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Gender is a confounding factor in pain trials: women reportmore 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% confidence 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 stratified for gender, a difference between treatment groups could result
from an uneven distribution regarding these factors. Our findings 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 influence of sex and gender on pain and the efficacy
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 infemales 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,
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 findings of sex
differences are reliable (Craft, 2003). An experimentalhuman study identified 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 finding, may be an
example of the increasing insight into sex specific biological
aspects. However, the external validity has to be tested in
sufficiently 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
Pain 112 (2004) 248253
www.elsevier.com/locate/pain
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
* Corresponding author. Tel.:C47 23 07 37 00; faxC47 23 07 36 90.
E-mail address: [email protected] (L.A. Rosseland).
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conducted an experimental trial in 10 women and 10 men.
Primary outcome measure was sex specific 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 conflicting, 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.
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 TheNorwegian 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 first study (Fig. 1A) the patients were pre-
medicated with oral diazepam 0.100.15 mg/kg (Valiumw,
Roche, Basel, Switzerland). General anaesthesia was
induced with alfentanil 0.01 mg/kg (Rapifenw, Janssen-
Cilag, Beerse, Belgium), propofol 2 mg/kg (Diprivanw,
Astra-Zeneca, Caponago, Italy) and maintained with
sevoflurane (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 pre-
medicated. 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.
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 intra-
articular 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
first hour postoperatively (2 h in study 1), scored a final 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 periodregistered 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 mildpain were subjects to follow-up with
registration of pain intensity and rescue drug consumption
for 32 h intrial 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.
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% confidence 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 Confidence 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%
confidence interval from 1.23 to 1.74).
4.2. Pain scales
The distribution of VAS scores corresponding to theVRS-
scores was equal in the two genders. Severe pain corre-
sponded 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 mmVAS (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% confidence interval
from 24.9 to 32.0) in men and 28.4 min (24.2 to 32.5) in
women.
Fig. 1. Flow chartshowingdistributionof 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).
Table 1
Table1 Cross-table on sex and baseline pain in 219 patients
VRS 01 VRS 2 VRS 3 VRS 4 Total
Male 57 66 9 1 133
Female 14 43 27 2 86
Total 71 109 36 3 219
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).
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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 findings have obvious implications for the interpret-
ation of previously reported RCTs on intra-articular
analgesia and for the design of new trials. The level of
statistical significance is very high (P!0.0001).
This evaluation is based on a limited number of patients
(nZ219), but the finding was consistent in three RCTs at
four different hospitals.
Patients scoring no or mild pain in the first study (nZ32)
continued to score significantly lower pain intensity and
used significantly 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 inwhich baseline pain was measured before the test drug was
given. In other published trials of postoperative intra-
articular 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. Thepre-medicatedpatients in study
1 required analgesics later than in study 2 or study 3. In study
1 an induction dose of alfentanil, sevoflurane and nitrous
oxide provided analgesiaduring 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-inflammatory drugs
like ketorolac (Boden et al., 1994), infiltration 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 unevendistribution between treatment groups might therefore be
even larger than shown in our trials.
Assessment of baseline pain is recommended in placebo-
controlled 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 significant 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 butexcluded all patients whohad
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 onintra-articular analgesics. The unexpected discovery of a sex-
related difference in acutepain was the most striking, and the
only factor of significance compared to disease severity
indicators and surgical techniques. After major orthopaedic
surgery female gender was a risk factor for severe post-
operative pain together with high pre-operative pain severity,
high expected pain severity andpain 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
Table 2
Distribution of sex and number of meniscectomies, other interventions and
diagnostic procedures
Meniscectomies Other
interventions
Diagnostic Total
Male 61 6 8 75
Female 49 9 12 70
Total 110 15 20 145
PZ0.28 (Pearson chi square).
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distribution, statistically significant or not, may lead to a
significant 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 intra-
articular 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 significantly 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
significant 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 theplacebo 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 significant 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 difficult (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 findings. Observed gender differ-
ences are thus independent of the pain scale used.
5.4. Patientobserver interaction
The sex of the observer may influence 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 significantly greater in women. These
findings 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 flawed.
In particular, trials in which baseline pain was not measured
and gender not stratified 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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