Sex differences in analgesia: a randomized trial of [micro] versus [kappa] opioid agonists.

Objectives: We sought to evaluate whether there is a sex difference in the analgesic response to [micro] versus [kappa] opioids in the management of acute moderate to severe pain of injury in the emergency department.

Methods: The study was a randomized, double-blind, clinical trial comparing the prototypical [micro]-receptor agonist, morphine sulfate, to the prototypical [kappa] agonist, butorphanol. The primary endpoints were degree of relief by visual analog scores at 30 and 60 minutes. Statistical analysis was performed using Mann-Whitney U test for nonparametric analysis and repeated-measures analysis of variance.

Results: Ninety-four patients were entered in the study, with 49 (52%) males and 45 (48%) females. Forty-six received morphine sulfate and 48 received butorphanol. There was no difference in demographics in the two groups. At 60 minutes, females had significantly lower visual analog scores with butorphanol compared with morphine (P = 0.046). At 60 minutes, there was a trend for a difference in response of males versus females to morphine, with males responding better than females (P = 0.06).

Conclusion: Females had better pain scores with butorphanol than morphine at 60 minutes.

Key Words: butorphanol, gender, [kappa] opioid agonist, [micro] opioid agonist, morphine, pain

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Acute painful injuries due to trauma are frequent presenting complaints in the emergency department (ED). Treatment for these patients is paramount for several reasons. Pain accounts for more than 30 million ED visits annually in the United States, and inadequate relief of pain is a frequent cause of return visits to the ED. Pain is often referred to as the fifth vital sign. Assessment of pain, as well as aggressive and effective relief of pain, is mandated by new standards published by the Joint Commission on Accreditation of Healthcare Organizations. (1) (2) Unrelieved pain has adverse physical and psychological effects. The consequences of ineffective pain control may include further injury to an already compromised limb, difficulty with reduction of a fracture or other definitive treatment, and the inability of a patient to participate in his or her medical care.

Two commonly used opioid analgesics for uncomplicated patients are morphine sulfate and butorphanol. Both are opioids; however, their mechanism of action differs in that morphine acts as a [micro] receptor agonist and butorphanol primarily as a [kappa] agonist. (3) Preliminary studies suggest that there may be a sex difference in response to the site of action of these two medications. Females may receive more relief and fewer side effects from those acting at [kappa] sites. Past studies comparing male versus female responses to [kappa] agonists have involved oral and IV medications for dental pain. (4-6) There are no previous studies comparing the two medications between the sexes for acute injury.

Reprint requests to Amy A. Ernst, MD, FACEP, Division of Emergency Medicine, Department of Medicine, University of California, Davis, 2315 Stockton Blvd., PSSB 2100, Sacramento, CA 95817. Email: [e-mail]

Accepted October 28, 2002.

The purpose of the present study is to evaluate the overall sex differences in the analgesic response to the parenteral agents morphine and butorphanol for the relief of moderate to severe painful injuries secondary to trauma in the ED. The main outcome measures were degree of relief at 30 and 60 minutes in males and females. The null hypothesis was that morphine and butorphanol would be equally effective in relief of pain in males and females.

Methods

Study Design

We conducted a prospective, randomized, double-blind, clinical trial to evaluate the overall sex differences in the analgesic response of the parenteral agents morphine and butorphanol for the relief of moderate to severe painful injuries in the ED. The study was reviewed and approved by the institutional review board.

Study Setting and Population

The study was performed in an academic, urban ED with an annual census of approximately 60,000 visits. Patients 18 to 65 years of age qualified for this protocol if they presented to the ED for moderate to severe pain associated with acute injury and they required IV medication for pain control. The treating clinician assessed the need for IV pain medication. Patients included those with acute uncomplicated fractures, dislocations, severe sprains, or other isolated injuries. Participants were excluded if the injury was not acute, if there were multiple injuries to other areas of the body, if there was any underlying serious illness such as diabetes or renal failure, if there was an altered sensorium, or if there was an allergy to either of the two medications. Participants who had received prior analgesic medications were also excluded. Other reasons for exclusion included inability to understand written English, drug or alcohol use, refusal to participate, or inability to perform visual analog scale (VAS) readings. (7)

Study Protocol

Demographic data obtained included age, sex, chief complaint, and diagnosis of the participant. Vital signs at 0, 30, 60, and 120 minutes were recorded, and side effects of pruritus, nausea/vomiting, or sedation, and satisfaction were recorded.

Patients were randomly assigned to receive either 2.5 to 5 mg (0.5-1 cc) morphine sulfate that could be repeated or 0.5 to 1 mg (0.5-1 cc) butorphanol that could be repeated. This fits the dose range for morphine sulfate of 2 to 10 mg IV and butorphanol of 0.5 to 2 mg IV. A computerized random list of medications was previously generated by the pharmacy. Medication dose vials were distributed by the pharmacy, with only a number label to blind the physician and patient.

Both medications were distributed by pharmacy in 2-cc vials that appeared as clear liquids. All participants, including patients and care providers, were unaware of treatments assigned. All patients had IV lines placed.

Instructions on use of the visual analog scales were given to subjects and investigators before commencing enrollment. Subjects were directly asked about pain and ranked the amount via VAS. Subjects rated the pain at times 0, 30, 60, and 120 minutes with the aid of a 100-mm VAS. (7) Need for further pain medication and adverse effects (sedation, nausea/vomiting, pruritus) were recorded. A "treatment failure" was defined as needing further analgesic treatment for recurrent or persistent pain within the 120 minutes of the study. The protocol was stopped if allergic reactions developed, if there was a treatment failure, or if the participant requested withdrawal.

Sedation was measured by Likert scale and patient satisfaction on a 1 to 10 scale, with 1 being dissatisfied and 10 being very satisfied. Nausea and pruritus were given scale numbers for analysis. Vomiting was ranked as a qualitative yes or no. Blood for laboratory testing was sent at the discretion of the physician and was not part of the study routine. Comparison of systolic and diastolic blood pressures and heart rate were made at 0, 30, 60, and 120 minutes.

Endpoints

The main outcome measure was degree of relief at 30 and 60 minutes as measured on a VAS. Secondary endpoints included relief at 120 minutes (determined by patients), treatment failures determined by need for further pain medication, satisfaction with pain control, and side effects. Patients remained in the ED until they were definitively treated or admitted for operative care. Patients were observed for a varied time afterward to establish complete relief without need for further IV medication. If discharged, they were given oral medication to be taken at home and were to return for follow-up if needed.

Statistical Analysis

Statistical analysis was performed using SPSS. (8) Baseline demographic characteristics of the two groups were compared using [chi square] and Fisher's exact test for categorical data. Mann-Whitney U nonparametric tests were used to compare VAS readings at 0-, 30-, 60-, and 120-minute time frames and satisfaction for morphine versus butorphanol. A 2 X 4 repeated-measures analysis of variance (ANOVA) was calculated. Degree of sedation and nausea/vomiting in the two groups was compared using Mann-Whitney U tests. Numbers of patients in the two groups having adverse effects were compared and 95% confidence intervals were given where applicable. A priori power calculations determined that with 42 in each of the two groups, a clinical difference in efficacy of 15% could be detected with 80% power.

Results

A total of 94 patients were entered in the study over an 18-month study period. This was a convenience sampling of patients. All eligible subjects were approached for enrollment. Forty-six subjects received morphine and 48 received butorphanol. No subject complained about painful injection of the medication. The code of randomization was broken after enrollment of the 94 patients was complete (Fig. 1).

Demographic characteristics of the two groups receiving morphine versus butorphanol were similar. There was no difference in sex of participants (45 females versus 49 males; difference, 4%; 95% confidence interval [CI], -2-10), age, chief complaint, or final diagnosis in the two groups. Distribution of medications was also similar. Twenty-two females received morphine and 23 received butorphanol (difference, 0.2%; 95% CI, -2-2). Twenty-four males received morphine and 25 received butorphanol (difference, 0.2%; 95% CI, -2-2). There was no difference in location of injury by type of medication given (P = 0.3) or in final diagnosis by type of medication given for males or females (P = 0.65). These results are summarized in Table 1.

[FIGURE 1 OMITTED]

Vital signs were statistically different at 30 minutes for diastolic blood pressure between the sexes. Otherwise, there were no differences in blood pressure or vital signs between males and females or between the morphine and butorphanol groups. At 30 minutes, diastolic blood pressure was higher in males (mean, 77 mm Hg) than in females (mean, 68 mm Hg). There were no differences in initial doses or in repeat doses by medication or by sex. Results are summarized in Table 2.

There was no difference in VAS readings at time 0 (P = 0.32), indicating that initial pain in the two groups was similar. Thirty, 60, and 120 minutes after receiving medication, there were no differences in VAS readings for morphine sulfate versus butorphanol in the combined sex groups, indicating that both medications were effective in treating pain. At time 60 minutes, females found that butorphanol was superior to morphine by VAS readings (P = 0.046). When comparing male versus female scores for morphine, there was a trend for males to respond better to morphine sulfate at 60 minutes (P = 0.06).

Using repeated-measures ANOVA, there was a significant difference over time in effectiveness of both medications (P < 0.0001). Pairing of time and medication used resulted in no significant difference (P = 0.68), nor was there a difference of scoring over time with sex (P = 0.75). There was a within-group difference (P = 0.010), reflective of the female response to butorphanol. These results are summarized in Table 3.

There was no difference in satisfaction with medications when ranked on a 10-point scale, indicating that both medications worked to alleviate pain of acute injury. Treatment failures requiring rescue medication before the 120-minute period were noted in four receiving morphine (three male and one female) and in three receiving butorphanol (three male). P values and 95% CIs are given in Table 4.

Mild sedation was noted in 10 patients receiving morphine and 13 patients receiving butorphanol. No patient experienced moderate or severe sedation, there was no respiratory compromise, and no naloxone was required. Nausea and/or vomiting were noted in two patients receiving morphine and in six receiving butorphanol, and pruritus was noted in one patient receiving morphine. One patient received Compazine for nausea. Treatment failures and adverse effects are summarized in Table 4.

Discussion

There is evidence that three major classes of opioid receptors exist in the central nervous system, designated [micro], [kappa], and [delta]. There are distinct selectivity profiles for each class with unique distributions in the brain and spinal cord. (3), (9-13) The profile of receptors is inferred from both clinical observation and animal pharmacology.

Drugs such as morphine and those related to morphine act primarily at [micro] receptors and are known as morphine-like opioid agonists. Although primarily [micro] opioid agonists, they do have other receptor agonist properties, although less so. About one-third of morphine is protein bound when therapeutic concentrations are in plasma. Morphine sulfate does not persist in tissues, and 24 hours after a dose, concentration is low. Morphine sulfate is absorbed in the gastrointestinal tract and eliminated in the kidney by glomerular filtration, mostly as by-products. [micro] Agonists provide excellent analgesia; however, they produce significant side effects of nausea, vomiting, respiratory depression, and euphoria.

Drugs acting at [kappa]-receptor sites are known as "opioids with mixed actions" and include pentazocine (Talwin), butorphanol (Stadol), and nalbuphine (Nubain). Butorphanol is a unique agent that appears to have neither agonist nor antagonist action at [micro] receptors. (3), (9-13) The half-life of butorphanol is about 3 hours. It is absorbed in the gastrointestinal tract and peaks 15 minutes to 1 hour after administration. (3) [kappa] receptors are located in the brain, brainstem, and spinal cord, and selective [kappa] agonists produce analgesia and sedation but less respiratory depression than [micro] agonists. Side effects include respiratory depression, disorientation, and dysphoria. (3)

Previous studies have shown sex differences in response to [micro] and [kappa] agonists in animals. In studies of morphine in male versus female rodents, males had higher brain levels of morphine than females, although serum levels were not higher. (14), (15) More recent studies in rodents have shown that sex differences may be related not to [micro] receptors but to [kappa]-receptor activity and to certain stimuli. (16), (17) Several studies have shown that the morphine response may be gonadal hormone dependent rather than related to other pharmacokinetic reasons. (18), (19) In addition, hormones have been found to potentially play a role in [kappa]-agonist activity. (20)

In rats and in humans, there is an elevated pain threshold in pregnancy, which is most apparent during late pregnancy. (21) This is related to hormone levels that can be produced in nonpregnant rats by introduction of the same hormone levels as pregnant rats. (22) The analgesic system inherent in the pregnant animal is [kappa] mediated. (21-24) This effect appears to be mediated by 17-[beta]-estradiol and progesterone in the rat and is also dependent on endogenous hormones. (22) Epidural morphine is currently the medication of choice to treat pain of labor; however, these studies indicate that a [kappa] agonist may work better to attenuate pain of deliver. (23) Testosterone may have an effect by interacting negatively with [kappa] opioids, whereas female hormones such as estrogen may potentiate the action of [kappa] opioids. There are no recent studies in the literature that address this factor in humans, however.

The physiologic basis for this sex difference in analgesic response to [kappa] opioids is unknown. A study in male versus female Sprague-Dawley rats showed sex differences in effects of [kappa] and [delta] opioids, but not in [micro] opioids. The sex differences were assay-, dose-, and/or time-dependent. (25)

The results of our trial show that there is a gender effect in response to opioid analgesics, with women preferring the [kappa] agonist butorphanol to morphine. At 60 minutes, it provided more complete relief for women with acute injury. This study demonstrates that although both medications worked to alleviate pain in males and females, women respond better to butorphanol. There are no previous studies of sex difference in analgesia in the acute emergency department setting or in acute traumatic injury pain. This is the first study comparing the responses of males and females to [micro] versus [kappa] agonists in the acutely injured patient.

Vital signs may reflect degree of pain. In our study, there were differences in diastolic blood pressures at 30 minutes, with females less than males. This may reflect an overall sex difference in blood pressures or, as lower blood pressures may indicate more adequate pain control, these results could reflect the female response to medications. More study on this issue is needed.

Patients with acute injury may have many differing etiologies. We excluded those with complicating factors, other etiologies, or underlying illness. Demographics in the groups were similar, as were initial pain scores, showing that the groups were similar in amount and character of initial pain.

Morphine and butorphanol were chosen, as these are prototypical [micro]- and [kappa]-receptor agonists commonly used and available for acute painful injuries. Both are narcotics and considered effective in providing analgesia. Dosages were chosen on the basis of recommendations in Goodman and Gilman's The Pharmacological Basis of Therapeutics (3) and the Physician's Desk Reference. (13)

Previous studies comparing opioids acting at different receptor sites are rare. A recent study of postoperative dental pain showed that females receiving pentazocine showed better analgesia than males receiving the same treatment. Numbers in the study were small and all patients received local and IV medication before the IV study medication of morphine or pentazocine along with the [gamma]-amino butyric acid agonist baclofen. (26) A follow-up study by Gear et al (5) on post-operative dental pain evaluated the effect of sex on analgesia produced by pentazocine in subjects not receiving another medication. The analgesic response to pentazocine in 10 females was compared with that in 8 males, wherein pentazocine worked significantly better in females. In 1996, Gear et al (4) compared nalbuphine and butorphanol in males and females undergoing wisdom tooth extraction. Women responded better to these medications than men. There was no weight or age effect. The half-life of the medications may have been a factor. A more recent study in wisdom tooth extraction compared nalbuphine to placebo in 62 men and 69 women in escalating doses. Women responded better to all doses of nalbuphine than men. (6) In this study, other drugs were given; however, that may have influenced results. Of note in this study is that men receiving a low dose of nalbuphine actually had an increase in pain intensity.

In previous studies, as in our present study, there was no sex difference in side effects to [kappa] agonists, indicating there is no pharmacokinetic basis for the sex differences. (4) Adverse effects such as nausea and vomiting, sedation, and respiratory depression have been reported with both morphine and butorphanol. (3) Respiratory depression is reported to be less frequent with [kappa]-receptor agonists than with [micro]-receptor agonists. We reported similar numbers of adverse events in our groups. Both medications were tolerated well, with only one patient requiring administration of an antiemetic. Sedation occurred in approximately 10% of patients; however, naloxone was not needed in the course of treatment.

One of the study's main limitations is use of patient self-report of pain. The description of pain and the intensity vary, based on many features including psychosocial background. In previous studies, it was demonstrated that psychology, physiology, education, age, sex, and cognitive levels affect treatment of pain. (27-29) The best ways to measure pain have been studied extensively and validated previously. (7) Visual analog scales such as that used in the present study eliminate some of the potential biases. In addition, changes in pain were analyzed using repeated-measures ANOVA that takes into account the effect of the medication on the individual patient. We also chose patients with moderate to severe pain initially and those with an isolated injury, thus leading to further reduction in potential bias.

Conclusion

There are a number of factors including pain receptors, pharmacokinetics, and hormone levels (estrogen and testosterone) that may influence sex differences in response to pain medication. This study showed that females preferred the [kappa] agonist butorphanol to morphine for acute traumatic injury. [kappa]-Receptor agonists should be chosen preferentially for female patients with acute traumatic injury pain.

One of the symptoms of approaching nervous break-down is the belief that one's work is terribly important, and that to take a holiday would bring all kinds of disaster. If I were a medical man, I should prescribe a holiday to any patient who considered his work important.

--Bertrand Russell

Table 1. Demographics of morphine versus butorphanol groups (a)

Characteristic   Frequency     95% CI; range     P value

Gender (No.)

  Male              49        Diff 4%; -2 to 10
  Female            45

Age (mean)

 Morphine           38        Diff 3%; -2 to 8    0.23
 Butorphanol        41

Chief complaint

  UE                41%       For UE versus LE:
  LE                48%       Diff 1%; -4 to 1    0.3
  Other             11%

Diagnosis

  Fracture          49%       Diff 2%; -2 to 2    0.65
  No fracture       52%

Females (No.)

  Morphine          22        Diff 0.2%; -2 to 2
  Butorphanol       23

Males (No.)

 Morphine           24        Diff 0.2%; -2 to 2
 Butorphanol        25

(a) CI, confidence interval; Diff, difference; UE, upper extremity; LE,
lower extremity.

Table 2. Vital signs and dosages by gender and drug (a)

                                         Females
                                   (Mean [+ or -] SD)

HR 0 (beats/p min)            90 [+ or -] 12
BP 0 (systolic/diastolic)    138 [+ or -] 29/79 [+ or -] 18
HR 30 (beats/p min)           79 [+ or -] 12
BP 30 (systolic/diastolic)   127 [+ or -] 16/68 [+ or -] 7 (b)
HR 60                         79 [+ or -] 11
BP 60                        126 [+ or -] 16/74 [+ or -] 12
HR 120                        77 [+ or -] 13
BP 120                       128 [+ or -] 21/76 [+ or -] 11
Initial dose (cc)           0.86 [+ or -] 0.3
Repeat dose (cc)             0.8 [+ or -] 0.25

                                          Males

HR 0 (beats/p min)            90 [+ or -] 17
BP 0 (systolic/diastolic)    134 [+ or -] 19/78 [+ or -] 22
HR 30 (beats/p min)           81 [+ or -] 14
BP 30 (systolic/diastolic)   131 [+ or -] 19/77 [+ or -] 12 (b)
HR 60                         80 [+ or -] 14
BP 60                        132 [+ or -] 20/68 [+ or -] 33
HR 120                        81 [+ or -] 14
BP 120                       122 [+ or -] 16/78 [+ or -] 9
Initial dose (cc)           0.86 [+ or -] 0.2
Repeat dose (cc)             0.9 [+ or -] 0.23

                                      Morphine

HR 0 (beats/p min)            88 [+ or -] 15
BP 0 (systolic/diastolic)    137 [+ or -] 25/82 [+ or -] 14
HR 30 (beats/p min)           80 [+ or -] 14
BP 30 (systolic/diastolic)   127 [+ or -] 10/71 [+ or -] 12
HR 60                         76 [+ or -] 10
BP 60                        127 [+ or -] 19/77 [+ or -] 14
HR 120                        76 [+ or -] 13
BP 120                       123 [+ or -] 20/76 [+ or -] 11
Initial dose (cc)           0.87 [+ or -] 0.29
Repeat dose (cc)             0.8 [+ or -] 0.25

                                     Butorphanol

HR 0 (beats/p min)            93 [+ or -] 15
BP 0 (systolic/diastolic)    135 [+ or -] 22/75 [+ or -] 24
HR 30 (beats/p min)           80 [+ or -] 13
BP 30 (systolic/diastolic)   131 [+ or -] 10/73 [+ or -] 10
HR 60                         82 [+ or -] 13
BP 60                        131 [+ or -] 18/66 [+ or -] 31
HR 120                        82 [+ or -] 14
BP 120                       127 [+ or -] 19/78 [+ or -] 9
Initial dose (cc)           0.84 [+ or -] 0.23
Repeat dose (cc)            0.83 [+ or -] 0.24

(a) HR, heart rate; BP, blood pressure.
(b) 30-minute diastolic BP difference in males versus females, P = 0.03;
95% CI, 8-18.

Table 3. VAS results (a), (b), (c), (d)

                                         P value,          P value,
                                      morphine versus  morphine versus
                                        butorphanol      butorphanol
              Butorphanol  Morphine   males (n = 49)   females (n = 45)

0 min

  VAS median  7.55         7.6             0.92              0.49
  IQR         6.02-8.57    6.8-8.5

30 min

  VAS median  4.85         5.5             0.91              0.19
  VAS median  2.7          2.1
  [DELTA]
  IQR         3.1-6.65     3.25-7.2

60 min

  VAS median  4.5          5.6             0.94              0.046
  VAS median  0.35         0.1
  [DELTA]
  IQR         3.2-6.2      3.1-7.15

120 min

  VAS median  3.5          5.8             0.64              0.12
  VAS median  1            0.2
  [DELTA]
  IQR         1.5-6.7      3.07-7.27

               P value,       P value
              morphine by  butorphanol by
                gender         gender
               (n = 46)      (n = 48)

0 min

  VAS median     0.49           0.702
  IQR

30 min

  VAS median     0.22           0.78
  VAS median
  [DELTA]
  IQR

60 min

  VAS median     0.06           0.9
  VAS median
  [DELTA]
  IQR

120 min

  VAS median     0.101          0.94
  VAS median
  [DELTA]
  IQR

(a) VAS, visual analog scale; IQR, interquartile range; ANOVA, analysis
of variance.
(b) Repeated measures ANOVA: P < 0.001 for time change.
(c) Pairing time and medication multivariate ANOVA: P = 0.68.
(d) Pairing time and gender, multivariate ANOVA: P = 0.75.

Table 4. Satisfaction, treatment failures, and adverse effects (a)

                         Morphine                      P value
                          sulfate     Butorphanol       Diff;
                        (n = 45)       (n = 49)        95% CI

Satisfaction            7 [+ or -] 3  7 [+ or -] 3      0.74
(mean [+ or -] SD)

Treatment failures (%)   4 (8.1)      3 (6.7)       5%; -1 to 9

Sedation (%)            10 (20)      13 (26)        4%; -13 to 22

Nausea/vomiting (%)      2 (5)        6 (12)        8%; -3 to 18

Pruritis                 1            0                 N/A

(a) Diff, difference; CI, confidence interval; N/A, not applicable.

From Patient Care Services, Department of Emergency Medicine, University of California, Davis Medical Center, and the Division of Emergency Medicine, Department of Medicine, University of California, Davis, Sacramento, CA.

Supported by a Sigma Theta Tau International/Glaxo Wellcome New Investigator grant.

Presented at the National Society for Academic Emergency Medicine Conference, Atlanta, GA, May 2001.

Copyright [c] 2004 by The Southern Medical Association 0038-4348/04/9701-0035

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RELATED ARTICLE: Key Points

* Butorphanol and morphine are commonly used pain medications in the emergency department.

* Butorphanol is a [kappa] agonist and morphine is a [micro] agonist.

* Females preferred butorphanol ([kappa] agonist) to morphine for pain management in acute injury.

Penny L. Miller, MS, FNP, and Amy A. Ernst, MD, FACEP