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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: l.a.rosseland@klinmed.uio.no (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.

References

Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of

the mu-opioid agonist remifentanil in humans causes hyperalgesia

during withdrawal. Pain 2003;106:4957.

Barden J, Edwards JE, Moore RA, McQuay H. Ibuprofen 400 mg is

effective in women, and women are well represented in trials. BMC

Anesthesiol 2002;2.Boden BP, Fassler S, Cooper S, Marchetto PA, Moyer RA. Analgesic effect

of intraarticular morphine, bupivacaine, and morphine/bupivacaine

after arthroscopic knee surgery. Arthroscopy 1994;10:1047.

Breivik EK, Haanaes HR, Barkvoll P. Upside assay sensitivity in a dental

pain model. Eur J Pain 1998;2:17986.

Cepeda MS, Carr DB. Women experience more pain and require more

morphine than men to achieve a similar degree of analgesia. Anesth

Analg 2003;97:14648.

Chan ST. Intra-articular morphine and bupivacaine for pain relief after

therapeutic arthroscopic knee surgery. Singapore Med J 1995;36:357.

Collins SL, Moore RA, McQuay HJ. The visual analogue pain intensity

scale: what is moderate pain in millimetres? Pain 1997;72:957.

Craft RM. Sex differences in drug- and non-drug-induced analgesia. Life

Sci 2003;72:267588.

L.A. Rosseland, A. Stubhaug / Pain 112 (2004) 248253252

8/3/2019 2945979248366223753

6/6

Dalsgaard J, Felsby S, Juelsgaard P, Froekjaer J. Low-dose intra-articular

morphine analgesia in day case knee arthroscopy: a randomized double-

blinded prospective study. Pain 1994;56:1514.

Denti M, Randelli P, Bigoni M, Vitale G, Marino MR, Fraschini N. Pre- and

postoperative intra-articular analgesia for arthroscopic surgery of the

knee and arthroscopy-assisted anterior cruciate ligament reconstruction.

A double-blind randomized, prospective study. Knee Surg Sports

Traumatol Arthrosc 1997;5:20612.

Denton J, Beecher HK. New analgesics. Methods in the clinical evaluation

of new analgesics. J Am Med Assoc 1949;141:10517.

Ferreira SH, Nakamura M. II-Prostaglandin hyperalgesia: the peripheral

analgesic activity of morphine, enkephalins and opioid antagonists.

Prostaglandins 1979;18:191200.

Fillingim RB. Sex, gender, and pain: women and men really are different

[Review] [101 refs]. Curr Rev Pain 2000;4:2430.

Franceschi F, Rizzello G, Cataldo R, Denaro V. Comparison of morphine

and ropivacaine following knee arthroscopy. Arthroscopy 2001;17:

47780.

Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD. The

kappa opioid nalbuphine produces gender-and dose-dependent analge-

sia and antianalgesia in patients with postoperative pain. Pain 1999;83:

33945.

Guignard BMD. Acute opioid tolerance: intraoperative remifentanil

increases postoperative pain and morphine requirement [Article].

Anesthesiology 2000;93:40917.

Haynes TK, Appadurai IR, Power I, Rosen M, Grant A. Intra-articular

morphine and bupivacaine analgesia after arthroscopic knee surgery.

Anaesthesia 1994;49:546.

Hill RC, Turner P. Importance of initial pain in post-operative assessment

of analgesic drugs. J Clin Pharmacol 1969;SeptemberOctober:3217.

Ho ST,Wang JJ, Liaw WJ, Wong CS, CherngCH. Analgesic effectof intra-

articular morphine after arthroscopic knee surgery in Chinese patients.

Acta Anaesthesiol Sin 1995;33:7984.

Jaureguito JW, Wilcox JF, Cohn SJ, Thisted RA, Reider B. A comparison

of intraarticular morphine and bupivacaine for pain control after

outpatient knee arthroscopy. A prospective, randomized, double-

blinded study. Am J Sports Med 1995;23:3503.

Joris JL, Dubner R, Hargreaves KM. Opioid analgesia at peripheral sites: atarget for opioids released during stress and inflammation? Anesth

Analg 1987;66:127781.

Joshi GP, McCarroll SM, OBrien TM, Lenane P. Intraarticular analgesia

following knee arthroscopy. Anesth Analg 1993;76:3336.

Kalso E, Tramer MR, Carroll D, McQuay HJ, Moore RA. Pain relief from

intra-articular morphine after knee surgery: a qualitative systematic

review [Review] [47 refs]. Pain 1997;71:12734.

Kalso E, Smith L, McQuay H, Moore A. No pain,no gain: clinical

excellence and scientific rigour-lessons learned from IA morphine. Pain

2002;98:26975.

Karlsson J, Rydgren B, Eriksson B, Jarvholm U, Lundin O, Sward L,

Hedner T. Postoperative analgesic effects of intra-articular bupivacaine

and morphine after arthroscopic cruciate ligament surgery. Knee Surg

Sports Traumatol Arthrosc 1995;3:559.

Khoury GF, Chen AC, Garland DE, Stein C. Intraarticular morphine,bupivacaine, and morphine/bupivacaine for pain control after knee

videoarthroscopy. Anesthesiology 1992;77:2636.

LeResche L. Epidemiologic perspectives on sex differences in pain. In:

Fillingim RB, editor. Sex, gender and pain. Seattle: IASP Press; 2000.

p. 23349.

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 USA 2003;100:486772.

Niemi L, Pitkanen M, Tuominen M, Bjorkenheim JM, Rosenberg PH.

Intraarticular morphine for pain relief after knee arthroscopy performed

under regional anaesthesia. Acta Anaesthesiol Scand 1994;38:4025.

Pleym H, Spigset O, Kharasch ED, Dale O. Gender differences in drug

effects: implications for anesthesiologists [Review] [128 refs]. Acta

Anaesthesiol Scand 2003;47:24159.

Robinson ME, Wise EA. Gender bias in the observation of experimental

pain. Pain 2003;104:25964.

Rollman GB, Lautenbacher S, Jones KS. Sex and gender differences in

responses to experimentally induced pain in humans. In: Fillingim RB,

editor. Sex, gender, and pain. Seattle: IASP Press; 2000. p. 16590.

Rosseland LA, Stubhaug A, Skoglund A, Breivik H. Intra-articular

morphine for pain relief after knee arthroscopy. Acta Anaesthesiol

Scand 1999;43:2527.

Rosseland LA, Stubhaug A, Grevbo F, Reikeras O, Breivik H. Effective

pain relief from IA saline with or without morphine 2 mg in patients

with moderate-to-severe pain after knee arthroscopy. A randomized,double-blind controlled clinical study. Acta Anaesthesiol Scand 2003a;

47:7328.

Rosseland LA, Stubhaug A, Sandberg L, Breivik H. Intra-articular (IA)

catheter administration of postoperative analgesics. A new trial design

allows evaluation of baseline pain, demonstrates large variation in need

of analgesics, and finds no analgesic effect of IA ketamine compared

with IA saline. Pain 2003b;104:2534.

Rosseland LA, Helgesen KG, Breivik H, Stubhaug A. Moderate-to-severe

pain after knee arthroscopy is relieved by intraarticular saline: a

randomized controlled trial. Anesth Analg 2004;98:154651.

Soderlund A, Westman L, Ersmark H, Eriksson E, Valentin A, Ekblom A.

Analgesia following arthroscopy-a comparison of intra-articular

morphine, pethidine and fentanyl. Acta Anaesthesiol Scand 1997;41:

611.

Stubhaug A, Breivik H. Postoperative analgesic trials: some importantissues. In: Baillieres, editor. Clinical anaesthesiology. London: Bailliere

Tindal; 1995. p. 55584.

Taenzer AH, Clark C, Curry CS. Gender affects report of pain and function

after arthroscopic anterior cruciate ligament reconstruction. Anesthe-

siology 2000;93:6705.

Thomas T, Robinson C, Champion D, McKell M, Pell M. Prediction and

assessment of the severity of post-operative pain and of satisfaction

with management. Pain 1998;75:17785.

Unruh AM. Gender variations in clinical pain experience [Review] [235

refs]. Pain 1996;65:12367.

Vinik HR, Kissin I. Rapid development of tolerance to analgesia during

remifentanil infusion in humans. Anesth Analg 1998;86:130711.

Walker JS, Carmody JJ. Experimental pain in healthy human subjects:

gender differences in nociception and in response to ibuprofen. AnesthAnalg 1998;86:125762.

Westmoreland CL, Hoke JF, Sebel PS, Hug Jr CC, Muir KT. Pharmaco-

kinetics of remifentanil (GI87084B) and its major metabolite(GI90291)

in patients undergoing elective inpatient surgery [see comment].

Anesthesiology 1993;79:893903.

L.A. Rosseland, A. Stubhaug / Pain 112 (2004) 248253 253