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Naloxone Fails to antagonize nitrous oxide analgesia for clinical pain
Pain, 13 (1982) 165-170
165
Elsevier Biomedical Press
Naloxone Fails to Antagonize Nitrous Oxide Analgesia for Clinical Pain Jon D. Levine ,,i, N e w t o n C. G o r d o n 2 a n d H o w a r d L. Fields 3 J Division of Rheumatology, Department of Medicine, 2 Dit~ision of Oral and Maxiliofacial Surgery, and 3 Department of NeuroloD,, Schools of Dentistry, and Medicine, University of California, San Francisco, Calif. 94143 (U.S.A.) (Received 26 May 198 i, accepted 4 November i 981)
Summary
In 30 patients with dental postoperative pain we tested the hypothesis that the analgesic effects of nitrous oxide (N20), a mild analgesic, may be mediated via endogenous opioids. Using the visual analog scale to assess pain, significant analgesia was induced by 33~o N20. N20-induced analgesia was not significantly antagonized by 10 mg of intravenous naloxone. In the setting of clinical pain there appears to be little if any contribution of endogenous opioids to N20-induced analgesia.
Introduction
Although nitrous oxide (N20) is commonly used as an analgesic agent, little is known about its mechanism of action. The observation that narcotic antagonists block analgesia induced by N20 or other gaseous agents in animals [3,6] raised the possibility that part of N20's action is mediated by the release of endogenous opioids. However, this antagonism has not been found in all studies [9,20]. Furthermore, the antagonism of N20-induced analgesia by narcotic antagonists differs significantly from their antagonism of opiate-induced analgesia. Thus, compared to its antagonism of opioid analgesia, antagonism of N20 analgesia by naloxone requires higher doses, and is either incomplete or has a briefer duration [3,7,21]. To date, naloxone's effects on N20 analgesia in humans has only been studied with experimentally induced pain [4,7,21]. However, narcotic analgesics are known * To whom all correspondence should be addressed. 0304-3959/82/0000-0000/$02.75 © 1982 Elsevier Biomedical Press
166 to have different effects on clinical and experimental pain [2]. We previously demonstrated that morpldne produces a dose-dependent analgesia for patients with dental postoperative pain [15]. In the present study we have used this same paradigm to evaluate naloxone reversal of N20 analgesia.
Methods
Thirty patients between the ages of 18 and 32 were studied. Consent to act as a subject was obtained using a form that followed the guidelines of the UCSF Committee on Human Experimentation. All subjects underwent a ~tai-,dardized surgical procedure for the removal of impacted third molars (wisdom teeth). Patients were premedicated with 10 mg of diazepam and during surge,ry 1~-40% r,itrous oxide and local nerve block with 3% mepivicaine without vasoconstriction were used to assure rapidly reversible anesthesia. Patients rated their pain by placing a vertical mark on a 10 cm undivided horizontal line which had the words 'no pain' at the left (0 cm) and 'worst pain ever' ~t the right (10 cm) end. The position of the mark, in millimeters, provided the meagure of pain level. The sensitivity and reproducibility of this scale has been documented elsewhere [ 1,11,18, i 91. Two hours after induction of anaesthesia patients rated their pain level and then were randomly assigned to 1 of 3 treatment groups of 10 patients eac.h. The first two groups received 33% N20 (2 l/min N20:4 l/rain 02) continuously throughout the remainder of the experiment (Fig. I). Ten minutes after N20 was started, pain level was again measured. One of these two groups then received a placebo and the other naloxone (10 mg), double blind, via an indwelling venous ca~,heter. A final pain level measurement was made 40 min after the intravenous drug was administered. To provide a control for the natural history of this pain, a third group of patients rated their pain at the same time as the patients in the other two groups but received no treatment.
Results
Fig. 1 demonstrates the analgesic effect of nitrous oxide (N20) in patients receiving either placebo or naloxone. Ten minutes following the start of N20 administration mean pain level decreased a small but significant amount in both groups of patients from 5.57 to 4.35 (22%) compared to the untreated control group (P < 0.01, Student's t-test). This reduction in mean pain level is approximately 33% compared with the no-treatment group whose pain rose from 5.53 to 6.61. By comparison, in a previous study, using the same type of patient and rating method, 8 mg of intravenous morphine reduced pain by an average of 57%. Despite the relatively small magnitude of the mean pain reduction, 90% of patients receiving N20 reported some reduction. In contrast, none of the no-treatment patients reported a reduction in pain. At 40 rain after starting N20 the patients who received
167
N20 also had lower mean pain levels than patients in the natural history group (P < 0.05, Student's t-test). The group who received N20 and then naloxone had mean pain identical to the NzO group that received placebo, that is, there is no
+2I +1 LU _.J
//// /
_z Ill
O
:<2[
U
.2l
I
N 2°
I
ADMINISTRATION
I
20 40 MINUTES
I
60
Fig. i. The time course of pain following extraction of impacted wisdom teeth in the 3 groups of patients: (O) no-treatment; (O) N20 followed by naloxone; and (A) N20 followed by placebo. The shaded bar shows the onset and duration of N20 administration. The intravenous drug (placebo or naloxone) was administered to patients receiving naloxone immediately following the 20 min pain rating.
apparent naloxone effect. Thus, N 2 0 appears to have a significant analgesic effect which is not affected by administration of b;gh doses of naloxone. The finding that mean pain levels in groups receiving placebo do not diverge from the pain level in the groups receiving naloxone was unexpected. We have previously demonstrated using this same postoperative pain paradigm that patients receiving naloxone have significantly greater pain than those receiving placebo [I 3,14]. Thus, in patients receiving NzO, if a placebo effect were present, one would expect patients who received naloxone to report greater pain than those who received placebo. One possible explanation of this failure to observe a naloxone effect is that N20 somehow interferes with the expression of placebo analgesia. In fact, N20 has been reported to reduce some of morphine's inhibitory actions on sensory systems in animals [5] and human subjects [17]. Under some circumstances placebo analgesia may fail to occur if some patients in the study do not receive an active analgesic drug [8]. The absence of such a group in the present experiment is an alternative explanation of our failure to produce a placebo effect in patients receiving N20.
168 Discussion
It is well-established that N20 produces effective, though incomplete analgesia for dental postoperative pain [16]. The present study indicates that the visual scale is a sensitive measure of N20 analgesia. Comparing the present results to our previous study of morphine using the visual analog scale and the same dental postoperative pain paradigm, 33~ N20 produces less relief than 8 mg of morphine i.v. However, using this clinical pain paradigm we were unable to demonstrate a significant antagonism of N20 analgesia by a dose of naloxone that effectively blocks both morphine and placebo analgesia [10,12]. Our results apparently conflict with previous studies demonstrating partial antagonism of N20 analgesia by opiate antagonists. Berkowitz et al. [3] demonstrated naloxone antagonism of N20 analgesia in mice and rats, but even with very large doses of naloxone (30 mg/kg/rat) significant residual N20 analgesia was still obs,ived. Furthermore, although tolerance to N20 for analgesia was reported, cross-tolerance between opiates and N20 was not studied. Tolerance to continued N20 administration was also seen in the present study. In human subjects, Chapman and Benedetti [4] reported a significant trend toward naloxone antagonism of N20 analgesia for experimental tooth pulp pain. They used a relatively low dose of naloxone (0.4 mg) and found that the degree of reversal of the N20 effect was extremely small (apparently less than 107o using a categorical scale). Yang et al. [21] reported that N20 analgesia for tourniquet pain was significantly antagonized by 4 and 8 mg of naloxone. With the higher dose of naloxone more than 50% of the N20 analgesic effect was apparently reversed. Although our results conflict with tb~,se of Yang et al. there were significant methodological differences between our experiment and theirs. First, we used a clinical paradigm with a continuous pain whose onset preceded naloxone administration. Second, we used a visual analog scale, which is continuous and may not distinguish sensory from affective components of pain. Finally since doing the tourniquet test once may affect subsequent pain ratings in the same subject the pain ratings on the tourniquet test in pre-injection control periods are not strictly comparable to subsequent tests on the same subject. Thus the m~gnitude of the N20 effect and of its reversal by naloxone is difficult to assess in their study. If the N20 effect were more pronounced on the sensory component of pair~, naloxone antagonism might be expected to be greater for an experimental pain studied with an intensity ~cale. It is interesting in this regard that in Chapman's study of tooth pulp stimulation, the effects of N20 on the cerebral evoked potential were completely reversed by doses of naloxone which had only a minimal effect on reported pain severity. This suggests that N20 may have different effects on different aspects of sensory processing. in previous studies [13,14] using the same clinical paradigm to study naloxone, we demonstrated that compared to placebo, naloxone significantly enhances pain. In these studies, patients had had their surgery performed under mepivacaine and N20 analgesia. The present results indicate that our previous finding of naloxone hyperalgesia was not due to reversal of an N20-induced analgesic effect. Thus the literature suggests both agonist and antagonist relationships between
169
N20 and opioid analgesics. Future studies will be required to determine the conditions for activation of the opioid-mediated analgesia system and which aspects of pain are controlled. Only then will it be possible to evaluate the complex interaction between endogenous opioids and N20 on the experience of pain.
Acknowledgements We are indebted to Jane Best, RN and Jean Lewis, RN for technic?,i assis~,ance with data collection, Dr. E.I. Eger for critical review of the manuscript, Ms. Evangelina Leash for editorial assistance and Ms. Molly Nugent for preparation of the manuscript. This research was supported by National Institute for Dental Research Grant No. DE 05369.
References ! Aitken, R.C.B., A growing edge of measurement of feelings, Proc. roy. Soc. Med., 62 (1969) 989-992. 2 Beecher, H.K., The Measurement of Subjective Responses: Quantitative Effects of Drugs, Oxford University Press, New York, 1959. 3 Berkowitz, B.A., Finck, A.D. and Ngai, S.H., Nitrous oxide analgesia: reversal by naloxone and development of tolerance, J. Pharmacol. exp. Ther., 203 (1977) 539-547. 4 Chapman, C.R. and Benedetti, C., Nitrous oxide effects on cerebral evoked potential to pain, Anesthesiology, 5 ! ( i 979) 135- ! 38. 5 Chin, J.D., Crankshaw, D.P. and Kendig, J.J., Changes in the dorsal root potential with diazepam and with the analgesic aspirin, nitrous oxide, morphine and meperidine, Neuropharmacology, 13 (1974) 305-315. 6 Finck, A.D., Ngai, S.H. and Berkowitz, B.A., Antagonism of general anesthesia by naloxone in the rat, Anesthesiology, 46 (I 977) 241-245. 7 Gilman, M.A., Kok, L. and Lichtigfield, F.J., Paradoxical effect of naloxone on nitrous oxide analgesia in man, Europ. J. Pharmacol., 61 (1980) 175-177. 8 Gracely,' R., Personal communication ( ! 98 I). 9 Harper, MH., Winter, P.M., Johnson, B.H. and Eger, E.I., Naloxone does not antagonize general anaesthesia in the rat, Anesthesiology, 49 (1978) 3-5. 10 Jaffe, J.H. and Martin, W.R., Opioid analgesics and antagonists. In: A.G. Gilman et al. (Eds.), The Pharmacological Basis of Therapeutics, 6th edn., Macmillan, New York, 1980, pp. 494-534. !1 Joyce, C.R.B., Zutshi, D.W., Hrubes, V. and Mason, R.M., Comparisons of fixed interval and visual analog scales for rating chronic pain, Europ. J. clin. Pharmacol., 8 (1975) 425-430. 12 Levine, J.D., Gordon, N.C. and Fields, H.L., The mechanism of placebo analgesia, Lancet, ii (1978) 654-657. 13 Levine, J.D., Gordon, N.C., Jones, R.T. and Fields, H.L., The narcotic antagonist naloxone enhances clinical pain, Nature (Lond.), 272 (1978) 826-827. 14 Levine, J.D., Gordon, N.C. and Fields, H.L., Naloxone dose dependently produces analgesia and hyperalgesia in postoperative pain, Nature (Lond.), 278 (1979) 740-741. 15 Levine, J.D., Gordon, N.C., Smith, R. and Fields, H.L., Analgesic respenses to morphine and placebo in individuals with post-operative pain, Pain, i 0 ( ! 98 i) 379- 389. 16 Marshall, B.E. and Woilman, H., General anaesthetics. In: A.G. Gilman et al. (Eds.). The Pharmacological Basis of Therapeutics, 6th edn., MacMillan, New York, 1980, pp. 276-299. 17 Maruyama, Y., Shimoji, K., Shimizu, H., Sato, Y., Kuribayaski, H. and Kaied~l, R., Effects of morphine on human spinal cord and peripheral nervous activities, Pain, 8 (1980) 63-73.
170 18 Scott, J. and Huskisson, E.C., Graphic representation of pain, Pain, 2 (1976) 175-184. 19 Reviil, S.I., Robinson, J.O., Rosen, M. and Hogg, M.I.J., The reliability of a linear analogue for evaluating pain, Anaesthesia, 31 (1976) 1191-1198. 20 Smith, R.A., Wilson. M. and Miller, K.W., Naloxone has no effect on nitrous oxide anesthesia, Anesthesiology, 49 (1978) 6-8. 21 Yang, J.C., Clark, W.C. and Ngai, S.H., Antagonism of nitrous oxide analgesia by naloxone in man. Anesthesiology, 52 (1980) 414-417.
165
Elsevier Biomedical Press
Naloxone Fails to Antagonize Nitrous Oxide Analgesia for Clinical Pain Jon D. Levine ,,i, N e w t o n C. G o r d o n 2 a n d H o w a r d L. Fields 3 J Division of Rheumatology, Department of Medicine, 2 Dit~ision of Oral and Maxiliofacial Surgery, and 3 Department of NeuroloD,, Schools of Dentistry, and Medicine, University of California, San Francisco, Calif. 94143 (U.S.A.) (Received 26 May 198 i, accepted 4 November i 981)
Summary
In 30 patients with dental postoperative pain we tested the hypothesis that the analgesic effects of nitrous oxide (N20), a mild analgesic, may be mediated via endogenous opioids. Using the visual analog scale to assess pain, significant analgesia was induced by 33~o N20. N20-induced analgesia was not significantly antagonized by 10 mg of intravenous naloxone. In the setting of clinical pain there appears to be little if any contribution of endogenous opioids to N20-induced analgesia.
Introduction
Although nitrous oxide (N20) is commonly used as an analgesic agent, little is known about its mechanism of action. The observation that narcotic antagonists block analgesia induced by N20 or other gaseous agents in animals [3,6] raised the possibility that part of N20's action is mediated by the release of endogenous opioids. However, this antagonism has not been found in all studies [9,20]. Furthermore, the antagonism of N20-induced analgesia by narcotic antagonists differs significantly from their antagonism of opiate-induced analgesia. Thus, compared to its antagonism of opioid analgesia, antagonism of N20 analgesia by naloxone requires higher doses, and is either incomplete or has a briefer duration [3,7,21]. To date, naloxone's effects on N20 analgesia in humans has only been studied with experimentally induced pain [4,7,21]. However, narcotic analgesics are known * To whom all correspondence should be addressed. 0304-3959/82/0000-0000/$02.75 © 1982 Elsevier Biomedical Press
166 to have different effects on clinical and experimental pain [2]. We previously demonstrated that morpldne produces a dose-dependent analgesia for patients with dental postoperative pain [15]. In the present study we have used this same paradigm to evaluate naloxone reversal of N20 analgesia.
Methods
Thirty patients between the ages of 18 and 32 were studied. Consent to act as a subject was obtained using a form that followed the guidelines of the UCSF Committee on Human Experimentation. All subjects underwent a ~tai-,dardized surgical procedure for the removal of impacted third molars (wisdom teeth). Patients were premedicated with 10 mg of diazepam and during surge,ry 1~-40% r,itrous oxide and local nerve block with 3% mepivicaine without vasoconstriction were used to assure rapidly reversible anesthesia. Patients rated their pain by placing a vertical mark on a 10 cm undivided horizontal line which had the words 'no pain' at the left (0 cm) and 'worst pain ever' ~t the right (10 cm) end. The position of the mark, in millimeters, provided the meagure of pain level. The sensitivity and reproducibility of this scale has been documented elsewhere [ 1,11,18, i 91. Two hours after induction of anaesthesia patients rated their pain level and then were randomly assigned to 1 of 3 treatment groups of 10 patients eac.h. The first two groups received 33% N20 (2 l/min N20:4 l/rain 02) continuously throughout the remainder of the experiment (Fig. I). Ten minutes after N20 was started, pain level was again measured. One of these two groups then received a placebo and the other naloxone (10 mg), double blind, via an indwelling venous ca~,heter. A final pain level measurement was made 40 min after the intravenous drug was administered. To provide a control for the natural history of this pain, a third group of patients rated their pain at the same time as the patients in the other two groups but received no treatment.
Results
Fig. 1 demonstrates the analgesic effect of nitrous oxide (N20) in patients receiving either placebo or naloxone. Ten minutes following the start of N20 administration mean pain level decreased a small but significant amount in both groups of patients from 5.57 to 4.35 (22%) compared to the untreated control group (P < 0.01, Student's t-test). This reduction in mean pain level is approximately 33% compared with the no-treatment group whose pain rose from 5.53 to 6.61. By comparison, in a previous study, using the same type of patient and rating method, 8 mg of intravenous morphine reduced pain by an average of 57%. Despite the relatively small magnitude of the mean pain reduction, 90% of patients receiving N20 reported some reduction. In contrast, none of the no-treatment patients reported a reduction in pain. At 40 rain after starting N20 the patients who received
167
N20 also had lower mean pain levels than patients in the natural history group (P < 0.05, Student's t-test). The group who received N20 and then naloxone had mean pain identical to the NzO group that received placebo, that is, there is no
+2I +1 LU _.J
//// /
_z Ill
O
:<2[
U
.2l
I
N 2°
I
ADMINISTRATION
I
20 40 MINUTES
I
60
Fig. i. The time course of pain following extraction of impacted wisdom teeth in the 3 groups of patients: (O) no-treatment; (O) N20 followed by naloxone; and (A) N20 followed by placebo. The shaded bar shows the onset and duration of N20 administration. The intravenous drug (placebo or naloxone) was administered to patients receiving naloxone immediately following the 20 min pain rating.
apparent naloxone effect. Thus, N 2 0 appears to have a significant analgesic effect which is not affected by administration of b;gh doses of naloxone. The finding that mean pain levels in groups receiving placebo do not diverge from the pain level in the groups receiving naloxone was unexpected. We have previously demonstrated using this same postoperative pain paradigm that patients receiving naloxone have significantly greater pain than those receiving placebo [I 3,14]. Thus, in patients receiving NzO, if a placebo effect were present, one would expect patients who received naloxone to report greater pain than those who received placebo. One possible explanation of this failure to observe a naloxone effect is that N20 somehow interferes with the expression of placebo analgesia. In fact, N20 has been reported to reduce some of morphine's inhibitory actions on sensory systems in animals [5] and human subjects [17]. Under some circumstances placebo analgesia may fail to occur if some patients in the study do not receive an active analgesic drug [8]. The absence of such a group in the present experiment is an alternative explanation of our failure to produce a placebo effect in patients receiving N20.
168 Discussion
It is well-established that N20 produces effective, though incomplete analgesia for dental postoperative pain [16]. The present study indicates that the visual scale is a sensitive measure of N20 analgesia. Comparing the present results to our previous study of morphine using the visual analog scale and the same dental postoperative pain paradigm, 33~ N20 produces less relief than 8 mg of morphine i.v. However, using this clinical pain paradigm we were unable to demonstrate a significant antagonism of N20 analgesia by a dose of naloxone that effectively blocks both morphine and placebo analgesia [10,12]. Our results apparently conflict with previous studies demonstrating partial antagonism of N20 analgesia by opiate antagonists. Berkowitz et al. [3] demonstrated naloxone antagonism of N20 analgesia in mice and rats, but even with very large doses of naloxone (30 mg/kg/rat) significant residual N20 analgesia was still obs,ived. Furthermore, although tolerance to N20 for analgesia was reported, cross-tolerance between opiates and N20 was not studied. Tolerance to continued N20 administration was also seen in the present study. In human subjects, Chapman and Benedetti [4] reported a significant trend toward naloxone antagonism of N20 analgesia for experimental tooth pulp pain. They used a relatively low dose of naloxone (0.4 mg) and found that the degree of reversal of the N20 effect was extremely small (apparently less than 107o using a categorical scale). Yang et al. [21] reported that N20 analgesia for tourniquet pain was significantly antagonized by 4 and 8 mg of naloxone. With the higher dose of naloxone more than 50% of the N20 analgesic effect was apparently reversed. Although our results conflict with tb~,se of Yang et al. there were significant methodological differences between our experiment and theirs. First, we used a clinical paradigm with a continuous pain whose onset preceded naloxone administration. Second, we used a visual analog scale, which is continuous and may not distinguish sensory from affective components of pain. Finally since doing the tourniquet test once may affect subsequent pain ratings in the same subject the pain ratings on the tourniquet test in pre-injection control periods are not strictly comparable to subsequent tests on the same subject. Thus the m~gnitude of the N20 effect and of its reversal by naloxone is difficult to assess in their study. If the N20 effect were more pronounced on the sensory component of pair~, naloxone antagonism might be expected to be greater for an experimental pain studied with an intensity ~cale. It is interesting in this regard that in Chapman's study of tooth pulp stimulation, the effects of N20 on the cerebral evoked potential were completely reversed by doses of naloxone which had only a minimal effect on reported pain severity. This suggests that N20 may have different effects on different aspects of sensory processing. in previous studies [13,14] using the same clinical paradigm to study naloxone, we demonstrated that compared to placebo, naloxone significantly enhances pain. In these studies, patients had had their surgery performed under mepivacaine and N20 analgesia. The present results indicate that our previous finding of naloxone hyperalgesia was not due to reversal of an N20-induced analgesic effect. Thus the literature suggests both agonist and antagonist relationships between
169
N20 and opioid analgesics. Future studies will be required to determine the conditions for activation of the opioid-mediated analgesia system and which aspects of pain are controlled. Only then will it be possible to evaluate the complex interaction between endogenous opioids and N20 on the experience of pain.
Acknowledgements We are indebted to Jane Best, RN and Jean Lewis, RN for technic?,i assis~,ance with data collection, Dr. E.I. Eger for critical review of the manuscript, Ms. Evangelina Leash for editorial assistance and Ms. Molly Nugent for preparation of the manuscript. This research was supported by National Institute for Dental Research Grant No. DE 05369.
References ! Aitken, R.C.B., A growing edge of measurement of feelings, Proc. roy. Soc. Med., 62 (1969) 989-992. 2 Beecher, H.K., The Measurement of Subjective Responses: Quantitative Effects of Drugs, Oxford University Press, New York, 1959. 3 Berkowitz, B.A., Finck, A.D. and Ngai, S.H., Nitrous oxide analgesia: reversal by naloxone and development of tolerance, J. Pharmacol. exp. Ther., 203 (1977) 539-547. 4 Chapman, C.R. and Benedetti, C., Nitrous oxide effects on cerebral evoked potential to pain, Anesthesiology, 5 ! ( i 979) 135- ! 38. 5 Chin, J.D., Crankshaw, D.P. and Kendig, J.J., Changes in the dorsal root potential with diazepam and with the analgesic aspirin, nitrous oxide, morphine and meperidine, Neuropharmacology, 13 (1974) 305-315. 6 Finck, A.D., Ngai, S.H. and Berkowitz, B.A., Antagonism of general anesthesia by naloxone in the rat, Anesthesiology, 46 (I 977) 241-245. 7 Gilman, M.A., Kok, L. and Lichtigfield, F.J., Paradoxical effect of naloxone on nitrous oxide analgesia in man, Europ. J. Pharmacol., 61 (1980) 175-177. 8 Gracely,' R., Personal communication ( ! 98 I). 9 Harper, MH., Winter, P.M., Johnson, B.H. and Eger, E.I., Naloxone does not antagonize general anaesthesia in the rat, Anesthesiology, 49 (1978) 3-5. 10 Jaffe, J.H. and Martin, W.R., Opioid analgesics and antagonists. In: A.G. Gilman et al. (Eds.), The Pharmacological Basis of Therapeutics, 6th edn., Macmillan, New York, 1980, pp. 494-534. !1 Joyce, C.R.B., Zutshi, D.W., Hrubes, V. and Mason, R.M., Comparisons of fixed interval and visual analog scales for rating chronic pain, Europ. J. clin. Pharmacol., 8 (1975) 425-430. 12 Levine, J.D., Gordon, N.C. and Fields, H.L., The mechanism of placebo analgesia, Lancet, ii (1978) 654-657. 13 Levine, J.D., Gordon, N.C., Jones, R.T. and Fields, H.L., The narcotic antagonist naloxone enhances clinical pain, Nature (Lond.), 272 (1978) 826-827. 14 Levine, J.D., Gordon, N.C. and Fields, H.L., Naloxone dose dependently produces analgesia and hyperalgesia in postoperative pain, Nature (Lond.), 278 (1979) 740-741. 15 Levine, J.D., Gordon, N.C., Smith, R. and Fields, H.L., Analgesic respenses to morphine and placebo in individuals with post-operative pain, Pain, i 0 ( ! 98 i) 379- 389. 16 Marshall, B.E. and Woilman, H., General anaesthetics. In: A.G. Gilman et al. (Eds.). The Pharmacological Basis of Therapeutics, 6th edn., MacMillan, New York, 1980, pp. 276-299. 17 Maruyama, Y., Shimoji, K., Shimizu, H., Sato, Y., Kuribayaski, H. and Kaied~l, R., Effects of morphine on human spinal cord and peripheral nervous activities, Pain, 8 (1980) 63-73.
170 18 Scott, J. and Huskisson, E.C., Graphic representation of pain, Pain, 2 (1976) 175-184. 19 Reviil, S.I., Robinson, J.O., Rosen, M. and Hogg, M.I.J., The reliability of a linear analogue for evaluating pain, Anaesthesia, 31 (1976) 1191-1198. 20 Smith, R.A., Wilson. M. and Miller, K.W., Naloxone has no effect on nitrous oxide anesthesia, Anesthesiology, 49 (1978) 6-8. 21 Yang, J.C., Clark, W.C. and Ngai, S.H., Antagonism of nitrous oxide analgesia by naloxone in man. Anesthesiology, 52 (1980) 414-417.