Neuroleptics Antagonize Nalbuphine Antianalgesia

The Journal of Pain, Vol 7, No 3 (March), 2006: pp 187-191 Available online at www.sciencedirect.com

Neuroleptics Antagonize Nalbuphine Antianalgesia Robert W. Gear,* Janice S. Lee,* Christine Miaskowski,† Newton C. Gordon,* Steven M. Paul,‡ and Jon D. Levine§ *Departments of Oral and Maxillofacial Surgery, † Physiological Nursing, ‡ Epidemiology and Biostatistics, and § Medicine, Graduate Program in Neuroscience, University of California San Francisco, San Francisco, California.

Abstract: To evaluate the role of ␴ receptors in the sexually dimorphic antianalgesic effect of agonist-antagonist ␬ opioids, 2 neuroleptics, haloperidol, a ␴ receptor antagonist, and chlorpromazine, which has minimal effect at ␴ receptors, were administered with the agonist-antagonist ␬ opioid nalbuphine in patients with postoperative pain. Before surgical extraction of bony impacted mandibular third molar teeth, patients received haloperidol (1 mg), chlorpromazine (10 mg), or placebo by oral administration. After surgery, the pain intensity did not differ significantly between the 3 treatment groups, suggesting lack of analgesic effect produced by either haloperidol or chlorpromazine. All patients were then administered nalbuphine (5 mg, intravenous). As previously reported, the group that did not receive a preoperative neuroleptic exhibited sexually dimorphic analgesia, with women experiencing greater analgesia than men. Antianalgesia was also observed, with men experiencing late onset increased pain compared with baseline, starting approximately 1 hour after nalbuphine administration. Both neuroleptics blocked nalbuphine antianalgesia, resulting in enhanced analgesia and elimination of the sex differences. Because chlorpromazine and haloperidol enhanced nalbuphine analgesia and eliminated sexual dimorphism, the receptor at which neuroleptics act to antagonize the “antianalgesia” might be a common site of action to both drugs. Perspective: This study demonstrates that neuroleptics can block the antianalgesic effect of agonistantagonist ␬ opioids. These findings could help inform the development of novel analgesics. © 2006 by the American Pain Society Key words: Kappa opioid, sexual dimorphism, chlorpromazine, haloperidol, pain, gender.

he agonist-antagonist ␬ opioids nalbuphine, pentazocine, and butorphanol produce greater analgesia in women than in men experiencing postoperative pain.9,12,15 We have proposed that this sexually dimorphic analgesia results from the ability of this class of opioids to produce antianalgesia as well as analgesia, with men experiencing greater antianalgesia. In a placebo-controlled dose response study of analgesia for postoperative dental pain, we observed that men receiving a low dose of nalbuphine (5 mg) actually experienced greater pain than those receiving placebo.13 Subsequent studies demonstrated that co-administration of a low

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Received August 5, 2005; Revised September 20, 2005; Accepted October 6, 2005. Supported by National Institutes of Health grant NR03923. Address reprint requests to Jon D. Levine, MD, PhD, Box 0440, 521 Parnassus Ave, Room C-522, University of California San Francisco, San Francisco, CA 94143-0440. E-mail: [email protected] 1526-5900/$32.00 © 2006 by the American Pain Society doi:10.1016/j.jpain.2005.10.005

dose of the opioid antagonist naloxone enhanced nalbuphine analgesia in both women and men and eliminated sexual dimorphism,10,11,14 suggesting that nalbuphineinduced antianalgesia is sensitive to naloxone and is present in both women and men. To explain these findings, we suggested that nalbuphine produces opposing effects by acting at distinct “analgesia” and “antianalgesia” receptors, and that the antianalgesia receptor is more sensitive to naloxone antagonism.14 However, the specific receptor that mediates these effects remains to be identified. Although the analgesic effect of nalbuphine is probably mediated by ␬ opioid receptors—nalbuphine is known to act as a ␬ opioid receptor agonist,29 and ␬-receptor agonists, including nalbuphine, produce analgesia5,16—little is known about the receptor that mediates the antianalgesic effect of nalbuphine. One possibility, the ␴ receptor, was first described by Martin et al20 as a subtype of opioid receptor. Moreover, agonist-antagonist ␬ opioids can activate ␴ receptors, an action that has 187

188

Neuroleptics Antagonize Nalbuphine Analgesia

Table 1.

Study Participant Sample Characteristics SEX MEN

WOMEN

PREOPERATIVE TREATMENT

PLACEBO

HALOPERIDOL

CHLORPROMAZINE

PLACEBO

HALOPERIDOL

CHLORPROMAZINE

Weight (kg) Surgical severity Baseline VAS pain (cm) Time to baseline (min) Sample size

78.3 ⫾ 4.8 4.5 ⫾ 0.1 4.3 ⫾ 0.3 89 ⫾ 8 15

76.6 ⫾ 3 4.3 ⫾ 0.2 5.2 ⫾ 0.5 89 ⫾ 7 16

67.3 ⫾ 6 4.2 ⫾ 0.3 5.6 ⫾ 0.6 86 ⫾ 8 15

60.6 ⫾ 3.7 4.7 ⫾ 0.3 5.7 ⫾ 0.5 82 ⫾ 10 15

60.3 ⫾ 3.6 4.4 ⫾ 0.2 6.2 ⫾ 0.5 86 ⫾ 7 21

65.1 ⫾ 3.3 4.4 ⫾ 0.3 6.5 ⫾ 0.5 81 ⫾ 11 20

NOTE. Characteristics of study participants. Surgical severity scores6 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 values for each extracted tooth. Differences between the groups for each demographic characteristic were tested in separate 1-way analysis of variance for women and men, there were no significant differences for any of the demographic characteristics. Data are mean ⫾ standard error of the mean. Abbreviation: VAS, visual analog scale.

been shown to antagonize opioid analgesia.2,3 Although some investigators have reported that ␴-receptor agonism is not antagonized by naloxone,22,23,25 more recently others have provided evidence for a naloxonesensitive ␴ receptor.4,28 To test the hypothesis that the antianalgesic effect of nalbuphine is mediated by a ␴ receptor, we administered a known ␴-receptor antagonist, the neuroleptic haloperidol, in combination with nalbuphine to patients with postoperative pain. Because haloperidol also acts as an antagonist at other receptors,1 we administered another neuroleptic, chlorpromazine, in combination with nalbuphine as a control. Chlorpromazine binds to dopamine as well as other receptors in common with haloperidol but has much lower affinity for ␴ receptors.21

Materials and Methods In this study, 102 patients underwent surgery for removal of third molar teeth, including at least one bony impacted mandibular third molar (see Table 1 for group characteristics). Before surgery, patients were randomly assigned to receive orally administered haloperidol (1 mg), chlorpromazine (10 mg), or placebo. The surgical protocol included intravenously administered diazepam, nitrous oxide and oxygen administered by inhalation, and local anesthetic injection (mepivacaine without vasoconstrictor to obtain a nerve block of short duration).12,13,17,18 After surgery after criteria for its administration were reached (see below), all patients received nalbuphine (5 mg, intravenous). This study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Committee on Human Research at the University of California, San Francisco. Informed consent was obtained from each research subject. Pain intensity was quantified by asking patients to mark a 10-cm visual analog scale (VAS), which was anchored on the left side with the words “No Pain” and on

the right with the words “Worst Pain Imaginable.” Pain ratings were obtained at 20-minute intervals beginning 50 minutes after the onset of local anesthesia (ie, the beginning of the surgical procedure). Nalbuphine was administered through an indwelling intravenous line 10 minutes after the baseline VAS pain rating, which was defined as the first VAS pain rating ⱖ3 cm occurring at least 70 minutes after the start of surgery. The duration of the experiment, measured from the time of nalbuphine administration, was 3 hours.

Data Analysis To test for significant differences in the effect of haloperidol and chlorpromazine on nalbuphine analgesia, a 2-way repeated-measures analysis of variance (ANOVA) with one between-subjects factor (ie, treatment with 3 levels, nalbuphine, nalbuphine combined with haloperidol, and nalbuphine combined with chlorpromazine) and one within-subjects factor (ie, time with 9 levels). The dependent variable was analgesic response, defined as the difference between the pain rating at each time point after test drug administration and the baseline VAS pain rating just before nalbuphine administration. Separate ANOVAs were done for women and men. Differences were considered to be significant if the P value was less than .05. The Mauchly criterion was tested to determine whether the assumption of sphericity for the within-subjects effects was met; because the Mauchly criterion was not satisfied, Greenhouse-Geisser adjusted P values are presented. If significant between-subjects effects were found, Scheffé post hoc analyses were performed to determine the basis of the differences.

Results Men To determine whether haloperidol or chlorpromazine enhanced nalbuphine analgesia in men (Fig 1A), a 2-way

ORIGINAL REPORT/Gear et al

189

Figure 1. The effect of preoperatively administered haloperidol (1 mg), chlorpromazine (10 mg), or placebo on the analgesic effect of nalbuphine (5 mg) plotted as analgesia scores calculated as baseline VAS pain score (dashed horizontal line) minus the postadministration VAS pain scores at various time points during the 3 hours after administration. See Table 1 for number of study participants in each group. Data are plotted as mean ⫾ standard error of the mean.

repeated-measures ANOVA was performed, which demonstrated a significant time ⫻ treatment interaction (F16,344 ⫽ 3.256, P ⫽ .012) and a significant main effect of treatment (F2,43 ⫽ 7.462, P ⫽ .002). Scheffé post hoc analysis showed that the 2 groups that received active preoperative drug (haloperidol or chlorpromazine) both differed significantly from the nalbuphine/placebo group (P ⫽ .006 and .008, respectively) but not from each other (P ⫽ .996), indicating that both haloperidol and chlorpromazine enhanced nalbuphine analgesia in men. To determine whether either haloperidol or chlorpromazine produced an independent effect on pain, 2 between-subjects ANOVAs were performed with one factor (treatment with 3 levels, as above). Separate analyses were run for 2 dependent variables, baseline VAS pain rating (ie, pain intensity before nalbuphine administration) and time from commencement of surgery to the baseline VAS rating (Table 1). If haloperidol or chlorpromazine significantly affected either baseline VAS pain intensity or time to baseline, these ANOVAs should demonstrate significant differences between the 3 treatment groups for one or both of these variables. The main effect of treatment was not, however, significant for either variable, arguing against an independent effect on pain by haloperidol or chlorpromazine in men.

Women To determine whether haloperidol or chlorpromazine enhanced nalbuphine analgesia in women (Fig 1B), a 2-way repeated-measures ANOVA was performed. Although there was a significant main effect of time (F8,424 ⫽ 6.351, P ⬍ .001), neither the time ⫻ treatment interaction nor the main effect of treatment reached significance (F16,424 ⫽ 0.540, not significant, and F2,53 ⫽ 1.190, not significant, respectively). To determine whether either haloperidol or chlorpromazine produced an effect on pain independently of

nalbuphine, similar between-subjects ANOVAs were performed. As for men, neither the intensity of baseline pain nor the time from surgery to drug administration differed significantly among the 3 treatment groups in women, arguing against a significant independent effect on pain produced by either haloperidol or chlorpromazine.

Sexual Dimorphism We previously showed that agonist-antagonist ␬ opioids including nalbuphine produce significantly greater analgesia in women than in men, indicating the presence of a sexual dimorphism. To determine the effect of haloperidol and chlorpromazine on sexual dimorphism in nalbuphine analgesia, separate 2-way repeated-measures ANOVAs with one between-subjects factor (sex with 2 levels) and one within-subjects factor (time with 9 levels) were performed for each neuroleptic. Neither the main effect of sex nor the sex ⫻ time interaction was significant for the effect of nalbuphine after either haloperidol or chlorpromazine administration (haloperidol main effect of sex, F1,35 ⫽ 0.335, not significant; sex ⫻ time interaction, F8,280 ⫽ 0.64, not significant; chlorpromazine main effect of sex, F1,33 ⫽ 0.43, not significant; sex ⫻ time interaction, F8,264 ⫽ 1.56, not significant). Consistent with our previously reported result,12,13 however, women receiving nalbuphine alone did experience significantly greater analgesia than did men (main effect of sex, F1,28 ⫽ 11.9, P ⫽ .002; sex ⫻ time interaction, F8,224 ⫽ 4.071, P ⫽ .026).

Discussion Although sexually dimorphic agonist-antagonist ␬ opioid analgesia appears to be pain model– dependent8 (see Fillingim and Gear7 for review), our findings for clinical pain have consistently shown that such differences exist

190 Table 2.

Neuroleptics Antagonize Nalbuphine Analgesia

Binding Affinity Constants (ki) of Neuroleptics for Various Receptor Subtypes

CPZ HAL CPZ/HAL Log10(CPZ/HAL) mg HAL ⫽ 1 mg CPZ: mg CPZ ⫽ 1 mg HAL:

ACHM

H1

5HT2

␣1

␣2

5HT1

D1

D4

D2

␴

60 20k 0.003 ⫺2.5 333 0.003

9.1 3k 0.003 ⫺2.5 330 0.003

1.4 31.5 0.044 ⫺1.4 23 0.04

0.6 6.2 0.096 ⫺1 10 0.1

750 3.8K 0.197 ⫺0.7 5 0.2

5k 5k 1 0 1 1

56 45 1.24 0.1 1 1

12.3 10.3 1.19 0.1 1 1

15 7 2.14 0.3 0.5 2

163 2.6 62.7 1.8 0.02 62.7

NOTE. Binding affinity of chlorpromazine (CPZ) and haloperidol (HAL) for neurotransmitter receptors. Numbers are expressed as ki values for haloperidol and chlorpromazine receptor binding, and the ki(CPZ) : ki(HAL) ratio for each receptor type arranged in ascending order from left to right. Receptors on the right bind with higher affinity to haloperidol relative to chlorpromazine. The bottom 2 rows indicate the mg equivalents of the 2 neuroleptics for each of the receptors (the formula weights for the 2 drugs are approximately equal). See references19,24,26,27 for sources of data in this table. Abbreviations: AChM, muscarinic acetylcholine; ␣1, alpha-1 adrenergic; ␣2, alpha-2 adrenergic; H1, histamine-1; 5HT1, serotonin-1; 5HT2, serotonin-2; D1, dopamine-1; D2, dopamine-2; D4, dopamine-4.

for all 3 drugs in this class.9,12,15 Furthermore, our recent findings suggested that this sexual dimorphism results from induction of an antianalgesic effect that is greater in men than in women13 and can be blocked by co-administration of the opioid antagonist naloxone.14 To test the hypothesis that antianalgesia results from action at a ␴ receptor, we administered the ␴-receptor antagonist haloperidol with nalbuphine to patients who underwent surgical removal of bony impacted third molar teeth. Men, but not women, who received haloperidol experienced significantly greater analgesia than those who received nalbuphine alone, supporting the hypothesis, at least for men. Also, although the analgesia produced by nalbuphine alone was significantly greater in women, it was not significantly different between men and women in patients who received haloperidol, indicating elimination of the sexual dimorphism in agonist-antagonist ␬ opioid–induced analgesia. However, chlorpromazine, which was used as a control for haloperidol because of its much lower affinity for ␴ receptors, similarly enhanced nalbuphine analgesia and eliminated the sexual dimorphism. Although this similarity in the effects of chlorpromazine and haloperidol in the current study does not exclude a role for the ␴ receptor in agonist-antagonist ␬ opioid–induced antianalgesia, it does not allow such a conclusion, at least in the present study in which only 1 dose of each neuroleptic was administered. Higher and lower doses of both neuroleptics might allow a more definitive conclusion to be reached. Although both haloperidol and chlorpromazine enhanced nalbuphine analgesia in men, enhancement in women was not statistically significant. In the absence of dose-response studies, failure to observe neuroleptic enhancement of analgesia in women could be related to the use of a suboptimal dose. Alternatively, because there is less enhancement in women, a larger number of patients might be required to demonstrate enhancement in women. Additional studies will be needed to exclude this possibility.

In a pharmacodynamic analysis of our data from more than 304 postoperative pain patients who were administered placebo, various doses of nalbuphine alone, or nalbuphine combined with various doses of naloxone, we found that the data best fit a 2-receptor model (ie, “analgesia” and “anti-analgesia” receptors) (Kshirsagar, 2005, unpublished data). Because neuroleptics do not bind opioid receptors, it is unlikely that they antagonize antianalgesia by directly blocking the binding of nalbuphine to the antianalgesia receptor as would be expected with naloxone; rather, their action is probably downstream. Neuroleptics possess antagonist properties at a number of receptors (Table 2); it remains to be established which, if any, of these receptors plays a role in antianalgesia. Identification of the receptor at which agonist-antagonist ␬ opioids induce antianalgesia is important for understanding of the mechanism(s) of sexual dimorphism in analgesic responses and could inform the development of novel selective antagonist drugs targeted at antianalgesia receptors. Eliminating agonist-antagonist ␬ opioid–induced antianalgesia would not only produce greater analgesia by using lower doses of this class of drugs, but it would also decrease its side effects. In summary, we report that 2 neuroleptics, haloperidol and chlorpromazine, block the antianalgesic effect of the agonist-antagonist ␬ opioid nalbuphine in men and eliminate the sexual dimorphism in nalbuphine analgesia. Taken together with our previous observations that the opioid receptor antagonist naloxone also eliminates sexual dimorphism and enhances analgesia,14 these results suggest that the circuit that mediates antianalgesia involves more than one type of neurotransmitter receptor.

Acknowledgments We thank Gretchen Summer, RN, PhD, for excellent technical assistance.

ORIGINAL REPORT/Gear et al

References 1. Baldessarini RJ, Tarazi FI: Drugs and the treatment of psychiatric disorders: Psychosis and mania, in Gilman AG, Hardman JG, Limbird LE (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics. New York, NY, McGraw-Hill, 2001, pp 485-520 2. Chien CC, Pasternak G.W: Functional antagonism of morphine analgesia by (⫹)-pentazocine: Evidence for an antiopioid sigma 1 system. Eur J Pharmacol 250:R7-8, 1993 3. Chien CC, Pasternak GW: Selective antagonism of opioid analgesia by a sigma system. J Pharmacol Exp Ther 271:15831590, 1994 4. Couture S, Debonnel G: Some of the effects of the selective sigma ligand (⫹)pentazocine are mediated via a naloxone-sensitive receptor. Synapse 39:323-331, 2001 5. Errick JK, Heel RC: Nalbuphine: A preliminary review of its pharmacological properties and therapeutic efficacy. Drugs 26:191-211, 1983 6. Faucett J, Gordon N, Levine J: Differences in postoperative pain severity among four ethnic groups. J Pain Symptom Manage 9:383-389, 1994 7. Fillingim RB, Gear RW: Sex differences in opioid analgesia: Clinical and experimental findings. Eur J Pain 8:413-425, 2004 8. Fillingim RB, Ness TJ, Glover TL, Campbell CM, Price DD, Staud R: Experimental pain models reveal no sex differences in pentazocine analgesia in humans. Anesthesiology 100: 1263-1270, 2004 9. Gear RW, Gordon NC, Heller PH, Paul S, Miaskowski C, Levine JD: Gender difference in analgesic response to the kappa-opioid pentazocine. Neurosci Lett 205:207-209, 1996 10. Gear RW, Gordon NC, Miaskowski C, Paul SM, Heller PH, Levine JD: Dose ratio is important in maximizing naloxone enhancement of nalbuphine analgesia in humans. Neurosci Lett 351:5-8, 2003 11. Gear RW, Gordon NC, Miaskowski C, Paul SM, Heller PH, Levine JD: Sexual dimorphism in very low dose nalbuphine postoperative analgesia. Neurosci Lett 339:1-4, 2003 12. Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD: Kappa-opioids produce significantly greater analgesia in women than in men. Nat Med 2:1248-1250, 1996 13. Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD: The kappa opioid nalbuphine produces genderand dose-dependent analgesia and antianalgesia in patients with postoperative pain. Pain 83:339-345, 1999

191 Limbird LE (eds.): Goodman & Gilman’s The Pharmacological Basis of Therapeutics. New York, NY, McGraw-Hill, 2001, pp 569-619 17. Levine JD, Gordon NC: Influence of the method of drug administration on analgesic response. Nature 312:755-756, 1984 18. Levine JD, Gordon NC, Taiwo YO, Coderre TJ: Potentiation of pentazocine analgesia by low-dose naloxone. J Clin Invest 82:1574-1577, 1988 19. Leysen JE, Gommeren W, Mertens J, Luyten WH, Pauwels PJ, Ewert M, Seeburg P: Comparison of in vitro binding properties of a series of dopamine antagonists and agonists for cloned human dopamine D2S and D2L receptors and for D2 receptors in rat striatal and mesolimbic tissues, using [125I] 2’-iodospiperone. Psychopharmacology (Berl) 110:2736, 1993 20. Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE: The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197:517-532, 1976 21. Matsumoto RR, Pouw B: Correlation between neuroleptic binding to sigma(1) and sigma(2) receptors and acute dystonic reactions. Eur J Pharmacol 401:155-160, 2000 22. McCann DJ, Weissman AD, Su TP: Sigma-1 and sigma-2 sites in rat brain: Comparison of regional, ontogenetic, and subcellular patterns. Synapse 17:182-189, 1994 23. Quirion R., Bowen WD, Itzhak Y, Junien JL, Musacchio JM, Rothman RB, Su TP, Tam SW, Taylor DP: A proposal for the classification of sigma binding sites. Trends Pharmacol Sci 13:85-86, 1992 24. Takahashi S, Sonehara K, Takagi K, Miwa T, Horikomi K, Mita N, Nagase H, Iizuka K, Sakai K: Pharmacological profile of MS-377, a novel antipsychotic agent with selective affinity for sigma receptors. Psychopharmacology (Berl) 145:295302, 1999 25. Tam SW: Naloxone-inaccessible sigma receptor in rat central nervous system. Proc Natl Acad Sci U S A 80:67036707, 1983 26. Tam SW, Cook L: Sigma opiates and certain antipsychotic drugs mutually inhibit (⫹)-[3H] SKF 10,047 and [3H]haloperidol binding in guinea pig brain membranes. Proc Natl Acad Sci U S A 81:5618-5621, 1984 27. Terai M, Usuda S, Kuroiwa I, Noshiro O, Maeno H: Selective binding of YM-09151-2, a new potent neuroleptic, to D2-dopaminergic receptors. Jpn J Pharmacol 33:749-755, 1983

14. Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD: Action of naloxone on gender-dependent analgesic and anti-analgesic effects of nalbuphine in humans. J Pain 1:122-127, 2000

28. Tsao LI, Su TP: Naloxone-sensitive, haloperidol-sensitive, [3H](⫹)SKF-10047-binding protein partially purified from rat liver and rat brain membranes: An opioid/sigma receptor? Synapse 25:117-124, 1997

15. Gordon NC, Gear RW, Heller PH, Paul S, Miaskowski C, Levine JD: Enhancement of morphine analgesia by the GABAB agonist baclofen. Neuroscience 69:345-349, 1995

29. Zhu J, Luo LY, Li JG, Chen C, Liu-Chen LY: Activation of the cloned human kappa opioid receptor by agonists enhances [35S]GTPgammaS binding to membranes: Determination of potencies and efficacies of ligands. J Pharmacol Exp Ther 282:676-684, 1997

16. Gutstein HB, Akil H: Opioid analgesics, in Hardman JG,