Abstract
Objective
Responses to opioid analgesics are highly variable and the understanding of contributing factors is limited. This laboratory study was designed to examine the contributions of sex and race to inter-individual variability in responses to opioids.
Design
A randomized, double blind, mixed design was implemented in the evaluation of analgesic response to a μ-opioid agonist and mixed agonist-antagonist, using three well-validated experimental pain assays (thermal, pressure, and ischemic).
Subjects
Participants included a total of 142 healthy subjects (76M/66F), 119non-Hispanic whites and 23 African Americans.
Intervention
Three sessions of pain testing were completed prior to and following an intravenous administration of morphine (0.08 mg/kg), butorphanol (0.016 mg/kg), and placebo (saline) in counterbalanced order.
Outcome Measures
A change score was calculated from the difference between the pre-drug and post-drug values. Three separate change scores (morphine, saline, and butorphanol) were computed for each experimental pain variable. Mixed-model analyses of covariance were performed on analgesic change scores.
Results
Significant sex differences emerged for pre-drug pain measures with minimal differences for race. Sex differences in opioid analgesia were not demonstrated. However, significant race differences and race X drug interactions emerged for thermal, pressure, and ischemic pain measures. The pattern of results generally indicated that for pressure and ischemic pain, African American subjects showed greater analgesic responses to both medications compared to non-Hispanic whites. For thermal pain threshold, butorphanol but not morphine analgesia was greater for African Americans versus non-Hispanic whites.
Conclusions
Findings are among the first to demonstrate race differences in a laboratory study of opioid analgesia.
Keywords: Individual Differences, Experimental Pain, Opioid Analgesia, Race
Introduction
Pain and analgesic responses are characterized by robust inter-individual variability. While sex differences have been reported in experimental pain responses and in the prevalence and severity of clinical pain conditions, evidence regarding sex differences in opioid analgesic responses has been more variable. Sex differences in preclinical studies indicate male rodents demonstrate an increased μ-opioid analgesic response in comparison to their female counterparts (1-3). However, evidence regarding sex differences in opioid analgesia among humans is less consistent (4;5). Clinical studies have demonstrated greater analgesic responses to mixed action opioid agonist-antagonists among women compared to men (6-8), while studies examining sex differences in μ-opioid analgesia have yielded mixed results (9;10).
Laboratory pain studies are even less conclusive with minimal sex differences indicated (9). In contrast to clinical studies, a trend toward greater butorphanol analgesia was found among male compared to female volunteers tested against cold pressor pain (11). Although sex differences in μ-opioid analgesia in laboratory studies have demonstrated limited support (12), pharmacodyamic differences have been revealed, indicating women experience a slower onset of analgesia and increased side effects to μ-opioids (13-15). Interestingly, conclusions from a recent meta-analysis of clinical and experimental pain studies indicated that overall, women demonstrated a greater analgesic response to morphine compared to men with insufficient evidence to support sex differences amongst other exogenous opioids (5).
In addition to sex differences, previous studies have demonstrated racial and ethnic group differences in clinical and experimental pain responses (10;16;17). Compared to non-Hispanic whites (NHW), African Americans (AA) have been found to report greater pain and disability associated with several clinical pain conditions (18;19). Also, laboratory pain studies consistently demonstrate greater pain sensitivity across multiple stimulus modalities among AA (10;17). However, research regarding racial and ethnic group differences in opioid analgesia is limited. In a study of patients with cancer pain, Kaiko and colleagues reported that “Blacks” receiving 8 mg of morphine displayed analgesia that was comparable to “Whites” receiving 16 mg of morphine (20). While a handful of clinical studies examining analgesic responses in other ethnic groups have been conducted, no study to date has compared analgesic responses in African Americans and non-Hispanic whites using laboratory pain methods (21-23).
The current study was designed to further delineate individual differences in opioid analgesia using laboratory pain models. The study included a large subject sample, multiple pain measures, the comparison of two opioid analgesic agents, and a control for nonspecific effects using a placebo condition. The choice of analgesic agents was based on previous literature suggesting that the pattern or magnitude of sex differences may vary across these two classes of opioids (5). Moreover, given our interest in race group differences, the use of these two different opioids allowed us to determine whether the previous findings of greater analgesic responses among AA would be replicated in a laboratory setting and whether the findings would be specific to morphine or might extend to a mixed-action agonist antagonist. For this study, a commonly prescribed μ-opioid, morphine, and a mixed action agonist with a favorable side effect profile, butorphanol, were selected. The design of the study allowed for the evaluation of sex and race differences. Given the inconsistencies noted in the literature regarding sex differences and opioid analgesia, one goal of the study was to implement a within-subject laboratory design to help elucidate and clarify sex differences in opioid analgesia. A second goal of the study was to evaluate possible race differences. Based on previous studies (20;24), we hypothesized that AA would show greater morphine analgesia than NHW.
Methods
Seventy six males (8 AA, 68 NHW) and 66 females (15 AA, 51 NHW) were recruited through Institutional Review Board (IRB) approved posted advertisements. The sample contained only healthy non-smoking individuals between the ages of 18 and 45 without clinical pain, psychiatric disturbance, substance use disorder, or use of centrally acting medications assessed by a health history questionnaire. All participants were screened by the study physician. Demographic information including age, sex, ethnicity and race was collected by self-report. The terms African American (AA) and non-Hispanic white (NHW) are used to differentiate between participant race in the study. However, when citing the work of other authors, the terms specified in their publications are incorporated in the text to accurately represent the group terms utilized. Fifty-six percent of women were taking oral contraceptives. Testing was scheduled between days four and 20 after the onset of menses to avoid result influenced by the perimenstrual time frame which has been associated with heightened pain sensitivity (9). Prior to participation in each experimental session, subjects reported that they had refrained from taking over-the-counter medications within the past 24 hours, caffeine in the past 2 hours, and reported no significant health changes. Participants were paid $25 an hour for their involvement in the study.
General Experimental Procedures
The research was conducted at the General Clinical Research Center at the University of Florida. The study involved four sessions, the first being an introduction to the study protocol and the following three involving the administration of morphine, butorphanol and saline in a double-blind, randomized order. All subjects provided verbal and written informed consent and completed a number of psychological and health related questionnaires prior to participation in the research protocol. Following the introductory session, the three remaining experimental sessions were identical in procedure with the exception of drug administration (saline, morphine or butorphanol) which was implemented in a counterbalanced order.
Experimental procedures used in this study followed the general protocol implemented successfully in our previous studies (13;25). Specifically, two experimenters and a registered nurse conducted the testing sessions. One experimenter was responsible for the sensory testing component by the bedside and the other experimenter operated the equipment and recorded the data. The gender of the bedside experimenter remained consistent for each experimental session. The clinical research nurse was responsible for monitoring of vital signs, administering the placebo/analgesic drug, and completing blood draws. Subjects maintained a semi-recumbent position in a hospital bed during all study procedures. An intravenous (IV) cannula was inserted at the beginning of each experimental session followed by a 10-minute rest period. Six minutes into the rest period, vital signs were taken including blood pressure, heart rate, respiratory rate; mean arterial pressure, end tidal carbon dioxide level, and oxygen (O2) saturation with a blood pressure monitor and capnograph coupled with a nasal cannula. Ten minutes following IV placement, the pre-drug sensory testing protocol was completed including thermal pain, pressure pain, and ischemic pain measures (described below). The order of thermal and pressure pain was randomly determined for each subject and maintained for all sessions. The ischemic pain procedure was always completed last to reduce carry-over effects. Following pre-drug sensory testing, a 15-minute rest period was observed followed by the double blind IV administration of 0.08mg/kg of morphine, 0.016mg/kg butorphanol, or saline over five minutes. These doses approximate a low to moderate clinical dose with estimated equianalgesia (26). Fifteen minutes following drug administration post-drug sensory testing was repeated in a manner identical to the pre-drug testing. A timeline of the experimental session is presented in Figure 1. All clinically significant adverse effects (either reported by the subjects or observed by the experimenters) were documented. The protocol and all procedures were approved by the University of Florida’s IRB. Informed consent was obtained from each subject.
Figure 1.
Timeline representing the temporal structure of procedures during each experimental session. The boxed text represents the procedures (white) and rest breaks (gray) implemented during the experimental session. The numbers below the timeline reflect the approximate time in minutes at which experimental procedures were conducted. The bidirectional arrows between thermal pain and pressure pain indicate that these two procedures were conducted in counterbalanced order. Reprinted and adapted from Fillingim RB, Ness TJ, Glover TL, Campbell CM, Hastie BA, Price DD, Staud R: Morphine responses and experimental pain: Sex differences in side effects and cardiovascular responses but not analgesia. Journal of Pain 6:116-124, 2005, with permission from Elsevier.
Pain Testing Procedures
Similar to our previous studies (13;25), experimental pain procedures were conducted during the introductory session to reduce novelty effects. Digitally recorded instructions were provided to the subjects during the introductory session for each of the experimental pain procedures. During the three experimental sessions, the same procedures were implemented prior to and following drug administration with verbal instructions reiterated before each procedure.
Pressure Pain Threshold
Pressure pain threshold (PPT) was assessed with a handheld algometer (Pain Diagnostics and Therapeutics, Great Neck, NY). Mechanical pressure was applied with a 1-cm2 probe with a constant rate of pressure of 1kg/second, which helps reduce artifact related to reaction time. Subjects were instructed to report (verbally or by raising their hand) their first feeling of pain as a result of the pressure. Three sites were used to assess PPTs on the right side of the body: the center of the upper trapezius (posterior to the clavicle), the upper masseter (approximately midway between the ear opening and the corner of the mouth) and the ulna (dorsal forearm, approximately 8 cm distal to the elbow). The site order was randomly counterbalanced and a minimum of three trials (with readings within 1 kg) were recorded at each position. The average of the three assessments for each site was calculated and used in subsequent analysis.
Thermal Pain Procedures
Threshold and tolerance
The first thermal procedure involved assessment of warmth threshold, heat pain threshold, and heat pain tolerance. Contact heat stimuli were delivered using a computer-controlled Medoc Thermal Sensory Analyzer (Pathway Pain & Sensory evaluation System, Ramat Yishai, Israel), which includes a Peltier-element-based stimulator. Temperature levels were monitored by a contactor-contained thermistor, and returned to a preset baseline of 32°C by active cooling at a rate of 10°C/s. The 3 cm × 3 cm contact probe was applied to the right ventral forearm. In separate series of trials, warmth threshold (WTh), heat pain threshold (HPTh) and heat pain tolerance (HPTo) were assessed using an ascending method of limits. From a baseline of 32°C, probe temperature increased at a rate of 0.5°C/s until the subject responded by pressing a button to indicate when they first felt warmth (WTh), pain (HPTh), and when no longer able to tolerate the pain (HPTo). This slow rise-time was selected as a test of pain evoked mainly by stimulation of C-nociceptive afferents, as has been previously demonstrated (27;28). Four trials of WTh, HPTh and HPTo were presented to each subject. The position of the thermode was altered slightly between trials (though it remained on the ventral forearm) in order to avoid either sensitization or response suppression of cutaneous heat nociceptors. For each measure, the average of all four trials was computed for use in subsequent analyses.
Temporal summation of thermal pain
The second thermal procedure involved administration of brief, repetitive, suprathreshold heat pulses to assess temporal summation of heat pain (29). Series of ten repetitive pulses were applied to the right dorsal forearm using the Contact Heat Evoked Potential Stimulator (CHEPS), which combines heat-foil technology with a Peltier element, thereby achieving heating and cooling rates of at least 40 °C /sec. Three series of ten stimuli were applied at three different target temperatures set during the introductory session. The target temperatures were 46, 48 and 50°C. For each series, the baseline temperature was 35°C, the target temperature was delivered for 700 msec, and the interstimulus interval (at the baseline temperature) was 2.5 seconds. Subjects rated the peak pain for each of the ten heat pulses using a numerical rating scale (0 represented no pain and 100 represented the most intense pain imaginable). The average rating across all 10 trials for each temperature was used in subsequent analyses.
Modified Submaximal Tourniquet Procedure
Following completion of the pressure and thermal pain procedures, a rest period of 5-minutes was implemented prior to beginning the tourniquet procedure (30;31). The right arm was exsanguinated by elevating it above heart level for 30 seconds, after which the blood flow to the arm was occluded with a standard blood pressure cuff positioned proximal to the elbow and inflated to 240 mm Hg using a Hokanson E20 Rapid Cuff Inflator (D.E. Hokanson, Bellevue, WA, USA). In response to recorded instructions, subjects performed 20 hand grip exercises of two second duration at four second intervals at 50% of their maximum grip strength. Subjects were instructed to report when they first felt pain (ischemic pain threshold, IPTh) then to continue until the pain became intolerable (ischemic pain tolerance, IPTo), at which point the procedure was stopped. The IPTh and IPTo time points were recorded. Every 30 seconds during the procedure, subjects were prompted to alternately rate either the “intensity” or “unpleasantness” of pain using a combined numerical (0-20) and verbal descriptor box scales (e.g., intensity: 0- no pain sensation to >18-extremely intense; unpleasantness: 0-neutral to >17-very intolerable), which provides ratio-level scaling of both the sensory (intensity) and affective (unpleasantness) dimensions of pain. These scales have been used extensively in our laboratory with good results (12). An overall ishchemic pain intensity (IPInt) and unpleasantness (IPUnpl) summary score were created by summing all intensity ratings and all unpleasantness ratings obtained during the procedure, providing cumulative ischemic intensity and unpleasantness rating totals. Additionally, cardiovascular measures (systolic, diastolic, and mean arterial blood pressure, and heart rate) were recorded every 60 seconds. An uninformed 15-minute time limit was observed. To replace missing values created by subjects terminating the procedure before the time limit, the last rating provided was carried forward.
Side Effects
The clinical research nurse recorded side effects that were observed or reported by the participant. Specifically, the nurse recorded whether the participant experienced each of the following side effects: nausea, emesis, dizziness/lightheadedness, pallor, diaphoresis, headache, pruritus, and fainting. Also, any other less common side effects that occurred were recorded as “other.” For analytic purposes, the total number of side effects experienced was computed for each drug administration.
Data Analysis
Each subject could participate in up to four separate testing sessions. Data from the introductory session were excluded from analysis, as this session was intended solely to reduce novelty effects in the subsequent medication sessions. Pre-drug pain measures were defined as the average of up to three pre-drug sessions. For participants who discontinued the protocol before completion, pre-drug measures were computed based on the available pre-drug data. Ethnic group differences were analyzed by comparing NHW (n= 119) to AA (n= 23). The drug effect for each pain measure was determined by a change score calculated as the difference between the pre-drug value and the post-drug value. The difference scores were computed such that positive numbers represent a reduction in pain and negative numbers represent an increase in pain. Thus, subjects had three separate change scores (morphine, saline, and butorphanol) for each experimental pain variable. Analgesic analyses included only those participants who completed the entire study. Additionally, if subjects reached the cutoff on tolerance measures during pre-drug assessment, change scores were not computed (ceiling effect) for that specific measure. In this study, 17 subjects (14 NHW/3AA) were excluded from analysis of HPTo and 42 subjects (35NHW /7AAW) were excluded from IPTo; however, these subjects were included in all other analyses. Data were analyzed with SAS software. Each pre-drug pain measure was analyzed using an analysis of variance (ANOVA) with sex and race as between subject variables. Analgesic measures were subjected to a mixed-model analysis of covariance (ANCOVA) with sex and race as between-subject variables, drug condition (morphine and butorphanol) as the within-subjects variables, and saline response as the covariate. Significant effects from the omnibus tests were further explicated using follow-up comparisons. Significance level was set at p < 0.05. Due to the low number of subjects in the African American group, interpretations were limited to two-way interactions.
Results
Demographic Characteristics
Demographic characteristics are presented in Table 1. The average age for both groups of men and women participants was 23. A significantly greater proportion of African American participants was female compared to male (p = .049). A total of 9 (2 AA F, 4 NHW F, 1 AA M, 2 NHW M) participants discontinued the study before completion. Five subjects discontinued because of side effects of the medications, including nausea and dysphoria, and the remainder dropped out for other reasons such as vasovagal response to the IV insertion or due to scheduling difficulties. Information regarding side effects is addressed in greater detail below.
Table 1.
Demographic characteristics
| Variable | Women (n=66) | Men (n=76) |
|---|---|---|
| Age (years) | 23.1 | 23.1 |
| Race (%) | ||
| African American | 22.7 | 10.5 |
| Non-Hispanic White | 77.3 | 89.5 |
| Weight (kg) | 65.8 | 81.9 |
| Body mass index | 23.8 | 25.1 |
| Morphine dose (mg) | 5.3 | 6.6 |
| Butorphanol dose (mg) | 1.0 | 1.3 |
Pre-drug Pain Responses
Pre-drug data were analyzed for all participants on whom data were available. As noted in Table 2, significant sex differences were found for warmth threshold (p < 0.0001), temporal summation of thermal pain at 50°C (p = 0.035), heat pain tolerance (p = 0.0003), and pressure pain thresholds at the masseter (p < 0.0001), trapezius (p = 0.0003), and ulna (p < 0.0001). Women reported lower warmth threshold and heat pain tolerance, higher heat pain intensity at 50°C, and lower pressure pain thresholds. Sex differences for ischemic pain measures were not statistically significant (p > 0.05). Race differences were analyzed by comparing NHW to AA subjects; results are presented in Table 3. One significant difference emerged, AA reported higher ischemic pain threshold (p = 0.0015).
Table 2.
Pre-drug response to pain measures by sex
| Variable | Women (n=66) Mean (SD) |
Men (n=76) Mean (SD) |
|---|---|---|
| WTh (°C)** | 33.8 (0.6) | 34.4 (1.2) |
| HPTh (°C) | 41.4 (2.6) | 42.2 (2.4) |
| HPTo (°C)** | 46.1 (2.3) | 47.7 (2.4) |
| Average rating @ 46°C | 37.5 (25.2) | 34.6 (24.7) |
| Average rating @ 48°C | 56.2 (26.3) | 50.3 (26.9) |
| Average rating @ 50°C* | 72.7 (22.8) | 63.2 (26.6) |
| PPT masseter (kg)** | 2.3 (0.7) | 3.0 (0.8) |
| PPT trapezius (kg)** | 3.8 (1.6) | 4.7 (1.6) |
| PPT ulna (kg)** | 3.8 (1.5) | 4.8 (1.7) |
| IPTh (sec) | 136.6 (109.9) | 128.3 (80.2) |
| IPTo (sec) | 484.0 (272.6) | 530.5 (252.5) |
| IPInt | 209.8 (57.4) | 200.5 (64.6) |
| IPUnpl | 212.2 (59.0) | 206.5 (64.8) |
Abbreviations: HPTh, heat pain threshold; HPTo, heat pain tolerance; PPT, pressure pain threshold; IPTh, ischemic pain threshold; IPTo, ischemic pain tolerance; IPInt, ischemic pain intensity; IPUnpl, ischemic pain unpleasantness.
Sig. (2-tailed) p < .05,
Sig. (2 tailed) p < .001
Table 3.
Pre-drug response to pain measures by non-Hispanic whites and African Americans
| Variable | non-Hispanic whites (n=119) Mean (SD) |
African Americans (n=23) Mean (SD) |
|---|---|---|
| WTh (°C) | 34.1 (0.9) | 34.2 (1.3) |
| HPTh (°C) | 41.8 (2.4) | 41.9 (2.8) |
| HPTo (°C) | 47.2 (2.4) | 45.9 (2.7) |
| Aver rating @ 46°C | 36.3 (23.8) | 34.3 (30.7) |
| Aver rating @ 48°C | 53.2 (25.6) | 52.1 (32.5) |
| Aver rating @ 50°C | 67.0 (24.9) | 69.7 (28.1) |
| PPT masseter (kg) | 2.7 (0.8) | 2.8 (0.8) |
| PPT trapezius (kg) | 4.3 (1.6) | 4.4 (1.7) |
| PPT ulna (kg) | 4.3 (1.7) | 4.4 (1.6) |
| IPTh (sec)* | 121.0 (81.3) | 189.9 (134.6) |
| IPTo (sec) | 525.7 (259.1) | 422.1 (266.0) |
| IPInt | 204.9 (60.4) | 204.5 (67.3) |
| IPUnpl | 209.8 (60.8) | 205.8 (69.7) |
Abbreviations: HPTh, heat pain threshold; HPTo, heat pain tolerance; PPT, pressure pain threshold; IPTh, ischemic pain threshold; IPTo, ischemic pain tolerance; IPInt, ischemic pain intensity; IPUnpl, ischemic pain unpleasantness.
Sig. (2-tailed) p < 0.005
Analgesic Responses to Morphine and Butorphanol Grouped by Sex and Race
No sex differences emerged for any analgesic measure (all p’s > 0.10). Analgesic responses for morphine and butorphanol for NHW and AA are presented in Table 4.
Table 4.
Analgesic response to morphine, butorphanol, and saline for Non-Hispanic Whites and African Americans
| Non-Hispanic Whites (n=84-113) |
African Americans (n= 14-20) |
|||||
|---|---|---|---|---|---|---|
| Mean (SD) | Mean (SD) | |||||
| Variable | Morphine | Saline | Butorphanol | Morphine | Saline | Butorphanol |
| WTh (°C) | 0.4 (0.8) | 0.4 (0.7) | 0.5 (0.9) | 0.3 (0.6) | 0.2 (0.9) | 0.7 (1.2) |
| HPTh (°C)X | 0.4 (1.7) | 0.03 (1.4) | −0.003 (1.9) | 0.4 (2.0) | 0.4 (1.53) | 1.3 (1.7) |
| HPTo (°C) | 0.5 (1.0) | −0.2 (0.8) | 0.3 (1.2) | 0.5 (1.0) | 0.3 (1.0) | 0.7 (1.9) |
| Aver rating @ 46°C | 1.8 (13.0) | −1.6 (12.6) | 3.4 (11.7) | −2.0 (7.3) | −5.4 (14.2) | −1.8 (13.0) |
| Aver rating @ 48°C | 3.1 (10.4) | −2.4 (11.5) | 5.4 (12.2) | 3.9 (16.5) | 3.9 (21.3) | −1.4 (20.4) |
| Aver rating @ 50°Cŧ | 2.7 (9.5) | −2.1 (9.7) | 5.6 (9.4) | 0.75 (18.0) | −0.9 (10.3) | 5.6 (16.5) |
| PPT masseter (kg) | 0.2 (0.5) | −0.1 (0.5) | 0.3 (0.5) | 0.3 (0.7) | −0.03 (0.4) | 0.5 (0.8) |
| PPTtrapezius(kg)* | 0.3 (0.9) | −0.3 (0.8) | 0.6 (1.2) | 0.7 (1.1) | −0.4 (0.7) | 1.1 (1.4) |
| PPT ulna (kg)* | 0.4 (1.1) | −0.05 (0.8) | 0.5 (1.1) | 1.0 (1.3) | −0.2 (1.0) | 0.7 (1.2) |
| IPTh (sec)** | 24.0 (89.2) | 13.4(73.2) | 30.6 (87.1) | 108.1(154.5) | 30.5(220.9) | 136.6 (164.3) |
| IPTo (sec) | 116.2(103.9) | 13.8(100.2) | 117.9(175.1) | 122.3(154.3) | 14.4(173.4) | 170.7(201.7) |
| IPInt* | 27.8 (27.8) | 9.0 (28.6) | 31.0 (50.6) | 42.4 (48.1) | 5.9 (62.6) | 53.8 (64.3) |
| IPUnpl*ŧ | 28.1 (28.6) | 10.8 (32.8) | 35.4 (45.8) | 44.2 (52.4) | 5.4 (65.5) | 54.8 (55.7) |
Abbreviations: HPTh, heat pain threshold; HPTo, heat pain tolerance; PPT, pressure pain threshold; IPTH, ischemic pain threshold; IPTo, ischemic pain tolerance; IPInt, ischemic pain intensity; IPUnpl, ischemic pain unpleasantness.
Significant main effect for ethnic group with saline response as a covariate (p < .05),
(p< .0001)
Significant main effect for drug with saline response as a covariate (p < .05)
Significant for ethnic group X drug interaction with saline response as a covariate (p < .05)
Heat Pain Measures
Drug effects on warmth threshold (WTh) did not differ by sex or race (p’s > 0.10). For HPTh a significant race X drug interaction was found (p = 0.02). Analysis of simple effects for HPTh difference scores indicated that AA showed significantly greater butorphanol analgesia than NHW, while morphine responses did not differ across the two race groups. There were no other significant race differences in thermal analgesic responses (p’s > 0.05). A main effect of drug was found for heat pain ratings at 50 degrees (p = 0.036), indicating that the analgesic response was greater for butorphanol than for morphine for both NHW and AA.
Pressure Pain Measures
Main effects of race emerged for pressure pain threshold analgesic scores at the trapezius (p = 0.041) and the ulna (p = 0.013), such that AA showed greater analgesia across both drugs compared to NHW. No significant differences were present for pressure pain analgesic scores at the masseter (p’s > 0.05).
Ischemic Pain Measures
Significant race differences were present for analgesic scores for ischemic pain threshold (p < 0.0001), ischemic pain intensity (p = 0.022), and ischemic pain unpleasantness (p = 0.028). In each case, across both drugs, AA showed more robust analgesic responses than NHW.
Side Effects
No significant race differences in side effects emerged (p = 0.79). The total number of side effects was significantly greater for women than men across both morphine and butorphanol (p = 0.02). Also, butorphanol produced a greater number of side effects than morphine (p = 0.0015). The most common side effects experienced were nausea (reported by 21.2% of subjects after morphine and 26.3% after butorphanol) and lightheadedness/dizziness (22.6% for morphine and 48.9% for butorphanol). The frequencies of common side effects by sex and race are presented in Table 5. There were no serious adverse events.
Table 5.
Side effects to morphine and butorphanol by sex and race
| % Women (n=63) |
% Men (n=74) |
% non-Hispanic Whites (n=115) |
% African Americans (n=22) |
||
|---|---|---|---|---|---|
| Morphine | Nausea | 30 | 14 | 20 | 27 |
| Emesis | 13 | 1 | 5 | 14 | |
| Dizziness | 29 | 18 | 22 | 27 | |
| Butorphanol | Nausea | 30 | 23 | 24 | 38 |
| Emesis | 13 | 1 | 6 | 10 | |
| Dizziness | 56 | 43 | 49 | 48 |
Discussion
The purpose of this study was to evaluate sex and race differences in analgesic responses to morphine (μ-agonist) and butorphanol (mixed agonist-antagonist) using three well validated experimental pain models (thermal, pressure, and ischemic). One of the key features of this study was the opportunity to compare responses to analgesic agents within subjects. Consistent with the literature, results demonstrated significant sex differences in pre-drug pain measures. Minimal race differences in pre-drug measures were found. Unexpectedly, the study did not reveal sex differences in morphine analgesia. Less noteworthy, the absence of sex differences in butorphanol analgesia is consistent with previous laboratory findings (5). In contrast to no sex differences, significant race differences emerged for several measures of opioid analgesia. Specifically, AA demonstrated greater analgesic responses to both morphine and butorphanol compared to NHW on measures of pressure and ischemic pain. For heat pain threshold measures, AA demonstrated greater butorphanol (but not morphine) analgesia than NHW.
Group differences in basal pain responses generally aligned with patterns noted in the literature (9;32). Previous findings indicate that women demonstrate increased sensitivity to pressure, electrical, temporal summation, and muscle pain measures. Women in the study reported lower warmth threshold, heat pain tolerance, and pressure pain thresholds; and higher heat pain intensity ratings at 50°C. Ethnic/race group differences have also been consistently reported in experimental pain sensitivity with AA and Hispanics demonstrating lower tolerance for heat, cold pressor, and ischemic pain (10;17;33;34). In the present study, significant findings for pre-drug measures were limited to AA reporting higher ischemic pain thresholds. Of note, increased ischemic pain thresholds in AA have been previously reported (10;17;34).
A primary goal of this study was to further investigate individual differences in opioid analgesia specific to sex and race. Notably, race demonstrated a more significant relationship to individual differences in opioid analgesia than sex-related influences. Interestingly, the greater analgesia among AA was not accompanied by increased side effects, suggesting a potentially larger therapeutic window for opioids in this population. In contrast, despite similar analgesic responses across sexes, women experienced significantly more side effects from both medications, consistent with previous findings (15;35;36). While numerous clinical and laboratory studies have investigated sex differences in exogenous opioid analgesia, there is a dearth of information onethnic and race differences in opioid analgesia.
Given the increasing ethnic and racial diversity in the United States, understanding the association of these variables with opioid analgesia is particularly important. By 2050, 47% of the U.S. population will be represented by minority groups with 88.6 % of the population growth by 2100 attributable to non-Anglo individuals (37;38). Ethnic/racial disparity in pharmacological management of pain is prevalent in the literature (39-43). Unfortunately, many studies involve a retrospective review of medical records and do not allow for an evaluation of the effectiveness of the analgesic intervention, and it is difficult to determine if the discrepant dosage pattern represents over-prescribing to some populations or under prescription to others (41).
A few studies have attempted to address ethnic group/race differences in analgesic responses. Kaiko and colleagues evaluated pain relief scores from patients diagnosed with cancer and chronic pain in controlled trials of analgesia (20). Results indicated that “Black” patients receiving 8 mg of intramuscular morphine reported pain relief comparable to that experienced by “Whites” receiving 16 mg of morphine. A second study demonstrated similar results with “Caucasian” subjects requiring higher doses of morphine to obtain pain relief post-surgically compared to “African” and “Asian” subjects (24). The current laboratory findings indicating that AA reported greater opioid analgesic responses than NHW subjects provide additional evidence in support of these earlier clinical findings (20;24).
Results warrant speculation of possible underlying mechanisms contributing to ethnic group/race differences in analgesic response. Studies have indicated opioid pharmacokinetic and pharmacodynamic properties are influenced by genetic and non-genetic factors (44). Cepeda and colleagues assessed ventilation responses to morphine in “Caucasians, native Indians, and Latinos (21).” Differences were found with native Indians demonstrating increased susceptibility to respiratory depression contrasted to Caucasians. In a second study, morphine clearance was analyzed in eight “Chinese” and eight “white” men (44). The rate of morphine clearance and gastrointestinal side effects (nausea and emesis) were higher in the Chinese subjects. White subjects demonstrated greater ventilatory depression and blood pressure reduction. Although ethnic differences were apparent, analgesic efficacy was not included in the analysis of either study.
A number of different genetic polymorphisms have been identified that may contribute to individual differences in opioid analgesia. Allelic variations of CYP2D6 resulting in either poor or excessive metabolisers have been associated with altered opioid metabolism specifically in “African” populations (45). Another potential candidate gene is the μ-opioid receptor gene (OPRM1). The rare allele of the A118G single nucleotide polymorphism of OPRM1 occurs more frequently in “European” and “Asian” populations compared to “African American” populations (46). Interestingly, though the findings are mixed, this SNP has been associated with attenuated mu-opioid analgesic responses (47-49), as well as basal pain sensitivity (50). Further research including the investigation of genetic contributions to ethnic and race differences in opioid analgesia is warranted.
In the present study, race differences in analgesic responses were more consistent for ischemic and mechanical pain than heat pain. One explanation for this is that heat pain was not particularly sensitive to the opioids administered, as post-drug changes in heat pain measures were quite modest in magnitude. Another potential consideration is whether race differences in baseline pain sensitivity may have contributed to differences in analgesic effects, since pre-clinical studies have demonstrated an inverse relationship between basal pain sensitivity and analgesic, antinociceptive response (51-53). However, this seems unlikely to account for the present findings for several reasons. First, race group differences in analgesic responses emerged on most pain measures, while differences in basal pain sensitivity were limited. Second, extending pre-clinical findings to the present study, previous evidence of increased sensitivity to pain among AA (10;17) would predict poorer analgesia among AA compared to NHW, rather than the more robust analgesic responses that we observed (51). Third, in a recent cluster analysis completed on data gathered from the present study, subgroups of individuals who differed in their analgesic response patterns did not differ in their baseline pain responses (54).
These findings should be interpreted in light of the limitations of the study. First, given that this is a laboratory study, the findings may not apply to clinical settings. However, one of the strengths of experimental pain models is the opportunity to investigate analgesic effects while controlling for a number of confounding factors that can influence results. Second, participants in the study were healthy, young adults and thus the results obtained may not generalize to the population as a whole. Third, our group sizes were disproportionate with a significantly greater number of NHW subjects contrasted to AA subjects. Replication with a larger number of AA subjects and other ethnic and race groups is warranted. Fourth, due to sample size we were not able to analyze the sex by drug by race interaction. Future studies with a larger sample size would help delineate the relationship among these contributing factors. Fifth, we conducted large number of statistical tests and did not apply a correction to control experimentwise error. Thus, some of our significant findings could have emerged due to chance alone. Finally, we administered only one dose of each opioid; therefore, whether race group differences in analgesic response are dose-dependent cannot be determined.
Conclusions
Sex and race differences in clinical and experimental pain have been consistently reported. However, findings regarding opioid analgesia are less conclusive. Inconsistencies have been reported on sex differences in opioid analgesia in clinical and experimental studies with some indication that in general, women experience a greater morphine analgesia than men. Few studies have explored ethnic and race differences in opioid analgesia. The design of the current laboratory study allowed a within-group analysis of two opioid analgesic agents and a placebo condition and the evaluation of sex and race differences. While no sex differences emerged, significant race differences in analgesia were observed across both drugs and for multiple pain measures. The findings from this study are novel and indicate that race-related factors significantly contribute to individual differences in laboratory measures of morphine and butorphanol analgesia.
Acknowledgements
This work was supported by NIH/NINDS grant NS041670, NINDS training grant NS045551, and CTSA grant RR029890. Roger Fillingim, Ph.D. is a stockholder in Algynomics.
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