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A double-blind comparison between epidural morphine and epidural clonidine in patients with chronic non-cancer pain
123
Pain, 34 (1988) 123-128 Elsevier
PA1 01254
A double-blind comparison between epidural morphine and epidural clonidine in patients with chronic non-cancer pain Chris Glynn, David Dawson ’ and Rosemary
Sanders
2
Oxford Regional Pain Relief Unit, and Pain Relief Research Unit, Abingdon Hospital, Abingdon OX14 IAG (U.K.), and Nuffieid Department of Anaesthetics, The Radcliffe Infirmary, Oxford OX2 6HE (U.K.) (Received
28 August
1987, revision received and accepted
2 March
1988)
In a random&d double-blind study of 20 patients with chronic pain, epidural morphine 5 mg in 5 ml of saline was S-arY compared with epidural clonidine 150 pg in 5 ml of saline. Thirteen patients had a clinical and radiological diagnosis of arachnoiditis, 6 had low back pain and 1 had post-operative scar pain. There were 18 females and 2 males with an average age of 52 years, range 22-76 years. There was no difference found between the 2 solutions in the resultant analgesia measured by the visual analogue scale for pain, pain relief or the pain word score during the 3 h period of the study. No difference was found in the patient’s mood which was also measured with the visual analogue scale. Two patients had no analgesia from either injection, 2 patients did not obtain any relief from clonidine and another 2 obtained no relief from morphine. Six patients reported that clonidine was better than morphine, 5 reported that morphine and clonidine were the same and 3 reported that morphine was better than clonidine. The duration of analgesia from the clonidine varied from 6 h to 1 month; the duration of analgesia from morphine varied from 6 to 24 h. Clonidine was associated with sedation and a fall in blood pressure of greater than 20 mm Hg in all patients, 1 patient required ephedrine to treat hypotension. Twelve patients had pruritus, 7 nausea and 2 vomiting following the morphine. Statistically there was no difference found between morphine and clonidine for short-term (3 h) analgesia in these patients. The duration of analgesia from clonidine in 2 patients was about 1 month while that from morphine did not exceed 24 h. The side effects from clonidine were less than those for morphine. This group of patients was unable to differentiate between epidural morphine and clonidine for short-term analgesia. Further evidence of the importance of the spinal noradrenergic system in the transmission and treatment of patients with chronic pain.
Key words:
Epidural
morphine;
Epidural
clonidine;
Non-cancer
Introduction It has been reported that epidural clonidine provides analgesia for patients with deafferenta-
t Present address: Department firmary, Bradford, U.K. 2 Present address: Department eral Hospital, Banbury, U.K.
of Anaesthetics,
Bradford
of Anaesthetics,
Horton
Gen-
Correspondence to: Chris Glynn, Pain Relief Research Abingdon Hospital, Abingdon OX14 lAG, U.K.
Unit,
03043959/88/$03.50
0 1988 Elsevier Science Publishers
In-
pain
tion pain associated with spinal cord injury. In addition, it has been shown that in some patients this analgesia is better than that provided by epidural morphine [5]. There is a deal of experimental evidence available in animals which suggests that clonidine given intrathecally is as effective as morphine for acute pain [15]. Clonidine has been reported to be an analgesic in man [2,7,12] and has also been reported to be effective for post-operative pain when given epidurally [lo]. Other reports of the use of epidural clonidine have all suggested that it is only analgesic when used in
B.V. (Biomedical
Division)
124
conjunction with morphine [2]. However, the evidence presented from the comparison of epidural clonidine and epidural morphine in patients with deafferentation pain suggests that for this type of pain clonidine is a more effective analgesic than is morphine 151. This result may also mean that the transmission of pain at the dorsal horn of the spinal cord in patients with deafferentation pain is different from that in patients with other types of pain. The clinical observation that there are certain patients with pain or types of pain which may be marphine insensitive [l] suggests that there may be a different transmission system for these patients or these types of pain. There is no good experimental model for chronic pain and so any further investigation of the possible role of epidural clonidine in the treatment of chronic pain necessitates epidural injection in patients with chronic pain, A recent publication has shown that repeated epidural injections of clonidine in animals produced no evidence of neurotoxicity in the spinal cord [S]. The evidence available suggests that epidural clonidine may have a role in the treatment of patients with chronic pain and that its presumed mode of action is at the dorsal horn of the spinal cord [2,5,6,7,10, 11.151. In order to investigate this role epidural clonidine was compared with the gold standard of spinal analgesics, rno~~ne. This study was a randomised, double-blind comparison of the 2 drugs in patients with chronic pain.
Patients
Twenty patients with chronic pain agreed to participate in the randomised double-blind study which had the approval of the local Ethics Committee. The patient details are shown in Table I: all the patients with the diagnosis of arachnoiditis [3] and myelographic evidence of scarring [9] as well as the clinical findings of neurological changes in the lower limb. Five of the 6 patients with low back pain also had radiological evidence of arachnoiditis but no neurological changes in the lower limbs.
Method On day 1 an epidural catheter was inserted in the upper lumbar region by either CC or RS. The position of this catheter was confirmed by numbness following the injection of 10 ml of 0.5% bupivacaine. All the questionnaires and the remaining 2 epidural injections were administered by DD. The patients were asked to record their pain, pain relief and mood using a visual analogue scale and also their pain using a simple ‘f-word description. These were completed before each injection and every 5 min for the first 30 min, then every 0.5 h for 3 h following the injection. The patients were asked about possible adverse effects of the injections at each of the recording times and the blood pressure was recorded at approximately 15 min intervals. On day 2 each patient was randomly allocated to receive either morphine 5 mg or clonidine 150 pg in 5 ml of physiological saline. On day 3, providing the patient’s pain had returned, the patient received the other solution with recordings being taken as described. If the patient’s pain had not returned, than the second injection was not given until the pain had returned.
Statistical analysis The pain intensity was rated as the difference between pain at zero time and at each subsequent observation and the pain intensity differences were summed to obtain an estimate of the area under the time-effect curve for the total effect (SPID). Thus there are 2 results for pain intensity; 1 for the visual analogue scale, VASSPID, and 1 for the word score, wordSPID [14]. Relief estimates were scored directly, ranging from 0 for no relief to 100 for total relief. Relief scores were totalled to obtain an estimate of total pain relief (TOTPAR) [14]. The mood scores were summed to obtain an estimate of the area under the time-effect curve for the total effect. The results for each VASSPID, wordSPIT), TOTPAR and the mood score from each injection in each patient were compared using the Wilcoxon paired test.
125
Results Analgesia No statistical difference was found between the 2 solutions on any of the analgesic parameters recorded, that is this group of patients was unable to differentiate between epidural morphine and epidural clonidine as far as pain intensity on either scale or pain relief was concerned (Figs. 1 and 2). Two patients recorded no analgesia with either drug, 5 patients recorded better analgesia with morphine, 5 patients recorded that the 2 drugs were equal and 8 patients recorded that clonidine was better than morphine. Four patients did not record any pain relief after clonidine, 2 of whom had no response from either drug and 2 of whom had relief from morphine only. Two patients obtained analgesia from clonidine but no relief from morphine. Thus 16 of the 20 patients recorded pain relief from clonidine and 3 of these TABLE
found that morphine was the better, 5 could not distinguish between the drugs and 8 found that clonidine was the better. The responses of the individual patients to each drug are shown in Table I. Two patients who received clonidine first had no pain on day 2 and had to wait 1 month until the pain returned for the second injection. This did not occur with any of the patients who had morphine first, as their pain had returned to ‘normal’ by day 2. The patients with ‘deafferentation’-type pain viz., arachnoiditis and post-operative scar pain, obtained better analgesia from the clonidine than from morphine, whereas the patients with low back pain obtained better analgesia from the morphine than from the clonidine.
Mood There was no statistical
difference
found be-
I
DEMOGRAPHIC DETAILS OF THE PATIENTS ANALGESIA FOLLOWING EACH INJECTION
STUDIED
TOGETHER
WITH
THE
OVERALL
RESULTS
0 = no analgesia; + = analgesia; + + = better analgesia. No.
Age
Sex
Diagnosis
(years)
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
42 76 50 43 49 66 22 50 56 37 53 76 55 47 53 38 52
f f f f f f f f f f f f f f f m f
18 19 20
64 66 44
m f f
1
Arachnoiditis Arachnoiditis Low back pain Arachnoiditis * Arachnoiditis Arachnoiditis * Low back pain Arachnoiditis Arachnoiditis Arachnoiditis Arachnoiditis Arachnoiditis Arachnoiditis Low back pain Arachnoiditis Low back pain Postoperative scar pain Arachnoiditis Arachnoiditis Low back pain
Duration of pain (months) 8 7 20 2 8 8 1 13 7 3 10 4 4 4 10 6 6 L
6 4
* Indicates the patients who had 1 month’s analgesia from the clonidine.
Effect of epidural Morphine
Clonidine
0 0 ++ + + + + + 0 + + + +
0
0 +
0 ++
+
0
+ + ++ + ++ 0 ++ + + ++ + +
I
+
++ ++ +
+ + ++
OF THE
126
LLI
100 80 60 :I .E 2 40-
80 L 60 -0 g 40-
20 n E
”
0 -t
111 I
O-
Intensity Relief
1 9 I - I ’ 1 ’ I . f ’ I . r . 1 1
10
30
50
70
90 110 Minutes
130
150
170
190
Fig. 1. This figure shows the means with S.D. of the reported pain intensity and pain relief following epidural morphine 5 mg in 5 ml of physiological saline, for the 3 h of the study.
tween either solution when the results of the mood visual analogue scales were compared (Fig. 3). Side effects Epidural morphine produced side effects in all but 4 patients, these were pruritus in 12, nausea in 7 and vomiting in 2 patients. Epidural clonidine produced a fall in blood pressure in all patients of greater than 20 mm Hg but this hypotension required treatment in only 1 patient. All patients were supine during the study and the blood pressure had returned to normal or almost normal by the end of the study period of 3 h. Epidural
Clonidine
looT 80
-
60 :I -2 40 a
-
10
30
50
70
90
110 130 Minutes
150
170
190
210
Fig. 2. This figure shows the means with S.D. of the reported pain intensity and pain relief following epidural clonidine 150 pg in 5 ml of physiological saline, for the 3 h of the study.
-m
Clonidine
*
Morphine
I . I . I . , . I . I 10
30
50
70
90
110
130
, 150
I . I ’ 170
190
Minutes
Fig. 3. This figure shows the means with S.D. of the reported mood scores following epidural morphine 5 mg in 5 ml of physiological saline and epidural clonidine 150 pg in 5 ml of physiological saline.
clonidine produced in all patients.
greater sedation
than morphine
Discussion
The results of this study suggest that these patients with chronic pain cannot distinguish between epidural clonidine and epidural morphine when measuring short-term analgesia (3 h). The epidural route was chosen because it is known that drugs given by this route result in l-100 times as much drug in the CSF as in the blood and so the major effect of the drug is assumed to be at the spinal cord. This ratio of dural transmission has also been reported with epidural clonidine [4]. Thus the assumption is that the major effect of the drug is at the spinal cord and this is an accepted mechanism for morphine which is considered to be the most effective spinal analgesic. The study was designed to compare spinal analgesia provided by morphine with clonidine. In this way two of the known spinal analgesic pathways, the opioid and the noradrenergic, could be examined in the same patient. The results suggest that the noradrenergic system may be as important as the opioid system in these patients. This may be due to the preponderance of patients (13) with arachnoiditis which is considered to be a cause of
127
deafferentation pain and as such has been reported to be morphine insensitive [13]. Morphine did not provide any analgesia for 4 patients only and 2 of these did not obtain any relief with clonidine, nor with local anaesthetics which produced numbness in the area of their pain. Two patients reported analgesia with morphine and none with clonidine. Thus the 2 systems appear to be involved in the pain transmission in 16 patients, 13 of these patients reported that clonidine was equal to or better than morphine which suggests that the noradrenergic system may be as or more important than the opioid system in the transmission of chronic pain in these patients. The data shown in Figs. 1 and 2 may indicate that morphine overall is the more effective analgesic, but statistical analysis did not confirm this; a study of a greater number of patients may confirm this suggestion. It is interesting to note that the patients with the ‘deafferentation’-type pain, viz., arachnoiditis and post-operative scar pain, obtained better analgesia with clonidine than they did with morphine. These patients all had demonstrable neurological changes which would fit with the diagnosis of deafferentation pain [3], whereas the patients with low back pain, who had no demonstrable abnormal neurology, obtained better analgesia with morphine than with clonidine. Thus it would seem that epidural clonidine may have a role in the treatment of patients with deafferentation pain, and recently published data support this concept that epidural clonidine is most effective in those patients with abnormal neurology [6]. The double-blind nature of the study was compromised by the incidence of the side effects because 16 of the 20 patients had the classical side effects from morphine, pruritus, nausea and vomiting. The clonidine was always associated with a fall in blood pressure but only 1 patient required therapy. Thus the study was single-blind once the side effects were identified, usually after between 30 and 60 min. However, as Figs. 1 and 2 show the changes in pain intensity and pain relief were well established by 30 min; indeed, there was very little change after 30 min for either drug in either of these parameters. It is interesting to note that the unpleasant side effects of morphine in 16
patients did not alter the reported pain intensity or relief. The patient was unaware of which solution was being injected but the observer (DD) knew. However, the observer (DD), who gave all the injections and also recorded all the results, had not met the patients before the first injection which should limit the placebo effect. These data mean that clonidine has fewer side effects than does morphine when the drugs are given epidurally. Thus epidural clonidine has fewer side effects and is as good as or better than epidural morphine for pain relief in these patients with chronic pain. The design of the study is such that it may not identify placebo reactors, as the control group also received an active drug, morphine. This means that clonidine has been compared to the best available spinal analgesic at the expense of identification of placebo reactors. It is unlikely that the 18 of the 20 patients who obtained pain relief were all placebo reactors because (1) not all patients showed responses to all drugs, and (2) the change in pain intensity and relief showed a distinct time course. The reason for not designing a placebocontrolled study was that at the end of such a study all that could be said would be that clonidine was as good, better or worse than placebo, whereas in this study, clonidine has compared favourably to the best available spinal analgesic. There is an interesting observation in this study of antiplacebo reactors, ‘Negato,’ as the 2 patients who did not obtain any analgesia from epidural morphine, clonidine or local anaesthetic seemed to do their best to confuse the study. One of these patients reported the same score for all parameters throughout the study period, that is, pain intensity of 100, pain relief of 0, mood score of 0, and the highest on the word score. This patient had previously had good analgesia from local anaesthetics. The other patient reported once, but at different times during the study, no pain, total pain relief, best mood and lowest on the word score, i.e., there was no correlation between any of these ‘odd’ results, they were reported by this patient randomly. This would seem to be an overt attempt to confuse the results. Another possibility is thaf these 2 patients did not understand the scoring system; the first patient maintained that she understood the system but that none of the injec-
128
tions had any effect. The second patient scored logically on all scales throughout the study, apart from the ‘one result.’ It is also possible that records were ‘true,’ but, given what is understood about patients with chronic pain, it is most likely that these 2 patients are reporting something else, not pain. Thus the design of this study may not identify placebo reactors but what it may have shown is that there are patients who respond in the opposite way to placebo reactors. This is not at all surprising, given the nature of the placebo response and the response of some patients to chronic pain, that is, there must also be antiplacebo (Negato) responders. The 2 patients who obtained approximately 1 month’s pain relief with epidural clonidine illustrate the enigma of injections in patients with chronic pain, i.e., that long-term relief has been reported at one time from afl injections, whether active or inactive. The reason for this long-term response varies with the patient, the doctor, the time and the place. At one end of the spectrum it may be a placebo response and at the other end a physiological response, with alteration of the transmission of pain in the spinal cord, by clonidine in this instance. Thus the evidence from this study and those previously published [2,5,6,7,10, 11,151 suggest that epidural clonidine may have a role in the treatment of patients with chronic pain. Its possible role in the treatment of patients with arachnoiditis is emphasised because in the 2 patients (10%) who obtained 1 month’s relief with epidural clonidine, this effect was repeatable provided that the drug was given epidurally.
Acknowledgements The authors would like to thank Dr. B. Winsley and the staff of the Pharmacy of The John Radcliffe Hospital for preparing the solutions. We would also like to thank Dr. H.J. McQuay for his statistical advice and Mrs. L. Rennells for her help in preparing this manuscript.
References 1 Am&, S. and Am&, B., Differential effects of epidural morphine in the treatment of cancer related pain, Acta Anaesth. Stand., 29 (1985) 32-36. 2 Coombs, D.W., Saunders, R.L., Lachance, D., Savage, S.. Ragnarsson, T.S. and Jensen, L.E., Intrathecal morphine tolerance: use of intrathecal clonidine, DADLE and intraventricular morphine, Anesthesiology, 62 (1985) 358-363. 3 Dubuisson, D., Nerve root damage and arachnoiditis. In: P.D. Wall and R. Melzack (Eds.), Textbook of Pain. Churchill Livingstone, Edinburgh, 1984, pp. 435-450. 4 Glynn, C.J., Intrathecal and epidural opiates. In: K. Budd (Ed.), Ball&e’s Clinical Anaesthesiology. Update in Opiates, Ball&e, London, 1988, pp. 915-933. 5 Glynn, C.J., Jamous, M.A., Teddy, P.J., Moore, R.A. and Lloyd, J.W., Role of spinal noradrenergic system in transmission of pain in patients with spinal cord injury, Lancet. ii (1986) 1249-1250. 6 Glynn, C.J., Jamous, M.A., Dawson, D., Sanders, R., Teddy, P.J., Moore, R.A. and Lloyd, J.W., The role of epidural clonidine in the treatment of patients with intractable pain, Pain, Suppl. 4 (1987) S45. 7 Goldstein, J., Clonidine as an analgesic, Biol. Psychiat., 18 (1983) 1339-1340. 8 Gordh, T., Post, C. and Olsson, Y., Evaluation of the toxicity of subarachnoid clonidine, guanfacine and substance P-antagonist on rat spinal cord and nerve roots, Anesth. Analg., 65 (1986) 1303-l 311. 9 Jorgensen, J., Hansen, P.H., Steenskov, V. and Ovesen, N., A clinical and radiological study of chronic lower spinal arachnoiditis, Neuroradiology, 9 (1975) 139-144. 10 Kalia, P.K., Madan, R., Batra, R.K., Latha, L., Vardhan, V. and Code, G.R., Clinical study on epidural clonidine for post-operative analgesia, Ind. J. Med. Res., 83 (1986) 550-552. 11 Petros, A.J. and Bowen-Wright, R.M., Epidural and oral clonidine in domiciliary control of deafferentation pain, Lance& i (1987) 1034. 12 Tamsen, A. and Gordh, T., Epidural clonidine produces analgesia, Lancet, ii (1984) 231-232. R.R., Deafferentation. In: P.D. Wall and R. 13 Tasker, Melzack (Eds.), Texbook of Pain, Churchill Livingstone, Edinburgh, 1984, pp. 119-132. 14 Walenstein, S. and Houde, R.W., The clinical evaluation of analgesic effectiveness, In: S. Ehrenpreis and A. Neidle (Eds.), Methods in Narcotic Research, Marcel Dekker, New York, 1975, pp. 127-145. of spinal adrenergic system 15 Yaksh, T.L., Pharmacology which modulates spinal nociceptive processing, Pharmacol. B&hem. Behav., 22 (1985) 845-858.
Pain, 34 (1988) 123-128 Elsevier
PA1 01254
A double-blind comparison between epidural morphine and epidural clonidine in patients with chronic non-cancer pain Chris Glynn, David Dawson ’ and Rosemary
Sanders
2
Oxford Regional Pain Relief Unit, and Pain Relief Research Unit, Abingdon Hospital, Abingdon OX14 IAG (U.K.), and Nuffieid Department of Anaesthetics, The Radcliffe Infirmary, Oxford OX2 6HE (U.K.) (Received
28 August
1987, revision received and accepted
2 March
1988)
In a random&d double-blind study of 20 patients with chronic pain, epidural morphine 5 mg in 5 ml of saline was S-arY compared with epidural clonidine 150 pg in 5 ml of saline. Thirteen patients had a clinical and radiological diagnosis of arachnoiditis, 6 had low back pain and 1 had post-operative scar pain. There were 18 females and 2 males with an average age of 52 years, range 22-76 years. There was no difference found between the 2 solutions in the resultant analgesia measured by the visual analogue scale for pain, pain relief or the pain word score during the 3 h period of the study. No difference was found in the patient’s mood which was also measured with the visual analogue scale. Two patients had no analgesia from either injection, 2 patients did not obtain any relief from clonidine and another 2 obtained no relief from morphine. Six patients reported that clonidine was better than morphine, 5 reported that morphine and clonidine were the same and 3 reported that morphine was better than clonidine. The duration of analgesia from the clonidine varied from 6 h to 1 month; the duration of analgesia from morphine varied from 6 to 24 h. Clonidine was associated with sedation and a fall in blood pressure of greater than 20 mm Hg in all patients, 1 patient required ephedrine to treat hypotension. Twelve patients had pruritus, 7 nausea and 2 vomiting following the morphine. Statistically there was no difference found between morphine and clonidine for short-term (3 h) analgesia in these patients. The duration of analgesia from clonidine in 2 patients was about 1 month while that from morphine did not exceed 24 h. The side effects from clonidine were less than those for morphine. This group of patients was unable to differentiate between epidural morphine and clonidine for short-term analgesia. Further evidence of the importance of the spinal noradrenergic system in the transmission and treatment of patients with chronic pain.
Key words:
Epidural
morphine;
Epidural
clonidine;
Non-cancer
Introduction It has been reported that epidural clonidine provides analgesia for patients with deafferenta-
t Present address: Department firmary, Bradford, U.K. 2 Present address: Department eral Hospital, Banbury, U.K.
of Anaesthetics,
Bradford
of Anaesthetics,
Horton
Gen-
Correspondence to: Chris Glynn, Pain Relief Research Abingdon Hospital, Abingdon OX14 lAG, U.K.
Unit,
03043959/88/$03.50
0 1988 Elsevier Science Publishers
In-
pain
tion pain associated with spinal cord injury. In addition, it has been shown that in some patients this analgesia is better than that provided by epidural morphine [5]. There is a deal of experimental evidence available in animals which suggests that clonidine given intrathecally is as effective as morphine for acute pain [15]. Clonidine has been reported to be an analgesic in man [2,7,12] and has also been reported to be effective for post-operative pain when given epidurally [lo]. Other reports of the use of epidural clonidine have all suggested that it is only analgesic when used in
B.V. (Biomedical
Division)
124
conjunction with morphine [2]. However, the evidence presented from the comparison of epidural clonidine and epidural morphine in patients with deafferentation pain suggests that for this type of pain clonidine is a more effective analgesic than is morphine 151. This result may also mean that the transmission of pain at the dorsal horn of the spinal cord in patients with deafferentation pain is different from that in patients with other types of pain. The clinical observation that there are certain patients with pain or types of pain which may be marphine insensitive [l] suggests that there may be a different transmission system for these patients or these types of pain. There is no good experimental model for chronic pain and so any further investigation of the possible role of epidural clonidine in the treatment of chronic pain necessitates epidural injection in patients with chronic pain, A recent publication has shown that repeated epidural injections of clonidine in animals produced no evidence of neurotoxicity in the spinal cord [S]. The evidence available suggests that epidural clonidine may have a role in the treatment of patients with chronic pain and that its presumed mode of action is at the dorsal horn of the spinal cord [2,5,6,7,10, 11.151. In order to investigate this role epidural clonidine was compared with the gold standard of spinal analgesics, rno~~ne. This study was a randomised, double-blind comparison of the 2 drugs in patients with chronic pain.
Patients
Twenty patients with chronic pain agreed to participate in the randomised double-blind study which had the approval of the local Ethics Committee. The patient details are shown in Table I: all the patients with the diagnosis of arachnoiditis [3] and myelographic evidence of scarring [9] as well as the clinical findings of neurological changes in the lower limb. Five of the 6 patients with low back pain also had radiological evidence of arachnoiditis but no neurological changes in the lower limbs.
Method On day 1 an epidural catheter was inserted in the upper lumbar region by either CC or RS. The position of this catheter was confirmed by numbness following the injection of 10 ml of 0.5% bupivacaine. All the questionnaires and the remaining 2 epidural injections were administered by DD. The patients were asked to record their pain, pain relief and mood using a visual analogue scale and also their pain using a simple ‘f-word description. These were completed before each injection and every 5 min for the first 30 min, then every 0.5 h for 3 h following the injection. The patients were asked about possible adverse effects of the injections at each of the recording times and the blood pressure was recorded at approximately 15 min intervals. On day 2 each patient was randomly allocated to receive either morphine 5 mg or clonidine 150 pg in 5 ml of physiological saline. On day 3, providing the patient’s pain had returned, the patient received the other solution with recordings being taken as described. If the patient’s pain had not returned, than the second injection was not given until the pain had returned.
Statistical analysis The pain intensity was rated as the difference between pain at zero time and at each subsequent observation and the pain intensity differences were summed to obtain an estimate of the area under the time-effect curve for the total effect (SPID). Thus there are 2 results for pain intensity; 1 for the visual analogue scale, VASSPID, and 1 for the word score, wordSPID [14]. Relief estimates were scored directly, ranging from 0 for no relief to 100 for total relief. Relief scores were totalled to obtain an estimate of total pain relief (TOTPAR) [14]. The mood scores were summed to obtain an estimate of the area under the time-effect curve for the total effect. The results for each VASSPID, wordSPIT), TOTPAR and the mood score from each injection in each patient were compared using the Wilcoxon paired test.
125
Results Analgesia No statistical difference was found between the 2 solutions on any of the analgesic parameters recorded, that is this group of patients was unable to differentiate between epidural morphine and epidural clonidine as far as pain intensity on either scale or pain relief was concerned (Figs. 1 and 2). Two patients recorded no analgesia with either drug, 5 patients recorded better analgesia with morphine, 5 patients recorded that the 2 drugs were equal and 8 patients recorded that clonidine was better than morphine. Four patients did not record any pain relief after clonidine, 2 of whom had no response from either drug and 2 of whom had relief from morphine only. Two patients obtained analgesia from clonidine but no relief from morphine. Thus 16 of the 20 patients recorded pain relief from clonidine and 3 of these TABLE
found that morphine was the better, 5 could not distinguish between the drugs and 8 found that clonidine was the better. The responses of the individual patients to each drug are shown in Table I. Two patients who received clonidine first had no pain on day 2 and had to wait 1 month until the pain returned for the second injection. This did not occur with any of the patients who had morphine first, as their pain had returned to ‘normal’ by day 2. The patients with ‘deafferentation’-type pain viz., arachnoiditis and post-operative scar pain, obtained better analgesia from the clonidine than from morphine, whereas the patients with low back pain obtained better analgesia from the morphine than from the clonidine.
Mood There was no statistical
difference
found be-
I
DEMOGRAPHIC DETAILS OF THE PATIENTS ANALGESIA FOLLOWING EACH INJECTION
STUDIED
TOGETHER
WITH
THE
OVERALL
RESULTS
0 = no analgesia; + = analgesia; + + = better analgesia. No.
Age
Sex
Diagnosis
(years)
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
42 76 50 43 49 66 22 50 56 37 53 76 55 47 53 38 52
f f f f f f f f f f f f f f f m f
18 19 20
64 66 44
m f f
1
Arachnoiditis Arachnoiditis Low back pain Arachnoiditis * Arachnoiditis Arachnoiditis * Low back pain Arachnoiditis Arachnoiditis Arachnoiditis Arachnoiditis Arachnoiditis Arachnoiditis Low back pain Arachnoiditis Low back pain Postoperative scar pain Arachnoiditis Arachnoiditis Low back pain
Duration of pain (months) 8 7 20 2 8 8 1 13 7 3 10 4 4 4 10 6 6 L
6 4
* Indicates the patients who had 1 month’s analgesia from the clonidine.
Effect of epidural Morphine
Clonidine
0 0 ++ + + + + + 0 + + + +
0
0 +
0 ++
+
0
+ + ++ + ++ 0 ++ + + ++ + +
I
+
++ ++ +
+ + ++
OF THE
126
LLI
100 80 60 :I .E 2 40-
80 L 60 -0 g 40-
20 n E
”
0 -t
111 I
O-
Intensity Relief
1 9 I - I ’ 1 ’ I . f ’ I . r . 1 1
10
30
50
70
90 110 Minutes
130
150
170
190
Fig. 1. This figure shows the means with S.D. of the reported pain intensity and pain relief following epidural morphine 5 mg in 5 ml of physiological saline, for the 3 h of the study.
tween either solution when the results of the mood visual analogue scales were compared (Fig. 3). Side effects Epidural morphine produced side effects in all but 4 patients, these were pruritus in 12, nausea in 7 and vomiting in 2 patients. Epidural clonidine produced a fall in blood pressure in all patients of greater than 20 mm Hg but this hypotension required treatment in only 1 patient. All patients were supine during the study and the blood pressure had returned to normal or almost normal by the end of the study period of 3 h. Epidural
Clonidine
looT 80
-
60 :I -2 40 a
-
10
30
50
70
90
110 130 Minutes
150
170
190
210
Fig. 2. This figure shows the means with S.D. of the reported pain intensity and pain relief following epidural clonidine 150 pg in 5 ml of physiological saline, for the 3 h of the study.
-m
Clonidine
*
Morphine
I . I . I . , . I . I 10
30
50
70
90
110
130
, 150
I . I ’ 170
190
Minutes
Fig. 3. This figure shows the means with S.D. of the reported mood scores following epidural morphine 5 mg in 5 ml of physiological saline and epidural clonidine 150 pg in 5 ml of physiological saline.
clonidine produced in all patients.
greater sedation
than morphine
Discussion
The results of this study suggest that these patients with chronic pain cannot distinguish between epidural clonidine and epidural morphine when measuring short-term analgesia (3 h). The epidural route was chosen because it is known that drugs given by this route result in l-100 times as much drug in the CSF as in the blood and so the major effect of the drug is assumed to be at the spinal cord. This ratio of dural transmission has also been reported with epidural clonidine [4]. Thus the assumption is that the major effect of the drug is at the spinal cord and this is an accepted mechanism for morphine which is considered to be the most effective spinal analgesic. The study was designed to compare spinal analgesia provided by morphine with clonidine. In this way two of the known spinal analgesic pathways, the opioid and the noradrenergic, could be examined in the same patient. The results suggest that the noradrenergic system may be as important as the opioid system in these patients. This may be due to the preponderance of patients (13) with arachnoiditis which is considered to be a cause of
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deafferentation pain and as such has been reported to be morphine insensitive [13]. Morphine did not provide any analgesia for 4 patients only and 2 of these did not obtain any relief with clonidine, nor with local anaesthetics which produced numbness in the area of their pain. Two patients reported analgesia with morphine and none with clonidine. Thus the 2 systems appear to be involved in the pain transmission in 16 patients, 13 of these patients reported that clonidine was equal to or better than morphine which suggests that the noradrenergic system may be as or more important than the opioid system in the transmission of chronic pain in these patients. The data shown in Figs. 1 and 2 may indicate that morphine overall is the more effective analgesic, but statistical analysis did not confirm this; a study of a greater number of patients may confirm this suggestion. It is interesting to note that the patients with the ‘deafferentation’-type pain, viz., arachnoiditis and post-operative scar pain, obtained better analgesia with clonidine than they did with morphine. These patients all had demonstrable neurological changes which would fit with the diagnosis of deafferentation pain [3], whereas the patients with low back pain, who had no demonstrable abnormal neurology, obtained better analgesia with morphine than with clonidine. Thus it would seem that epidural clonidine may have a role in the treatment of patients with deafferentation pain, and recently published data support this concept that epidural clonidine is most effective in those patients with abnormal neurology [6]. The double-blind nature of the study was compromised by the incidence of the side effects because 16 of the 20 patients had the classical side effects from morphine, pruritus, nausea and vomiting. The clonidine was always associated with a fall in blood pressure but only 1 patient required therapy. Thus the study was single-blind once the side effects were identified, usually after between 30 and 60 min. However, as Figs. 1 and 2 show the changes in pain intensity and pain relief were well established by 30 min; indeed, there was very little change after 30 min for either drug in either of these parameters. It is interesting to note that the unpleasant side effects of morphine in 16
patients did not alter the reported pain intensity or relief. The patient was unaware of which solution was being injected but the observer (DD) knew. However, the observer (DD), who gave all the injections and also recorded all the results, had not met the patients before the first injection which should limit the placebo effect. These data mean that clonidine has fewer side effects than does morphine when the drugs are given epidurally. Thus epidural clonidine has fewer side effects and is as good as or better than epidural morphine for pain relief in these patients with chronic pain. The design of the study is such that it may not identify placebo reactors, as the control group also received an active drug, morphine. This means that clonidine has been compared to the best available spinal analgesic at the expense of identification of placebo reactors. It is unlikely that the 18 of the 20 patients who obtained pain relief were all placebo reactors because (1) not all patients showed responses to all drugs, and (2) the change in pain intensity and relief showed a distinct time course. The reason for not designing a placebocontrolled study was that at the end of such a study all that could be said would be that clonidine was as good, better or worse than placebo, whereas in this study, clonidine has compared favourably to the best available spinal analgesic. There is an interesting observation in this study of antiplacebo reactors, ‘Negato,’ as the 2 patients who did not obtain any analgesia from epidural morphine, clonidine or local anaesthetic seemed to do their best to confuse the study. One of these patients reported the same score for all parameters throughout the study period, that is, pain intensity of 100, pain relief of 0, mood score of 0, and the highest on the word score. This patient had previously had good analgesia from local anaesthetics. The other patient reported once, but at different times during the study, no pain, total pain relief, best mood and lowest on the word score, i.e., there was no correlation between any of these ‘odd’ results, they were reported by this patient randomly. This would seem to be an overt attempt to confuse the results. Another possibility is thaf these 2 patients did not understand the scoring system; the first patient maintained that she understood the system but that none of the injec-
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tions had any effect. The second patient scored logically on all scales throughout the study, apart from the ‘one result.’ It is also possible that records were ‘true,’ but, given what is understood about patients with chronic pain, it is most likely that these 2 patients are reporting something else, not pain. Thus the design of this study may not identify placebo reactors but what it may have shown is that there are patients who respond in the opposite way to placebo reactors. This is not at all surprising, given the nature of the placebo response and the response of some patients to chronic pain, that is, there must also be antiplacebo (Negato) responders. The 2 patients who obtained approximately 1 month’s pain relief with epidural clonidine illustrate the enigma of injections in patients with chronic pain, i.e., that long-term relief has been reported at one time from afl injections, whether active or inactive. The reason for this long-term response varies with the patient, the doctor, the time and the place. At one end of the spectrum it may be a placebo response and at the other end a physiological response, with alteration of the transmission of pain in the spinal cord, by clonidine in this instance. Thus the evidence from this study and those previously published [2,5,6,7,10, 11,151 suggest that epidural clonidine may have a role in the treatment of patients with chronic pain. Its possible role in the treatment of patients with arachnoiditis is emphasised because in the 2 patients (10%) who obtained 1 month’s relief with epidural clonidine, this effect was repeatable provided that the drug was given epidurally.
Acknowledgements The authors would like to thank Dr. B. Winsley and the staff of the Pharmacy of The John Radcliffe Hospital for preparing the solutions. We would also like to thank Dr. H.J. McQuay for his statistical advice and Mrs. L. Rennells for her help in preparing this manuscript.
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