Do sex differences exist in opioid analgesia? A systematic... : PAIN (original) (raw)
1. Introduction
The administration of exogenous opioids is a cornerstone in the treatment of acute, severe pain. Since no other class of drugs has the analgesic efficacy of opioids, this will remain true also in the near future, despite the sometimes troubling side-effect profile (e.g., sedation, nausea/vomiting, and respiratory depression) of opioid analgesics. Physicians involved in the treatment of acute pain encounter large inter-individual differences in both the therapeutic analgesic effects of opioids and their unwanted side effects. Thus, the treatment of acute pain with opioids is often challenging. Rodent studies show that the variability in responses to opioids is related to a variety of factors including genetics (with genetic differences in pain sensitivity and response to opioids), the applied nociceptive assay, age and the sex of the subjects and type of opioid tested [18,20–22,45,47,53,67]. The contribution of sex as factor in opioid efficacy is increasingly appreciated in human studies as well [20,22,47,53]. However, the direction of the sex differences in opioid analgesia in humans remains poorly understood and some reported the differences to be either negligible or absent. This may be related to methodological differences, including differences in the receptor selectivity (e.g., predominantly μ opioids versus mixed μ/κ opioids) and/or pharmacokinetic and dynamic profiles of the opioids tested, differences in nociceptive models (e.g., postoperative pain from abdominal surgery, third molar surgery, acute trauma pain, experimental pain), and differences in the modes of drug administration (e.g., patient-controlled analgesia (PCA), regular intravenous injections, oral treatment). In the current systematic review we perform a meta-analysis on the currently available literature where males and females are assayed for μ and mixed μ/κ opioid-induced analgesia or antinociception. The specific aim of this analysis is to control for the extraneous and possibly confounding variables noted above, allowing for a less biased assessment of putative sex differences in opioid analgesia. This was done by performing four separate meta-analyses separating clinical from laboratory studies and within each class of studies by examining μ-opioids and mixed μ/κ opioids separately.
2. Methods
In December 2009 we searched seven electronic databases (PubMED, EMBASE, Web of Science, the Cochrane Library, CINAHL, PsychINFO and Academic Search Premier) for papers assaying opioid analgesia in men and women, with specific searches for each database. No language restrictions were applied. Search strategies for PubMED, EMBASE, Web of Science and the Cochrane Library are given in Appendix 1. Next, we checked relevant review papers for additional references. After removing duplicates, all papers were examined for the following specific content items: These are (i) original human data, (ii) subject/patient age of 18 or older and (iii) assessing possible sex-related differences (or the lack thereof) in acute opioid analgesia or antinociception (acute opioid analgesia was defined as opioid-induced pain relief in patients with pre-existing acute pain – such as postoperative pain or trauma-related pain; acute opioid antinociception was defined as opioid-induced pain relief in experimental pain studies.) When any of these criteria were not met, the paper was excluded from further analysis. All remaining papers were read in full. A final criterion was that papers presented a quantitative comparison of opioid effect between males and females. If so, the papers were included in the analysis. If not, the papers were excluded. Where possible, graphical data were re-analyzed to obtain quantitative data or the authors were contacted to obtain such data. Papers that studied more than one opioid were included with each opioid as a separate study. Similarly, data from a paper that reported on opioid effect in distinct gene variants were included per genotype. Two reviewers (MN and AD) independently performed the selection procedure. Differences in opinion were resolved by consensus and when required a third reviewer was consulted (TS).
The following variables were extracted from the papers that were included in the analysis: author affiliation, prospective or retrospective study design, number of men and women participating in the study, age of the participants, the particular opioid under study, setting (e.g., postoperative setting, emergency department), type of pain relief (intravenous patient-controlled analgesia (PCA), intravenous bolus dose technique, oral), duration of treatment, and in case of clinical studies, the type of surgery. A distinction was made between clinical studies and experimental studies. Clinical studies were defined as studies on analgesia in patients with acute pain from various sources. Experimental studies were defined as studies in which artificial pain models were applied to measure an antinociceptive opioid effect. Experimental studies could be performed in healthy volunteers or patients. Finally, a distinction was made between the opioid receptor subtype at which the tested opioid has its predominant action (μ- or κ-agonist). The following opioids were considered predominantly acting at the μ-opioid receptor: morphine, morphine-6-glucuronide, meperidine, fentanyl, alfentanil, sufentanil, remifentanil, buprenorphine, beta-endorphin, and hydromorphone. The following opioids were considered having a mixed action on μ- and κ-opioid receptors (i.e., μ/κ opioids): butorphanol, nalbuphine, and pentazocine. In case the study had multiple arms comparing opioid/placebo against opioid/active compound (e.g., naloxone), the opioid/placebo arm was included in the analysis. Studies that tested multiple compounds simultaneously were included in the analysis only when the second compound was considered not to influence the study outcome. This, for example, is the case when an opioid is combined with low-dose naloxone and both agents are given via the oral route, as no antianalgesic effect is to be expected from low-dose oral naloxone.
Outcomes that were included in the meta-analysis for clinical studies were opioid consumption in PCA studies (in mg or mg/h) and change in pain score relative to pre-drug baseline in studies on single treatments (intravenous and oral). In case opioid consumption was given as total amount and amount corrected by weight, the weight corrected data were included in the analysis. In case opioid consumption was given per age cohort, the overall mean data were included in the analysis. Only when we tested age as a covariate, the data were entered in the analysis per age cohort. For experimental studies outcomes that were included in the analysis were change in pain perception, change in pain tolerance or threshold, and plasma concentration causing a 50% effect in change in pain tolerance. In case multiple experimental pain tests were performed the results of the cold-pressure test was included in the analysis as this was the most commonly employed test.
Separate meta-analyses were performed on studies on opioids acting at μ-opioid receptors and those that act predominantly at κ-opioid receptors (μ/κ-opioids). Similarly, we separated studies on analgesia (in patients with pre-existing acute pain) and studies on antinociception (experimental pain studies in pain-free subjects). We argued that sex differences may exist in one set of studies (on μ or μ/κ-opioids; on clinical or experimental studies) but possibly not in any of the other sets. Meta-analyses were done with the Comprehensive Meta-Analysis Software package version 2.0 for Windows (Biostat Inc., Englewood, NJ, USA). Data were analyzed using random effects’ models, assuming two sources of variance: within-study error and between-study error. For each study the standardized difference in means between the sexes and the corresponding 95% confidence intervals were calculated and presented in a Forest plot. Standardized differences in means of 0.2 are interpreted as a small effect, 0.5 as an intermediate effect and 0.8 as a large effect. If the standard deviations were not reported, they were calculated from provided standard errors or _P_-values. A sensitivity analysis was performed to assess the effect of a single study on the meta-analysis outcome by leaving one study out at a time. Heterogeneity was assessed by graphic inspection and by measuring the degree of inconsistency in the studies’ results (_I_2). To study heterogeneity, the effect of covariates’ (moderators) age, PCA treatment duration and study size on the standardized difference in means between men and women were explored by meta-regression analysis. Meta-regression was restricted to data sets of at least 12 unique studies in the meta-analysis. Publication bias was assessed by calculating the fail-safe N and/or funnel plots. The meta-analysis was performed according to published guidelines (PRISMA 2009) and algorithms [59,70].
3. Results
3.1. Number of studies
The flow chart of the studies identified in the searches and the process of elimination is given in Fig. 1. After removal of duplicates, 2461 papers were reviewed of which 2407 were eliminated for various reasons (papers containing no original data, animal studies, studies in children, and papers not reporting on sex differences (or the lack thereof) in analgesia or antinociception). The remaining 55 papers were carefully examined and assessed for eligibility in the analysis. Sixteen papers were removed: one paper had overlap with another study [34], one paper used hemodynamic end-points as a marker of analgesia and was performed during anesthesia [28], and fourteen papers did not report an outcome that was considered sufficiently suitable by the reviewers to allow extraction of meaningful quantitative data on opioid analgesic/antinociceptive effect in men versus women [2,3,5–8,11,15,33,35,36,39,44,55,56,63,71]. For example, studies in which two opioid receptor agonists were given to a patient or studies reporting PCA button pressing rather than opioid use were omitted. The leading authors of some papers were contacted with the request for data per sex. In two cases this lead to the ability to incorporate their papers in the final analysis (e-mail correspondence with Kazutaka Ikeda on September 29, 2009 [32] and Kuyang-Yi Chang on December 9, 2009 [16]). Thirty-nine papers remained. One of our co-authors provided three unpublished data sets (James Zacny, 2010, unpublished observations] which were incorporated. In several papers multiple studies were extracted: one paper included an experimental and a clinical study, one paper reported on three different opioids, two on two opioids, one paper reported on the data from three unpublished data sets and finally one paper included data from two distinct genetic variants that were included as two separate studies. The review process lead to a total of 50 unique studies: 36 studies on μ-opioid analgesics and fourteen studies on μ/κ-opioid analgesics.
Flow chart of studies identified and selected for this review.
3.2. μ-Opioids
3.2.1. Clinical studies
Twenty-five clinical studies were entered in the meta-analysis, which compared μ-opioid analgesic effect in a total of 5971 male and 6388 female patients (On-line Table 1) [1,9,12,14,16,17,24,26,32,40,42,46–49,52,54,66,68,69]. The majority of studies were postoperative pain studies in a variety of surgeries using PCA as method of pain relief (_n_=15, of which 11 used morphine, two fentanyl, one buprenorphine and one meperidine) and reported opioid consumption. The majority of surgeries were abdominal (including gastro-intestinal, gynecological and urological) or orthopedic surgeries. The duration of PCA ranged from 17 to 72h. Ten studies examined pain relief in response to one or multiple opioid infusions. In these studies pain relief was assessed minutes to hours postdosing (earliest examination at 15min postinfusion). In seven studies pain relief upon opioid administration in the emergency setting was studied, in three postoperative pain relief was measured. Eleven (of 25) studies had a retrospective design (of which 5 were on PCA morphine).
Across all studies heterogeneity was high with equi-efficacy of the opioids tested between the sexes: _I_2=93%, standardized difference in means=0.094, 95% c.i. −0.079–0.268, _P_=0.286 (Fig. 2). Analysis of prospective and retrospective studies yielded results not different from the combined analysis (data not shown). Subgroup analysis on studies using morphine (irrespective of the method of pain relief) yielded no difference in opioid effect between men and women (_n_=19, standardized difference in means=0.183, 95% c.i. −0.009–0.374, _I_2=94%, _P_=0.062). Restricting the analysis to PCA studies (irrespective of the opioid used) yielded a significant greater opioid effect in women albeit with high heterogeneity: _n_=15, standardized difference in means=0.219, 95% c.i. 0.023–0.415, _I_2=91%, _P_=0.028). Restricting the analysis to PCA morphine studies showed an even greater effect in women, again with high heterogeneity: _n_=11, standardized difference in means=0.364, 95% c.i. 0.165–0.563, _I_2=92%, _P_=0.003. Meta-regression indicated no effect from the covariates’ age or study size. Meta-regression did show a clear effect from PCA duration: the longer the duration of PCA measurements, the greater the difference in men and women on opioid efficacy (with a greater efficacy in women). This effect approached a standardized difference in means of 0.8 at a PCA duration of 72h.
Comparison of μ-opioid analgesics used in clinical studies in men and women: statistics and Forest plots of the standardized differences in means between groups with 95% confidence intervals (C.Is.) for each study. In red all studies on morphine PCA.
3.2.2. Experimental studies
Eleven experimental pain studies contributed to the meta-analysis, which included 245 men and 352 women (On-line Table 1) ([19,30,32,58,60,61,64,72], plus one study from Zacny JP (2010 unpublished observation)). Six studies were on the effect of morphine; the others included the following μ-opioids: M6G, fentanyl, alfentanil, meperidine and oxymorphone. Experimental pain was induced with a variety of tests: cold pressor test in seven studies, pressure pain in one, and electrical pain in three studies (On-line Table 1). Also the outcome parameters varied: response latency, pain threshold to pressure pain, pain tolerance to electrical pain and drug-induced difference in pain intensity report. Across all studies, a significant moderate sex effect was present in the data with greater opioid effect in women, although the 95% confidence interval was broad: standardized difference in means=0.346; 95% c.i. 0.010–0.688, _I_2=66%, _P_=0.047 (Fig. 3). The sensitivity analysis showed that removal of individual studies on morphine had a small effect on the outcome (data not shown). Subgroup analysis indicated that studies on morphine (_n_=6) showed significant sex dependency (with a 30% greater effect size): standardized difference in means=0.445, 95% c.i. 0.122–0.767, _P_=0.043 In contrast grouping the other (non-morphine) opioids did not yield a significant effect: standardized difference in means=0.273, 95% c.i. −0.132–0.678, _P>_0.05. These data indicate a significant but moderate sex effect in the data on morphine but not in the data on non-morphine opioids.
Comparison of μ-opioid analgesics used in experimental pain studies in men and women: statistics and Forest plots of the standardized differences in means between groups with 95% confidence intervals (C.Is.) for each study. [uo] = unpublished observation (see Table 1). In red all studies on morphine.
3.3. Mixed action μ/κ opioids
3.3.1. Clinical studies
A total of seven studies were included in the analysis (Table 1) [37,38,41,50,54,62]. The total number of men and women tested in these studies was 102 and 93, respectively. Three studies were on the effect of nalbuphine, one on butorphanol, one on pentazocine and one on the combination pentazocine and low-dose naloxone. In six studies, the clinical pain model employed was postoperative oral surgery pain; in one study nalbuphine consumption using PCA was assessed in patients following abdominal or orthopedic surgery. All studies had a prospective design. Across the seven studies a clear significant effect was observed with greater μ/κ-opioid efficacy in female patients: standardized difference in means=0.841; 95% c.i. 0.250–1.432, _I_2=72%, _P_=0.005 (Fig. 4A). The sensitivity analysis indicates that no study had a dominant effect on the outcome. Suggestions of publication bias arose from the funnel plot (data not shown) and fail-safe N (= 3). Four of the 7 studies originate from one center, all on third molar surgery, all finding greater μ/κ-opioid efficacy in female patients (On-line Table 1).
Comparison of κ-opioid analgesics in men and women: statistics and Forest plots of the standardized differences in means between groups with 95% confidence intervals (C.Is.) for each study. A. Clinical studies, B. Experimental pain studies. [uo] = unpublished observation (see Table 1).
3.3.2. Experimental pain studies
The seven studies included had a total of 141 men and 146 women (On-line Table 1) ([29,31,57,73], plus two studies from Zacny JP (2010 unpublished observations)). The opioids tested were pentazocine in 4 studies, butorphanol in two studies and nalbuphine in one study. The experimental pain models used were cold pressor test in 3 studies, ischemic pain test in 3 studies and pressure pain in one study. In one paper a distinction was made between volunteers with 0 or 1 variant allele of the MC1r gene and volunteers with 2 or more variants. These groups are reported as distinct data sets (i.e., studies). Across all studies no systematic sex effect was observed: standardized difference in means=−0.040, 95% c.i. −0.380–0.299, _I_2=44%, _P_=0.816 (Fig. 4B). In contrast to all other studies, the study in subjects with 2 or more variant alleles of the MC1r gene showed a greater effect of pentazocine in women than men (standardized difference in means=1.8) [54]. Removal of this study had no significant effect on the outcome of the meta-analysis. In comparison, in subjects with no or just one variant allele there was a trend towards a greater effect in men.
4. Discussion
In the past decade numerous findings in animals and humans indicate sexual dimorphism in many regions of the CNS as well as sexually diergic behaviors [10,27]. It is therefore not surprising that an increasing number of studies examined the contribution of sex to pain perception and analgesia and, indeed, many studies have reported such differences [18,20–22,45,47,53,67]. Interestingly while animal studies show a tendency for opioids to act more efficaciously in males, human studies are less clear in the presence and direction of any sex effect [22,47]. We addressed these later issues in the current systematic analysis of the literature on opioid analgesia.
For μ-opioids the picture that emerges from our analysis is that a sex difference of moderate effect size cannot be ruled out in experimental pain studies with μ-opioids being more efficacious in women (effect size 0.35). When focusing on just morphine, the effect in women becomes more evident (effect size 0.45). Clinical studies on μ-opioids are more ambiguous. Heterogeneity was high and across all studies no significant sex effect was observed. The heterogeneity in these clinical studies is no surprise, when considering the large difference across studies with such variables as type of opioids, setting, type of surgery, method of pain relief, end-point, treatment duration and ethnicity, all of which may affect the study outcome. Subgroup analysis on studies just using morphine did not change the outcome. However, despite the heterogeneity, analysis on PCA studies did yield a significant effect with greater opioid consumption in men than women (effect size 0.22), again indicating greater opioid efficacy in female patients. Further sub-analysis on PCA studies that used morphine showed a 65% greater effect size (0.36). These clinical data are indicative for a significant sex effect in morphine analgesia with greater morphine efficacy in women.
In contrast to PCA studies, there was no sex effect in studies that measured pain relief over a relatively short period (<4h). In these studies one intravenous morphine dose was given and pain relief was measured, or multiple doses were given to measure the total opioid dose required to titrate the patient to comfort. In fact, in the largest study of our data set, in which patients were titrated to comfort in the first postoperative hours, a sex effect was present, but the direction opposite to that observed in PCA studies (i.e., morphine more efficacious in men) [1]. We relate this, apart from methodological issues and the fact that different modalities are measured in studies on pain relief versus opioid consumption, to differences in study duration (duration of PCA studies ranged from 17 to 72h). We previously performed a pharmacokinetic–pharmacodynamic modeling study on the effect of morphine on antinociception in healthy men and women [64]. Main findings were that morphine was more potent in women but had a slower onset of action in women, and there were no sex differences in morphine's pharmacokinetics. The cause for the slower onset time remains unknown but may be explained by a slower passage of morphine across the blood-barrier in women or to sex differences in receptor kinetics [74,75]. The slower onset of morphine in women causes greater analgesic effect in men directly following injection, despite greater morphine potency in women. Only at later times the analgesic efficacy in women is greater than that in men [64]. The result of the meta-regression on PCA duration further strengthens our arguments: PCA duration was positively correlated with increased morphine analgesic effect in women; at 72h the standardized difference in means reached a value of 0.8.
No significant effect in the meta-regression was observed for the covariate age. Just two studies that specifically examined the interaction between age and sex observed the loss of sex differences at ages>60years [1,26]. In contrast, studies examining sex effect in men and women at postmenopausal ages (>50years) did still find a sex effect [16,17,46,48,49,69]. It is of interest to note that two studies on PCA in children and adolescents (age range 7–20years) were unable to find sex difference in morphine consumption (data not included in the analysis) [25,51]. Hence, while studies focusing on just age show a significant reduction in opioid consumption in older patients [1,26], our data show no significant age×sex interaction, suggesting a reduction in opioid consumption in older patients but with persistence of a sex difference.
Most of the studies reported opioid dosages in mg (or mg/kg) but opioid concentrations in plasma were not measured. As women have a greater body fat percentage and the μ-opioids that were given all are relatively lipophilic, it may be assumed that plasma opioid concentrations differed between the sexes, with lower concentrations in females. We argue that this is especially true in clinical studies since in experimental studies most volunteers were young and healthy with a BMI well below 25. This then suggests that we underestimated the true magnitude of the sex difference in μ-opioid analgesia.
For μ/κ-opioids we observed no proof for a significant sex effect in experimental pain studies. An exception was the observation of significant greater analgesia from pentazocine in females with an inactive MC1r gene compared to males (with an intact or an inactive MC1r gene) [57]. The MC1r gene is involved in skin/hair pigmentation, immunomodulation and also plays a role in pain and analgesia. The data indicate the existence of a MC1r gene×sex interaction for μ/κ-opioids causing greater analgesic efficacy in female patients. In contrast to the experimental pain studies the data from clinical studies indicate a large sex effect (effect size 0.8) with greater analgesic efficacy in female patients. Five of the 7 studies examined the effect of μ/κ-opioids on pain following third molar resection (On-line Table 1). It may well be that third molar surgery encompasses specific inflammatory and/or nociceptive pain components with high sensitivity to κ-opioids in females only. Given the fact that 4 studies with a positive effect in female patients originated from one center we encourage others to replicate these studies and also study μ/κ-opioid sex effects in other clinical pain settings.
We included PCA studies on both μ- and μ/κ-opioids in our analysis. PCA allows the patient to titrate him or herself to comfort. However, due to possible sex differences in side effects, a sex difference in opioid consumption may occur because of differences in button pressing to avoid these side effects (such as nausea which occurs more frequently in women, see below). If true, this then should lead to a difference in pain rating during the period of PCA use with greater pain scores in women. However, PCA studies that assessed pain relief found no differences in pain scores between men and women and also the number of total demands did not differ [4,9,16,26,49,50]. One study reported greater pain as measured by postoperative VAS-scores in male patients on PCA morphine [17]. This suggests that the sex differences that we observed in PCA studies in general and PCA morphine in particular are predominantly due to a true difference in analgesic efficacy.
Most studies reporting on sex differences in opioid-induced emesis (predominantly studies on morphine) report a higher incidence in women [13,30,76]. Prospective studies on morphine-induced respiratory depression show a greater effect of morphine in women [23,65]. These data suggest that morphine-induced side effects have a greater incidence or are more pronounced in women. Hence, sex differences in morphine effect may not be restricted to the pain system but are probably an inherent property of the endogenous opioid receptor system being activated by morphine.
Our observations that women display greater opioid analgesia than men are completely opposite to what has been found in the rodent literature. This is not easily explained but could be related to methodological issues. Animal studies generally test pain threshold, while in humans mostly opioid consumption is measured in clinical studies that display greater opioid effect in women. It may well be that different pain modalities display distinct sex effects across different species. Furthermore, we observed that study duration has a significant influence on study outcome, a sign that opioid pharmacokinetics plays a significant role in the development of sex differences. Most studies do not take into account possible sex differences in pharmacokinetics of the tested opioid. Hence, sex and species differences in opioid pharmacokinetics (and closely related duration of the experiment) may influence study outcome (this may be due to differences in speed at the which the drug passes the blood–brain barrier, receptor kinetics, the production of active metabolites, drug clearance from the body, etc.) [61,64,74,75]. Another possibility is that in contrast to rodents, the pain circuitry of adult humans is less under the influence of sex hormones. For example, our data indicate that human sex differences persist beyond menopausal age, while in several animal studies a modulatory role of sex hormones is apparent [20,22,47,53]. With the Sex, Gender, and Pain SIG Consensus Working Group of the International Association for the Study of Pain we agree that sex differences in analgesia exist and that attention now needs to focus on mechanisms and clinical implications [43].
Conflicts of interest statement
Marieke Niesters is supported by TREND (Trauma RElated Neuronal Dysfunction), a non-profit consortium of academic hospitals, technical research groups and companies focused on the study of Complex Regional Pain Syndrome type 1 (Delft, The Netherlands). None of the authors report any competing interests relating to the topic of this paper.
Acknowledgement
We thank Jan W. Schoones of the Walaeus Library of the Leiden University Medical center for his help in the development of the search strategy.
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**Appendix A Supplementary data
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.pain.2010.06.012.
Keywords:
Sex differences; Analgesia; Opioids; μ-Opioids; μ/κ-Opioids; Clinical studies; Experimental studies; Gender; Sex
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