men reported 57% (P!0.001: Table 1). Thus, female gender was a risk factor for early postoperative pain (with-in 2 h) of at least moderate intensity with a relative risk (RR) of 1.47 (95% condence interval from 1.23 to 1.74). 4.2. Pain scales The distribution of VAS scores corresponding to the VRSscores was equal in the two genders. Severe pain corresponded to 66 mm VAS (95% CI 6170) in women and 69 mm VAS (95% CI 6277) in men (PZ0.46). Moderate pain corresponded to 45 mm VAS (95% CI 4248) in women and 43 mm VAS (95% CI 4046) in men (PZ0.33). Mild pain corresponded to median 12 mm VAS (range 820) in women and 17.5 mm (132) VAS in men (PZ0.69). No pain corresponded to median 1.5 mm (range 010) VAS in women and 2 mm (05) VAS in men (PZ0.89). 4.3. Pain observation time The median time (2575% inter-quartile range) from the end of surgery to requiring an analgesic after surgery (moderate pain or more) was 25 min (1550 min) in study 1, 19.5 (1529.5) min in study 2, and 11.5 (815) minutes in study 3. Median time to moderate pain was shorter in women (14.5 min) than men (18 min)(PZ0.03)(trials 13, nZ145). Types of surgical intervention were evenly distributed between the sexes (Table 2). Mean duration of surgical procedures was 28.4 min (95% condence interval from 24.9 to 32.0) in men and 28.4 min (24.2 to 32.5) in women.

Table 1 Table1 Cross-table on sex and baseline pain in 219 patients VRS 01 Male Female Total Fig. 1. Flow chart showing distribution of early postoperative pain (02 h) in patients who participated in one of the three studies reported, A (Rosseland et al., 2003b), B (Rosseland et al., 2003a) or C (Rosseland et al., 2004). 57 14 71 VRS 2 66 43 109 VRS 3 9 27 36 VRS 4 1 2 3 Total 133 86 219

Pain intensity were assessed with a verbal rating scale (VRS); 0, no pain; 1, mild pain; 2, moderate pain; 3, severe pain; and 4, intolerable pain. P!0.0001 (Pearson chi square).

L.A. Rosseland, A. Stubhaug / Pain 112 (2004) 248253 Table 2 Distribution of sex and number of meniscectomies, other interventions and diagnostic procedures Meniscectomies Male Female Total 61 49 110 Other interventions 6 9 15 Diagnostic 8 12 20 Total 75 70 145

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PZ0.28 (Pearson chi square).

5. Discussion 5.1. Incidence and severity of baseline pain Our trial design allowed us to study the natural course of pain after arthroscopic surgery until analgesia was required. The incidence and severity of acute postoperative pain after arthroscopic procedures was generally low, but that of moderate to severe pain was markedly higher in women. These ndings have obvious implications for the interpretation of previously reported RCTs on intra-articular analgesia and for the design of new trials. The level of statistical signicance is very high (P!0.0001). This evaluation is based on a limited number of patients (nZ219), but the nding was consistent in three RCTs at four different hospitals. Patients scoring no or mild pain in the rst study (nZ32) continued to score signicantly lower pain intensity and used signicantly fewer rescue analgesics compared with those who scored moderate to severe pain postoperatively (Rosseland et al., 2003b). The three trials reported here are the only published studies of intra-articular analgesics in which baseline pain was measured before the test drug was given. In other published trials of postoperative intraarticular analgesia, the test drug was given at the conclusion of surgery, before the requirement for analgesia was established, and without scoring a baseline pain. Thus a low postoperative pain score in such a trial could be a natural course rather than the effect of any test drug, and an excess of patients with such low scoring in the treatment group could easily be misinterpreted as a treatment effect. Similarly, relatively fewer women in the treatment group could lead to a spurious impression of a treatment effect. The anaesthetic technique used in our three studies was designed to prevent carry-over effects of the anaesthesia into the postoperative period. The pre-medicated patients in study 1 required analgesics later than in study 2 or study 3. In study 1 an induction dose of alfentanil, sevourane and nitrous oxide provided analgesia during surgery, and in study 2 and 3 remifentanil was the only analgesic agent used. Remifentanil has an ultra-short half-life of 4 min (Westmoreland et al., 1993) and is now suspected to induce hyperalgesia if an infusion is stopped without longer-acting opioids being given (Angst et al., 2003; Guignard, 2000; Vinik and Kissin, 1998). Most other intra-articular trials have used anaesthetic techniques more likely to give postoperative carry-over

effect, e.g. by use of longer-acting opioids such as fentanyl (Boden et al., 1994), non-steroidal anti-inammatory drugs like ketorolac (Boden et al., 1994), inltration of local anaesthetics (Dalsgaard et al., 1994; Rosseland et al., 1999), or regional anaesthesia (Niemi et al., 1994). The variation in individual analgesic effect and duration of these drugs will increase the variance in those trials. The risk of uneven distribution between treatment groups might therefore be even larger than shown in our trials. Assessment of baseline pain is recommended in placebocontrolled analgesic trials (Denton and Beecher, 1949; Stubhaug and Breivik, 1995). The level of pre-treatment pain affects the ability to discriminate between treatment and placebo (Hill and Turner, 1969). Pain trials, which include only patients with moderate-to-severe pain, have greater assay sensitivity and the sample size can be much reduced (Breivik et al., 1998). The intra-articular catheter technique (Rosseland et al., 2003b) allows inclusion of patients with signicant baseline pain. If this technique is not used, an even distribution of all known risk factors for postoperative pain is mandatory. Our studies show that female gender is the most important risk factor, while type of surgery, length of surgery, and use of tourniquet are of minor importance (Rosseland et al., 2003a,b, 2004). Other confounding risk factors may have been missed in this analysis. We did not, for instance, register pre-operative pain intensity but excluded all patients who had taken analgesics the last 24 h. A thorough pre-operative examination of the patients expectations and their history on previous pain experiences might also have given a deeper insight. However, we explored acute pain in a day case surgical pain model and possible pain relieving effects on intra-articular analgesics. The unexpected discovery of a sexrelated difference in acute pain was the most striking, and the only factor of signicance compared to disease severity indicators and surgical techniques. After major orthopaedic surgery female gender was a risk factor for severe postoperative pain together with high pre-operative pain severity, high expected pain severity and pain duration above 6 months (Thomas et al., 1998). Anxiety and depression did not correlate with postoperative pain severity. Gender differences in anaesthetic drug effects have also been demonstrated (Pleym et al., 2003), but these cannot explain the differences in postoperative pain, since our observation time exceeded the expected duration of the anaesthetic drugs used. 5.2. Confounded trials of IA analgesics We believe the gender difference documented in our trial should have a major impact on the interpretation of previously published trials of intra-articular analgesics. Since these trials did not measure any baseline pain, even a minor female over-representation in the placebo-group will tend to increase the difference in pain outcome measures compared with the treatment groups. Any imbalance in sex

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distribution, statistically signicant or not, may lead to a signicant difference in outcome. Two published RCTs on intra-articular morphine in which pain intensity was assessed early, before the expected onset of analgesia by intra-articular morphine, may illustrate this. Franceschi et al. compared intra-articular ropivacaine 75 mg with intraarticular morphine 2 mg in saline 20 ml or IA saline 20 ml (placebo) (Franceschi et al., 2001). The distributions of female/male patients were 7/13, 9/11 and 11/9, respectively. Pain intensity was assessed immediately after surgery and intra-articular injection, and 1, 4, 6, 12 and 24 h after drug administration. The mean immediate pain intensities on arrival in the postanaesthesia care unit were 3, 21 and 40 mm VAS, respectively. A very low initial pain (3 mm VAS) in patients receiving ropivacaine 75 mg at the end of arthroscopy is not surprising. However, the great difference in pain intensity in the two other groups immediately after intra-articular injection may explain why the patients who were given intra-articular morphine also at the later registration time points had signicantly less pain compared with placebo. Quite possibly, female dominance in the placebo group may have played a major role. Boden et al. compared intra-articular morphine 1 mg with intra-articular bupivacaine 100 mg, morphine and bupivacaine in combination and intra-articular saline 20 ml (Boden et al., 1994). This RCT also suggested a signicant analgesic effect of intra-articular morphine compared with placebo. The distribution of female/male patients were 2/8 in the intra-articular morphine group and 3/4 in placebo. The sample size is small (nZ7 in the placebo group), and the uneven sex distribution may explain why mean pain intensity at 30 min were 55 mm VAS in the placebo group, but only 25 mm VAS in the IA morphine group. The authors did not address this unfortunate unbalance in baseline characteristics. They observed that the differences in pain intensity were signicant at 30 min, as well as after 60, 90 and 120 min after test drug administration and concluded that there was a positive effect of intra-articular morphine. In several other trials, the distribution of gender between treatment groups was not reported, making interpretation even more difcult (Chan, 1995; Denti et al., 1997; Haynes et al., 1994; Ho et al., 1995; Jaureguito et al., 1995; Joshi et al., 1993; Karlsson et al., 1995; Khoury et al., 1992; Soderlund et al., 1997). Since group size was small (n!20) in all these trials, the likelihood of randomisation failure is high. 5.3. Pain scales Our patients scored pain intensity on both a 5-point VRS and the 0100 mm VAS under identical conditions. The VAS-scores corresponding to moderate and severe pain was identical in male and female patients. Collins et al. (1997) reported similar ndings. Observed gender differences are thus independent of the pain scale used.

5.4. Patientobserver interaction The sex of the observer may inuence on pain assessments. This gender role expectation of pain is a documented confounder in experimentally designed pain trials, in which assessment of pain outcome measures is performed by the observer and not the participants (Robinson and Wise, 2003). The patients registered all pain outcome measurements in this study. The investigators, who were male, did not interfere. However, the design of these three trials does not allow us to analyse the impact of the observers gender in interaction with male or female patients. We believe this effect to be negligible.

6. Conclusion The trial designs allowed us to study the natural course of pain after arthroscopic surgery until analgesia was required. The intensity of acute postoperative pain is low in many patients, but at the same time the incidence of at least moderate pain is signicantly greater in women. These ndings have major implications for the interpretation of previously published trials on intra-articular analgesia, and suggest that all trials of pre-emptive design may be awed. In particular, trials in which baseline pain was not measured and gender not stratied for, may have reached incorrect conclusions.

Acknowledgements We are grateful to the two anonymous reviewers for very stimulating critics and comments on a previous version of this paper.

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