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A comparison of the effects of morphine sulphate and nitrous oxide analgesia on chronic pain states in man
Journal of the Neurological Sciences, 1981, 49: 41-45
41
© Elsevier/North-Holland Biomedical Press
A COMPARISON OF THE EFFECTS OF MORPHINE SULPHATE A N D NITROUS OXIDE ANALGESIA ON CHRONIC PAIN STATES IN MAN
M. A. GILLMAN and F.J. LICHTIGFELD
1032 Medical City, 106 Eloff Street, Johannesburg (South Africa) (Received 2 June, 1980) (Revised, received 14 July, 1980) (Accepted 16 July, 1980)
SUMMARY
The effect of nitrous oxide and morphine sulphate on chronic pain states in man are compared. The similarity of effect indicate that nitrous oxide acts on the morphine receptor. In all cases where analgesia was produced naloxone reversal occurred. These results provide additional evidence for a dual system hypothesis of pain perception and that nitrous oxide analgesia is mediated by the endogenous opiate system. In the light of these findings, the possibility of using nitrous oxide to replace morphine sulphate as a screening test for deep brain stimulation analgesia is discussed.
INTRODUCTION
Chapman et al. (1943) first reported the similarities of the analgesic effect of nitrous oxide with those of morphine on acute experimental pain, and we have shown that nitrous oxide analgesia in man (Gillman et al. 1980), is mediated by the endogenous opiates. We report here on the comparative effect of these 2 agents on chronic pain states. A morphine saturation test is used to select suitable cases for deep brain stimulation analgesia in chronic intractable pain states. We compared this test with that in which nitrous oxide was used as the opiate receptor stimulant.
Reprint requests to Dr. M. A. Gillman.
42 MATERIALS AND METHODS Informed consent was obtained from 7 patients aged 28--40 years. Of these, 2 patients had paraplegic pain and 5 traumatic low back pain. All patients had been referred for possible analgesia via deep brain implant stimulation as a last resort. The morphine saturation test was done as follows: The pain level was subjectively rated from 0 to 10 (Sternbach et al. 1974), at the beginning of the test and then prior to each 1.5 mg of morphine. The dose of morphine sulphate i.v. was begun with 1.5 mg, and was increased by 1.5 mg increments until 30 mg had been administered at 1-min intervals. A relatively high dose of morphine is required in this test in order to produce full saturation of opiate receptor sites. Each dose of morphine was flushed into the vein with physiological saline. Naloxone 0.8 mg was administered i.v. 1 min after the last dose of morphine and pain ratings taken at 1-min intervals, till the end of the test. The nitrous oxide was administered by means of a Quantiflex nitrous oxide dental analgesia machine. This is not a closed-circuit system, but adequate gas concentrations are obtained. The oxygen flow was kept constant at 3 1/min throughout the experiments. The patients were asked to rate their pain subjectively on a scale from 0 to 10. The concentration of nitrous oxide was raised by 0.5 1 increments, with 2-min intervals at each level, until the subjective pain rating level was zero, or until the nitrous oxide flow was a maximum of 8 1/min. Naloxone 0.8 mg was given by i.v. bolus injection when the pain level was at its lowest. In one patient no change in the subjective pain rating occurred, and in this case the injection was given whilst a level of 8 l/min of nitrous oxide has been breathed for 2 min. At least 72 h elapsed between the 2 tests. Although some of the patients had experienced opiate therapy, none had received such treatment for at least 6 months prior to the tests. All medication was suspended 12 h before each test. A longer period free of medication would have been undesirable since the patients were suffering severe pain. Ideally, it would have been preferable to run each test with a placebo control. However, in this case, each patient would have had to undergo-4 tests. Since the patient was exposed to one unnecessary test anyway, this was considered to be inappropriate from an ethical standpoint. To obviate biased observations, all tests were done single blind, and in addition, an uninformed but experienced recorder made all observations. RESULTS In 4 subjects (see Table 1) the nitrous oxide and morphine tests followed very similar courses. Nausea and vomiting prevented a satisfactory termination of the morphine saturation test in 1 case. Vomiting also interfered with the morphine saturation test in patient 2 and probably prevented a parallel course between the 2 tests in this case. By chance, the morphine saturation test was done on days when the initial
40
31
38
36
38
34 F
28
1
2
3
4
5
6
7
a Biphasic response, see text.
F
M
M
F
M
F
Age and sex (yr)
Patient
low back
low back
paraplegic pain
low back
low back
paraplegic pain
low back
Pain type
6
5
3
7
8
6
8
initial pain
Nitrous oxide
0 (2.5/min)
0 (31/rain)
0 (41/min)
1½ (81/min)
2 (81/min)
6 (81/min)
0 (31/min)
pain prior to naloxone
Numbers in parentheses refer to doses of drug at which these pain levels were assessed.
TABLE 1
reversal after 10 min pain decreased to 5 momentary deepening reversal 5 min; momentary deepening
0 (30 mg)
0-6a (30 mg)
1 (30 mg)
reversal 2 min reversal 2 min
reversal 15 min; momentary deepening
test terminated patient vomited
reversal after 15 min 0 (15 mg)
reversal 15 min
reversal 2 rain; slight deepening?
momentary deepening but no reversal 8 (15 mg)
momentary deepening but no reversal
effect of naloxone only slight reversal analgesia after 1 h - patient vomited
pain prior to naloxone 0 (30 mg)
initial pain
reversal analgesia 15 min
effect of naloxone
Morphine
4~
44 pain ratings were lower than when the nitrous oxide was used. This may account for the fact that the nitrous oxide was not able entirely to abolish the pain in subjects 3 and 4 at 8 l/min. In the case of patient 5, the nitrous oxide test ran the expected course. However, the morphine saturation test showed a biphasic pattern. At 7.5 mg of morphine this patient's pain disappeared, but as the dose was increased from this level there was an increase in pain, until at 30 mg he had twice as much pain as at the beginning of the experiment. This may indicate a hypersensitivity to morphine in this subject, causing a hyperexcitable response (Berryhill et al. 1979). Here, as in patient 7 and possibly patient 6, within 30 s of naloxone administration, there was a transitory deepening of the nitrous oxide effect. This deepening also occurred with the morphine test in patients 5 and 6. Although all these patients admitted feeling "further away", the duration of this phase was only approximately 30 s, and was so quick that they were unable to assess any changes in their pain ratings. This paradoxical effect of naloxone has been seen previously (Gillman et al. 1980), but this is the first report of this phenomenon with morphine.
DISCUSSION
The fact that naloxone caused deepening of both the nitrous oxide and morphine effect gives further support for the dual system hypothesis of pain perception. This hypothesis was suggested to explain the biphasic actions of naloxone on nitrous oxide analgesia. Briefly, we consider that, since naloxone is a specific opiate antagonist devoid of agonistic properties, these biphasic effects indicate the presence of 2 antagonistic systems subserving pain perception; one producing analgesia and the other algesia (Gillman et al. 1980). It is possible that the biphasic changes seen with subject 5 in the morphine saturation test is due to a differential effect of morphine on pre- and post-synaptic receptors. This differential effect was invoked by Carlsson (1976) to explain the biphasic pattern of hypermotility following apomorphine administration. Low doses acted preferentially on the pre-synaptic receptor and higher doses acted on the post-synaptic elements. This postulate is further supported by Jacquet and Lajtha (1973). They have shown hypo- and hyperalgesia in animals with morphine in a similar dose-dependent manner. This comparative study lends further support to the possibility that nitrous oxide analgesia is mediated by the opiate system. Recent work has indicated the possible existence of separate enkephalin and morphine receptors (Chang and Cuatrecasas 1979). The similarity between the changes caused by nitrous oxide and morphine may indicate that the nitrous oxide acts at the morphine receptor. All patients tested preferred the effects of the nitrous oxide to that of the morphine. Although nausea and vomiting has been reported in dental relative analgesia with nitrous oxide, the incidence of this is less than 1~ (Langa 1968). Inhalation sedation or relative dental analgesia is a term used to describe non-anaesthetic concentrations of nitrous oxide in the presence
45
of at least atmospheric concentrations of oxygen. No patients in this study complained of nausea, caused by nitrous oxide. Our study suggests that nitrous oxide could act as an adjunct or even perhaps replace the morphine saturation test. ACKNOWLEDGEMENTS
The authors acknowledge the excellent secretarial and technical assistance of Ms. Shirley Solomon, Mr. E. Maduna, and Mr. L. Katz. Nitrous oxide was the gift of Afrox South Africa Ltd. and Naloxone the gift of Endo Lab. Inc. REFERENCES Berryhill, R. E., J.L. Benumof and D. S. Janowsky (1979) Morphine-induced hyperexcitability in man, Anesthesiology, 50: 65-66. Carlsson, A. (1976) Central catecholamines. In: C. Carlson, J. Engel and L. Hansson (Eds.), NeuroPsychiatric Effects of Adrenergic Beta-receptor Blocking Agents, Urban and Schwarzenberg, Berlin, p. 3. Chang, K.J. and P. Cuatrecasas (1979) Multiple opiate receptors, enkephalin and morphine, bind to receptors of different specificity, J. biol. Chem., 254: 2610. Chapman, W. P., J. G. Arrowood and H.K. Beecher (1943) The analgesic effects of low concentrations of nitrous oxide compared in man with morphine sulphate, J. clin. Invest., 22 : 871-875. Gillman, M.A., L. Kok and F.J. Lichtigfeld (1980) Paradoxical effect of naloxone on nitrous oxide analgesia in man, Europ. J. Pharm., 2 : 175-177. Jacquet, Y. F. and A, Lajtha (1973) Morphine action at central nervous system sites in rat - - Analgesia or hyperalgesia depending on site and dose, Science, 182 : 49(~492. Langa, H. (1968)Techniques of administration (Chapter 7). In: H. Langa, Relative Analgesia in Dental Practice - - Inhalation Analgesia with Nitrous Oxide, Saunders, Philadelphia, PA, p. 164. Sternbach, R. A., R. W. Murphy, G. Timmermans, J. H. Greenwood and W. H. Akeson (1974) Measuring the severity of clinical pain. In: J. J. Bonica (Ed.), Pain (Advances in Neurology, Vol. 4), Raven Press, New York, NY, pp. 281 288.
41
© Elsevier/North-Holland Biomedical Press
A COMPARISON OF THE EFFECTS OF MORPHINE SULPHATE A N D NITROUS OXIDE ANALGESIA ON CHRONIC PAIN STATES IN MAN
M. A. GILLMAN and F.J. LICHTIGFELD
1032 Medical City, 106 Eloff Street, Johannesburg (South Africa) (Received 2 June, 1980) (Revised, received 14 July, 1980) (Accepted 16 July, 1980)
SUMMARY
The effect of nitrous oxide and morphine sulphate on chronic pain states in man are compared. The similarity of effect indicate that nitrous oxide acts on the morphine receptor. In all cases where analgesia was produced naloxone reversal occurred. These results provide additional evidence for a dual system hypothesis of pain perception and that nitrous oxide analgesia is mediated by the endogenous opiate system. In the light of these findings, the possibility of using nitrous oxide to replace morphine sulphate as a screening test for deep brain stimulation analgesia is discussed.
INTRODUCTION
Chapman et al. (1943) first reported the similarities of the analgesic effect of nitrous oxide with those of morphine on acute experimental pain, and we have shown that nitrous oxide analgesia in man (Gillman et al. 1980), is mediated by the endogenous opiates. We report here on the comparative effect of these 2 agents on chronic pain states. A morphine saturation test is used to select suitable cases for deep brain stimulation analgesia in chronic intractable pain states. We compared this test with that in which nitrous oxide was used as the opiate receptor stimulant.
Reprint requests to Dr. M. A. Gillman.
42 MATERIALS AND METHODS Informed consent was obtained from 7 patients aged 28--40 years. Of these, 2 patients had paraplegic pain and 5 traumatic low back pain. All patients had been referred for possible analgesia via deep brain implant stimulation as a last resort. The morphine saturation test was done as follows: The pain level was subjectively rated from 0 to 10 (Sternbach et al. 1974), at the beginning of the test and then prior to each 1.5 mg of morphine. The dose of morphine sulphate i.v. was begun with 1.5 mg, and was increased by 1.5 mg increments until 30 mg had been administered at 1-min intervals. A relatively high dose of morphine is required in this test in order to produce full saturation of opiate receptor sites. Each dose of morphine was flushed into the vein with physiological saline. Naloxone 0.8 mg was administered i.v. 1 min after the last dose of morphine and pain ratings taken at 1-min intervals, till the end of the test. The nitrous oxide was administered by means of a Quantiflex nitrous oxide dental analgesia machine. This is not a closed-circuit system, but adequate gas concentrations are obtained. The oxygen flow was kept constant at 3 1/min throughout the experiments. The patients were asked to rate their pain subjectively on a scale from 0 to 10. The concentration of nitrous oxide was raised by 0.5 1 increments, with 2-min intervals at each level, until the subjective pain rating level was zero, or until the nitrous oxide flow was a maximum of 8 1/min. Naloxone 0.8 mg was given by i.v. bolus injection when the pain level was at its lowest. In one patient no change in the subjective pain rating occurred, and in this case the injection was given whilst a level of 8 l/min of nitrous oxide has been breathed for 2 min. At least 72 h elapsed between the 2 tests. Although some of the patients had experienced opiate therapy, none had received such treatment for at least 6 months prior to the tests. All medication was suspended 12 h before each test. A longer period free of medication would have been undesirable since the patients were suffering severe pain. Ideally, it would have been preferable to run each test with a placebo control. However, in this case, each patient would have had to undergo-4 tests. Since the patient was exposed to one unnecessary test anyway, this was considered to be inappropriate from an ethical standpoint. To obviate biased observations, all tests were done single blind, and in addition, an uninformed but experienced recorder made all observations. RESULTS In 4 subjects (see Table 1) the nitrous oxide and morphine tests followed very similar courses. Nausea and vomiting prevented a satisfactory termination of the morphine saturation test in 1 case. Vomiting also interfered with the morphine saturation test in patient 2 and probably prevented a parallel course between the 2 tests in this case. By chance, the morphine saturation test was done on days when the initial
40
31
38
36
38
34 F
28
1
2
3
4
5
6
7
a Biphasic response, see text.
F
M
M
F
M
F
Age and sex (yr)
Patient
low back
low back
paraplegic pain
low back
low back
paraplegic pain
low back
Pain type
6
5
3
7
8
6
8
initial pain
Nitrous oxide
0 (2.5/min)
0 (31/rain)
0 (41/min)
1½ (81/min)
2 (81/min)
6 (81/min)
0 (31/min)
pain prior to naloxone
Numbers in parentheses refer to doses of drug at which these pain levels were assessed.
TABLE 1
reversal after 10 min pain decreased to 5 momentary deepening reversal 5 min; momentary deepening
0 (30 mg)
0-6a (30 mg)
1 (30 mg)
reversal 2 min reversal 2 min
reversal 15 min; momentary deepening
test terminated patient vomited
reversal after 15 min 0 (15 mg)
reversal 15 min
reversal 2 rain; slight deepening?
momentary deepening but no reversal 8 (15 mg)
momentary deepening but no reversal
effect of naloxone only slight reversal analgesia after 1 h - patient vomited
pain prior to naloxone 0 (30 mg)
initial pain
reversal analgesia 15 min
effect of naloxone
Morphine
4~
44 pain ratings were lower than when the nitrous oxide was used. This may account for the fact that the nitrous oxide was not able entirely to abolish the pain in subjects 3 and 4 at 8 l/min. In the case of patient 5, the nitrous oxide test ran the expected course. However, the morphine saturation test showed a biphasic pattern. At 7.5 mg of morphine this patient's pain disappeared, but as the dose was increased from this level there was an increase in pain, until at 30 mg he had twice as much pain as at the beginning of the experiment. This may indicate a hypersensitivity to morphine in this subject, causing a hyperexcitable response (Berryhill et al. 1979). Here, as in patient 7 and possibly patient 6, within 30 s of naloxone administration, there was a transitory deepening of the nitrous oxide effect. This deepening also occurred with the morphine test in patients 5 and 6. Although all these patients admitted feeling "further away", the duration of this phase was only approximately 30 s, and was so quick that they were unable to assess any changes in their pain ratings. This paradoxical effect of naloxone has been seen previously (Gillman et al. 1980), but this is the first report of this phenomenon with morphine.
DISCUSSION
The fact that naloxone caused deepening of both the nitrous oxide and morphine effect gives further support for the dual system hypothesis of pain perception. This hypothesis was suggested to explain the biphasic actions of naloxone on nitrous oxide analgesia. Briefly, we consider that, since naloxone is a specific opiate antagonist devoid of agonistic properties, these biphasic effects indicate the presence of 2 antagonistic systems subserving pain perception; one producing analgesia and the other algesia (Gillman et al. 1980). It is possible that the biphasic changes seen with subject 5 in the morphine saturation test is due to a differential effect of morphine on pre- and post-synaptic receptors. This differential effect was invoked by Carlsson (1976) to explain the biphasic pattern of hypermotility following apomorphine administration. Low doses acted preferentially on the pre-synaptic receptor and higher doses acted on the post-synaptic elements. This postulate is further supported by Jacquet and Lajtha (1973). They have shown hypo- and hyperalgesia in animals with morphine in a similar dose-dependent manner. This comparative study lends further support to the possibility that nitrous oxide analgesia is mediated by the opiate system. Recent work has indicated the possible existence of separate enkephalin and morphine receptors (Chang and Cuatrecasas 1979). The similarity between the changes caused by nitrous oxide and morphine may indicate that the nitrous oxide acts at the morphine receptor. All patients tested preferred the effects of the nitrous oxide to that of the morphine. Although nausea and vomiting has been reported in dental relative analgesia with nitrous oxide, the incidence of this is less than 1~ (Langa 1968). Inhalation sedation or relative dental analgesia is a term used to describe non-anaesthetic concentrations of nitrous oxide in the presence
45
of at least atmospheric concentrations of oxygen. No patients in this study complained of nausea, caused by nitrous oxide. Our study suggests that nitrous oxide could act as an adjunct or even perhaps replace the morphine saturation test. ACKNOWLEDGEMENTS
The authors acknowledge the excellent secretarial and technical assistance of Ms. Shirley Solomon, Mr. E. Maduna, and Mr. L. Katz. Nitrous oxide was the gift of Afrox South Africa Ltd. and Naloxone the gift of Endo Lab. Inc. REFERENCES Berryhill, R. E., J.L. Benumof and D. S. Janowsky (1979) Morphine-induced hyperexcitability in man, Anesthesiology, 50: 65-66. Carlsson, A. (1976) Central catecholamines. In: C. Carlson, J. Engel and L. Hansson (Eds.), NeuroPsychiatric Effects of Adrenergic Beta-receptor Blocking Agents, Urban and Schwarzenberg, Berlin, p. 3. Chang, K.J. and P. Cuatrecasas (1979) Multiple opiate receptors, enkephalin and morphine, bind to receptors of different specificity, J. biol. Chem., 254: 2610. Chapman, W. P., J. G. Arrowood and H.K. Beecher (1943) The analgesic effects of low concentrations of nitrous oxide compared in man with morphine sulphate, J. clin. Invest., 22 : 871-875. Gillman, M.A., L. Kok and F.J. Lichtigfeld (1980) Paradoxical effect of naloxone on nitrous oxide analgesia in man, Europ. J. Pharm., 2 : 175-177. Jacquet, Y. F. and A, Lajtha (1973) Morphine action at central nervous system sites in rat - - Analgesia or hyperalgesia depending on site and dose, Science, 182 : 49(~492. Langa, H. (1968)Techniques of administration (Chapter 7). In: H. Langa, Relative Analgesia in Dental Practice - - Inhalation Analgesia with Nitrous Oxide, Saunders, Philadelphia, PA, p. 164. Sternbach, R. A., R. W. Murphy, G. Timmermans, J. H. Greenwood and W. H. Akeson (1974) Measuring the severity of clinical pain. In: J. J. Bonica (Ed.), Pain (Advances in Neurology, Vol. 4), Raven Press, New York, NY, pp. 281 288.