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© 1999 International Anesthesia Research Society
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Abstract |
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We examined the effects of several opioids that vary in intrinsic efficacy at the µ-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50°C and 52°C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids.
Implications: Compared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone.
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Introduction |
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The concept of a drug's intrinsic efficacy encompasses several assumptions generally made in pharmacology, including: 1) a given drug effect is proportional to receptor occupancy, 2) a maximal effect can be produced by occupying only a proportion of the available receptors, and 3) the maximal effects produced by a drug can vary across dependent measures (1,2). By definition, lower efficacy opioids must bind to more receptors than higher efficacy opioids to produce a given effect. Different effects of a drug also depend on activation of different numbers of receptors, which can be altered by changing various parameters of the task, such as the intensity of the nociceptive stimulus in antinociceptive procedures. When the intensity is increased, the potency of any drug will decrease as more receptors must be occupied, and there will be a point at which drugs that must bind to a large proportion of receptors (i.e., lower efficacy drugs) cannot occupy enough receptors to produce a given effect. In these situations, lower efficacy opioids produce antinociception using low-intensity stimuli but fail to produce antinociception using high-intensity stimuli (3–8). Thus, there is an interaction between the intrinsic efficacy of an opioid and the stimulus intensity (or the efficacy requirement of the task) in producing antinociception.
Previous studies have examined the interactions among opioids with varying degrees of intrinsic efficacy in cases in which the lower efficacy opioid fails to produce antinociception on its own. In these instances, the lower efficacy opioid competitively antagonizes the effects of higher efficacy opioids. For example, in a rat warm water tail withdrawal procedure using 55°C water, the low-efficacy opioids nalbuphine and butorphanol fail to produce antinociception and shift the dose-effect curves for the high-efficacy opioids alfentanil and etonitazene to the right in a competitive manner (6,7).
Few studies have examined the interactions among opioids in situations in which both drugs produce antinociceptive effects. One question posed in the present study was whether the interaction among opioids is directly dependent on the efficacy of the drug. That is, do higher efficacy opioids interact with morphine differently than lower efficacy opioids interact with morphine? The answer could have important implications regarding the use of opioid analgesic combinations in clinical situations and the theoretical underpinnings of drug interactions. Therefore, we designed the present study to examine the interaction between morphine and several other drugs in an antinociceptive procedure. To establish the generality of the findings, we used multiple stimulus intensities (water temperatures), and morphine's antinociceptive effects were examined in combination with the high-efficacy opioid levorphanol, the intermediate-efficacy opioids dezocine and buprenorphine, and the low-efficacy opioids butorphanol and nalbuphine (9–13).
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Method |
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Animals used in this study were maintained in accordance with the guidelines of, and the experiments were approved by, the Animal Care and Use Committee of the University of North Carolina. The subjects were Long-Evans hooded rats weighing 250–275 g at the beginning of the experiment, and they were individually housed in a climate-controlled colony room maintained on a 12-h light/dark cycle. After several weeks of ad libitum feeding, rats were handled and food-deprived until they weighed approximately 80% of their free-feeding weight, and they were maintained at that weight for the remainder of the experiment. Each drug and drug combination was examined in groups of 8–10 rats, and each group was used to examine the effects of morphine alone, another opioid alone, and the combination tests.
The tail withdrawal procedure used has been described extensively elsewhere (8). Briefly, rats were gently restrained along the edge of a table, and their tails were immersed in a cup containing either 40°C, 50°C, or 52°C water. The water was maintained at a particular temperature using hot water baths. The latency until tail withdrawal was measured using a hand-held stopwatch, and a cutoff of 15 s was used to avoid tissue damage. Control tests were conducted to obtain baseline latencies for 40°C, 50°C, and 52°C water. Two baseline latencies were obtained and averaged for a particular rat. Throughout a test, all trials with the warm water were conducted at least 3 min apart, and the order of testing was counterbalanced across rats.
After baseline trials, a cumulative dosing test procedure was initiated. Fifteen minutes after the first injection of the test drug, the latency until tail withdrawal from both 50°C and 52°C water was recorded. After these tests, another injection was administered, which increased the cumulative dose by either 0.25, 0.5, or 1.0 log units. In this manner, entire dose-effect curves could be generated within a single session. In combination tests, the test dose of the opioid was administered immediately before the first dose of morphine.
The test latencies were converted to percent antinociceptive effect using the following formula: percent antinociceptive effect = [(test - baseline)/(15 - baseline)] x 100. The percent antinociceptive effect was plotted as a function of drug dose. Doses that produced a 50% effect (ED50 dose) were determined using log-linear interpolation from at least three points on the ascending limb of the dose-effect curve. The effects of each drug combination were compared with the predicted effects of the combination (i.e., summing the effects of the drugs when administered alone). This comparison was made by using two-way analysis of variance with dose (i.e., dose of morphine) and effects (i.e., observed and predicted) as the factors. The 
level was set at 0.05. Where appropriate, an apparent pKB analysis was conducted to estimate the antagonist dose required to produce a twofold shift in the agonist dose-effect curve. The apparent pKB value was estimated using the following formula: pKB = -log (B/DR-1), where B is the dose of antagonist in moles and DR is the dose ratio of the ED50 of the combination and the ED50 of morphine alone.
The following drugs were used: morphine sulfate, buprenorphine hydrochloride (provided by the National Institute on Drug Abuse, Rockville, MD), butorphanol tartrate (supplied by Bristol-Myers, Wallingford, CT), nalbuphine hydrochloride, levorphanol tartrate (both purchased from Research Biochemical Inc., Natcik, MA), and dezocine hydrochloride (Astra Pharmaceutical Products, Inc., Westborough, MA). Doses for all drugs are expressed in terms of their salts. All drugs were dissolved in distilled water and administered intraperitoneally in an injection volume of 0.5–1.0 mL/kg.
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Results |
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Figure 1 shows the effects of the relatively high-efficacy agonists morphine and levorphanol, the intermediate-efficacy agonists buprenorphine and dezocine, and the low-efficacy agonists butorphanol and nalbuphine in the tail withdrawal procedure using two stimulus intensities (50°C and 52°C water). Morphine, levorphanol, buprenorphine, and dezocine produced dose-dependent increases in percent antinociception with maximal effects obtained in each stimulus intensity. Based on ED50 values, morphine, levorphanol, buprenorphine, and dezocine were approximately 1.9-, 1.3-, 2.4-, and 2.8-fold more potent at the lower intensity stimulus. Butorphanol produced dose-dependent increases in percent antinociceptive effect in the low-temperature water with maximal effects obtained at 56 mg/kg but failed to produce appreciable antinociception in the high-temperature water. In contrast, nalbuphine failed to produce antinociception using either stimulus intensity.
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Figure 2 shows the effects of morphine after pretreatment with various doses of levorphanol (top panels), buprenorphine (center panels), and dezocine (bottom panels) using a low- (left panels) and high- (right panels) stimulus intensity. Data points over "C" represent the effects of these drugs when administered alone (also shown in Figure 1). Administration of these opioids before redetermination of the effects of morphine generally resulted in dose-dependent leftward and/or upward shifts in the morphine dose-effect curve. The extent to which levorphanol and dezocine increase the effects produced by morphine was not different (P > 0.05) from that predicted based on the summation of the effects of each drug (dose) when administered alone; that is, the interaction between these opioids and morphine was effect-additive. Each combination of buprenorphine with morphine resulted in an interaction that was less than effect-additive (P < 0.05); that is, the combination resulted in less antinociception than would have been predicted from the drug effects alone.
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Figure 3 (top panels) shows the effects of combining four doses of butorphanol with morphine using low- (left panel) and high- (right panel) stimulus intensities. Butorphanol alone produced dose-dependent increases in antinociception at the lower temperature (points over "C") and, when combined with morphine, generally produced dose-dependent leftward and upward shifts in the dose-effect curve. As with levorphanol and dezocine, this interaction was not different from that predicted given the effects of the two drugs administered alone (P > 0.05). Using the higher temperature water, butorphanol failed to produce antinociception (points over "C") and produced dose-dependent rightward and downward shifts in the morphine dose-effect curve. The apparent pKB estimate for 0.3 mg/kg butorphanol versus morphine was 5.6.
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Figure 3 also shows the effects of combining 3.0 and 30 mg/kg nalbuphine with morphine (bottom panels) using low- (left panel) and high- (right panel) stimulus intensities. Administered alone, nalbuphine failed to produce antinociception at either temperature (points over "C") and, in combination, produced dose-dependent rightward and downward shifts in the morphine dose-effect curve. Apparent pKB estimates determined for nalbuphine (3.0 mg/kg) versus morphine were 5.2 at both temperatures.
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Discussion |
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The relative intrinsic efficacy of opioids has previously been determined using a number of experimental methods and procedures, including irreversible antagonists (1,9,13–15), tolerance/cross-tolerance regimens (16,17), different training doses in drug discrimination procedures (10–12), and suppression and precipitation of withdrawal effects in opioid-dependent subjects (18). Collectively, these studies indicate an rank order of intrinsic efficacy at the µ-opioid receptor of the drugs used in the present study as: levorphanol
morphine > dezocine buprenorphine > butorphanol > nalbuphine. Each of these drugs has significant affinity for other types of opioid receptors (e.g., 
receptors); however, studies from our laboratory using irreversible and competitive antagonists and cross-tolerance regimens have demonstrated that the antinociceptive effects of these drugs in this procedure are mediated by actions at the µ-opioid receptor (19; unpublished observations). Because of this affinity for multiple receptors and because these drugs differ in intrinsic efficacy, this group of drugs has been called agonists, partial agonists, or agonist/antagonists. As described below, referring to the drug's intrinsic efficacy accounts for these apparently different actions. In the present study, we examined the effects of opioids that differ in their relative intrinsic efficacy at the µ receptor in a rat warm water tail withdrawal procedure using low- and relatively high-stimulus intensities (i.e., water temperatures). When administered alone, morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception at both stimulus intensities, whereas butorphanol produced maximal levels of antinociception at the low-intensity stimulus and failed to produce antinociception at the high-intensity stimulus. The effects of these opioids contrast to those obtained with nalbuphine, which failed to produce antinociception at either stimulus intensity. These findings extend previous studies indicating that the level of antinociception produced by an opioid is determined by both the opioid's intrinsic efficacy and the intensity of the nociceptive stimulus (3–7). The data for butorphanol (antinociception at one temperature, no effect at the other temperature) demonstrate that these stimulus intensities are functionally different, which validates using the phrase "low-intensity and high-intensity stimuli."
By definition, lower efficacy opioids must occupy a larger number of receptors to produce a given effect and thus have a lower receptor reserve. By increasing the stimulus intensity, the number of receptors that must be activated concomitantly increases. This will result in a rightward shift of the dose-effect curve, as occurred with morphine, dezocine, levorphanol, and buprenorphine. Once the number of receptors that must be occupied exceeds the available number of receptors, the opioids can no longer produce a maximal effect in that procedure, which seems to have occurred with butorphanol. Nalbuphine could not activate enough receptors to produce the effect at either stimulus intensity. Based on the magnitude of the potency change across stimulus intensities, coupled with the maximal effect obtained, the rank order of efficacy of the opioids used in the present study was: levorphanol = morphine dezocine = buprenorphine > butorphanol > nalbuphine, which is identical to the rank order among these opioids determined in other assays (see above).
In the present study, we also examined the effects of the low-efficacy opioids nalbuphine and butorphanol in combination with morphine. Although nalbuphine failed to produce antinociception at either stimulus intensity tested, it produced a dose-dependent antagonism of morphine's antinociceptive effects, which was observed at both stimulus intensities. In cases in which parallel rightward shifts were observed, apparent pKB values of 5.2 were found at both water temperatures, which suggests that the same receptor population mediated the effects of nalbuphine in both cases (20). Similarly, butorphanol failed to produce antinociception at the higher stimulus intensity and produced a dose-dependent antagonism of morphine's antinociceptive effects. Such findings extend previous investigations indicating that, under conditions in which butorphanol and nalbuphine fail to produce an antinociceptive effect, these opioids will competitively antagonize the effects of higher efficacy µ-opioids (6,7).
One question not addressed in the studies that evaluated interactions among opioids with varying degrees of intrinsic efficacy is the nature of the interaction under conditions in which the both test opioids produce maximal antinociceptive effects. Specifically, can these interactions be predicted on the basis of the efficacy of the test opioids? We examined this issue in the present study by comparing the interactions between morphine and various opioids that differ in intrinsic efficacy at the µ-opioid receptor but are capable of producing maximal effects under some conditions. All of the opioids tested that produced antinociceptive effects alone also dose-dependently enhanced morphine's effects when administered in combination. With levorphanol, dezocine, and butorphanol at the low-intensity stimulus, the effects of the combination could be predicted based on the summation of the effects produced by the two drugs when administered alone; that is, the interaction between the two opioids was effect-additive. The interaction between the two opioids does not depend on the intrinsic efficacy of the opioid per se, but rather the level of effect produced by that opioid under those conditions. The level of effect produced is influenced by the intrinsic efficacy of the drug, as described above, which suggests an indirect influence of intrinsic efficacy on the degree of enhancement observed when administered in combination.
In contrast to these findings, the interaction between buprenorphine and morphine was generally less than effect-additive. Previous work has shown buprenorphine to have an unusual profile regarding interactions with higher efficacy opioids (21). In particular, buprenorphine produced antinociception in conditions with low-intensity stimuli at some time points and antagonized the effects of higher efficacy opioids at other time points (i.e., agonist and antagonist effects at the same temperature, depending on the pretreatment interval). This unusual interaction may be partially due to buprenorphine's slow rate of dissociation from the receptor (22). The interaction between morphine and buprenorphine observed in the present study also may be partially due to this slow rate of dissociation in which both agonist and antagonist effects of buprenorphine are evident, thereby resulting in a less than effect-additive interaction.
The present findings are in accordance with predictions derived from receptor theory (2) and are similar to the findings obtained with opioids in other assays. For example, several studies have demonstrated that lower efficacy opioids, such as nalbuphine and butorphanol, only partially depress respiration function, as opposed to higher efficacy opioids, which completely suppress respiration (23). In such cases, the combination of a lower and a higher efficacy opioid should result in a partial antagonism of the higher efficacy opioid's effects (24). For this reason, lower efficacy opioids are being combined with higher efficacy opioids in interoperative and postoperative situations (25). The rationale for this combination is that the lower efficacy opioid antagonizes some of the less desirable side effects, such as respiratory depression, pruritus, and nausea, of the higher efficacy opioid (25). For moderate degrees of pain, these lower efficacy opioids produce high levels of antinociception on their own and may be used in combination with a higher efficacy opioid with no danger of attenuating antinociception. In cases of severe pain, however, in which lower efficacy opioids do not produce maximal levels of pain relief, it could be predicted that the combination of one of these lower efficacy opioids with a higher efficacy opioid would result in an attenuation of not only the undesirable side effects, but also the higher efficacy opioid's antinociceptive effects. In the present study, we examined the effects of these opioids on thermal pain; however, it could be predicted that the relationships between agonist and antagonist effects are the same across different types of nociceptive stimuli.
In summary, the level of antinociception produced by an opioid is determined by the intensity of the nociceptive stimulus and the intrinsic efficacy of the opioid. The level of antinociception produced by a particular opioid in a particular situation can be used to predict how that drug will interact with another opioid, such that if antinociception is produced when administered alone, an effective-additive interaction will take place. In contrast, if one of the opioids fail to produce an antinociceptive response when administered alone or has an unusual pharmacokinetic profile (e.g., buprenorphine), then an antagonistic or less than effect-additive interaction will take place.
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Acknowledgments |
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This work was supported by United States Public Service Grant DA10277 from the National Institute on Drug Abuse. DM and MAS were supported by Predoctoral Fellowships DA05669 and DA05173, respectively. CDC was supported by Training Grant DA07244 from the National Institute on Drug Abuse.
The authors thank members of the Behavioral Pharmacology Laboratory for assistance in the experiments and for comments on an earlier version of the manuscript.
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Footnotes |
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This manuscript partially fulfilled the requirements for a Doctor of Philosophy Degree from the University of North Carolina at Chapel Hill for DM.
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References |
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TopAbstractIntroductionMethodResultsDiscussionReferences |
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- Mjanger E, Yaksh TL. Characteristics of dose-dependent antagonism by beta-funaltrexamine of the antinociceptive effects of intrathecal mu agonists. Exp Ther 1991;258:544–50.
- Kenakin TP. Pharmacologic analysis of drug-receptor interaction. 2nd ed. New York:Raven, 1993.
-
O'Callaghan JP, Holtzman SG. Quantification of the analgesic activity of narcotic antagonists by a modified hot-plate procedure. J Pharmacol Exp Ther 1975;192:497–505.
[Abstract/Free Full Text] - Shaw JS, Rourke JD, Burns KM. Differential sensitivity of antinociceptive tests to opioid agonists and partial agonists. Br J Pharmacol 1988;95:578–84.[Web of Science][Medline]
- Saeki S, Yaksh TL. Suppression of nociceptive responses by spinal mu opioid agonists: effects of stimulus intensity and agonist efficacy. Anesth Analg 1993;77:265–74.[Web of Science][Medline]
-
Walker EA, Butelman ER, DeCosta BR, Woods JH. Opioid thermal antinociception in rhesus monkeys: receptor mechanisms and temperature dependency. Pharmacol Exp Ther 1993;267:280–6.
[Abstract/Free Full Text] -
Butelman ER, Winger G, Zernig G, Woods JH. Butorphanol: characterization of agonist and antagonist effects in rhesus monkeys. J Pharmacol Exp Ther 1995;272:845–53.
[Abstract/Free Full Text] - Morgan D, Picker MJ. Contribution of individual differences to discriminative stimulus, antinociceptive and rate-decreasing effects of opioids: importance of the drug's intrinsic efficacy at the mu receptor. Behav Pharmacol 1996;7:261–84.[Web of Science][Medline]
-
Adams JU, Paronis CA, Holtzman SG. Assessment of relative intrinsic activity of mu-opioid analgesics in vivo by using ß-funaltrexamine. J Pharmacol Exp Ther 1990;255:1027–32.
[Abstract/Free Full Text] -
France CP, Woods JH. Discriminative stimulus effects of opioid agonists in morphine-dependent pigeons. J Pharmacol Exp Ther 1990;254:626–32.
[Abstract/Free Full Text] -
Young AM, Masaki MA, Geula C. Discriminative stimulus effects of morphine: effects of training dose on agonist and antagonist effects of mu opioids. J Pharmacol Exp Ther 1992;261:246–57.
[Abstract/Free Full Text] - Picker MJ, Yarbrough J, Hughes CE, et al. Agonist and antagonist effects of mixed action opioids in the pigeon drug discrimination procedure: influence of training dose, intrinsic efficacy and interanimal differences. Ther 1993;266:756–67.
-
Zimmerman DM, Leander JD, Reel JK, Hynes MD. Use of B-funaltrexamine to determine mu opioid receptor involvement in the analgesic activity of various opioids ligands. J Pharmacol Exp Ther 1987;241:374–8.
[Abstract/Free Full Text] - Zernig G, Issaevitch T, Broadbear JH, et al. Receptor reserve and affinity of mu opioid agonists in mouse antinociception: correlation with receptor binding. Life Sci 1995;57:2113–25.[Web of Science][Medline]
- Morgan D, Picker MJ. The µ opioid irreversible antagonist beta-funaltrexamine differentiates the discriminative stimulus effects of opioids with high and low efficacy at the µ opioid receptor. Psychopharmacology 1998;140:20–8.[Medline]
-
Young AM, Kapitsopoulos G, Makhay MM. Tolerance to morphine-like stimulus effects of mu opioid agonists. J Pharmacol Exp Ther 1991;257:795–805.
[Abstract/Free Full Text] -
Paronis CA, Holtzman SG. Development of tolerance to the analgesic activity of mu agonists after continuous infusion of morphine, meperidine or fentanyl in rats. Pharmacol Exp Ther 1992;262:1–9.
[Abstract/Free Full Text] - Woods JH, Gmerek DE. Substitution and primary dependence studies in animals. Depend 1985;14:233–47.
- Tiano MJ, Walker EA, Dykstra LA. Cross-tolerance to etorphine differentiates µ-opioid agonists in a rat tail withdrawal assay. Analgesia 1998;3:251–7.
-
Walker EA, Makhay MM, House JD, Young AM. In vivo apparent pA2 analysis for naltrexone antagonism of discriminative stimulus and analgesic effects of opiate agonists in rats. Pharmacol Exp Ther 1994;271:959–68.
[Abstract/Free Full Text] -
Walker EA, Zernig G, Woods JH. Buprenorphine antagonism of mu opioids in the rhesus monkey tail-withdrawal procedure. J Pharmacol Exp Ther 1995;273:1345–52.
[Abstract/Free Full Text] - Hambrook J, Rance M. The interaction of buprenorphine with the opiate receptor: lipophilicity as a determining factor in drug-receptor kinetics. In: Kosterlitz H, ed. Opiates and endogenous peptides. Amsterdam:North-Holland, 1976:295–301.
-
Gustafsson LL, Schildt B, Jacobsen K. Adverse effects of extradural and intrathecal opiates: report of a nationwide survey in Sweden. Br J Anaesth 1982;54:479–86.
[Abstract/Free Full Text] - Blaise GA, Nugent M, McMichan JC, Durant PAC. Side effects of nalbuphine while reversing opioid-induced respiratory depression: report of four cases. Can J Anaesth 1990;37:794–7.[Web of Science][Medline]
- Parker RK, Holtmann B, White PF. Patient-controlled epidural analgesia: interactions between nalbuphine and hydromorphone. Anesth Analg 1997;84:757–63.[Abstract]
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