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Psychosomatic Medicine 66:198-206 (2004)
© 2004 American Psychosomatic Society

ORIGINAL ARTICLES

Sex Differences in Pain and Hypothalamic-Pituitary-Adrenocortical Responses to Opioid Blockade

Mustafa al’Absi, PhD, Lorentz E. Wittmers, MD, PhD, Deanna Ellestad, RN, Glenn Nordehn, DO, Suck Won Kim, MD, Clemens Kirschbaum, PhD and Jon E. Grant, MD

From the Departments of Behavioral Sciences (M.A., D.E.), Family Medicine (M.A., G.N.), and Physiology (M.A., L.E.W.), University of Minnesota School of Medicine, Duluth, Minnesota; Department of Psychiatry (S.W.K., J.E.G.), University of Minnesota, Minneapolis, Minnesota; and Experimental Psychology (C.K.), University of Düsseldorf, Germany.

Address correspondence and reprint requests to Mustafa al’Absi, PhD, Department of Behavioral Sciences, University of Minnesota School of Medicine, Duluth, MN 55812. E-mail: malabsi{at}umn.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: Sex differences in pain sensitivity and stress reactivity have been well documented. Little is known about the role of the endogenous opioid system in these differences. This study was conducted to compare adrenocortical, pain sensitivity, and blood pressure responses to opioid blockade using naltrexone in men and women.

METHODS: Twenty-six participants completed 2 sessions during which placebo or 50 mg of naltrexone was administered, using a double-blind, counterbalanced design. Thermal pain threshold and heat tolerance were assessed. Participants also rated pain during a 90-second cold pressor test (CPT) and completed the McGill Pain Questionnaire (MPQ) after each pain challenge. Blood and saliva samples and cardiovascular and mood measures were obtained throughout the sessions.

RESULTS: Plasma cortisol, adrenocorticotropin, beta endorphin, prolactin, and salivary cortisol levels increased similarly in men and women after naltrexone administration compared with placebo. Women reported more pain during both pain procedures and had lower thermal pain tolerance. In response to naltrexone, women exhibited reduced blood pressure responses and reduced MPQ pain ratings after CPT. No effects of naltrexone on these measures were found in men.

CONCLUSIONS: Although men and women exhibited similar hormonal responses to opioid receptor blockade, women reported less pain and showed smaller blood pressure responses during CPT. Results suggest differential effects of the endogenous opioid system on pain perception and blood pressure in men and women.

Key Words: pain, • stress, • gender differences, • cortisol, • adrenocorticotropin, • naltrexone.

Abbreviations: CPT = cold pressor test;; HPA = hypothalamic–pituitary–adrenocortical;; HR = heart rate;; MPQ = McGill Pain Questionnaire;; SV = stroke volume.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Several laboratories have demonstrated significant sex differences in pain sensitivity, addictive processes, and hypothalamic–pituitary–adrenocortical (HPA) responses to stress. Clinical and laboratory studies have shown that women report higher pain levels or exhibit less pain tolerance than men (1–6). Women also exhibit reduced free cortisol levels and reduced adrenocorticotropin (ACTH) responses to stress (7–9). Experiments in animals have also demonstrated sex differences in the effects of opioid receptor agonists (10–13). For example, female rats acquire self-administration of opiates at a faster rate than males (14), and females consume significantly greater amounts of heroin and morphine than males (15,16). These differences have been documented using other drugs and in both animals and humans (17–20). The extent to which endogenous opioid functions play a role in these sex differences remains to be determined.

Endogenous opioids are naturally occurring, opiate-like substances that are important in antinociception and in the regulation of mood (21–23). Accumulated evidence suggests that the endogenous opioid system modulates HPA activity (24,25). Removing the opioidergic inhibitory inputs to the corticotrophin-releasing factor–producing neurons in the hypothalamus using opioid receptor blockade medications increases ACTH and cortisol (26–28), and these actions provide an assessment strategy for the functional evaluation of the hypothalamic opioid tone. Although several studies have evaluated effects of opioid receptor blockade on the HPA axis (24,29,30), little research has addressed sex differences in the opioid-HPA interactions in healthy humans or effects of opioid blockade on pain perception and cardiovascular reactivity.

Recent evidence indicates that functional differences in the endogenous opioid system may contribute to sex differences in pain sensitivity (31,32). For example, research has shown that opioid medications that act predominantly on kappa receptors produce greater pain reduction in women than in men who underwent surgery for the removal of their third molars (33). This may indicate enhanced kappa-opioid pain modulation in women (31). Experiments in animals have also demonstrated sex differences in the functions of the mu opioid receptors (eg, 34,35), with males exhibiting greater antinociception effects of mu opioid receptor agonists than females (10,36).

The experiment presented here was designed to evaluate sex differences in HPA hormone production, blood pressure (BP) changes, and pain perception after opiate receptor blockade with naltrexone. The study used a double-blind, counterbalanced design and included 2 assessment sessions, conducted after administration of placebo or naltrexone.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Participants
Participants (ages 18–40 years) were recruited from the university community by posters and newspaper advertisements. Inclusion criteria were as follows: absence of major medical or psychiatric illnesses as evaluated by self-report, no prior or current treatment for hypertension, weight within 30% of Metropolitan Life Insurance Company norms, and alcohol consumption of no more than 2 drinks per day. Participants meeting the initial inclusion criteria were scheduled for a medical examination to confirm health status and absence of contraindications to treatment with naltrexone.

Specific exclusion criteria for all participants included the following: 1) current or past history of hypertension; 2) history of renal or hepatic disease; 3) current cardiac or other chronic diseases (eg, angina, coronary heart disease, arrhythmias, diabetes, hyperlipemia, neurological disorders, thyroid, respiratory disorders; 4) current opiate dependence, recent daily opiate use, or use of any narcotic medication within 3 days before the study; 5) history of a major psychiatric disorder (eg, depression, schizophrenia, alcohol and drug abuse); 6) routine use of prescriptive medication of any kind; and 7) pregnancy. Twenty-six participants (11 women and 15 men) were eligible to participate and underwent a medical screening to confirm their eligibility.

Participants signed a consent form approved by the Institutional Review Board of the University of Minnesota and received a monetary incentive for participation (US $20 per hour).

Apparatus and Measures
Thermal Stimuli
Thermal pain stimuli were delivered to the skin of the left volar forearm using a 2-cm2 Peltier contact thermode affixed in place with a Velcro strap and computer controlled. Temperature was monitored by a contactor-contained thermistor (Medoc TSA 2001, Minneapolis, MN), and the thermode was returned to the adapting temperature (32°C) between trials by active cooling at a rate of 10°C/s.

Thermal pain threshold and tolerance were assessed using an ascending method of limits with a staircase ramp of 1°C/s, following procedures similar to those used previously (37). Subjects were instructed to press a button when the thermal stimulus first felt painful. For the tolerance assessment, subjects were instructed to press the button when the pain became intolerable. The assessment was repeated 4 times, and the average of the last 3 trials was calculated to determine thermal pain threshold and tolerance. To avoid sensitization or habituation, the position of the thermode was moved approximately 1 cm after each trial (but still remained on the ventral forearm). The maximum temperature allowed was 50°C, and if participants failed to report pain threshold or pain tolerance before reaching the maximum, a value of 50°C was entered for that variable. Fifteen participants (5 women and 10 men) reached this cutoff in the placebo condition, and a similar number of participants (4 women and 11 men) reached this cutoff in the naltrexone condition.

Participants also rated the pain of a series of thermal stimuli. There were 5 thermal intensities: 45, 46, 47, 48, and 49°C, and after each stimulus, the participant rated intensity of pain using a visual, numerical scale that has a range from 0 (not at all painful) to 100 (extremely painful), with additional labels on 25 (somewhat painful), 50 (moderately painful), and 75 (very painful). An enlarged poster of this scale (50-cm length and 20-cm width) was placed in front of the participant during the thermal test. Each stimulus was presented 4 times in random order, and responses were averaged for each temperature. Participants also completed the short form of the McGill Pain Questionnaire (MPQ) (38), which includes sensory and affective subscales. MPQ instructions asked participants to recall the most intense pain they felt during the thermal pain test.

Cold Pressor Test (CPT)
The CPT apparatus consisted of a 1-gallon container that was filled with ice-water slurry (temperature: 0.0–4.0°C). This test has been established as a reliable and valid method of pain induction (39–41). Two methods of assessment were used to evaluate CPT pain. Participants rated their pain using the visual, numerical rating scale described above. They rated their pain at 15-second intervals throughout the 90-second exposure to the CPT and the subsequent 90-second recovery period. In addition, participants’ global pain experience was evaluated using the MPQ.

Subjective State Reports
Participants completed mood state ratings before each blood sample was collected (Figure 1). Ratings covered 2 factors, Positive Affect and Distress, adopted from scales that were previously used in similar studies and found to be sensitive in laboratory protocols (42–44). Each item references an 8-point scale anchored by the end points, "Not at All" and "Very Strong." Items that cover Positive Affect include ratings of how cheerful, content, calm/relaxed, happy, in control, and interested the participant felt. Distress items include ratings on how irritable, anxious/tense, sad/depressed, angry, confused, and impatient the participant felt. In addition, during the screening session participants completed the State-Trait Anxiety Inventory (Trait-Form (45), and the Perceived Stress scale (46)).



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  		Figure 1. Outline of the study time protocol. CPT, cold pressor test; BP, blood pressure; MPQ, McGill Pain Questionnaire.

 
Cardiovascular Measures
Systolic and diastolic BP were measured using a Dinamap oscillometric monitor (Critikon, Tampa, FL). Stroke volume (SV) was measured using an impedance cardiograph system (CIC 2000, Sorba Medical System, Inc., Brookfield, WI). The dZ/dt wave is the first derivative obtained from ensemble-averaged waveforms of the primary impedance signal (DZ). This wave was averaged over 30-second epochs, and along with the electrocardiogram, was used to calculate SV using Kubicek’s equation (47). Locations of electrode placement followed standard guidelines (48). This method has been demonstrated to be valid for within- and between-group comparisons of hemodynamic profiles (49,50).

Hormonal Measures
During each session, 8 blood and saliva samples were collected at time points indicated in Figure 1. Samples were assayed for ACTH, total cortisol, beta-endorphin, and prolactin. Blood collection was accomplished using a 20-gauge intravenous Teflon catheter inserted in a left forearm vein. The catheter was fitted with a rubber infusion plug through which samples were drawn. Normal sterile saline for injection was used to keep the system patent between blood draws. Each sample was collected in an 8-mL Vacutainer tube with EDTA preservative. At the end of the session, the samples were centrifuged and stored at -70°C. ACTH and beta-endorphin were assayed using RIA kits (Nicols Institute, Bad Nauheim, Germany) with a lower sensitivity of 1 pg/ mL. Prolactin was assayed using ELISA (DSL, Sinsheim, Germany) with a lower sensitivity of 0.14 ng/mL. Plasma cortisol was assayed using EIA (DSL, Sinsheim, Germany) with a lower sensitivity of 0.1 µg/dL. Inter- and intraassay coefficients of variance for these assays were less than 10%. Saliva samples were collected using cotton dental rolls held in the mouth until saturated and collected into a plastic tube (Salivette tubes, Sarstedt, Rommelsdorf, Germany). Salivary cortisol assays were conducted using a time-resolved immunoassay with fluorometric endpoint detection. The assay has a minimum sensitivity of 0.5 nmol/L (51).

Procedures
During the screening session, participants went through the CPT and the thermal pain test to become familiar with the procedures and therefore reduce anxiety that might be associated with these tests during the laboratory sessions. Participants were scheduled for 2 sessions of approximately 4 hours each, scheduled a minimum of 72 hours apart. To control for circadian rhythm effects, all testing sessions started at approximately 1200 hours. To control for the potential effects of menstrual phase, women were tested while in the follicular phase (ie, within 3–13 days after the onset of menstruation). Before each session, participants received a reminder concerning the restrictions on the use of any alcohol or analgesic medication for 24 hours before each session and narcotic medication for 3 days before their participation.

To begin each session, participants were connected to electrodes required for measuring stroke volume. Participants were then seated in a comfortable chair and an IV catheter was inserted. A BP cuff was attached, and participants were asked to sit for 30 minutes while predrug baseline BP readings were obtained at 5-minute intervals. This was followed by completing a brief questionnaire about mood states, drawing a blood sample, and collection of a saliva sample. Participants then ingested a capsule containing either 50 mg of naltrexone (Trexan, DuPont, DE) or placebo. Order of naltrexone/placebo administration was counterbalanced. The experimenter was blind to the order of placebo/naltrexone administration. Drug administration was followed by a 60-minute rest period to allow peak plasma concentration of naltrexone to be achieved. During this period, participants were allowed to read neutral-topic magazines or rest quietly. BP and stroke volume were measured every 10 minutes, and blood and saliva samples were collected every 20 minutes. This was followed by completing the state mood questionnaire. A time protocol is summarized in Figure 1.

Participants then completed the 2 pain stimuli as described above in a counterbalanced order. Cardiovascular measures were obtained twice during the CPT protocol. No measures were obtained during the thermal pain assessment. This was followed by another rest period for 50 minutes. During this period, cardiovascular parameters were measured every 10 minutes, and blood and saliva samples were collected every 20 minutes.

Dependent Variables and Data Analyses
The primary variables for this study were plasma and salivary cortisol, ACTH, beta-endorphin, prolactin concentrations, pain reports (intensity ratings and MPQ scores for the CPT and thermal pain), thermal pain threshold and tolerance, mood reports, systolic and diastolic BP (mm Hg), and heart rate (HR, beats/min). Cardiac output and total peripheral resistance were calculated based on established standards (48). Two participants attended only 1 session and were not included in the analyses. Because of technical difficulties in collecting blood samples, plasma hormones were incomplete for 8 participants (4 men and 4 women), but these participants had complete saliva samples to assay for free cortisol. None of the pain measures differed between participants with complete blood samples and those with missing blood samples (Fs (1, 22) < 2.76, ps > 0.11). Similarly, salivary cortisol measures, cardiovascular measures, and subjective state reports did not differ between these 2 groups (Fs (1, 22) < 1.5, ps > 0.23). Participants with complete blood draws, however, showed greater diastolic BP responses to CPT than those whose blood samples were not collected (F (1, 22) = 5.96, p < .05).

To assess effects of drug order (placebo then naltrexone vs. naltrexone then placebo) and order of pain procedure (CPT then thermal pain vs. thermal pain then CPT), we conducted a series of preliminary analyses of variance comparing the 2 drug orders and the 2 pain procedure orders. Results showed no effects of drug order on pain ratings during and after exposure to CPT, pain ratings of thermal stimuli, MPQ scores after both pain stimuli, or on thermal threshold (Fs (1, 22) < 2.5, ps > 0.12). A slight increase in thermal threshold was noted after naltrexone ingestion, when the order was placebo then naltrexone (F (1, 22) = 3.33, p = .08). Similarly, there were no effects of order of pain procedures on any of the pain measures (Fs (1, 22) < 2.6, ps > 0.12), with the exception of a tendency of thermal threshold to be higher during both placebo and naltrexone conditions when CPT was administered first (F (1, 21) = 3.66; p = .07). Accordingly, data were collapsed across drug and task order conditions for subsequent analyses.

Pain ratings were analyzed using a 2 (Drug Condition: placebo, naltrexone) x 2 (Sex) analyses of variance (ANOVA), using Sex as a between-subject factor, and Drug Condition as a within-subject variable. A 2 (Drug Condition) x 2 (Sex) x 8 (Samples) repeated ANOVA was conducted on the hormonal variables. Cardiovascular data were analyzed using 2 (Drug Condition) x 2 (Sex) x 4 (Period: predrug baseline, postdrug rest, during the CPT, and during recovery) ANOVAs, with Sex as a between-subject factor and Drug Condition and Period as within-subject factors. Analysis of mood data were conducted using a 2 (Drug Condition) x 2 (Sex) x 8 (Periods) ANOVA. We used Wilkes’ Lambda correction to test time effect and to correct for repeated measures (52).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Participant Characteristics
Table 1 shows the participants’ characteristics. Men and women showed no significant difference in age or years of education, but men tended to be taller, heavier, and have greater body mass index than women (Fs (1, 24) > 4.15, ps <= 0.05). Men and women had similar scores on measures of trait anxiety and perceived stress (Fs < 1).


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  		TABLE 1. Subject Characteristicsa
 
Mood States
Distress increased during the pain procedures, as indicated by the Period main effect (F (7, 15) = 3.06, p < .05), but there was no effect of the opioid blockade (F < 1.13). Women reported greater distress in both conditions than men (F (1, 21) = 11.94, p < .01). Positive affect was reduced after the pain procedures as evidenced by a main effect of period (F (7, 15) = 3.26, p < .05). No effect of naltrexone or differences between men and women were found on the positive affect scale (Fs < 1).

Pain Measures
Thermal Pain
Thermal pain threshold did not differ between men and women or in response to naltrexone (Fs < 1.1). Men showed greater thermal pain tolerance than women (F (1, 21) = 8.05, p = .01). Furthermore, women showed reduced tolerance after naltrexone compared with placebo, as evidenced by Sex x Drug interaction (F (1, 21) = 6.68, p = .02). Pain ratings increased with the increase in heat intensity (F (4, 18) = 29.69, p < .0001). Women generally reported greater pain on all thermal stimuli than men (F (1, 21) = 14.34, p < .001; Table 2). There was no effect of opioid blockade on pain ratings (F (1, 21) = 2.43, p > .13).


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  		TABLE 2. Pain Measures
 
Women reported greater pain than men on the MPQ total scores after thermal pain (F (1, 22) = 17.29, p < .001). This difference was also found on the MPQ sensory subscale (F (1, 22) = 20.84, p < .001).

Cold Pressor Test
Women reported greater pain than men during the CPT (F (1, 21) = 9.74, p < .01). Women also reported greater pain than men on the MPQ after CPT (F (1, 21) = 7.07, p < .05).

MPQ score was greater in the placebo condition than in the naltrexone (F (1, 21) = 6.41, p = .03). However, this difference was significant in women only, as indicated by Sex x Drug Condition interaction (F (1, 21) = 4.89, p < .05; Figure 2). Specific examination of MPQ sensory and affective subscales showed similar patterns (ps < 0.05).



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  		Figure 2. Mean total (upper), sensory subscale (middle), and affect subscale (lower figure) scores on the McGill Pain Questionnaire (MPQ) obtained after the cold pressor test on both sessions (placebo and naltrexone). Line bars indicate standard error of the mean.

 
Because of the sex difference in weight, we also compared measures that differed between men and women, using weight as a covariate. Sex differences in thermal pain tolerance remained significant (F (1, 21) = 5.22, p = .03). Women also showed reduced tolerance after naltrexone compared with placebo, as evidenced by Sex x Drug interaction (F (1, 21) = 6.66, p = .02). Women rated thermal stimuli as being more painful than men (F (1, 20) = 6.02, p = .02). Women had higher MPQ total scores and sensory subscale after thermal pain (Fs (1, 21) > 6.6, ps > 0.02). Differences between men and women in the pain ratings during the CPT and on the MPQ total scores were not significant (Fs (1, 21) < 2.90, ps > 0.10). However, the tendency for MPQ total and affective subscale scores to be reduced in the naltrexone condition compared with placebo in women remained, as indicated by Sex x Drug Condition interactions (Fs (1, 21) > 4.13, ps < 0.05). Different from results reported above, naltrexone was associated with reduced pain ratings of thermal stimuli (F (1, 20) = 5.24, p = .03).

BP and Hemodynamic Responses
Table 3 summarizes the mean values and standard error of the mean for the cardiovascular parameters measured during the predrug baseline, after the administration of the drug, during the CPT, and during recovery. Women showed higher heart rate (HR) than men, whereas men showed higher systolic BP than women, as indicated by significant main effects of Sex on both variables (Fs (1, 22) > 11.6, ps < 0.01). Men and women showed significant increases in systolic and diastolic BP and HR responses to the CPT (Fs (3, 20) > 18.7, ps < 0.0001). However, the systolic and diastolic BP responses to CPT were attenuated in the naltrexone condition in women, as evidenced by Sex x Drug Condition x Period interactions (Fs (3, 20) > 3.59, ps < 0.05) and by the results of the analyses of change scores (Fs (1, 22) > 8.55, ps < 0.01; Figure 3).


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  		TABLE 3. Cardiovascular Measuresa
 


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  		Figure 3. Mean changes of the diastolic blood pressure (DBP) and systolic blood pressure (SBP) in response to the cold pressor test in men and women after placebo and naltrexone. Line bars indicate standard error of the mean. Changes were calculated by subtracting blood pressure measures obtained during baseline rest from measures obtained during the cold pressor test.

 
Cardiac output changed across time, with reduced levels during CPT (F (3, 14) = 6.68, p < .01), but did not differ in response to naltrexone (F (1, 16) = 2.0, p > .17). Total peripheral resistance changed across period, with pronounced increase during the CPT, as shown by a main effect of Period (F (3, 14) = 14.48, p < .0001). In addition, a trend of relatively smaller total peripheral resistance, especially in men, was noted, as indicated by a trend Sex x Drug Condition interaction (F (1, 16) = 4.02, p = .06).

Hormonal Responses
Plasma cortisol concentrations were greater in the naltrexone than in the placebo condition, as indicated by a main effect of Drug Condition (F (1, 14) = 6.71, p < .05). Salivary cortisol concentrations also showed a similar pattern, with significant increases noted after the 2 pain procedures, as evidenced by a Period main effect (F (7, 14) = 7.88, p < .001). These increases were stronger after the administration of the 2 pain stimuli after the ingestion of naltrexone, as evidenced by a significant Period x Drug Condition interaction (F (7, 14) = 4.61, p < .01).

Similar to cortisol data, ACTH and beta-endorphin demonstrated significant increases after naltrexone (Figure 4; Fs (1, 14) > 7.90, ps < 0.01). No differences between men and women were found in these hormones after opioid blockade (Fs < 1). Naltrexone also increased prolactin levels (F (1, 14) = 18.38, p < .001), and this increase was more pronounced in women, as indicated by the significant Drug Condition x Gender interaction (F (1, 14) = 6.84, p < .05). Analyses using log-transformed data showed similar results.



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  		Figure 4. Mean plasma (A) and salivary cortisol (B), adrenocorticotropic hormone (ACTH; C), and beta-endorphin (D) concentrations obtained before and after consuming placebo or naltrexone and after performing the cold pressor test (CPT) and thermal pain test. Order of the 2 pain procedures was counterbalanced. Because of similar changes in men and women, data were collapsed across gender.

 
Correlation Analyses
A series of Pearson correlation analyses was conducted to assess the extent to which pain measures vary with hormonal and cardiovascular measures within each drug condition. In the placebo condition, resting systolic BP levels obtained during predrug baseline were associated with smaller scores on the MPQ sensory scale completed after CPT (r = 0.40, p < .05) and after the thermal pain procedure (r = 0.57, p < 0.005). Heart rate during CPT correlated positively with MPQ total and sensory scores (rs > 0.40), ps < 0.05).

During the naltrexone condition, higher systolic BP during baseline as well as during all the remaining periods of the session were associated with reduced MPQ total and sensory score after thermal pain (rs > 0.49, ps < 0.01). Systolic BP during CPT and during recovery correlated positively with thermal tolerance (rs > 0.48, ps < 0.01). High diastolic BP during and after CPT also negatively associated with MPQ total and sensory score obtained after the thermal pain (rs > 0.42, ps < 0.05). In addition, HR during the session positively correlated with pain ratings during CPT (rs > 0.44, ps < 0.05) and correlated negatively with thermal tolerance (rs > 0.44, ps < 0.05).

As to correlation between pain and hormonal measures, during the naltrexone condition, negative correlations were found between plasma cortisol levels and thermal threshold (rs = 0.48 to 0.57, ps < 0.05). Similar correlations were found with salivary cortisol levels (rs = 0.46 to 0.59, ps < 0.05). On the other hand, increased beta-endorphin concentrations in both conditions were associated with reduced thermal pain MPQ total, and affect scores (rs > 0.42, ps < 0.05).

In summary, higher resting systolic BP was associated with reduced pain sensitivity in both conditions, whereas high HR was associated with increased pain reports. After opioid blockade, greater cortisol levels were associated with reduced thermal pain threshold, whereas greater beta-endorphin levels in both conditions were associated with reduced pain ratings.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
This study demonstrated consistent effects of naltrexone on the HPA hormones in men and women, confirming the inhibitory effects of the endogenous opioid system on the HPA axis. The study showed that naltrexone was associated with attenuated systolic and diastolic BP responses to CPT and with reduced pain report after CPT as measured using the MPQ in women, but not in men. To our knowledge, this is the first study to systematically examine sex differences in the effects of an orally administered opioid antagonist, naltrexone, on cardiovascular and HPA function and in response to acute pain stimuli. The BP findings are in contrast to previous results in men showing enhanced BP responses to acute stress after opioid blockade (53,54).

Naltrexone did not alter subjective mood measures, suggesting that its effects on the HPA axis were specific to its opioid antagonistic impact rather than other nonspecific or metabolic factors. This is consistent with a recent study that addressed effects of a similar dose of naltrexone and indicated that these HPA effects were due to naltrexone itself rather than to its metabolites (55).

The reduced pain reports after naltrexone in women were opposite to the expected increase in pain sensitivity after opioid blockade. In light of previous findings suggesting that a high dose of naltrexone (100 mg) may have agonist properties in women (56), we speculate that a dose of 50 mg of naltrexone might have produced agonist/antagonist effects in women. This possibility, however, would be better tested by comparing dose–response curves in men and women. It is possible, for example, that this dose would produce differential effects on some of the opioid receptors, and as such differences between men and women may stem from differences in the optimal dose for opioid blockade. This possibility, if supported, will have clinical implications. There is growing interest in using this medication as a treatment agent for alcohol, opiate, and tobacco addiction, as well as impulsive disorders (55,57,58). The most frequently used dose is 50 mg/d, with little or no gender-specific information available on the effects of this dose.

Although this study did not address underlying mechanisms to explain sex differences in effects of naltrexone, we speculate, based on available research, that sex differences may in part be caused by effects of steroids on opiate receptors in several areas of the brain (59–61) and to differences in the role of the opioid system in the stress response (62). It is possible that the sensitivity, quantity, and ratio of the different classes of opioid receptors differ between males and females (63,64). For example, a recent study demonstrated sex differences in the mu-opioid receptors’ responses to sustained pain (65), and higher mu-opioid binding was previously found in women (61). It is intriguing to speculate that these sex differences in endogenous opioids play a role in the previously observed sex differences in behavioral and pharmacological responses to drugs, severity of substance abuse, and outcome of treatment efforts (18–20,66,67).

Results from this study add to accumulating research demonstrating functional differences between men and women in the endogenous opioid activity (31,32). They may have implications in terms of sex differences in effects of endogenous blockade in treatment, and they identify the need for further research on sex differences in the endogenous opioid functions and their involvement in the regulation of pain and addictive processes.

The present study is limited by the use of a standard dose of naltrexone without adjusting for differences in body weight, especially between men and women. The present study is also limited by the small sample size and relative homogeneity of the sample. For example, it is not clear whether sex differences in the effect of the endogenous opioid system are present in older individuals and in individuals with drug-dependency problems. Women were recruited while in the follicular phase of their cycle, limiting the generalizability of these findings. In addition, although hormonal responses to naltrexone were significant, the small sample size may not have provided adequate power to detect consistent effects of opioid blockade on mood and pain measures. Therefore, the current results should be considered preliminary. In addition to increasing the sample size, future research should include postmenopausal women and premenopausal women during different phases of the menstrual cycle in order to delineate additional factors that might contribute to or moderate effects of endogenous opioid blockade in women. Future work should also closely examine the extent to which sex differences in the influence of the endogenous opioid system contribute to the established sex differences in pain perception and addictive liability.

In summary, this study demonstrates significant cortisol, adrenocorticotropin, beta endorphin, and prolactin responses to endogenous opioid blockade in men and women. Women showed an analgesic effect and blunted BP response during the CPT. No effects of opioid blockade on these measures were found in men. These results indicate differential effects of the opioid antagonist, naltrexone, on pain perception and BP in women.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
This study was supported in part by an American Heart Association Grant-in-Aid support (Northland Affiliate) to the first author. During this study Dr. al’Absi was also funded by National Institute of Health Grants CA88272 and HL64794.

Received for publication June 12, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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