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Psychostimulant Drugs Potentiate Morphine Analgesia in the Formalin Test
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Journal of Pain and Symptom Management
Vol. 16 No. 4 October 1998
Original Article
Psychostimulant Drugs Potentiate Morphine Analgesia in the Formalin Test Suntanu Dalal, MSc, and Ronald Melzack, PhD Department of Psychology, McGill University, Montreal, Quebec, Canada H3A 1B1
Abstract Recent research has shown that the psychostimulant drug dextroamphetamine can increase the analgesia produced by opioids. Despite the strong, positive results in human clinical subjects and in animals, this combination is rarely used in clinical practice. The purpose of this paper is to investigate whether the psychostimulant drug methylphenidate (MP) can potentiate morphine analgesia in the rat formalin test, and to compare its effectiveness to that of dextroamphetamine (AMP). The formalin test was used because its long-lasting pain of moderate intensity resembles human clinical pain. Two different drug administration times were used to observe whether the early phase of the formalin response would be differentially affected by the drugs. At Drug Administration Time 1, rats received morphine 30 min prior to the formalin injection (⫺30 min) and MP or AMP 20 min prior to the formalin injection (⫺20 min). At Drug Administration Time 2, rats received morphine 10 min prior to the formalin injection (⫺10 min) and MP or AMP immediately prior to the formalin injection (0 min). All drugs were given subcutaneously. The results indicate that low doses of MP or AMP potentiate the analgesic effects of morphine. The clinical value of these drug combinations merits further investigation in animals and in humans. J Pain Symptom Manage 1998; 16:230–239 © U.S. Cancer Pain Relief Committee, 1998. Key Words Amphetamine, co-analgesia, combination analgesics, methylphenidate, opioids, psychostimulant drugs
Introduction There has been increasing research in recent years on drug combinations that produce analgesia in experimental animals and may be useful in clinical populations. The general purpose of the combinations is twofold: (1) to enhance analgesia by either synergism or additive effects, and (2) to reduce the side effects of the drugs by either reducing the dose of each drug
Address reprint requests to: Ronald Melzack, PhD, Department of Psychology, McGill University, 1205 Dr. Penfield Avenue, Montreal, Quebec, Canada H3A 1B1. Accepted for publication: February 4, 1998. © U.S. Cancer Pain Relief Committee, 1998 Published by Elsevier, New York, New York
or allowing the drugs to interact, so that one drug reduces the side effects of the other.1 A combination of opioids and psychostimulant drugs, such as amphetamine, has been investigated since the early 1940s. Although a review of the literature2 reveals favorable basic3–8 and clinical9–14 studies of this combination, these results have had little impact on clinical practice or pharmacological research.2 Recently, Bruera and his colleagues have advocated the use of psychostimulant drugs to counteract the sedative effects of chronic opioid administration in some cancer patients.12–14 The purpose of this study is to determine whether low doses of methylphenidate hydro0885-3924/98/$19.00 PII S0885-3924(98)00085-2
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chloride (Ritalin®) can potentiate morphine sulfate analgesia in the rat formalin test.15 Methylphenidate was studied, and was compared to dextroamphetamine sulfate (Dexedrine®), because it is currently being used in clinical studies and no animal studies have been conducted with it in the context of pain and analgesia. Physicians may also perceive methylphenidate (MP) to be more acceptable than dextroamphetamine (AMP), which is generally believed to be addictive. MP is widely used in children to manage attention deficit hyperactivity disorder (ADHD).16 MP and other psychostimulants are also used to treat narcolepsy and depression in the elderly,17 the extremely ill,18,19 or people who have not responded to the standard antidepressants.20 Importantly, patients treated for ADHD or depression with psychostimulant drugs rarely become tolerant to them19,21 and very few patients develop psychological dependence or become addicted. These phenomena also have been emphasized when opiods are used for pain management.22–24 The formalin test was chosen for the present study because it resembles clinically relevant pain in humans. The stimulus—subcutaneous formalin—is moderately intense and is inescapable so that the rat must actively cope with the pain for about 1 hour. Because the pain lasts for a relatively long time, it is possible to follow the time course of a drug manipulation. Furthermore, AMP has been shown to potentiate the effects of morphine in the formalin pain test.8
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The Formalin Test The formalin test consists of the injection of 50 l of 2.5% formalin (buffered formaldehyde in sterile saline) into a hind paw followed by the scoring of pain behavior with a four-point scale: 3—licking, biting, and/or vigorously shaking the injected paw; 2—injected paw elevated, no weight on the paw; 1—injected paw favored but still in contact with the ground, some weight on the paw; 0—no favoring of the paw, equal distribution of weight on both hind paws. Time spent in each of the categories was recorded throughout the test. The mean score for each 5-min interval is determined using a weighted means formula,15 and statistical analysis and graphing were carried out on the mean scores of these 5-min intervals. The ordinal nature of the categories has been validated by our laboratory.25 In the following analyses, 0 min is the time at which formalin is injected into the hind paw. The behavior of the rats was scored for the first 5 min following formalin injection (t ⫽ 0 min to t ⫽ ⫹5 min) and for the period from 20 to 50 min after the formalin injection (t ⫽ ⫹20 min to t ⫽ ⫹50 min). The reason for this time course was to permit observations during the peaks of the two phases of formalin pain. The “early” phase (0–5 min) seems to be a nociceptor-mediated pain in direct response to the noxious formalin stimulus; the “late” phase (20–50 min) appears to be due in part to inflammation and to changes which have occurred in the central nervous system.26 Between the two peaks, at 5–20 min, virtually no pain behavior is displayed.
Drugs
Methods Subjects The subjects were 300–450 g male LongEvans rats (Charles River, Canada). The rats were habituated to the testing apparatus and room for at least 1 hour on each of the 2 days prior to testing. On the test day, the rats were placed in the apparatus for a minimum of 30 min before any drugs were administered.
Apparatus
The formalin test apparatus was a 32 ⫻ 32 ⫻ 32 cm clear Plexiglas compartment. The floor had drill-holes to allow drainage. A mirror was placed below the floor at 45⬚ to allow easy observation of the paws during the course of testing.
The drugs used in the two experiments were: (1) morphine sulfate, (2) methylphenidate hydrochloride, and (3) dextroamphetamine sulfate. Morphine is widely considered to be the prototypical opioid, the standard against which the analgesic efficacy of all the other opioids is compared. AMP is the prototypical amphetamine, although its analgesic abilities are not well documented. The dextro- enantiomer is considered to be more active than the levo- or racemic formulations. The drugs and the doses that were used were based on the results of similar studies which used the formalin test. 27,28
Statistical Analyses Nonparametric statistical methods were used to analyze the data because it was difficult to as-
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sume a normal distribution with the size of groups used in the experiments (n ⫽ 5 or 6). The Mann-Whitney U test was used to compare the experimental groups to the saline control group at each dose of morphine.
Drug Administration Morphine sulfate (1.0 mg/kg, 2.5 mg/kg), MP (2.5 mg/kg, 5 mg/kg), or AMP (0.5 mg/ kg, 1.0 mg/kg) were each dissolved in 1.0 ml of sterile physiological saline. For each drug injection, an equal volume of saline served as the control. All drug injections were subcutaneous into the nape of the neck. At Drug Administration Time 1, rats received morphine 30 min prior to the formalin injection (⫺30 min) and MP or AMP 20 min prior to the formalin injec-
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tion (⫺20 min). At Drug Administration Time 2, rats received morphine 10 min prior to the formalin injection (⫺10 min) and MP or AMP immediately prior to the formalin injection (0 min). One of the reasons for two different drug administration times was to observe whether the early phase would be differentially affected by the drugs.
Results Experiment 1: Morphine and Methylphenidate The results show that both psychostimulant drugs potentiate morphine analgesia in the formalin test. The results of Experiment 1 are represented in Figures 1 and 2. Figure 1 shows
Fig. 1. Experiment 1, Drug Administration Time 1. Time course of mean formalin pain ratings for rats given morphine at ⫺30 min and methylphenidate at ⫺20 min: (A) is the “saline control for morphine injection,” in (B) morphine is held constant at 1.0 mg/kg, and in (C) morphine is held constant at 2.5 mg/kg. (D) summarizes the late-phase data from Figures 1A–C by averaging each group over 30 min for the period t ⫽ ⫹20 min to t ⫽ ⫹50 min. The vertical lines of the graphs represent the standard errors of the mean. Significant Mann-Whitney U’s, one-tailed, are indicated by * (P ⬍ 0.05) and ** (P ⬍ 0.01).
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the data for Drug Administration Time 1 (morphine administered at ⫺30 min and MP administered at ⫺20 min) and Figure 2 shows the data for Drug Administration Time 2 (morphine administered at ⫺10 min and MP administered at 0 min). Drug Administration Time 1. In the absence of morphine (saline controls for the morphine injection), there was a trend toward decreasing pain with increasing doses of MP, but only 2.5 mg/kg of MP caused a significant reduction in pain over saline (Fig. 1D). Figure 1D shows that when morphine was administered, there was a trend toward a decrease in pain with increasing doses of morphine, and that both doses of MP potentiated morphine to the same degree for a given dose of morphine. Signifi-
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cant differences from saline were found for both doses of MP given with either dose of morphine. From the time-course data represented in Figure 1B, it appears that the effects of MP on 1.0 mg/kg of morphine would diminish by the end of the formalin test; that is, the experimental conditions would come back up to the control condition even though the overall effects for the late phase may have been significant (see Fig. 1D). MP appeared to have reasonably constant effects on 2.5 mg/kg of morphine (Fig. 1C) because the experimental conditions did not come back up to the control level by the end of the test. Figures 1A–C show that the drug combinations could have an effect on the first 5-min interval following the formalin injection. Figure
Fig. 2. Experiment 1, Drug Administration Time 2. Time course of mean formalin pain ratings for rats given morphine at -10 min and methylphenidate at 0 min: (A) is the “saline control for morphine injection,” in (B) morphine is held constant at 1.0 mg/kg, and in (C) morphine is held constant at 2.5 mg/kg. (D) summarizes the late-phase data from Figures 2A–C by averaging each group over 30 min for the period t ⫽ ⫹20 min to t ⫽ ⫹50 min. The vertical lines on the graphs represent the standard errors of the mean. Significant Mann-Whitney U’s, one-tailed, are indicated by * (P ⬍ 0.05) and ** (P ⬍ 0.01).
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1A shows that both doses of MP in the “saline control for morphine injection” condition had significant, though small, effects compared to saline on the early phase. Figure 1B shows that pain was significantly lower than saline in the early phase for rats receiving either dose of MP in conjunction with 1.0 mg/kg of morphine. Figure 1C shows that only the high dose of MP (5.0 mg/kg) combined with 2.5 mg/kg of morphine significantly reduced pain in the early phase compared to saline. Drug Administration Time 2. Figure 2D shows that 5.0 mg/kg of MP caused a significant reduction of pain over saline in the “saline controls for the morphine injection” condition. Both doses of MP decreased pain when given with 1.0 mg/kg of morphine. Only 5.0 mg/kg of MP caused a significant decrease in pain over saline when given with 2.5 mg/kg of morphine. The time-course data represented in Figures 2B and 2C show that the analgesic effects of both doses of MP combined with either dose of morphine remained relatively constant for the duration of the formalin test. This result was expected. The analgesic effects in the late phase are probably constant because MP was administered just prior to the formalin injection. Even though 5.0 mg/kg of MP had an overall effect on its own in the “saline control for morphine injection” condition (see Fig. 2D), time-course data shows that the effect was absent by the end of the formalin test (Fig. 2A). In general, MP was not expected to have an effect on the early phase during Drug Administration Time 2 because MP was given immediately prior to the formalin injection. But Fig. 2A shows that 5.0 mg/kg of MP had a small but significant effect compared to saline on the early phase in the “saline control for morphine injection” condition. Figure 2B shows that 5.0 mg/kg of MP given in conjunction with 1.0 mg/kg of morphine significantly affected pain in the early phase, though the effect was small. Figure 2C shows that 2.5 mg/kg of MP given with 2.5 mg/kg of morphine affected pain in the early phase, but that the higher dose of MP (5.0 mg/kg) did not have a significant effect.
Experiment 2: Morphine and Dextroamphetamine Figure 3 shows the data for Drug Administration Time 1 (morphine administered at ⫺30
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min and AMP administered at ⫺20 min) and Figure 4 shows the data for Drug Administration Time 2 (morphine administered at ⫺10 min and AMP administered at 0 min). Drug Administration Time 1. Figure 3D shows that the “saline controls for the morphine injection” were not different from one another. In other words, AMP on its own had no analgesic effects. It also shows that when morphine was administered, there was a trend toward a decrease in pain scores with increasing doses of concomitant AMP. Significant differences from saline were found for both doses of AMP given with 1.0 mg/kg of morphine. Only the highest dose of AMP (1.0 mg/kg) administered with 2.5 mg/kg of morphine was significantly different from the saline control. Figures 3A–C show that the effects of the drugs were diminished by the end of the formalin test; that is, the scores of the experimental groups returned to the level of the control group even though the overall effects (as summarized in Fig. 3D) for the late phase may have been significant in some conditions. This return to control levels is probably due to the fact that the drugs were administered far in advance of the formalin injection. Figures 3A–C reveal that the drug combinations could have an effect on the first 5-min interval (the “early phase”) following the formalin injection. Figure 3A shows that both doses of AMP in the “saline control for morphine injection” condition had significant effects on the early phase. Figure 3B shows that pain was significantly lower in the early phase for rats receiving either dose of AMP in conjunction with 1.0 mg/kg of morphine. Figure 3C shows that the two AMP conditions are different from the control when given in conjunction with 2.5 mg/kg of morphine. Drug Administration Time 2. Figure 4D shows that the “saline controls for the morphine injection” were not different from one another, so AMP had no analgesic effects on its own. It also shows that when morphine was administered, there was a trend toward a decrease in pain scores with increasing doses of AMP. Significant differences from saline were found for both doses of AMP given with 1.0 mg/kg of morphine. AMP administered with 2.5 mg/kg of morphine was significantly different from
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the saline group only when the highest dose of AMP (1.0 mg/kg), but not 0.5 mg/kg of AMP, was administered. From the time-course data represented in Figures 4A–C, it appears that the potentiating effects of 0.5 mg/kg of AMP combined with morphine tended to diminish by the end of the formalin test, whereas the potentiating effects of 1.0 mg/kg of AMP combined with morphine seemed to remain relatively constant for the duration of the formalin test. The higher dose of AMP probably maintained its effect because it was administered just before the formalin injection. In general, AMP was not expected to have an effect on the early phase during Drug Administration Time 2 because AMP was given immedi-
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ately prior to the formalin injection. However, the results were more complex. Figure 4A shows that neither dose of AMP in the “saline control for morphine injection” condition had significant effects on the early phase. Figure 4B shows that pain was significantly lower than saline in the early phase for either dose of AMP in conjunction with 1.0 mg/kg of morphine. Figure 4C shows that only 1.0 mg/kg AMP given with 2.5 mg/kg of morphine significantly affected pain in the early phase.
Discussion The experiments show that MP and AMP, at appropriate doses, potentiate morphine analgesia in the formalin test. These experiments
Fig. 3. Experiment 2, Drug Administration Time 1. Time course of mean formalin pain ratings for rats given morphine at ⫺30 min and d-amphetamine at ⫺20 min: (A) is the “saline control for morphine injection,” in (B) morphine is held constant at 1.0 mg/kg, and in (C) morphine is held constant at 2.5 mg/kg. (D) summarizes the late-phase data from Figures 3A–C by averaging each group over 30 min for the period t ⫽ ⫹20 min to t ⫽ ⫹50 min. The vertical lines on the graphs represent the standard errors of the mean. Significant Mann-Whitney U’s, one-tailed, are indicated by * (P ⬍ 0.05) and ** (P ⬍ 0.01).
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investigated relatively low doses of the drugs, which caused little analgesia on their own, but when combined caused profound analgesia in the rat. These studies do not attempt to answer how or why psychostimulants can potentiate morphine analgesia, or whether the potentiation is additive or synergistic. Other studies have attempted to determine the mechanisms involved.27,28 Review papers on the standard uses of the psychostimulant drugs in humans indicate that both MP and AMP given orally are rapidly absorbed into the blood, easily cross the blood– brain barrier, and have quick clinical effects. The peak behavioral effects of MP and AMP usually occur within 1–2 hours of ingestion and decline within 3–5 hours.16
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MP produced less consistent results than did AMP. The doses of MP used in Experiment 1 (2.5 and 5.0 mg/kg) produced some analgesia on their own, in some instances, when compared to the saline control. When MP was combined with morphine, significantly greater analgesia was produced compared to the morphine-only conditions. Because the doses of MP used in this experiment could produce some analgesia on their own, it seems more likely that the MP may have an additive effect on morphine, but this cannot be stated conclusively due to the design of the study. There were substantial individual differences between animals within groups, which helps explain the large standard errors of the mean present in the results. In addition, the small
Fig. 4. Experiment 2, Drug Administration Time 2. Time course of mean formalin pain ratings for rats given morphine at ⫺10 min and d-amphetamine at 0 min: (A) is the “saline control for morphine injection,” in (B) morphine is held constant at 1.0 mg/kg, and in (C) morphine is held constant at 2.5 mg/kg. (D) summarizes the late phase data from Figures 4A–C by averaging each group over 30 min for the period t ⫽ ⫹20 min to t ⫽ ⫹50 min. The vertical lines of the graphs represent the standard errors of the mean. Significant Mann-Whitney U’s, onetailed, are indicated by * (P ⬍ 0.05) and ** (P ⬍ 0.01).
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Table 1 Summary of Early Phase Statistical Analysis Experiment
Figure
Morphine (mg/kg)
Stimulant (mg/kg) vs. saline
Mann-Whitney U value
P one-tail
Expt. 1 Drug Admin. Time 1
1A
Saline Cont
1B
1.0
1C
2.5
2A
Saline Cont
2B
1.0
2C
2.5
3A
Saline Cont
3B
1.0
3C
2.5
4A
Saline Cont
4B
1.0
4C
2.5
AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0
27.0 34.0 34.0 36.0 26.0 25.0 19.0 13.5 29.0 24.0 22.0 30.0 30.0 26.0 30.0 29.0 17.0 30.0 13.0 27.0 20.0 24.0 23.0 19.0
0.015 0.004 0.004 0.001 0.026 0.041 0.268 0.669 0.004 0.008 0.123 0.002 0.002 0.026 0.002 0.004 0.396 0.002 0.669 0.015 0.075 0.008 0.016 0.111
Expt. 1 Drug Admin Time 2
Expt. 2 Drug Admin Time 1
Expt. 2 Drug Admin Time 2
group sizes could have contributed to the variability. For almost any given combination, other than controls, there were extreme values such as at least one animal showing complete analgesia and at least one animal showing no analgesia. Experiment 1 demonstrates, in the first study with animals, that MP potentiates opioid analgesia, and Experiment 2 confirms Morgan’s observation that AMP potentiates opioid analgesia.8 The temporal pattern of the formalin test reveals some of the properties of the potentiation. It appears that administering morphine and a psychostimulant far in advance of the formalin injection (Drug Administration Time 1) can lead to substantial analgesia in the “early” phase as seen in Table 1. This result could be expected because the drugs would be at their peak blood levels in the rat. But even when the drugs are administered relatively close to the time of the formalin injection (Drug Administration Time 2), the psychostimulants can sometimes potentiate morphine analgesia, though the effect does not seem as great or as consistent as at Drug Administration Time 1. This result suggests that psychostimulant drugs exert their potentiating effects rather quickly. The results of the “late” phase data are evi-
dent in Figures 1D, 2D, 3D, and 4D and shown in Table 2. The greatest amount of analgesia is produced by a combination of morphine and the highest dose of psychostimulant used in these experiments (MP 5.0 mg/kg and AMP 1.0 mg/kg). This result was expected. The lower doses of psychostimulants (MP 2.5 mg/ kg and AMP 0.5 mg/kg) produced less consistent results, but generally, there still seems to be some analgesia. It is important to note that the doses used in these experiments were generally lower than those used in most other studies.3–8 Therefore, the analgesic effects of these drugs are bound to be less consistent than effects obtained in some of the other studies. In addition, the formalin test examines “tonic” pain that lasts longer than the “phasic” pain evoked by threshold-level tests. Moreover, it examines four behaviors as opposed to one reflexive behavior, and may, therefore, accentuate the individual differences in the responses of the animals to a particular drug treatment. The most consistent results were found in Experiment 2 with AMP. The doses of AMP used in the experiment (0.5 and 1.0 mg/kg) did not produce any analgesia on their own compared to the saline control. Yet when they were added to morphine (1.0 and 2.5 mg/kg),
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Table 2 Summary of Mean Late Phase Statistical Analysis Experiment
Figure
Morphine (mg/kg)
Stimulant (mg/kg) vs. saline
Mann-Whitney U value
P one-tail
Expt. 1 Drug Admin. Time 1
1D
Saline Cont
AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0
22.5 28.5 32.0 36.0 15.0 27.0 14.0 20.0 26.0 25.0 19.0 28.0 25.0 20.5 27.0 30.0 27.0 27.0 14.0 25.0 22.0 21.0 18.0 24.0
0.123 0.066 0.013 0.001 0.535 0.015 0.604 0.214 0.026 0.004 0.268 0.009 0.041 0.214 0.015 0.002 0.015 0.015 0.604 0.041 0.028 0.048 0.155 0.008
1.0 2.5
Expt. 1 Drug Admin Time 2
2D
Saline Cont 1.0 2.5
Expt. 2 Drug Admin Time 1
3D
Saline Cont 1.0 2.5
Expt. 2 Drug Admin Time 2
4D
Saline Cont 1.0 2.5
there was generally a difference between the AMP ⫹ morphine conditions and the morphine-only conditions. In other words, subanalgesic doses of AMP potentiated morphine analgesia. This result seems to indicate the possibility of a synergistic effect of AMP on morphine analgesia, but this cannot be stated conclusively due to the dose limitations of the study. Further studies of opioid plus psychostimulant combinations need to be conducted with animal models of chronic pain, such as the autotomy or experimental neuropathy tests. It is also important to study the side effects of these combinations. The only animal study that investigated the toxicity associated with the combination only dealt with acute toxicity and used the LD50 (lethal dose of a substance for 50% of a group of animals) as the dependent variable.6 The LD50 is an extremely radical measure of toxicity, because death is the endpoint of the test and it usually uses doses which are much higher than those used in a clinical situation. In addition, toxicity measured by the LD50 can only be determined in animal studies. It is possible that toxicity may occur during chronic administration of the psychostimulant drugs which would not arise with acute administration. However, a long-term study with can-
cer patients did not indicate any problems with chronic use. Bruera et al.12 noted that adverse effects of chronic MP and opioid administration in patients—e.g., hallucinations and paranoid aggressive reactions—were rare (4% of patients) and usually manifest themselves very early in treatment. These side effects resolved after discontinuation of the drug and there were no subsequent problems. To summarize, low doses of the psychostimulants MP or AMP potentiate low doses of morphine in the formalin test. These results support the small body of animal and human studies that have investigated these drug combinations, and indicate the need for futher studies of these drug combinations in animal models of chronic pain and patients with chronic pain.
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Journal of Pain and Symptom Management
Vol. 16 No. 4 October 1998
Original Article
Psychostimulant Drugs Potentiate Morphine Analgesia in the Formalin Test Suntanu Dalal, MSc, and Ronald Melzack, PhD Department of Psychology, McGill University, Montreal, Quebec, Canada H3A 1B1
Abstract Recent research has shown that the psychostimulant drug dextroamphetamine can increase the analgesia produced by opioids. Despite the strong, positive results in human clinical subjects and in animals, this combination is rarely used in clinical practice. The purpose of this paper is to investigate whether the psychostimulant drug methylphenidate (MP) can potentiate morphine analgesia in the rat formalin test, and to compare its effectiveness to that of dextroamphetamine (AMP). The formalin test was used because its long-lasting pain of moderate intensity resembles human clinical pain. Two different drug administration times were used to observe whether the early phase of the formalin response would be differentially affected by the drugs. At Drug Administration Time 1, rats received morphine 30 min prior to the formalin injection (⫺30 min) and MP or AMP 20 min prior to the formalin injection (⫺20 min). At Drug Administration Time 2, rats received morphine 10 min prior to the formalin injection (⫺10 min) and MP or AMP immediately prior to the formalin injection (0 min). All drugs were given subcutaneously. The results indicate that low doses of MP or AMP potentiate the analgesic effects of morphine. The clinical value of these drug combinations merits further investigation in animals and in humans. J Pain Symptom Manage 1998; 16:230–239 © U.S. Cancer Pain Relief Committee, 1998. Key Words Amphetamine, co-analgesia, combination analgesics, methylphenidate, opioids, psychostimulant drugs
Introduction There has been increasing research in recent years on drug combinations that produce analgesia in experimental animals and may be useful in clinical populations. The general purpose of the combinations is twofold: (1) to enhance analgesia by either synergism or additive effects, and (2) to reduce the side effects of the drugs by either reducing the dose of each drug
Address reprint requests to: Ronald Melzack, PhD, Department of Psychology, McGill University, 1205 Dr. Penfield Avenue, Montreal, Quebec, Canada H3A 1B1. Accepted for publication: February 4, 1998. © U.S. Cancer Pain Relief Committee, 1998 Published by Elsevier, New York, New York
or allowing the drugs to interact, so that one drug reduces the side effects of the other.1 A combination of opioids and psychostimulant drugs, such as amphetamine, has been investigated since the early 1940s. Although a review of the literature2 reveals favorable basic3–8 and clinical9–14 studies of this combination, these results have had little impact on clinical practice or pharmacological research.2 Recently, Bruera and his colleagues have advocated the use of psychostimulant drugs to counteract the sedative effects of chronic opioid administration in some cancer patients.12–14 The purpose of this study is to determine whether low doses of methylphenidate hydro0885-3924/98/$19.00 PII S0885-3924(98)00085-2
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chloride (Ritalin®) can potentiate morphine sulfate analgesia in the rat formalin test.15 Methylphenidate was studied, and was compared to dextroamphetamine sulfate (Dexedrine®), because it is currently being used in clinical studies and no animal studies have been conducted with it in the context of pain and analgesia. Physicians may also perceive methylphenidate (MP) to be more acceptable than dextroamphetamine (AMP), which is generally believed to be addictive. MP is widely used in children to manage attention deficit hyperactivity disorder (ADHD).16 MP and other psychostimulants are also used to treat narcolepsy and depression in the elderly,17 the extremely ill,18,19 or people who have not responded to the standard antidepressants.20 Importantly, patients treated for ADHD or depression with psychostimulant drugs rarely become tolerant to them19,21 and very few patients develop psychological dependence or become addicted. These phenomena also have been emphasized when opiods are used for pain management.22–24 The formalin test was chosen for the present study because it resembles clinically relevant pain in humans. The stimulus—subcutaneous formalin—is moderately intense and is inescapable so that the rat must actively cope with the pain for about 1 hour. Because the pain lasts for a relatively long time, it is possible to follow the time course of a drug manipulation. Furthermore, AMP has been shown to potentiate the effects of morphine in the formalin pain test.8
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The Formalin Test The formalin test consists of the injection of 50 l of 2.5% formalin (buffered formaldehyde in sterile saline) into a hind paw followed by the scoring of pain behavior with a four-point scale: 3—licking, biting, and/or vigorously shaking the injected paw; 2—injected paw elevated, no weight on the paw; 1—injected paw favored but still in contact with the ground, some weight on the paw; 0—no favoring of the paw, equal distribution of weight on both hind paws. Time spent in each of the categories was recorded throughout the test. The mean score for each 5-min interval is determined using a weighted means formula,15 and statistical analysis and graphing were carried out on the mean scores of these 5-min intervals. The ordinal nature of the categories has been validated by our laboratory.25 In the following analyses, 0 min is the time at which formalin is injected into the hind paw. The behavior of the rats was scored for the first 5 min following formalin injection (t ⫽ 0 min to t ⫽ ⫹5 min) and for the period from 20 to 50 min after the formalin injection (t ⫽ ⫹20 min to t ⫽ ⫹50 min). The reason for this time course was to permit observations during the peaks of the two phases of formalin pain. The “early” phase (0–5 min) seems to be a nociceptor-mediated pain in direct response to the noxious formalin stimulus; the “late” phase (20–50 min) appears to be due in part to inflammation and to changes which have occurred in the central nervous system.26 Between the two peaks, at 5–20 min, virtually no pain behavior is displayed.
Drugs
Methods Subjects The subjects were 300–450 g male LongEvans rats (Charles River, Canada). The rats were habituated to the testing apparatus and room for at least 1 hour on each of the 2 days prior to testing. On the test day, the rats were placed in the apparatus for a minimum of 30 min before any drugs were administered.
Apparatus
The formalin test apparatus was a 32 ⫻ 32 ⫻ 32 cm clear Plexiglas compartment. The floor had drill-holes to allow drainage. A mirror was placed below the floor at 45⬚ to allow easy observation of the paws during the course of testing.
The drugs used in the two experiments were: (1) morphine sulfate, (2) methylphenidate hydrochloride, and (3) dextroamphetamine sulfate. Morphine is widely considered to be the prototypical opioid, the standard against which the analgesic efficacy of all the other opioids is compared. AMP is the prototypical amphetamine, although its analgesic abilities are not well documented. The dextro- enantiomer is considered to be more active than the levo- or racemic formulations. The drugs and the doses that were used were based on the results of similar studies which used the formalin test. 27,28
Statistical Analyses Nonparametric statistical methods were used to analyze the data because it was difficult to as-
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sume a normal distribution with the size of groups used in the experiments (n ⫽ 5 or 6). The Mann-Whitney U test was used to compare the experimental groups to the saline control group at each dose of morphine.
Drug Administration Morphine sulfate (1.0 mg/kg, 2.5 mg/kg), MP (2.5 mg/kg, 5 mg/kg), or AMP (0.5 mg/ kg, 1.0 mg/kg) were each dissolved in 1.0 ml of sterile physiological saline. For each drug injection, an equal volume of saline served as the control. All drug injections were subcutaneous into the nape of the neck. At Drug Administration Time 1, rats received morphine 30 min prior to the formalin injection (⫺30 min) and MP or AMP 20 min prior to the formalin injec-
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tion (⫺20 min). At Drug Administration Time 2, rats received morphine 10 min prior to the formalin injection (⫺10 min) and MP or AMP immediately prior to the formalin injection (0 min). One of the reasons for two different drug administration times was to observe whether the early phase would be differentially affected by the drugs.
Results Experiment 1: Morphine and Methylphenidate The results show that both psychostimulant drugs potentiate morphine analgesia in the formalin test. The results of Experiment 1 are represented in Figures 1 and 2. Figure 1 shows
Fig. 1. Experiment 1, Drug Administration Time 1. Time course of mean formalin pain ratings for rats given morphine at ⫺30 min and methylphenidate at ⫺20 min: (A) is the “saline control for morphine injection,” in (B) morphine is held constant at 1.0 mg/kg, and in (C) morphine is held constant at 2.5 mg/kg. (D) summarizes the late-phase data from Figures 1A–C by averaging each group over 30 min for the period t ⫽ ⫹20 min to t ⫽ ⫹50 min. The vertical lines of the graphs represent the standard errors of the mean. Significant Mann-Whitney U’s, one-tailed, are indicated by * (P ⬍ 0.05) and ** (P ⬍ 0.01).
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the data for Drug Administration Time 1 (morphine administered at ⫺30 min and MP administered at ⫺20 min) and Figure 2 shows the data for Drug Administration Time 2 (morphine administered at ⫺10 min and MP administered at 0 min). Drug Administration Time 1. In the absence of morphine (saline controls for the morphine injection), there was a trend toward decreasing pain with increasing doses of MP, but only 2.5 mg/kg of MP caused a significant reduction in pain over saline (Fig. 1D). Figure 1D shows that when morphine was administered, there was a trend toward a decrease in pain with increasing doses of morphine, and that both doses of MP potentiated morphine to the same degree for a given dose of morphine. Signifi-
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cant differences from saline were found for both doses of MP given with either dose of morphine. From the time-course data represented in Figure 1B, it appears that the effects of MP on 1.0 mg/kg of morphine would diminish by the end of the formalin test; that is, the experimental conditions would come back up to the control condition even though the overall effects for the late phase may have been significant (see Fig. 1D). MP appeared to have reasonably constant effects on 2.5 mg/kg of morphine (Fig. 1C) because the experimental conditions did not come back up to the control level by the end of the test. Figures 1A–C show that the drug combinations could have an effect on the first 5-min interval following the formalin injection. Figure
Fig. 2. Experiment 1, Drug Administration Time 2. Time course of mean formalin pain ratings for rats given morphine at -10 min and methylphenidate at 0 min: (A) is the “saline control for morphine injection,” in (B) morphine is held constant at 1.0 mg/kg, and in (C) morphine is held constant at 2.5 mg/kg. (D) summarizes the late-phase data from Figures 2A–C by averaging each group over 30 min for the period t ⫽ ⫹20 min to t ⫽ ⫹50 min. The vertical lines on the graphs represent the standard errors of the mean. Significant Mann-Whitney U’s, one-tailed, are indicated by * (P ⬍ 0.05) and ** (P ⬍ 0.01).
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1A shows that both doses of MP in the “saline control for morphine injection” condition had significant, though small, effects compared to saline on the early phase. Figure 1B shows that pain was significantly lower than saline in the early phase for rats receiving either dose of MP in conjunction with 1.0 mg/kg of morphine. Figure 1C shows that only the high dose of MP (5.0 mg/kg) combined with 2.5 mg/kg of morphine significantly reduced pain in the early phase compared to saline. Drug Administration Time 2. Figure 2D shows that 5.0 mg/kg of MP caused a significant reduction of pain over saline in the “saline controls for the morphine injection” condition. Both doses of MP decreased pain when given with 1.0 mg/kg of morphine. Only 5.0 mg/kg of MP caused a significant decrease in pain over saline when given with 2.5 mg/kg of morphine. The time-course data represented in Figures 2B and 2C show that the analgesic effects of both doses of MP combined with either dose of morphine remained relatively constant for the duration of the formalin test. This result was expected. The analgesic effects in the late phase are probably constant because MP was administered just prior to the formalin injection. Even though 5.0 mg/kg of MP had an overall effect on its own in the “saline control for morphine injection” condition (see Fig. 2D), time-course data shows that the effect was absent by the end of the formalin test (Fig. 2A). In general, MP was not expected to have an effect on the early phase during Drug Administration Time 2 because MP was given immediately prior to the formalin injection. But Fig. 2A shows that 5.0 mg/kg of MP had a small but significant effect compared to saline on the early phase in the “saline control for morphine injection” condition. Figure 2B shows that 5.0 mg/kg of MP given in conjunction with 1.0 mg/kg of morphine significantly affected pain in the early phase, though the effect was small. Figure 2C shows that 2.5 mg/kg of MP given with 2.5 mg/kg of morphine affected pain in the early phase, but that the higher dose of MP (5.0 mg/kg) did not have a significant effect.
Experiment 2: Morphine and Dextroamphetamine Figure 3 shows the data for Drug Administration Time 1 (morphine administered at ⫺30
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min and AMP administered at ⫺20 min) and Figure 4 shows the data for Drug Administration Time 2 (morphine administered at ⫺10 min and AMP administered at 0 min). Drug Administration Time 1. Figure 3D shows that the “saline controls for the morphine injection” were not different from one another. In other words, AMP on its own had no analgesic effects. It also shows that when morphine was administered, there was a trend toward a decrease in pain scores with increasing doses of concomitant AMP. Significant differences from saline were found for both doses of AMP given with 1.0 mg/kg of morphine. Only the highest dose of AMP (1.0 mg/kg) administered with 2.5 mg/kg of morphine was significantly different from the saline control. Figures 3A–C show that the effects of the drugs were diminished by the end of the formalin test; that is, the scores of the experimental groups returned to the level of the control group even though the overall effects (as summarized in Fig. 3D) for the late phase may have been significant in some conditions. This return to control levels is probably due to the fact that the drugs were administered far in advance of the formalin injection. Figures 3A–C reveal that the drug combinations could have an effect on the first 5-min interval (the “early phase”) following the formalin injection. Figure 3A shows that both doses of AMP in the “saline control for morphine injection” condition had significant effects on the early phase. Figure 3B shows that pain was significantly lower in the early phase for rats receiving either dose of AMP in conjunction with 1.0 mg/kg of morphine. Figure 3C shows that the two AMP conditions are different from the control when given in conjunction with 2.5 mg/kg of morphine. Drug Administration Time 2. Figure 4D shows that the “saline controls for the morphine injection” were not different from one another, so AMP had no analgesic effects on its own. It also shows that when morphine was administered, there was a trend toward a decrease in pain scores with increasing doses of AMP. Significant differences from saline were found for both doses of AMP given with 1.0 mg/kg of morphine. AMP administered with 2.5 mg/kg of morphine was significantly different from
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the saline group only when the highest dose of AMP (1.0 mg/kg), but not 0.5 mg/kg of AMP, was administered. From the time-course data represented in Figures 4A–C, it appears that the potentiating effects of 0.5 mg/kg of AMP combined with morphine tended to diminish by the end of the formalin test, whereas the potentiating effects of 1.0 mg/kg of AMP combined with morphine seemed to remain relatively constant for the duration of the formalin test. The higher dose of AMP probably maintained its effect because it was administered just before the formalin injection. In general, AMP was not expected to have an effect on the early phase during Drug Administration Time 2 because AMP was given immedi-
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ately prior to the formalin injection. However, the results were more complex. Figure 4A shows that neither dose of AMP in the “saline control for morphine injection” condition had significant effects on the early phase. Figure 4B shows that pain was significantly lower than saline in the early phase for either dose of AMP in conjunction with 1.0 mg/kg of morphine. Figure 4C shows that only 1.0 mg/kg AMP given with 2.5 mg/kg of morphine significantly affected pain in the early phase.
Discussion The experiments show that MP and AMP, at appropriate doses, potentiate morphine analgesia in the formalin test. These experiments
Fig. 3. Experiment 2, Drug Administration Time 1. Time course of mean formalin pain ratings for rats given morphine at ⫺30 min and d-amphetamine at ⫺20 min: (A) is the “saline control for morphine injection,” in (B) morphine is held constant at 1.0 mg/kg, and in (C) morphine is held constant at 2.5 mg/kg. (D) summarizes the late-phase data from Figures 3A–C by averaging each group over 30 min for the period t ⫽ ⫹20 min to t ⫽ ⫹50 min. The vertical lines on the graphs represent the standard errors of the mean. Significant Mann-Whitney U’s, one-tailed, are indicated by * (P ⬍ 0.05) and ** (P ⬍ 0.01).
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investigated relatively low doses of the drugs, which caused little analgesia on their own, but when combined caused profound analgesia in the rat. These studies do not attempt to answer how or why psychostimulants can potentiate morphine analgesia, or whether the potentiation is additive or synergistic. Other studies have attempted to determine the mechanisms involved.27,28 Review papers on the standard uses of the psychostimulant drugs in humans indicate that both MP and AMP given orally are rapidly absorbed into the blood, easily cross the blood– brain barrier, and have quick clinical effects. The peak behavioral effects of MP and AMP usually occur within 1–2 hours of ingestion and decline within 3–5 hours.16
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MP produced less consistent results than did AMP. The doses of MP used in Experiment 1 (2.5 and 5.0 mg/kg) produced some analgesia on their own, in some instances, when compared to the saline control. When MP was combined with morphine, significantly greater analgesia was produced compared to the morphine-only conditions. Because the doses of MP used in this experiment could produce some analgesia on their own, it seems more likely that the MP may have an additive effect on morphine, but this cannot be stated conclusively due to the design of the study. There were substantial individual differences between animals within groups, which helps explain the large standard errors of the mean present in the results. In addition, the small
Fig. 4. Experiment 2, Drug Administration Time 2. Time course of mean formalin pain ratings for rats given morphine at ⫺10 min and d-amphetamine at 0 min: (A) is the “saline control for morphine injection,” in (B) morphine is held constant at 1.0 mg/kg, and in (C) morphine is held constant at 2.5 mg/kg. (D) summarizes the late phase data from Figures 4A–C by averaging each group over 30 min for the period t ⫽ ⫹20 min to t ⫽ ⫹50 min. The vertical lines of the graphs represent the standard errors of the mean. Significant Mann-Whitney U’s, onetailed, are indicated by * (P ⬍ 0.05) and ** (P ⬍ 0.01).
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Table 1 Summary of Early Phase Statistical Analysis Experiment
Figure
Morphine (mg/kg)
Stimulant (mg/kg) vs. saline
Mann-Whitney U value
P one-tail
Expt. 1 Drug Admin. Time 1
1A
Saline Cont
1B
1.0
1C
2.5
2A
Saline Cont
2B
1.0
2C
2.5
3A
Saline Cont
3B
1.0
3C
2.5
4A
Saline Cont
4B
1.0
4C
2.5
AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0
27.0 34.0 34.0 36.0 26.0 25.0 19.0 13.5 29.0 24.0 22.0 30.0 30.0 26.0 30.0 29.0 17.0 30.0 13.0 27.0 20.0 24.0 23.0 19.0
0.015 0.004 0.004 0.001 0.026 0.041 0.268 0.669 0.004 0.008 0.123 0.002 0.002 0.026 0.002 0.004 0.396 0.002 0.669 0.015 0.075 0.008 0.016 0.111
Expt. 1 Drug Admin Time 2
Expt. 2 Drug Admin Time 1
Expt. 2 Drug Admin Time 2
group sizes could have contributed to the variability. For almost any given combination, other than controls, there were extreme values such as at least one animal showing complete analgesia and at least one animal showing no analgesia. Experiment 1 demonstrates, in the first study with animals, that MP potentiates opioid analgesia, and Experiment 2 confirms Morgan’s observation that AMP potentiates opioid analgesia.8 The temporal pattern of the formalin test reveals some of the properties of the potentiation. It appears that administering morphine and a psychostimulant far in advance of the formalin injection (Drug Administration Time 1) can lead to substantial analgesia in the “early” phase as seen in Table 1. This result could be expected because the drugs would be at their peak blood levels in the rat. But even when the drugs are administered relatively close to the time of the formalin injection (Drug Administration Time 2), the psychostimulants can sometimes potentiate morphine analgesia, though the effect does not seem as great or as consistent as at Drug Administration Time 1. This result suggests that psychostimulant drugs exert their potentiating effects rather quickly. The results of the “late” phase data are evi-
dent in Figures 1D, 2D, 3D, and 4D and shown in Table 2. The greatest amount of analgesia is produced by a combination of morphine and the highest dose of psychostimulant used in these experiments (MP 5.0 mg/kg and AMP 1.0 mg/kg). This result was expected. The lower doses of psychostimulants (MP 2.5 mg/ kg and AMP 0.5 mg/kg) produced less consistent results, but generally, there still seems to be some analgesia. It is important to note that the doses used in these experiments were generally lower than those used in most other studies.3–8 Therefore, the analgesic effects of these drugs are bound to be less consistent than effects obtained in some of the other studies. In addition, the formalin test examines “tonic” pain that lasts longer than the “phasic” pain evoked by threshold-level tests. Moreover, it examines four behaviors as opposed to one reflexive behavior, and may, therefore, accentuate the individual differences in the responses of the animals to a particular drug treatment. The most consistent results were found in Experiment 2 with AMP. The doses of AMP used in the experiment (0.5 and 1.0 mg/kg) did not produce any analgesia on their own compared to the saline control. Yet when they were added to morphine (1.0 and 2.5 mg/kg),
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Table 2 Summary of Mean Late Phase Statistical Analysis Experiment
Figure
Morphine (mg/kg)
Stimulant (mg/kg) vs. saline
Mann-Whitney U value
P one-tail
Expt. 1 Drug Admin. Time 1
1D
Saline Cont
AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 AMP 0.5 AMP 1.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0 MP 2.5 MP 5.0
22.5 28.5 32.0 36.0 15.0 27.0 14.0 20.0 26.0 25.0 19.0 28.0 25.0 20.5 27.0 30.0 27.0 27.0 14.0 25.0 22.0 21.0 18.0 24.0
0.123 0.066 0.013 0.001 0.535 0.015 0.604 0.214 0.026 0.004 0.268 0.009 0.041 0.214 0.015 0.002 0.015 0.015 0.604 0.041 0.028 0.048 0.155 0.008
1.0 2.5
Expt. 1 Drug Admin Time 2
2D
Saline Cont 1.0 2.5
Expt. 2 Drug Admin Time 1
3D
Saline Cont 1.0 2.5
Expt. 2 Drug Admin Time 2
4D
Saline Cont 1.0 2.5
there was generally a difference between the AMP ⫹ morphine conditions and the morphine-only conditions. In other words, subanalgesic doses of AMP potentiated morphine analgesia. This result seems to indicate the possibility of a synergistic effect of AMP on morphine analgesia, but this cannot be stated conclusively due to the dose limitations of the study. Further studies of opioid plus psychostimulant combinations need to be conducted with animal models of chronic pain, such as the autotomy or experimental neuropathy tests. It is also important to study the side effects of these combinations. The only animal study that investigated the toxicity associated with the combination only dealt with acute toxicity and used the LD50 (lethal dose of a substance for 50% of a group of animals) as the dependent variable.6 The LD50 is an extremely radical measure of toxicity, because death is the endpoint of the test and it usually uses doses which are much higher than those used in a clinical situation. In addition, toxicity measured by the LD50 can only be determined in animal studies. It is possible that toxicity may occur during chronic administration of the psychostimulant drugs which would not arise with acute administration. However, a long-term study with can-
cer patients did not indicate any problems with chronic use. Bruera et al.12 noted that adverse effects of chronic MP and opioid administration in patients—e.g., hallucinations and paranoid aggressive reactions—were rare (4% of patients) and usually manifest themselves very early in treatment. These side effects resolved after discontinuation of the drug and there were no subsequent problems. To summarize, low doses of the psychostimulants MP or AMP potentiate low doses of morphine in the formalin test. These results support the small body of animal and human studies that have investigated these drug combinations, and indicate the need for futher studies of these drug combinations in animal models of chronic pain and patients with chronic pain.
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