Effects of nalbuphine, pentazocine and U50488H on gastric emptying and gastrointestinal transit in the rat

Transcription

1 British Journal of Anaesthesia 1998; 80: Effects of nalbuphine, pentazocine and U50488H on gastric emptying and gastrointestinal transit in the rat T. ASAI, W. W. MAPLESON, I. POWER Summary We studied the effect of mixed agonistantagonist opioids (nalbuphine and pentazocine) and a kappa opioid agonist (U50488H) on gastric emptying and gastrointestinal transit, and their interactions with morphine in rats. In each group, nalbuphine ( mg kg 1 ), pentazocine (1 30 mg kg 1 ), U50488H (1 100 mg kg 1 1) or saline was injected i.p. at 0 min. Another four groups of rats received morphine 13.4 mg kg 1 (ED75) and one of the following substances: saline, nalbuphine, pentazocine or U50488H. In both groups, at 30 min, radiolabelled saline 1 ml was infused into the stomach; at 1 h, gastric emptying and gastrointestinal transit were calculated by measuring the radioactivity in the gastrointestinal tract. Slopes for dose response curves were determined. Nalbuphine significantly, but only weakly, delayed gastric emptying (P ) and gastrointestinal transit (P 0.01). Pentazocine markedly inhibited both, whereas U50488H did not significantly inhibit either. The slopes of the dose response curves for nalbuphine, but not for pentazocine, on both gastric emptying and gastrointestinal transit were significantly less steep than those for morphine. Nalbuphine significantly antagonized the inhibitory effect of morphine on gastric emptying (P 0.005) and gastrointestinal transit (P 0.02), whereas pentazocine and U50488H did not. Nalbuphine and pentazocine delay gastric emptying and gastrointestinal transit, possibly by different mechanisms. (Br. J. Anaesth. 1998; 80: ) Keywords: interactions (drug) opioids; gastrointestinal tract gastric emptying; complications gastric statis; rat Opioids may bind to more than one receptor, and the intrinsic activity for each receptor may differ. 1 Some of them have no or weak intrinsic activities to produce agonist effects at one receptor (competitive or partial agonists). When a partial agonist and a full agonist are given concurrently, binding of the full agonist will be partially prevented by binding of the partial agonist, and thus the effect of the full agonist will be reduced. For example, the opioid nalbuphine antagonizes the antinociceptive effect of mu opioid receptor agonists. 2 Such opioids are called mixed agonist antagonist opioids, and include nalbuphine, nalorphine and pentazocine. 1 3 Mu opioid receptor agonists, such as morphine, delay gastric emptying and intestinal transit. 4 6 In contrast, kappa receptor opioid agonists have weak or no inhibitory effects. 4 5 Little is known about the effects and mechanisms of mixed agonist antagonist opioids on gastric emptying and intestinal transit. In mice, nalbuphine, nalorphine and pentazocine delayed gastrointestinal transit, but the inhibitory effect was weak. 7 9 We found only one report in which the effect of the mixed agonist antagonist on gastric emptying was studied in animals. 10 In that study, the residual volume of gastric contents was examined 30 min after infusion of dyed antacid into the stomach and injection of either pentazocine or saline in rats. The residual volume was greater in the pentazocine group than the saline group; however, the residual volume in the pentazocine group was greater than the volume of initial infusion of dyed antacid. Antacid itself delays gastric emptying and increases gastric acid secretion ; therefore, the effects of pentazocine are not clear. More than one opioid, such as nalbuphine and morphine, may be given concurrently during surgery The interactive effects of these drugs and the effect on gastrointestinal motility are not known. We decided to study the effects of a mu agonist (morphine), mixed agonist antagonists (nalbuphine and pentazocine) and a highly selective kappa agonist (U50488H) on gastric emptying and gastrointestinal transit; we also studied the interactive effects of these opioids. Materials and methods The study was conducted under the Animal (Scientific Procedures) Act 1986 (Home Office Licence: PPL 40/954, PPL 40/1397). Male Wistar rats, each weighing g, were housed under standard controlled environmental conditions, with a 12 h light dark cycle. The animals were fasted for 24 h, but allowed free access to water until min before the start of the experiment. They were kept in individual wire-mesh cages to prevent coprophagy TAKASHI ASAI, MD, PHD Department of Anaesthesiology, Kansai Medical University, Fumizono-cho, Moriguchi City, Osaka 570, Japan. W. W. MAPLESON DSC, FINSTP, FRCA (HON) Deparment of Anaesthetics and Intensive Care Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN. I. POWER BSC (HONS), MD, FRCA Department of Anaesthesia and Pain Management, Royal North Shore Hospital, and University of Sydney St Leonards, NSW 2065, Australia. Accepted for publication: February 9, Presented in part at the Anaesthetic Research Society, Bristol Meeting, July 3 4, 1997 (British Journal of Anaesthesia 1997;79:676P).

2 Effects of opioids on gastrointestinal transit 815 Figure 1 Effect of nalbuphine (A, D), pentazocine (B, E) and U50488H (C, F) on gastric emptying and gastrointestinal transit of saline. Note the narrow range of doses for pentazocine and U50488H. Saline 1 ml, containing a radiolabelled marker ( 51 Cr), was given 30 min after i.p. injection of the drug. Gastric emptying and gastrointestinal transit were examined 30 min later. A fitted logit dose response curve (nalphine or pentazocine) or fitted parabola (U50488H) is shown, with the value obtained from each rat (open circles). Symbols are slightly displaced if there are similar values for any given dose. Values at zero dose are those for the saline control. during fasting. All experiments were started between 10:00 and 11:00. Nalbuphine, pentazocine (Sigma Chemical Co., UK) and U50488H (Upjohn Company, USA) were prepared freshly on each day of the experiment. A group of six rats was allocated for each set of circumstances. If more than one rat was excluded, another group of six rats was used until a group was completed in which no more than one rat was excluded. Data from the non-excluded rats from all groups for each study (5 10 rats) were used. Gastric emptying and gastrointestinal transit were studied, as described previously. 15 In brief, at 0 min, a substance or a combination of substances (see below), in a volume of 1.0 ml kg 1 for each substance was given i.p. At 30 min, 1.0 ml of saline containing radiolabelled sodium chromate was infused into the stomach. At 60 min, the rats were killed. The stomach and small intestine were removed, and the small intestine divided into 10 equal segments. The Table 1 ED 50 (mg kg 1 ) (95% confidence limits) of opioids injected intraperitoneally in inhibiting gastric emptying and gastrointestinal transit of 1 ml saline. The estimated values and their upper confidence limits are omitted when the values are much greater than the dose range used. *Data for morphine are from a previous report. 8 U50488H up to 100 mg kg 1 did not significantly delay gastric emptying and gastrointestinal transit Drugs Gastric emptying Gastrointestinal transit Morphine (n 52)* 2.8 (2.1, 3.8) 1.2 (0.87, 1.71) Nalbuphine (n 36) (28.1, ) (369, ) Pentazocine (n 29) 12.8 (8.2, 24.7) 39.8 (16.0, ) U50488H (n 28) radioactivity in the stomach and each segment of the intestine was counted. If there was chyme in the stomach or small intestine, the data were not used. Gastric emptying and gastrointestinal transit (expressed in terms of the geometric centre) in each rat and the percentage inhibition of gastric emptying or gastrointestinal transit for each test drug were calculated. 15 EFFECTS OF INDIVIDUAL OPIOID AGONIST We studied the effects on gastrointestinal motility of three different types of opioid receptor agonist: a mu opioid receptor agonist (morphine, mg kg 1 ); a Table 2 Slopes (logit (% gastric emptying) or logit (% geometric centre) per unit log dose) and differences in slopes of the logit curves (with 95% confidence limits (CL)) for the effect of opioids on gastric emptying and gastrointestinal transit of saline Drugs Slopes (95% CL) P Gastric emptying Morphine (n 52) 1.38 ( 1.48, 1.29) Nalbuphine (n 36) 0.48 ( 0.55, 0.40) Pentazocine (n 29) 1.67 ( 1.8, 1.5) Differences between drugs Morphine nalbuphine 0.91 ( 1.27, 0.55) Morphine pentazocine 0.29 ( 0.28, 0.86) 0.32 Gastrointestinal transit Morphine (n 52) 0.97 ( 1.05, 0.89) Nalbuphine (n 36) 0.23 ( 0.30, 0.16) Pentazocine (n 29) 1.03 ( 1.18, 0.88) Differences between drugs Morphine nalbuphine 0.74 ( 1.05, 0.44) Morphine pentazocine 0.06 ( 0.43, 0.54) 0.82

3 816 British Journal of Anaesthesia Table 3 Effect of nalbuphine, pentazocine or U50488H on the inhibitory effect of morphine on gastric emptying and gastrointestinal transit of saline (median). Non-parametric one-way analysis of variance (Kruskal Wallis test) showed a significant difference in gastric emptying (P 0.05) and gastrointestinal transit (P 0.01) between groups; the Minitab version of Mann Whitney U test was used to obtain P values and 95% confidence limits of the difference between rats that received morphine with saline and those that received a combination of morphine and an agonist. Six to seven rats were used for each group Treatment Gastric emptying Difference from morphine group Emptying (%) Confidence limits P Gastrointestinal transit Difference from morphine group Geometric centre Confidence limits P Morphine 13.4 mg kg 1 saline nalbuphine 1.0 mg kg (4.0, 32.2) (0.4, 2.1) pentazocine 1.0 mg kg ( 8.0, 11.0) ( 0.4, 0.9) 0.65 U50488H 1.0 mg kg ( 9.8, 19.3) ( 0.4, 0.8) 0.47 kappa opioid receptor agonist (U50488H, mg kg 1 ) 16 ; and a mixed agonist antagonist opioid (nalbuphine, mg kg 1, and pentazocine, 1 30 mg kg 1 ). However, only four rats were used for 100 mg kg 1 U50488H, because of limited availability of the drug. Data for morphin e have been reported already, 15 but were not used in any hypothesis tests. The experiments with the other three opioids were all conducted within the period over which the measurements with morphine were made. INTERACTIONS OF TWO OPIOID AGONISTS Another four groups of rats received morphine 13.4 mg kg 1 (ED 75 ) and one of the following substances: saline, nalbuphine, pentazocine or U50488H (the last three at 1.0 mg kg 1 ). STATISTICAL ANALYSIS The variation of percentage inhibition with the dose of each agent was modelled, except for results for U50488H, by fitting a sigmoid logit curve to fractional inhibition against log dose, to calculate ED 50 and ED 75 and, by means of the Fieller equation, the 95% confidence interval (CI) of those doses. 15 When the logit curve showed that the test drug did not inhibit gastric emptying or gastrointestinal transit by more than 50%, the Mann Whitney U test was used to compare gastric emptying and gastrointestinal transit between the drug and saline groups of rats; the values for all doses of the test drug were pooled for this analysis. P 0.05 was considered significant. For U50488H, it was not legitimate to fit a logit curve because of many negative values for percentage in hibition. Therefore, to see if there was an y tendency for inhibition to increase with increasing dose, a linear and a quadratic equation were fitted to the data and tested for significant negative slope and negative curvature, respectively. The 95% confidence intervals for median difference between saline and drug groups were calculated using the SINTERVAL command (sign test) in Minitab Release 8.2 (running on a Macintosh LC computer), which shows exact intervals for a stated confidence level close to 95%. The slope of each logit curve and the difference between the slopes for two drugs (e.g. morphine and nalbuphine), and the standard errors, emerge from the GLIM analysis. The 95% confidence intervals for the slopes and differences of slopes were calculated as described by Gardner and Altman. 17 To study the interactive effects of morphine and an agonist (nalbuphine, pentazocine or U50488H), non-parametric one-way analysis of variance (Kruskal Wallis test) was used to compare gastric emptying and gastrointestinal transit between the four groups. If this proved significant, the Mann Whitney U test was used to compare gastric emptying and gastrointestinal transit between rats that were subjected to morphine (and saline), and those that received a combination of morphine and another agonist (nalbuphine, pentazocine or U50488H). Results EFFECTS OF INDIVIDUAL OPIOID AGONIST Nalbuphine significantly delayed gastric emptying (P by Mann Whitney U test), but its inhibitory effect was weak (95% CI for the difference from saline: % at the maximum dose of nalbuphine, 30 mg kg 1 ) (fig.1; table 1). It also significantly decreased gastrointestinal transit (P 0.01), but its inhibitory effect was weak (95% CI for difference from saline: % at the maximum dose, 30 mg kg 1 ) (fig.1). Pentazocine significantly delayed both gastric emptying and gastrointestinal transit (fig.1; table 1). U50488H did not significantly inhibit either gastric emptying or gastrointestinal transit. The Mann Whitney U test showed no significant difference in either gastric emptying and gastrointestinal transit between U50488 and saline groups (table 1), and neither the slope of a fitted straight line nor the curvature of a fitted parabola was significant (fig.1). The slopes of the dose response curves for nalbuphine on both gastric emptying and gastrointestinal transit were significantly less steep than those for morphine (P 0.001) (table 2). In contrast, the slopes for pentazocine were similar to those for morphine (table 2). INTERACTIVE EFFECTS OF TWO OPIOID AGONISTS One-way analysis of variance showed that the values were significantly different between the four groups, for gastric emptying (P 0.05) and gastrointestinal transit (P 0.01) (table 3). Nalbuphine significantly antagonized the inhibitory effect of morphine on

4 Effects of opioids on gastrointestinal transit 817 tive kappa opioid receptor agonist, 16 did not significantly alter gastric emptying or gastrointestinal transit. When the fitted curves for the effect of each drug on gastric emptying and gastrointestinal transit are plotted in terms of percentage of control values (fig. 2), it is apparent that morphine nearly maximally inhibited both gastric emptying and gastrointestinal transit, whereas nalbuphine did not produce maximum inhibitory effects. For each opioid the inhibitory effect on gastric emptying was similar to that on gastrointestinal transit. These results are in contrast to the effects of alpha 2 adrenoceptor agonists, which strongly inhibited transit in the small intestine, but only weakly inhibited gastric emptying. 15 Altogether, it is likely that the opioid receptor is involved in controlling both gastric emptying and intestinal transit, whereas the alpha 2 adren oceptor is in volved main ly in controlling intestinal transit. Figure 2 Gastric emptying and gastrointestinal transit as percentages of the control values for (A) morphine, (B)nalbuphine and (C) pentazocine. The extrapolated part of the curve for pentazocine is shown by a broken line. ED 50 values and 95% confidence intervals are also shown. Data for morphine are from a previous study. 8 gastric emptying (P 0.02) and gastrointestinal transit (P 0.005), whereas pentazocine and U50488H did not (table 3). Discussion Nalbuphine and pentazocine significantly inhibited gastric emptying and gastrointestinal transit of saline, but the effects were weak for nalbuphine. These findings are consistent with previous reports, which have shown that nalbuphine and pentazocine have weak inhibitory effects on transit in the small intestine in mice. 7 9 In contrast, in accordance with previous reports in rats and mice, 4 5 U50488H, a highly selec- OPIOID RECEPTOR TYPES FOR THE INHIBITORY EFFECT OF NALBUPHINE AND PENTAZOCINE A partial agonist will show the following three features 1 : (1) the slope of the dose response curve of a partial agonist is less steep than that of a full agonist; (2) there is a ceiling to its effect; and (3) a partial agonist will partially antagonize the effects of large doses of a full agonist. The slope of the dose response curve for nalbuphine was significantly less than that of morphine (table 2); there was a ceiling to its effect (fig. 2); and nalbuphine antagonized the inhibitory effect of morphine (table 3). These results are consistent with the characteristics of a partial agonist in this case, a partial mu agonist. 1 In contrast, for pentazocine, the slope of the dose response curve did not differ significantly from that for morphine; there was no clear ceiling to its effect at the doses used; pentazocine did not significantly affect the inhibitory action of morphine. Therefore, it is likely that pentazocine delayed gastric emptying and gastrointestinal transit, not as a partial mu agonist, but possibly as a full mu opioid receptor agonist or a non-mu, non-kappa receptor agonist. The effect could be through the sigma receptor, as pentazocine has agonist activity at this receptor. Previous studies have shown that in some situations, nalbuphine acts as a partial mu agonist, whereas pentazocine cannot For example, nalbuphine antagonizes the antinociceptive effect of mu opioid receptor agonists. 2 It also antagonizes the inhibitory effect of mu opioid receptor agonists on respiration, and decreases the incidence of nausea, vomiting and pruritus after injection of a mu receptor agonist. 22 In contrast, pentazocine does not generally antagonize the antinociceptive effect of morphine Although a few studies showed that pentazocine antagonized the antinociceptive effect of morphine, this effect was considered to be mediated by the sigma receptor and the effect was not stereospecific In the isolated guinea-pig ileum, nalbuphine inhibited field-stimulationinduced contraction of the ileum through the mu opioid receptor, whereas pentazocine did so mainly through the kappa receptor

5 818 British Journal of Anaesthesia CLINICAL IMPLICATIONS In humans, both nalbuphine and pentazocine significantly inhibited gastric emptying of liquids This is consistent with the results obtained in the present study in rats. However, it is not known whether there is a ceiling to the inhibitory effect of these drugs in humans, and whether they interact with morphine (or other strong mu receptor agonists) in a similar manner to that in rats. The current and previous studies suggest that nalbuphine reduces the inhibitory effect of morphine on gastric emptying and intestinal transit, but it also reduces the antinociceptive effects. In contrast, pentazocine does not affect the antinociceptive effect of morphine or alter the inhibitory effect of morphine on gastric emptying and intestinal transit. Therefore, concurrent injection of nalbuphine and morphine or pentazocine and morphine, in theory, will not provide a potent analgesia with a relatively weak inhibitory effect on gastric emptying and intestinal transit. However, this theory needs to be tested in humans, because the pharmacological effects may differ between species. In conclusion, we have found that, in the rat, a mu agonist (morphine), but not a kappa agonist (U50488H), delayed gastric emptying and gastrointestinal transit. Nalbuphine and pentazocine delayed these, possibly by different mechanisms; nalbuphine, but not pentazocine, acted as a partial mu opioid receptor agonist. Acknowledgements We thank Mr C. Juniper, HNC, for skillful technical assistance, Dr W. D. Evans, Department of Medical Physics and Bioengineering, for advice and help in use of the gamma counter, and Mrs P. de Souza, Department of Haematology, for providing the radiolabelled liquid. We also thank the Upjohn Company, Michigan, USA, for the gift of U50488H. References 1. Martin WR. Pharmacology of opioids. Pharmacological Reviews 1984; 35: Ward JW, Foxwell M, Funderburk WH. The detection of analgesia produced by morphine antagonists in laboratory animals. Pharmacologist 1985; 7: Houde RW. Analgesic effectiveness of the narcotic agonist antagonists. British Journal of Clinical Pharmacology 1979; 7: 297S 308S. 4. Shook JE, Pelton JT, Hruby VJ, Burks TF. Peptide opioid antagonist separates peripheral and central opioid antitransit effects. Journal of Pharmacology and Experimental Therapeutics 1987; 243: Rivière PJM, Pascaud X, Chevalier E, Le Gallou B, Junien JL. Fedotozine reverses ileus induced by surgery or peritonitis: action at peripheral -opioid receptors. Gastroenterology 1993; 104: Green AF. Comparative effects of an algesics on pain threshold, respiratory frequency and gastrointestinal propulsion. British Journal of Pharmacology 1959; 14: Wong CL. The effect of nalbuphine on gastrointestinal transit in mice. European Journal of Pharmacology 1987; 135: Wong CL. The possible involvement of -adrenoceptors in the intestinal effect of nalbuphine in mice. Methods and Findings in Experimental and Clinical Pharmacology 1990; 12: Hayes AG, Tyers MB. Determination of receptors that mediate opiate side effects in the mouse. British Journal of Pharmacology 1983; 79: Danhof IE, Blackmore WP, Upton GL. Effect of pentazocine on gastric emptying and small intestinal propulsive motility in the rat. Toxicology and Applied Physiology 1966; 9: Clark BB, Lloyd Adams W. The effect of gastric antacids on gastric secretion as observed in the Cope pouch dog. Sodium bicarbonate, aluminum hydroxide gel, calcium carbonate, magnesium oxide and sodium citrate. Gastroenterology 1947; 9: Hurwitz A, Robinson RG, Vats TS, Whittier C, Herrin WF. Effects of antacids on gastric emptying. Gastroenterology 1976; 71: Cohen SE, Ratner EF, Kreitzman TR, Archer JH, Mignano LR. Nalbuphine is better than naloxone for treatment of side effects after epidural morphine. Anesthesia and Analgesia 1992; 75: Penning JP, Samson B, Baxter AD. Reversal of epidural morphine-induced respiratory depression and pruritus with nalbuphine. Canadian Journal of Anaesthesia 1988; 35: Asai T, Mapleson WW, Power I. Differential effects of clonidine and dexmedetomidine on gastric emptying and gastrointestinal transit in the rat. British Journal of Anaesthesia 1997; 78: Von Voightlander PF, Lahti RA, Ludens JH. U50488: a selective and structually novel non-mu (kappa) opioid agonist. Journal of Pharmacology and Experimental Therapeutics 1983; 224: Gardn er MJ, Altman DG. Statistics with confidence confidence intervals and statistical guidelines. London: British Medical Journal, Bowen WD, Hellewell SB, McGarry KA. Evidence for a multi-side model of the rat brain receptor. European Journal of Pharmacology 1989; 163: Chien CC, Pastern ak GW. Fun ction al an tagon ism of morphine analgesia by (+) pentazocine: evidence for an antiopioid 1 system. European Journal of Pharmacology 1993; 250: R7 R Cheng EY, May J. Nalbuphine reversal of respiratory depression after epidural sufentanil. Critical Care Medicine 1989; 17: Blaise GA, Nugent M, McMichan JC, Durant PAC. Side effects of nalbuphine while reversing opioid-induced respiratory depression: report of four cases. Canadian Journal of Anaesthesia 1990; 37: Cohen SE, Ratner EF, Kreitzman TR, Archer JH, Mignano LR. Nalbuphine is better than naloxone for treatment of side effects after epidural morphine. Anesthesia and Analgesia 1992; 75: Zimmerman DM, Leander JD, Reel JK, Hynes MD. Use of -funaltrexamine to determine mu opioid receptor involvement in the analgesic activity of various opioid ligands. Journal of Pharmacology and Experimental Therapeutics 1987; 241: Hui FW, Sun CLJ, Hanig JP. Opiate mixed agonist antagonist interactions with histamine antagonists vs. morphine. Neurobehavioral Toxicology and Teratology 1985; 7: Shimada A, Iizuka H, Yanagita T. Agonist antagonistic interactions of pentazocine with morphine studied in mice. Pharmacology, Biochemistry and Behavior 1984; 20: Taber RI, Greenhouse DD, Rendell JK, Irwin S. Agonist and antagonist interactions of opioids on acetic acid-induced abdominal stretching in mice. Journal of Pharmacology and Experimental Therapeutics 1969; 169: Chien CC, Pasternak GW. Selective antagonism of opioid analgesia by a sigma system. Journal of Pharmacology and Experimental Therapeutics 1994; 271: McMillan DE, Wolf PS, Carchman RA. Antagonism of the behavioral effects of morphine and methadone by narcotic antagonists in the pigeon. Journal of Pharmacology and Experimental Therapeutics 1970; 175: Walker EA, Young AM. Discriminative-stimulus effects of the low efficacy mu agonist nalbuphine. Journal of Pharmacology and Experimental Therapeutics 1993; 267: Hayes AG, Sheehan MJ, Tyers MB. Determination of the receptor selectivity of opioid agonists in the guinea-pig ileum and mouse vas deferens by use of -funaltrexamine. British Journal of Pharmacology 1985; 86: Miller L, Shaw JS, Whiting EM. The contribution of intrinsic activity to the action of opioids in vitro. British Journal of Pharmacology 1986; 87:

6 Effects of opioids on gastrointestinal transit Nimmo WS, Wilson J, Prescott LF. Narcotic analgesics and delayed gastric emptying during labour. Lancet 1975; i: Shah M, Rosen M, Vickers MD. Effect of premedication with diazepam, morphine or nalbuphine on gastrointestinal motility after surgery. British Journal of Anaesthesia 1984; 56: Yukioka H, Rosen M, Evans KT, Leach KG, Hayward MWJ, Saggu GS. Gastric emptying and small bowel transit time in volunteers after intravenous morphine and nalbuphine. Anaesthesia 1987; 42: Clements JA, Heading RC, Nimmo WS, Prescott LF. Kinetics of acetaminophen absorption and gastric emptying in man. Clinical Pharmacology and Therapeutics 1978; 24: