Enhancement of morphine analgesia by the GABAB agonist baclofen

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Pergamon

Neuroscience Vol. 69, No. 2, pp. 345-349, 1995 Elsevier Science Ltd Copyright © 1995 IBRO Printed in Great Britain. All rights reserved 0306-4522/95 $9.50 + 0.00

0306-4522(95)00335-5

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Neuroscience

E N H A N C E M E N T OF M O R P H I N E A N A L G E S I A BY THE GABA B A G O N I S T B A C L O F E N N. C. G O R D O N , * R. W. GEAR,'~ P. H. HELLER,:~ S. PAUL,§ C. MIASKOWSKIpr a n d J. D. L E V I N E ¶ , * * *¶Department of Oral and Maxillofacial Surgery, Graduate Programs in tOral Biology and ¶Neuroscience, and §llDepartments of Physiological Nursing, §Epidemiology and Biostatistics, ¶Medicine, and ¶Anatomy, University of California, San Franscisco 94143, U.S.A. :~Kaiser Foundation Hospital, Hayward, CA 94545, U.S.A. Key words: gender, pentazocine, kappa-opioid, mu-opioid, dental pain.

pain, morphine analgesia was significantly enhanced by baclofen compared to placebo. In contrast, baclofen did not affect the level of pentazocine analgesia: however, females receiving pentazocine showed significantly greater analgesia than males.

Opioid-GABAergic interactions for the treatment of post-operative pain were investigated in two doubleblind, placebo-controlled experiments. We first studied the effect of pre-operatively administered baciofen, a GABAB receptor agonist, on the analgesia produced by intravenously administered morphine, a predominantly /t-opioid analgesic. In a separate trial, we studied the effect of baclofen on the analgesia produced by pentazocine, a predominantly x-opioid analgesic. While baclofen alone did not affect the level of post-operative

The G A B A B agonist baclofen is c o m m o n l y used in the t r e a t m e n t o f spasticity associated with multiple sclerosis or spinal cord injury. 6 Studies in animals have also s h o w n t h a t baclofen, administered intrathecally 4°'42'43 or supraspinally, 27 produces antinociception. Studies o f its usefulness as a n analgesic in h u m a n s , however, have yielded variable results. F o r example, baclofen, administered as a single agent, reduced atypical facial pain 3° as well as the pain associated with low-back disorders, 8 trigeminal neuralgia, 13'22'31 a n d spinal lesions) 7 O n the other

**To whom correspondence should be addressed at: Division of Rheumatology, S-1334 (Box 0452), University of California at San Francisco, San Francisco, CA 94143-0452A, U.S.A. Abbreviation: VAS, visual analog scale.

Table I. Characteristics of participants receiving morphine Morphine Placebo Baseline VAS Time to opioid administration Surgical severity Age Gender (F/M) Baseline VAS (by gender) Placebo Baclofen

Morphine Baclofen

Statistics

ave 5.1

S.E.M. 0.5

ave 6.4

S.E.M. 0.5

84.7 4.2 22.5 11/6

3.7 0.2 0.7

81.1 4.3 23.4 13/5

1.1 0.2 0.7

0.9 -0.3 -0.9 )~2 = 0.01

n.s. n.s. n.s. n.s.

0.6 0.9

0.6 0.14

n.s. n.s.

Females 4.9 0.6 6,5 0.6

Males 5.5 6.3

t - 1.9

P n.s.

Characteristics of participants receiving morphine. Groups did not differ significantly on gender ratio, age, baseline VAS rating, time to post-operative morphine administration, or surgical severity. Also, baseline VAS ratings did not differ between males and females for either the placebo or baclofen groups. Surgical severity scores were assigned as follows: Upper third molar extractions: uncomplicated or tissue impacted teeth = 0.25, partial or full bony impacted teeth = 0.50. Lower third molar extractions: uncomplicated or tissue impacted teeth = 1, partial or full bony impacted teeth = 2. The surgical severity score for each patient is the sum of the assigned value for each extracted tooth. ~° 345

346

N.C. Gordon et al.

hand, baclofen failed to produce an analgesic effect in the treatment of post-operative dental pain, 38 post herpetic neuralgia, or diabetic neuropathy. 37 Currently, baclofen is not specifically recommended for use as an analgesic.6~5 Since spinal cord circuits that are important in opioid analgesia contain GABAergic (GABAB) receptors, 9'18'44 it is possible that co-activation of opioid receptors (i.e., by exogenous or endogenous opioids) and GABAB receptors (i.e., by baclofen or GABA) might produce an enhanced opioid analgesia compared to the analgesia produced by activation of opioid receptors alone. In this study, we specifically investigated the ability of baclofen, an agonist at GABA Breceptors, to enhance the analgesia produced by moderate doses of two opioid analgesics, morphine and pentazocine. For these two clinical trials a total of 69 patients underwent standardized surgery for removal of third molar teeth by the same oral surgeon. All procedures included removal of at least one bony impacted mandibular third molar. Moderately severe postoperative pain is more commonly associated with this procedure than with removal of maxillary or nonbony (i.e. soft-tissue) impactions. Before surgery, each patient was randomly assigned to receive, in a double-blind fashion, either oral baclofen, according to recommended protocol, 5'~6(5 mg, three times a day for three days, then 10mg 6h before surgery and again immediately before surgery) or an oral placebo on the same schedule. After surgery, each patient received, through an intravenous line, a double blind injection of either 6rag of morphine or 30 mg of pentazocine. Criteria for administration of the opioid were: (i) elapse of a period of at least 80 min after the onset of the local anesthetic; and (ii) a pain rating that was greater than one-quarter (2.5cm) of the maximum possible visual analog scale (VAS) rating (10 cm). Baseline pain level was defined as the VAS pain rating.just before opioid administration. The magnitude of the analgesic effect of the opioid for each participant was defined as the difference between the pain rating at each time point following opioid administration and the baseline VAS pain rating. The demographic characteristics of the participants in the morphine group are listed in Table 1. No statistically significant differences in age, gender, or severity of the surgical procedure were found between the participants who received morphine and baclofen and the participants who received morphine and placebo. Furthermore, no statistically significant differences were found between the two groups with respect to time of opioid administration and baseline VAS ratings suggesting that baclofen by itself had no analgesic effect which is in agreement with a previous study using a similar model of dental pain. 38 The two-way repeated measures ANOVA demonstrated a significant main effect of group [F(1,33)= 5.40, P = 0.03] but no significant main effect of time [F(8,264) = 0.64, P = 0.74] or group × time

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2 I I I I I I I I 3 tl 10 30 50 70 90 110130150170 Time post morphine (min)

Fig. 1. The effect of morphine on post-operative pain in the presence and absence of pre-operatively administered baclofen. "Change in pain level" (ordinate), recorded on a 10 cm VAS, represents change from the baseline level (dotted line) after various times. See Table l for number of participants in each group. Data are plotted as mean ±S.E.M. Circles: baclofen; squares: placebo. The surgical procedure and the methods of data collection have been described in detail previously.25~26 During surgery, patients received intravenous diazepam, nitrous oxide, and local anesthesia (carbocaine without vasoconstrictor to obtain a nerve block of short duration). The duration of the experiment, measured from the onset of local anesthesia, was 5 h. Baclofen (Geigy Pharmaceuticals) or identical inert placebo tablets compounded by the University of California, San Francisco, Drug Products Services Laboratory were dispensed to patients in coded envelopes. Approximately equianalgesic doses19 of morphine sulfate (6 mg) (Elkins Sinn, Inc.) or pentazocine (Talwin, Winthrop Laboratories) (30mg) in a coded syringe were administered intravenously. Differences in demographic characteristics between each of the opioid and placebo groups were determined using independent Student's t-tests or Chi square analyses. A two-way repeated measures ANOVA with one between subjects factor (i.e., drug group with 2 levels) and one within subjects factor (i.e. time with nine levels) covaring fot weight was performed. Differences were considered statistically significant at the P < 0.05 level. These studies were approved by the Committee on Human Research at the University of California at San Francisco. interaction [F(8,264) = 0.67, P = 0.67). These results indicate that the analgesic efficacy of morphine was enhanced by the administration of baclofen compared to placebo. Changes in pain level following morphine administration for the two groups are plotted in Fig. 1. The demographic characteristics of the participants in the pentazocine group are listed in Table 2. Although significantly more females (X2=4.21, P = 0.04) received baclofen and pentazocine compared to baclofen and placebo, there were no statistically significant differences in age or severity of surgical procedure between the participants who received pentazocine and baclofen and those who

Enhancement of morphine analgesia by the GABA B agonist baclofen

347

Table 2. Characteristics of participants receiving pentazocine Pantazocine Placebo Baseline VAS Time to opioid administration Surgical severity Age Gender (F/M) Baseline VAS (by gender) Placebo Baclofen

Pantazocine Baclofen

ave 4.6

S.E.M. 0.4

ave 5.6

S.E.M. 0.6

87.5 4.0 25.0 7/9

4.1 0.2 1.7

94.4 3.9 24.0 15/3

Females 5.0 0.8 5.4 0.6

Males 4.4 6.5

Statistics t - 1.31

P n.s.

4.5 0.3 0.9

- 1.14 0.32 0.55 Z 2 = 4.21

n.s. n.s. n.s. 0.04

0.5 2.2

0.66 0.75

n.s. n.s.

Characteristics of participants receiving pantazocine. There was significantly more females in the baclofen group than in the placebo group; otherwise, the groups did not differ significantly on age, baseline VAS rating, time to post-operative pentazocine administration, or surgical severity. Also, baseline VAS ratings did not differ between males and females for either the placebo or baclofen groups. Surgical severity scores were calculated in the same way as with the morphine groups (see Table 1).

received pentazocine and placebo. Furthermore, in agreement with the result reported above, there were no statistically significant differences with respect to time of opioid administration and baseline VAS ratings again suggesting that baclofen by itself had no

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I 30

I 50

I 70 90 110 130 150 170

T i m e post p e n t a z o c i n e (min) Fig. 2. The effect of pentazocine on post-operative pain in the presence and absence of preoperatively administered baclofen. "Change in pain level" (ordinate), recorded on a 10cm VAS, represents changes from the baseline level (dotted line) after various times. See Table 2 for number of participants in each group. Data are plotted as mean +_ S.E.M. Open symbols: males; filled symbols: females. Circles: baclofen; squares: placebo. Because there were statistically significant differences in the number of males and females in the baclofen and placebo groups, a three-way repeated measures ANOVA with two between subjects factors (i.e. drug group and gender) and the within subjects factor (i.e. time with 9 levels) covarying for weight was performed. Differences were considered statistically significant at the P < 0.05 level.

analgesic effect. The three-way repeated measures A N O V A demonstrated a significant main effect of gender [F(I,30) 6.71,P = 0.01] and a significant main effect of time [F(8,240 = 16.46, P <0.001]. These results indicate that females, regardless of drug group, had consistently better analgesic effects than males. The group x time interaction approached statistical significance [F(8,240) = 5. I O,P = 0.06] suggesting that the analgesic effects of pentazocine may be prolonged in females. Changes in pain level following pentazocine administration for the four groups are plotted in Fig. 2. The morphine data were reanalysed to evaluate for gender differences and no significant effects were found. The shorter duration of analgesia exhibited by the groups that received placebo and pentazocine, as compared to the groups that received placebo and morphine, is not unexpected in view of the wellknown differences in the time course of action of these two opioids. 39 The interaction of G A B A B agonists with opioids for the treatment of pain has not been extensively studied. However, the existence of a potentiating effect was suggested when baelofen was found to increase the time intervals between injections of the opioid fentanyl in post-operative patients. ~2 On the other hand, baclofen co-administered with fentanyl was no more effective than baclofen alone in providing analgesia to women undergoing voluntary abortion. 7 One possible site for a baclofen~opioid interaction is the spinal cord. Baclofen acts at G A B A ~ receptors 3'4'24and is thought to inhibit neurotransmitter release by increasing potassium currents and/or decreasing calcium currents. H'~429 Lamina II of the spinal cord dorsal horn, an important site for nociceptive processing, has been shown to be rich in G A B A B receptors, and up to 50% of these receptors disappear after dorsal rhizotomy or capsaicin treatment suggesting that many of these G A B A Breceptors

348

N.C. Gordon et al.

are located on the spinal terminals of primary afferent nociceptors. 34'35 These findings are consistent with reports that baclofen selectively decreases excitability of C-fiber primary afferent neurons and decreases neurotransmitter (e.g., substance P) release in the spinal cord. 5'9"16"23'35Since opioid receptors have also been found on the terminals of primary afferent nociceptors 2'44 and have also been shown to inhibit neurotransmitter release, 1,~8,2°'28 it is possible that an interaction between opioids and baclofen at the level of the medullary dorsal horn underlies the enhanced analgesia. A supraspinal site for b a c l o f e ~ o p i o i d interaction is also possible. Baclofen microinjected into the periaqueductal gray matter or into the rostroventral medulla produces antinociception. 27 Since G A B A B receptors have been shown to act as autoreceptors at GABAergic synapses, 33 baclofen might inhibit GABA release] Tonic synaptic activation of supraspinal G A B A a receptors is thought to enhance nociceptive sensitivity, and supraspinally administered opioids are thought to produce antinociception, at least in part, by suppressing this tonic activation of G A B A A receptors (for review, see Ref. 12). Thus, supraspinal baclofen potentiation of opioid analgesia might be mediated by c o m m o n suppression by both agents of pronociceptive G A B A receptor mediated neurotransmission. An interesting finding of the present study is the gender differences in analgesia produced by the

~-agonist, pentazocine, in contrast to the lack of effect of gender on the analgesia produced by the/~agonist, morphine. Previous research has demonstrated gender differences in nociceptive thesholds and tolerance to noxious stimuli. 2~'4j However, no studies done to date have evaluated for gender differences in the analgesic effects of opioid agonists. In summary we demonstrate in our model of post-operative dental pain that the GABAB agonist, baclofen, enhances the analgesic effect of the/~opioid agonist morphine but not the analgesic effect the x-opioid agonist, pentazocine. These findings suggest that agonist drugs targeted at the GABAa receptor may be useful in reducing the level and frequency of dosing for /~-opioid analgesics needed in the treatment of post-operative pain. We also show that gender differences exist in the analgesic effect produced by pentazocine but not morphine. These gender differences suggest that activation of different opioid receptor types produces analgesia by different mechanisms, some of which may be genderspecific. thank Drs Michael Gold, David Reichling and Kimberly Tanner for many helpful discussions during the course of this work, and Gina Long R.N. for excellent technical assistance. This work was supported by NIH grants NR03923, DE08973, T32-DE07204 and Kaiser Community Services Program. Acknowledgements--We

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