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REGIONAL ANESTHESIA AND PAIN MANAGEMENT

An Examination of the Interactions Between the Antinociceptive Effects of Morphine and Various µ-Opioids: The Role of Intrinsic Efficacy and Stimulus Intensity

Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Address correspondence to Drake Morgan, Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Blvd., Winston Salem, NC 27157.

	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.

	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).

	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 pK_B analysis was conducted to estimate the antagonist dose required to produce a twofold shift in the agonist dose-effect curve. The apparent pK_B value was estimated using the following formula: pK_B = -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.

	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.

View larger version (23K): [in this window] [in a new window]   Figure 1. Effects of morphine (average of five groups, n = 8–10), levorphanol (n = 8), buprenorphine (n = 10), dezocine (n = 8), butorphanol (n = 10), and nalbuphine (n = 8) on percent antinociceptive effect as assessed in a rat warm water tail withdrawal procedure using 50°C and 52°C water. Percent antinociceptive effect is plotted as a function of drug dose. Vertical bars represent the standard errors; when not indicated, the standard error fell within the data point.

View larger version (31K): [in this window] [in a new window]   Figure 2. Effects of morphine in combination with various doses of levorphanol (n = 8), buprenorphine (n = 10), and dezocine (n = 8) on percent antinociceptive effect as assessed in a rat warm water tail withdrawal procedure using 50°C and 52°C water. Data points over "C" represent the effects of the opioid when administered alone. Percent antinociceptive effect is plotted as a function of drug dose. Vertical bars represent the standard errors; when not indicated, the standard error fell within the data point.

View larger version (31K): [in this window] [in a new window]   Figure 3. Effects of morphine in combination with various doses of butorphanol (n = 10) and nalbuphine (n = 8) on percent antinociceptive effect as assessed in a rat warm water tail withdrawal procedure using 50°C and 52°C water. Data points over "C" represent the effects of the opioid when administered alone. Percent antinociceptive effect is plotted as a function of drug dose. Vertical bars represent the standard errors; when not indicated, the standard error fell within the data point.

	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 pK_B 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.

	Acknowledgments

 
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.

	Footnotes

 
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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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (32) Citing Articles via Google Scholar Google Scholar Articles by Morgan, D. Articles by Picker, M. J. Search for Related Content PubMed PubMed Citation Articles by Morgan, D. Articles by Picker, M. J.

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999