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Paradoxical effect of naloxone on nitrous oxide analgesia in man
European Journal of Pharmacology, 61 (1980) 175--177 © Elsevier/North-Holland Biomedical Press
175
Short communication P A R A D O X I C A L E F F E C T O F NALOXONE ON N I T R O U S OXIDE A N A L G E S I A IN MAN MARK A. GILLMAN 1,*, LYNDLEY KOK 2 and FREDERICK J. LICHTIGFELD 3
1 1032 Medical City, 106 Eloff Street, Johannesburg, South Africa, and 2 Department of Neurology, University of Witwatersrand Medical School, Johannesburg, South Africa, and 3 Sterhfontein Hospital, Krugersdorp, South Africa Received 19 November 1979, accepted 21 November 1979
M.A. GILLMAN, L. KOK and F.J. LICHTIGFELD, Paradoxical effect of naloxone on nitrous oxide analgesia in man, European J. Pharmacol. 61 (1980) 175--177. The effect of naloxone on nitrous oxide analgesia in man has been investigated. The paradoxical response so obtained indicates the possibility of a dual system mediating the pain response in man. These results support previous animal experiments indicating that nitrous oxide analgesia is mediated by the opiate receptors. Nitrous oxide
Ar~algesia
Naloxone
Opiates
1. Introduction
2. Materials and methods
Nitrous oxide has, for many years, been widely used as an anaesthetic agent. However, it is only recently that its analgesic properties have been exploited to any extent. Nitrous oxide becomes analgesic rather than anesthetic when it is mixed with at least atmospheric concentrations of oxygen. As the oxygen concentration increases from 20%, the chances of anesthesia occurring, become for all practical purposes eliminated. In addition, as the relative concentration of oxygen is raised, the awareness o f the subject increases, so that subject cooperation is possible. It has been suggested that the analgesic action of nitrous oxide is mediated by the release of opiate-like substances (Berkowitz et al., 1977). Since these studies had been carried out on experimental animals, it was decided to investigate the effect of naloxone, a narcotic antagonist, on nitrous oxide analgesia in human subjects.
Informed consent was obtained from 15 healthy volunteers of both sexes whose ages varied between 21 and 30 years. No information was given to them a b o u t the expected direction of the results. Furthermore, in some subjects the experiment was carried out more t h a n . once and on separate occasions (see table 1). In the case of subjects on which the experiment was repeated, at least one week was allowed between experiments. A method for inducing pain devised b y (Poser, 1971) was used in a modified form. A painful stimulus was given using a three centimetre square coarse cheese grate with six prongs, backed b y a piece o f stout cardboard. This was placed on the posterior surface of the metacarpal area of the hand. Graded pressure was applied b y a sphygm o m a n o m e t e r cuff w o u n d around the hand and enclosing the grate. The cuff was inflated at a constant rate, and pressure readings taken when the pain was first experienced, when of moderate intensity and when judged to be severe b y the subjects. The readings were
* To whom reprint requests should be addressed.
176
M.A. GILLMAN ET AL.
TABLE 1 Effect of nitrous oxide alone and in combination with naloxone of pain threshold 1 No. of subjects
No. of experiments
Gender of subjects
Nitrous oxide effect
Naloxone effects
11
17
3 male, 8 female
4
7
2 male, 2 female
Rise of pain threshold from basal levels Rise of pain threshold from basal levels
Rise of pain threshold further from nitrous oxide level Drop of pain threshold towards basal level and below analgesic level
1 In experiments repeated on the same subject, the change in pain threshold for that subject, was found to be similar in the second experiment (although consistent results were obtained in this respect, because of the small sample, it would be inappropriate to assume that this is a trait phenomenon).
taken under basal conditions and under nitrous oxide analgesia before and after administration of naloxone. Nitrous oxide was given b y continuous flow using a Quantiflex dental flow meter whilst the oxygen flow was being kept constant at 3 1/min throughout the experiment. An analgesic effect was obtained in all subjects at concentrations nitrous oxide of between 2 and 4 1/min. Once the analgesic effect was obtained, the subjects continued breathing the nitrous oxide mixture until after the effects of the naloxone had been measured on the pain threshold. The dose of naloxone required to give a measurable effect ranged between 0.8-1.2 mg b y the intravenous route. It must be noted here, that the doses used b y Berkowitz et al. were 5 mg/kg of animal bodyweight. Had these doses been used on human subjects, it would have meant, for an adult man a dose of 250 mg or more. Since no studies have to date been carried out on the safety and tolerance of such high doses in human subjects, we were constrained to use these lower doses. Control experiments, in which distilled water was injected without the knowledge of either experimenter or subject, were also carried out. All experiments were conducted in a single blind manner.
3. Results (see table 1) Nitrous oxide raised the pain threshold in all the subjects tested. The administration of
naloxone resulted in two distinct categories of results in the 15 subjects. In 4 subjects naloxone markedly lowered the nitrous oxide pain threshold, while in the remaining 11 subjects it enhanced the analgesic action of the nitrous oxide. Administration of distilled water produced no measurable changes in pain readings. The onset of the naloxone effect was very rapid, as was expected from a similar time coarse seen when naloxone is given to reverse opiate depression of respiration. The maxim u m effect usually occurred between 1 and 2 min after injection, this effect decaying within 4-5 min, the pain readings then returning to pre-naloxone levels. The experiment was terminated at this point. The subjective effects associated with naloxone reversal, was hyperalgesia, increasing awareness and distinct displeasure of the experience. With naloxone enhancement of nitrous oxide analgesia, the subject felt more euphoric, more distant and detached from the painful experience.
4. Discussion Our observation that naloxone altered the pain response lends further support to the hypothesis of an opiate receptor involvement in nitrous oxide analgesia. The observed analgesic effects of naloxone can probably not be explained on the basis of inherent analgesic
PARADOXICAL EFFECT OF NALOXONE ON NITROUS OXIDE ANALGESIA properties ascribed to the drug. It has been shown by various workers (Jasinski et al., 1967; Gevert and Goldstein, 1977), t h a t naloxone is devoid of intrinsic activity. (Lasagna, 1965) had also shown that doses of naloxone of about 2 mg appeared to have an analgesic effect, while higher doses were hyperalgesic, as their effects were worse than might have been expected from a placebo. Hughes and Kosterlitz (1977) suggested that a dual system exists in the control of pain. This comprises the release of opiate peptides decreasing pain perception while another substance (possibly also peptide in nature) acts centrally to either enhance pain perception directly or by antagonising the effect of the opiates. Jacquet and Lujtha (1974) have demonstrated a paradoxical effect of morphine in producing both hyperalgesia and hypoalgesia after micro-injection in the Periaquaductal Gray Matter, both effects being inhibited by naloxone. Jacquet and Marks (1976) have also suggested that two separate sets of receptors may be involved in order to explain their paradoxical results. Berryhill et al. (1979) have investigated a case of morphine-induced hyperexcitability in man, and consider that morphine could alter the inhibitory and excitatory effects of opiate-like systems in the brain that are in a state of dynamic balance. Any stimulation of endogenous opiate production could also lead to an increase in the production of the substance enhancing pain perception. This would tend to preserve a dynamic equilibrium between the two sets of systems, allowing for sensitivity of response while at the same time maintaining a fine control over fluctuation in response parameters. Watson et al. (1979) have stated t h a t the most salient feature that can be drawn from previous work on the opiate peptides is that the regulatory mechanism involved in these systems, results in a tight control of the concentration of these substances. The dualistic effect of naloxone which we ob-
177
served may indicate an altered state of the equilibrium induced by a differential effect of naloxone antagonism on the two systems. These findings represent the first experimental evidence in man, of the possibility of a dual system operating in pain perception, and that nitrous oxide analgesia, is mediated by the opioid peptides.
Acknowledgements We would like to acknowledge the assistance and grant received from Afrox (Pty) Ltd., as well as the loan of equipment from Clinical Enterprises (Pty) Limited, and Medishield (S.A.) Ltd.
References Berkowitz, B.A., A.D. Finck and S.H. Ngai, 1977, Nitrous oxide analgesia: reversal by naloxone and development of tolerance, J. Pharmacol. Exp. Ther. 203, 539. Berryhill, R.E., J.L. Benumof and D.S. Janowsky, 1979, Morphine-induced hyperexcitability in man, Anaesthesiology 50, 65. Gevert, P. and G. Goldstein, 1977, Effects of naloxone on experimentally induced ischemic pain and on mood in human subjects, Proc. Nat. Acad. Sci. U.S.A. 74, 1291. Hughes, J. and H.W. Kosterlitz, 1977, Opiate peptides, Brit. Med. Bull. 33,157. Jacquet, Y.F. and A. Lujtha, 1974, Paradoxical effects after micro injection of morphine in the periaqueductal gray matter in the rat, Science 185, 1055. Jacquet, Y.F. and N. Marks, 1976, The C-fragment of beta-lipotropin an endogenous neuroleptic or anti psychotogen, Science 194, 632. Jasinski, D.R., W.R. Martin and C.A. Haertzen, 1967, The human pharmacology and abuse potential of N-allylnoroxymorphone (naloxone), J. Pharmacol. Exp. Ther. 157,420. Lasagna, L., 1965, Drug interaction in the field of analgesic drugs, Proc. Roy. Soc. Med. 58 Suppl. 987. Poser, E.G., 1971, in: Fundamentals of Experimental Psychology, ed. C.L. Sheridan (Holt, Rhinehart and Winston, Inc., New York) p. 253. Watson, S.J., H. Akil, P.A. Berger and J.D. Barchas, 1979, Some observations on the opiate peptides and schizophrenia, Arch. Gen. Psych. 36, 35.
175
Short communication P A R A D O X I C A L E F F E C T O F NALOXONE ON N I T R O U S OXIDE A N A L G E S I A IN MAN MARK A. GILLMAN 1,*, LYNDLEY KOK 2 and FREDERICK J. LICHTIGFELD 3
1 1032 Medical City, 106 Eloff Street, Johannesburg, South Africa, and 2 Department of Neurology, University of Witwatersrand Medical School, Johannesburg, South Africa, and 3 Sterhfontein Hospital, Krugersdorp, South Africa Received 19 November 1979, accepted 21 November 1979
M.A. GILLMAN, L. KOK and F.J. LICHTIGFELD, Paradoxical effect of naloxone on nitrous oxide analgesia in man, European J. Pharmacol. 61 (1980) 175--177. The effect of naloxone on nitrous oxide analgesia in man has been investigated. The paradoxical response so obtained indicates the possibility of a dual system mediating the pain response in man. These results support previous animal experiments indicating that nitrous oxide analgesia is mediated by the opiate receptors. Nitrous oxide
Ar~algesia
Naloxone
Opiates
1. Introduction
2. Materials and methods
Nitrous oxide has, for many years, been widely used as an anaesthetic agent. However, it is only recently that its analgesic properties have been exploited to any extent. Nitrous oxide becomes analgesic rather than anesthetic when it is mixed with at least atmospheric concentrations of oxygen. As the oxygen concentration increases from 20%, the chances of anesthesia occurring, become for all practical purposes eliminated. In addition, as the relative concentration of oxygen is raised, the awareness o f the subject increases, so that subject cooperation is possible. It has been suggested that the analgesic action of nitrous oxide is mediated by the release of opiate-like substances (Berkowitz et al., 1977). Since these studies had been carried out on experimental animals, it was decided to investigate the effect of naloxone, a narcotic antagonist, on nitrous oxide analgesia in human subjects.
Informed consent was obtained from 15 healthy volunteers of both sexes whose ages varied between 21 and 30 years. No information was given to them a b o u t the expected direction of the results. Furthermore, in some subjects the experiment was carried out more t h a n . once and on separate occasions (see table 1). In the case of subjects on which the experiment was repeated, at least one week was allowed between experiments. A method for inducing pain devised b y (Poser, 1971) was used in a modified form. A painful stimulus was given using a three centimetre square coarse cheese grate with six prongs, backed b y a piece o f stout cardboard. This was placed on the posterior surface of the metacarpal area of the hand. Graded pressure was applied b y a sphygm o m a n o m e t e r cuff w o u n d around the hand and enclosing the grate. The cuff was inflated at a constant rate, and pressure readings taken when the pain was first experienced, when of moderate intensity and when judged to be severe b y the subjects. The readings were
* To whom reprint requests should be addressed.
176
M.A. GILLMAN ET AL.
TABLE 1 Effect of nitrous oxide alone and in combination with naloxone of pain threshold 1 No. of subjects
No. of experiments
Gender of subjects
Nitrous oxide effect
Naloxone effects
11
17
3 male, 8 female
4
7
2 male, 2 female
Rise of pain threshold from basal levels Rise of pain threshold from basal levels
Rise of pain threshold further from nitrous oxide level Drop of pain threshold towards basal level and below analgesic level
1 In experiments repeated on the same subject, the change in pain threshold for that subject, was found to be similar in the second experiment (although consistent results were obtained in this respect, because of the small sample, it would be inappropriate to assume that this is a trait phenomenon).
taken under basal conditions and under nitrous oxide analgesia before and after administration of naloxone. Nitrous oxide was given b y continuous flow using a Quantiflex dental flow meter whilst the oxygen flow was being kept constant at 3 1/min throughout the experiment. An analgesic effect was obtained in all subjects at concentrations nitrous oxide of between 2 and 4 1/min. Once the analgesic effect was obtained, the subjects continued breathing the nitrous oxide mixture until after the effects of the naloxone had been measured on the pain threshold. The dose of naloxone required to give a measurable effect ranged between 0.8-1.2 mg b y the intravenous route. It must be noted here, that the doses used b y Berkowitz et al. were 5 mg/kg of animal bodyweight. Had these doses been used on human subjects, it would have meant, for an adult man a dose of 250 mg or more. Since no studies have to date been carried out on the safety and tolerance of such high doses in human subjects, we were constrained to use these lower doses. Control experiments, in which distilled water was injected without the knowledge of either experimenter or subject, were also carried out. All experiments were conducted in a single blind manner.
3. Results (see table 1) Nitrous oxide raised the pain threshold in all the subjects tested. The administration of
naloxone resulted in two distinct categories of results in the 15 subjects. In 4 subjects naloxone markedly lowered the nitrous oxide pain threshold, while in the remaining 11 subjects it enhanced the analgesic action of the nitrous oxide. Administration of distilled water produced no measurable changes in pain readings. The onset of the naloxone effect was very rapid, as was expected from a similar time coarse seen when naloxone is given to reverse opiate depression of respiration. The maxim u m effect usually occurred between 1 and 2 min after injection, this effect decaying within 4-5 min, the pain readings then returning to pre-naloxone levels. The experiment was terminated at this point. The subjective effects associated with naloxone reversal, was hyperalgesia, increasing awareness and distinct displeasure of the experience. With naloxone enhancement of nitrous oxide analgesia, the subject felt more euphoric, more distant and detached from the painful experience.
4. Discussion Our observation that naloxone altered the pain response lends further support to the hypothesis of an opiate receptor involvement in nitrous oxide analgesia. The observed analgesic effects of naloxone can probably not be explained on the basis of inherent analgesic
PARADOXICAL EFFECT OF NALOXONE ON NITROUS OXIDE ANALGESIA properties ascribed to the drug. It has been shown by various workers (Jasinski et al., 1967; Gevert and Goldstein, 1977), t h a t naloxone is devoid of intrinsic activity. (Lasagna, 1965) had also shown that doses of naloxone of about 2 mg appeared to have an analgesic effect, while higher doses were hyperalgesic, as their effects were worse than might have been expected from a placebo. Hughes and Kosterlitz (1977) suggested that a dual system exists in the control of pain. This comprises the release of opiate peptides decreasing pain perception while another substance (possibly also peptide in nature) acts centrally to either enhance pain perception directly or by antagonising the effect of the opiates. Jacquet and Lujtha (1974) have demonstrated a paradoxical effect of morphine in producing both hyperalgesia and hypoalgesia after micro-injection in the Periaquaductal Gray Matter, both effects being inhibited by naloxone. Jacquet and Marks (1976) have also suggested that two separate sets of receptors may be involved in order to explain their paradoxical results. Berryhill et al. (1979) have investigated a case of morphine-induced hyperexcitability in man, and consider that morphine could alter the inhibitory and excitatory effects of opiate-like systems in the brain that are in a state of dynamic balance. Any stimulation of endogenous opiate production could also lead to an increase in the production of the substance enhancing pain perception. This would tend to preserve a dynamic equilibrium between the two sets of systems, allowing for sensitivity of response while at the same time maintaining a fine control over fluctuation in response parameters. Watson et al. (1979) have stated t h a t the most salient feature that can be drawn from previous work on the opiate peptides is that the regulatory mechanism involved in these systems, results in a tight control of the concentration of these substances. The dualistic effect of naloxone which we ob-
177
served may indicate an altered state of the equilibrium induced by a differential effect of naloxone antagonism on the two systems. These findings represent the first experimental evidence in man, of the possibility of a dual system operating in pain perception, and that nitrous oxide analgesia, is mediated by the opioid peptides.
Acknowledgements We would like to acknowledge the assistance and grant received from Afrox (Pty) Ltd., as well as the loan of equipment from Clinical Enterprises (Pty) Limited, and Medishield (S.A.) Ltd.
References Berkowitz, B.A., A.D. Finck and S.H. Ngai, 1977, Nitrous oxide analgesia: reversal by naloxone and development of tolerance, J. Pharmacol. Exp. Ther. 203, 539. Berryhill, R.E., J.L. Benumof and D.S. Janowsky, 1979, Morphine-induced hyperexcitability in man, Anaesthesiology 50, 65. Gevert, P. and G. Goldstein, 1977, Effects of naloxone on experimentally induced ischemic pain and on mood in human subjects, Proc. Nat. Acad. Sci. U.S.A. 74, 1291. Hughes, J. and H.W. Kosterlitz, 1977, Opiate peptides, Brit. Med. Bull. 33,157. Jacquet, Y.F. and A. Lujtha, 1974, Paradoxical effects after micro injection of morphine in the periaqueductal gray matter in the rat, Science 185, 1055. Jacquet, Y.F. and N. Marks, 1976, The C-fragment of beta-lipotropin an endogenous neuroleptic or anti psychotogen, Science 194, 632. Jasinski, D.R., W.R. Martin and C.A. Haertzen, 1967, The human pharmacology and abuse potential of N-allylnoroxymorphone (naloxone), J. Pharmacol. Exp. Ther. 157,420. Lasagna, L., 1965, Drug interaction in the field of analgesic drugs, Proc. Roy. Soc. Med. 58 Suppl. 987. Poser, E.G., 1971, in: Fundamentals of Experimental Psychology, ed. C.L. Sheridan (Holt, Rhinehart and Winston, Inc., New York) p. 253. Watson, S.J., H. Akil, P.A. Berger and J.D. Barchas, 1979, Some observations on the opiate peptides and schizophrenia, Arch. Gen. Psych. 36, 35.