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Topical glucocorticoid has no antinociceptive or anti-inflammatory effect in thermal injury
British Journal of Anaesthesia 1994; 72: 379-382
CLINICAL INVESTIGATIONS
Topical glucocorticoid has no antinociceptive or anti-inflammatory effect in thermal injury J. L . PEDERSEN, S. M0INICHE AND H . KEHLET
We have studied the antinociceptive and antiinflammatory effects of topical glucocorticoids in human thermal injury. The right and left legs of 12 healthy volunteers were allocated randomly to be treated with either 0.05% clobetasol propionate cream or placebo in a double-blind trial. Thermal injuries were induced with a thermode, which was heated to 49 °C for 5 min under standardized pressure. Clobetasol propionate or placebo cream was applied to the skin 1 h before burn injury, immediately after the injury and every 12 h for the next 3 days. Heat pain detection thresholds (HPDT), heat pain tolerance (HPT), mechanical pain detection thresholds (MPD T) and the intensity of burn-induced erythema (erythema index. El) were assessed inside the thermal injury and areas of hyperalgesia to pinprick outside the injury were determined before and regularly for 72 h after the burn injury. Burn injury caused a decrease in HPDT, HPT and MPDT, an increase in El and development of mechanical, secondary hyperalgesia. Clobetasol propionate had no effect on any of the nociceptive or inflammatory variables studied. (Br. J. Anaesth. 1994; 72: 379-382) KEY WORDS Pain: experimental. Pain: measurement Pharmacology: glucocorticoids.
Tissue injury causes inflammation, mediated by histamine, bradykinin, prostaglandins, substance P, cytokines and other mediators, leading to pain produced by stimulation of and changes in the excitability of the peripheral and central nervous system [1—5]. The alterations in nociceptive processing may be detected as primary and secondary hyperalgesia. Primary hyperalgesia refers to changes in sensibility within the injury and secondary hyperalgesia to changes in the undamaged tissue surrounding the injury. Clobetasol propionate 0.05 % is one of the most potent of currently available topical steroids. The glucocorticoids are highly effective antiinflammatory agents and may therefore modify nociceptive processing. We have not found any clinical studies of the antinociceptive effect of topical glucocorticoids applied in burn injury. The aim of the study therefore was to examine the effect of
topical clobetasol propionate cream on primary and secondary hyperalgesia and inflammation in thermal injury. SUBJECTS AND METHODS
We studied 12 healthy, unmedicated volunteers (10 male and two female), median age 31 yr (range 23-^14 yr), median height 179 cm (172-190 cm) and median weight 71 kg (60-88 kg). Informed consent was obtained from all subjects and the study was approved by the local Ethics Committee and the Danish National Health Board. Identical thermal injuries were produced on symmetrical skin areas on the medial surfaces of the right and left calf with a 15 x 25-mm thermode (Thermotest, Somedic A/B, Stockholm, Sweden). The thermode was applied to the skin at a standard pressure. The temperature of the thermode was 49 °C and it was applied for 5 min. This resulted in first or second degree burn injuries with small blisters measuring approximately 0.25 cm2 [6,7]. The right and left legs of each subject were allocated randomly to be treated with either 0.05 % clobetasol propionate cream (Dermovat, Glaxo, DK) or placebo cream (Glaxo, DK) in a double-blind trial. Thus the subjects acted as their own controls. Clobetasol propionate or placebo cream (0.2-0.3 g) was applied to the skin 1 h before burn injury, immediately after the injury and then every 12 h for the next 3 days. Primary hyperalgesia Thermal thresholds inside the injury were measured using a computerized thermode. The thermode was identical to that used for induction of the burn injuries. Heat pain detection threshold (HPDT) was defined as the lowest temperature perceived as painful and heat pain tolerance (HPT) was defined as the maximal tolerable temperature. Interpretation of "pain" was left to the subject, who was instructed to apply the same interpretation throughout the study. The measurements were made from a baseline temperature of 32 °C to a maximum temperature of 52 °C and the temperature was JURI LlNDY PEDERSEN, M.D., HENRIK KEHLET, M.D., PH.D.
(Department of Surgical Gastroenterology); STEEN M01NICHE, M.D. (Department of Anaesthesiology); Hvidovrc Hospital, University of Copenhagen, Kertegaard Alle' 30, 2650 Hvidovre, Denmark. Accepted for Publication: November 11, 1993. Correspondence to J.L.P.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 21, 2015
SUMMARY
BRITISH JOURNAL OF ANAESTHESIA
380
increased at a rate of 1 °C s '. The subjects were instructed to activate a push button when a sensation of pain was perceived (HPDT) and when maximal tolerable pain was perceived (HPT). HPDT was calculated as the average of three measurements performed at intervals of 9 s between each stimulation. Pain thresholds to mechanical stimulation (mechanical pain detection thresholds, MPDT) were determined by pinprick with nine progressively rigid nylon Frey's hairs (1 = 0.5 g, 9 = 16g) (Somedic A/B, Stockholm, Sweden). MPDT was denned as the smallest pressure (pinprick) which produced a sensation of pain inside the burn injury.
Post-burn erythema To estimate the severity of inflammation, the intensity of erythema inside the injury was assessed using a hand-held skin reflectance spectrophotometer (Dermaspectrometer, Cortex Technology, Hadsund, Denmark) [8]. The spectrophotometer provided a skin erythema index (El) based on the absorption characteristics of green and red light at 568 run and 655 run in the skin. Measurements were made in nine randomly chosen spots of the test areas. The median value and range were obtained. The development of blisters was recorded. Statistics The variables were evaluated using a non-parametric two-way analysis of variance for repeated measurements, the Sign test and Wilcoxon test for paired observations. When appropriate, Bonferroni's type I error correction for multiple tests of significance was used in Wilcoxon tests [9]. P < 0.05 was considered statistically significant.
o o
5 37 52 -i
_ 47u I
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 21, 2015
Secondary hyperalgesia The area of mechanical hyperalgesia that developed around the burn injury was assessed by pinprick with rigid (16 g) Frey's hairs. Borders of hyperalgesia were determined by stimulating along eight radial linear paths arranged from the centre of injury. Stimulation along each path began outside the hyperalgesic area where no sensation of pain was perceived, continuing towards the centre of the burn injury until the subject reported a definitive painful sensation. This point was marked and later traced onto a clear acetate sheet. From the eight points the area of secondary hyperalgesia to mechanical stimulation was calculated using a vector algorithm.
52 -,
42-
37 10-i 86-
2-
_ 40 -i
20-i 181614-
RESULTS
Results are summarized in figure 1. Primary hyperalgesia HPDT and HPT were not significantly different between the legs before treatment (HPDT, P = 0.91; HPT, P = 0.11) or immediately before injury (0 min) (HPDT, P = 0.26; HPT, P = 0.03) (Bonferroni's correction changed the level of significance to P < 0.025). HPDT and HPT decreased significantly (P < 0.01) from — 1 h to 0 min in both groups. After burn injury there was a further decrease (P < 0.01) in
1210 -10 3
24 48 Time after burn injury (h)
72
FIG. 1. Effect of thermal injury on heat pain detection thresholds (HPDT), heat pain tolerance (HPT), mechanical pain detection thresholds (MPDT), area of hyperalgesia to pinprick and erythema index (El) (arbitrary units) in the clobetasol propionate (A) and placebo ( • ) groups (n = 12). Time - 1 h indicates 1 h before thermal injury and 0 h indicates immediately before injury. Values are medians. For MPDT, 10 indicates that MPDT was over Frey's hair No. 9 (16 g). There were no significant differences between groups at any time (P < 0.05).
381
TOPICAL STEROIDS IN BURN INJURY both groups but there were no differences between steroid-treated and placebo-treated burn injuries at any time (HPDT, P = 1.00; HPT, P = 0.13). Pain thresholds to mechanical stimulation (MPDT) did not differ between legs before treatment (— 1 h, P = 1.00) or immediately before injury (Omin, P=1.00). MPDT decreased significantly (P < 0.01) from — 1 h to after burn injury in both groups but there were no differences between the treatment groups at any time after burn injury (P = 0.59). Secondary hyperalgesia
Post-burn erythema
ACKNOWLEDGEMENTS
El did not differ between groups before treatment ( - 1 h, P = 0.06) or before injury (0 min, P = 0.91). Blanching was observed from — 1 h to 0 min in placebo-treated (P = 0.02) but not in steroid-treated legs (P = 0.39). El increased significantly (P < 0.01) after burn injury in both treatment groups without significant differences between groups at any time after burn injury (P = 0.25). Development of blisters
Blisters developed in nine steroid-treated and in 12 placebo-treated burn injuries (P = 0.25). DISCUSSION
Glucocorticoids are known to inhibit the synthesis, release, or both, of several inflammatory mediators, for example prostaglandins and leukotrienes [10], bradykinin [11, 12], histamine [12, 13], platelet activating factor (PAF) [14], interleukin-1 (IL-1) [15] and tumour necrosis factor (TNF) [16], Most of these mediators have a sensitizing effect on nociceptors. We found no clinical reports on the antiinflammatory effect of glucocorticoids in human burn injuries, except for a letter [17] suggesting an antinociceptive and anti-inflammatory effect. Clobetasol propionate has been demonstrated to reduce erythema, pain and swelling after cryotherapy of dermal lesions [18]. Experimental studies have shown anti-inflammatory effects of topical steroids in burn injury, for example reduction of oedema and preserved dermal microcirculation [19-21]. Before undertaking this study, therefore, we expected that a high potency topical glucocorticoid would affect primary and secondary hyperalgesia in human first and second degree burn injury compared with placebo. However, we found that neither primary and secondary hyperalgesia nor the erythema and blister formation of the thermal injury were changed by steroid treatment. There are several possible reasons for this negative result. First, we applied clobetasol propionate 1 h before the heat trauma and this may have been too short, because one of the important mechanisms of
This study was supported by a grant from the John and Birte Meyer Foundation; Alfred Benzon's Fond; P. A. Messerschmidt and wife's Fond and Glaxo, Denmark. Dermovat and placebo cream were supplied by Glaxo, Denmark.
REFERENCES 1. Raja SN, Meyer RA, Campbell JN. Peripheral mechanisms of somatic pain. Anesthesiology 1988; 68: 571-590. 2. Treede RD, Meyer RA, Raja SN, Campbell JN. Peripheral and central mechanisms of cutaneous hyperalgesia. Progress in Neurobiology 1992; 38: 397-421. 3. Handwerker HO, Reeh PW. Pain and inflammation. In: Bond MR, Charlton JE, Woolf CJ, eds. Proceedings of the Vlth World Congress on Pain. Pain Research and Clinical Management. Amsterdam: Elsevier, 1991; 59—70. 4. Woolf CJ. Central mechanisms of acute pain. In: Bond MR, Charlton JE, Woolf CJ, eds. Proceedings of the Vlth World Congress on Pain. Pain Research and Clinical Management. Amsterdam: Elsevier, 1991; 25-34. 5. Dray A, Perkins M. Bradykinin and inflammatory pain. Trends in Neurological Sciences 1993; 16: 99-104. 6. Dahl JB, Brennum J, Arendt-Nielsen L, Jensen TS, Kehlet H. The effect of pre- versus postinjury infiltration with lidocaine on thermal and mechanical hyperalgesia after heat injury to the skin. Pain 1993; 53: 43-51. 7. Moiniche S, Dahl JB, Kehlet H. Time course of primary and secondary hyperalgesia after heat injury to the skin. British Journal of Anaesthesia 1993; 71: 201-205. 8. Bjerring P, Andersen PH. Skin reflectance spectrophotometry. Photodermatology 1987; 4: 167-171. 9. Andersen B, Holm P. Problems with p. Significance Testing in Medical Research. Basle: Editones Roche, 1992; 63-72. 10. Di Rosa M, Calignano A, Carnuccio R, Ialenti A, Sautebin L. Multiple control of inflammation by glucocorticoids. Agents and Actions 1985; 17: 284-289. 11. Hargreaves KM, Costello A. Glucocorticoids suppress level of immunoreactive bradykinin in inflamed tissue as evaluated by microdialysis probes. Clinical Pharmacology and Therapeutics 1990; 48: 168-178. 12. Pipkorn U, Proud D, Lichtenstein LM, Kagey-Sobotka A, Norman PS, Naclerio RM. Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticoids. New England Journal of Medicine 1987; 316: 1506-1510. 13. Stahle M, HSgermark 0 . Effect of topically applied clobetasol-17-propionate on histamine release in human skin. Acta Dermato-Venereologica (Stockholm) 1984; 64: 239-242. 14. Parente L, Flower RJ. Hydrocortisone and macrocortin inhibit the zymosan-induced release of lyso-PAF from rat peritoneal leucocytes. Life Sciences 1985; 36: 1225-1231. 15. Lew W, Oppenheim J, Matsushima K. Analysis of the suppression of IL-la and IL-lp" production in human peripheral blood mononuclear adherent cells by a gluco-
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 21, 2015
Secondary hyperalgesia developed after the burn injury in all legs, but there were no significant differences in area of secondary hyperalgesia between steroid-treated and placebo-treated legs at any time after burn injury (P = 0.52).
steroid action is controlling the expression of specific gene products (protein synthesis), which may take some hours [22, 23]. Second, injury leads to release of inflammatory mediators from depots in skin, for example IL-1 [24], as well as de novo synthesis, but the release from depots could well be steroidinsensitive. Third, although glucocorticoids may inhibit several inflammatory mediators, it is unlikely that all mediators in the burn-induced inflammatory response are influenced by steroids. Furthermore, the steroid-sensitive mediators, such as prostaglandins, may be suppressed only moderately by topical steroids in burn injury [21], therefore resulting in a largely unaltered response to burn injury. Finally, the multiplicity of and synergy between the inflammatory mediators may explain the lack of effect of glucocorticoids in thermal injury.
BRITISH JOURNAL OF ANAESTHESIA
382
16.
17. 18. 19. 20.
corticoid hormone. Journal of Immunology 1988; 140: 1895-1902. Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of cndotoxin resistance. Science 1986; 232: 977-980. Hindson TC, Hazell M, Wickramasinghe L. Clobetasol propionate ointment as first-aid for burns. Lancet 1987; 8541: 1087-1088. Hindson TC, Spiro J, Scon LV. Clobetasol propionate ointment reduces inflammation after cryotherapy. British Journal of Dermatology 1985; 112: 599-602. Robson MR, Kucan JO, Paik KI, Eriksson E. Prevention of dermal ischemia after thermal injury. Archtves of Surgery 1978; 113: 621-625. Robson MR, Del Beccaro EJ, Heggers JP. The effect of
21.
22. 23. 24.
prostaglandins on the microcirculation after burning, and the inhibition of the effect by specific pharmacological agents. Plastic and Reconstructive Surgery 1979; 63: 781-787. Bronaugh RL, Roller RG, CargiU R. The evaluation of topical anti-inflammatory activity on rat ears subjected to thermal injury. Journal of Investigative Dermatology 1978; 71: 263-265. Godowski PJ, Picard D, Yamamoto KR. Signal transduction and transcriptional regulation by glucocorticoid receptorLexA fusion proteins. Science 1988; 241: 812-816. Schleimer RP, Lichtenstein LM, Gillcspie E. Inhibition of basophil histamine release by anti-inflammatory steroids. Nature 1981; 292: 454-455. Kupper TS. Immune and inflammatory processes in cutaneous tissues. Mechanisms and speculations. Journal of Clinical Investigation 1990; 86: 1783-1789.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 21, 2015
CLINICAL INVESTIGATIONS
Topical glucocorticoid has no antinociceptive or anti-inflammatory effect in thermal injury J. L . PEDERSEN, S. M0INICHE AND H . KEHLET
We have studied the antinociceptive and antiinflammatory effects of topical glucocorticoids in human thermal injury. The right and left legs of 12 healthy volunteers were allocated randomly to be treated with either 0.05% clobetasol propionate cream or placebo in a double-blind trial. Thermal injuries were induced with a thermode, which was heated to 49 °C for 5 min under standardized pressure. Clobetasol propionate or placebo cream was applied to the skin 1 h before burn injury, immediately after the injury and every 12 h for the next 3 days. Heat pain detection thresholds (HPDT), heat pain tolerance (HPT), mechanical pain detection thresholds (MPD T) and the intensity of burn-induced erythema (erythema index. El) were assessed inside the thermal injury and areas of hyperalgesia to pinprick outside the injury were determined before and regularly for 72 h after the burn injury. Burn injury caused a decrease in HPDT, HPT and MPDT, an increase in El and development of mechanical, secondary hyperalgesia. Clobetasol propionate had no effect on any of the nociceptive or inflammatory variables studied. (Br. J. Anaesth. 1994; 72: 379-382) KEY WORDS Pain: experimental. Pain: measurement Pharmacology: glucocorticoids.
Tissue injury causes inflammation, mediated by histamine, bradykinin, prostaglandins, substance P, cytokines and other mediators, leading to pain produced by stimulation of and changes in the excitability of the peripheral and central nervous system [1—5]. The alterations in nociceptive processing may be detected as primary and secondary hyperalgesia. Primary hyperalgesia refers to changes in sensibility within the injury and secondary hyperalgesia to changes in the undamaged tissue surrounding the injury. Clobetasol propionate 0.05 % is one of the most potent of currently available topical steroids. The glucocorticoids are highly effective antiinflammatory agents and may therefore modify nociceptive processing. We have not found any clinical studies of the antinociceptive effect of topical glucocorticoids applied in burn injury. The aim of the study therefore was to examine the effect of
topical clobetasol propionate cream on primary and secondary hyperalgesia and inflammation in thermal injury. SUBJECTS AND METHODS
We studied 12 healthy, unmedicated volunteers (10 male and two female), median age 31 yr (range 23-^14 yr), median height 179 cm (172-190 cm) and median weight 71 kg (60-88 kg). Informed consent was obtained from all subjects and the study was approved by the local Ethics Committee and the Danish National Health Board. Identical thermal injuries were produced on symmetrical skin areas on the medial surfaces of the right and left calf with a 15 x 25-mm thermode (Thermotest, Somedic A/B, Stockholm, Sweden). The thermode was applied to the skin at a standard pressure. The temperature of the thermode was 49 °C and it was applied for 5 min. This resulted in first or second degree burn injuries with small blisters measuring approximately 0.25 cm2 [6,7]. The right and left legs of each subject were allocated randomly to be treated with either 0.05 % clobetasol propionate cream (Dermovat, Glaxo, DK) or placebo cream (Glaxo, DK) in a double-blind trial. Thus the subjects acted as their own controls. Clobetasol propionate or placebo cream (0.2-0.3 g) was applied to the skin 1 h before burn injury, immediately after the injury and then every 12 h for the next 3 days. Primary hyperalgesia Thermal thresholds inside the injury were measured using a computerized thermode. The thermode was identical to that used for induction of the burn injuries. Heat pain detection threshold (HPDT) was defined as the lowest temperature perceived as painful and heat pain tolerance (HPT) was defined as the maximal tolerable temperature. Interpretation of "pain" was left to the subject, who was instructed to apply the same interpretation throughout the study. The measurements were made from a baseline temperature of 32 °C to a maximum temperature of 52 °C and the temperature was JURI LlNDY PEDERSEN, M.D., HENRIK KEHLET, M.D., PH.D.
(Department of Surgical Gastroenterology); STEEN M01NICHE, M.D. (Department of Anaesthesiology); Hvidovrc Hospital, University of Copenhagen, Kertegaard Alle' 30, 2650 Hvidovre, Denmark. Accepted for Publication: November 11, 1993. Correspondence to J.L.P.
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 21, 2015
SUMMARY
BRITISH JOURNAL OF ANAESTHESIA
380
increased at a rate of 1 °C s '. The subjects were instructed to activate a push button when a sensation of pain was perceived (HPDT) and when maximal tolerable pain was perceived (HPT). HPDT was calculated as the average of three measurements performed at intervals of 9 s between each stimulation. Pain thresholds to mechanical stimulation (mechanical pain detection thresholds, MPDT) were determined by pinprick with nine progressively rigid nylon Frey's hairs (1 = 0.5 g, 9 = 16g) (Somedic A/B, Stockholm, Sweden). MPDT was denned as the smallest pressure (pinprick) which produced a sensation of pain inside the burn injury.
Post-burn erythema To estimate the severity of inflammation, the intensity of erythema inside the injury was assessed using a hand-held skin reflectance spectrophotometer (Dermaspectrometer, Cortex Technology, Hadsund, Denmark) [8]. The spectrophotometer provided a skin erythema index (El) based on the absorption characteristics of green and red light at 568 run and 655 run in the skin. Measurements were made in nine randomly chosen spots of the test areas. The median value and range were obtained. The development of blisters was recorded. Statistics The variables were evaluated using a non-parametric two-way analysis of variance for repeated measurements, the Sign test and Wilcoxon test for paired observations. When appropriate, Bonferroni's type I error correction for multiple tests of significance was used in Wilcoxon tests [9]. P < 0.05 was considered statistically significant.
o o
5 37 52 -i
_ 47u I
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 21, 2015
Secondary hyperalgesia The area of mechanical hyperalgesia that developed around the burn injury was assessed by pinprick with rigid (16 g) Frey's hairs. Borders of hyperalgesia were determined by stimulating along eight radial linear paths arranged from the centre of injury. Stimulation along each path began outside the hyperalgesic area where no sensation of pain was perceived, continuing towards the centre of the burn injury until the subject reported a definitive painful sensation. This point was marked and later traced onto a clear acetate sheet. From the eight points the area of secondary hyperalgesia to mechanical stimulation was calculated using a vector algorithm.
52 -,
42-
37 10-i 86-
2-
_ 40 -i
20-i 181614-
RESULTS
Results are summarized in figure 1. Primary hyperalgesia HPDT and HPT were not significantly different between the legs before treatment (HPDT, P = 0.91; HPT, P = 0.11) or immediately before injury (0 min) (HPDT, P = 0.26; HPT, P = 0.03) (Bonferroni's correction changed the level of significance to P < 0.025). HPDT and HPT decreased significantly (P < 0.01) from — 1 h to 0 min in both groups. After burn injury there was a further decrease (P < 0.01) in
1210 -10 3
24 48 Time after burn injury (h)
72
FIG. 1. Effect of thermal injury on heat pain detection thresholds (HPDT), heat pain tolerance (HPT), mechanical pain detection thresholds (MPDT), area of hyperalgesia to pinprick and erythema index (El) (arbitrary units) in the clobetasol propionate (A) and placebo ( • ) groups (n = 12). Time - 1 h indicates 1 h before thermal injury and 0 h indicates immediately before injury. Values are medians. For MPDT, 10 indicates that MPDT was over Frey's hair No. 9 (16 g). There were no significant differences between groups at any time (P < 0.05).
381
TOPICAL STEROIDS IN BURN INJURY both groups but there were no differences between steroid-treated and placebo-treated burn injuries at any time (HPDT, P = 1.00; HPT, P = 0.13). Pain thresholds to mechanical stimulation (MPDT) did not differ between legs before treatment (— 1 h, P = 1.00) or immediately before injury (Omin, P=1.00). MPDT decreased significantly (P < 0.01) from — 1 h to after burn injury in both groups but there were no differences between the treatment groups at any time after burn injury (P = 0.59). Secondary hyperalgesia
Post-burn erythema
ACKNOWLEDGEMENTS
El did not differ between groups before treatment ( - 1 h, P = 0.06) or before injury (0 min, P = 0.91). Blanching was observed from — 1 h to 0 min in placebo-treated (P = 0.02) but not in steroid-treated legs (P = 0.39). El increased significantly (P < 0.01) after burn injury in both treatment groups without significant differences between groups at any time after burn injury (P = 0.25). Development of blisters
Blisters developed in nine steroid-treated and in 12 placebo-treated burn injuries (P = 0.25). DISCUSSION
Glucocorticoids are known to inhibit the synthesis, release, or both, of several inflammatory mediators, for example prostaglandins and leukotrienes [10], bradykinin [11, 12], histamine [12, 13], platelet activating factor (PAF) [14], interleukin-1 (IL-1) [15] and tumour necrosis factor (TNF) [16], Most of these mediators have a sensitizing effect on nociceptors. We found no clinical reports on the antiinflammatory effect of glucocorticoids in human burn injuries, except for a letter [17] suggesting an antinociceptive and anti-inflammatory effect. Clobetasol propionate has been demonstrated to reduce erythema, pain and swelling after cryotherapy of dermal lesions [18]. Experimental studies have shown anti-inflammatory effects of topical steroids in burn injury, for example reduction of oedema and preserved dermal microcirculation [19-21]. Before undertaking this study, therefore, we expected that a high potency topical glucocorticoid would affect primary and secondary hyperalgesia in human first and second degree burn injury compared with placebo. However, we found that neither primary and secondary hyperalgesia nor the erythema and blister formation of the thermal injury were changed by steroid treatment. There are several possible reasons for this negative result. First, we applied clobetasol propionate 1 h before the heat trauma and this may have been too short, because one of the important mechanisms of
This study was supported by a grant from the John and Birte Meyer Foundation; Alfred Benzon's Fond; P. A. Messerschmidt and wife's Fond and Glaxo, Denmark. Dermovat and placebo cream were supplied by Glaxo, Denmark.
REFERENCES 1. Raja SN, Meyer RA, Campbell JN. Peripheral mechanisms of somatic pain. Anesthesiology 1988; 68: 571-590. 2. Treede RD, Meyer RA, Raja SN, Campbell JN. Peripheral and central mechanisms of cutaneous hyperalgesia. Progress in Neurobiology 1992; 38: 397-421. 3. Handwerker HO, Reeh PW. Pain and inflammation. In: Bond MR, Charlton JE, Woolf CJ, eds. Proceedings of the Vlth World Congress on Pain. Pain Research and Clinical Management. Amsterdam: Elsevier, 1991; 59—70. 4. Woolf CJ. Central mechanisms of acute pain. In: Bond MR, Charlton JE, Woolf CJ, eds. Proceedings of the Vlth World Congress on Pain. Pain Research and Clinical Management. Amsterdam: Elsevier, 1991; 25-34. 5. Dray A, Perkins M. Bradykinin and inflammatory pain. Trends in Neurological Sciences 1993; 16: 99-104. 6. Dahl JB, Brennum J, Arendt-Nielsen L, Jensen TS, Kehlet H. The effect of pre- versus postinjury infiltration with lidocaine on thermal and mechanical hyperalgesia after heat injury to the skin. Pain 1993; 53: 43-51. 7. Moiniche S, Dahl JB, Kehlet H. Time course of primary and secondary hyperalgesia after heat injury to the skin. British Journal of Anaesthesia 1993; 71: 201-205. 8. Bjerring P, Andersen PH. Skin reflectance spectrophotometry. Photodermatology 1987; 4: 167-171. 9. Andersen B, Holm P. Problems with p. Significance Testing in Medical Research. Basle: Editones Roche, 1992; 63-72. 10. Di Rosa M, Calignano A, Carnuccio R, Ialenti A, Sautebin L. Multiple control of inflammation by glucocorticoids. Agents and Actions 1985; 17: 284-289. 11. Hargreaves KM, Costello A. Glucocorticoids suppress level of immunoreactive bradykinin in inflamed tissue as evaluated by microdialysis probes. Clinical Pharmacology and Therapeutics 1990; 48: 168-178. 12. Pipkorn U, Proud D, Lichtenstein LM, Kagey-Sobotka A, Norman PS, Naclerio RM. Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticoids. New England Journal of Medicine 1987; 316: 1506-1510. 13. Stahle M, HSgermark 0 . Effect of topically applied clobetasol-17-propionate on histamine release in human skin. Acta Dermato-Venereologica (Stockholm) 1984; 64: 239-242. 14. Parente L, Flower RJ. Hydrocortisone and macrocortin inhibit the zymosan-induced release of lyso-PAF from rat peritoneal leucocytes. Life Sciences 1985; 36: 1225-1231. 15. Lew W, Oppenheim J, Matsushima K. Analysis of the suppression of IL-la and IL-lp" production in human peripheral blood mononuclear adherent cells by a gluco-
Downloaded from http://bja.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on June 21, 2015
Secondary hyperalgesia developed after the burn injury in all legs, but there were no significant differences in area of secondary hyperalgesia between steroid-treated and placebo-treated legs at any time after burn injury (P = 0.52).
steroid action is controlling the expression of specific gene products (protein synthesis), which may take some hours [22, 23]. Second, injury leads to release of inflammatory mediators from depots in skin, for example IL-1 [24], as well as de novo synthesis, but the release from depots could well be steroidinsensitive. Third, although glucocorticoids may inhibit several inflammatory mediators, it is unlikely that all mediators in the burn-induced inflammatory response are influenced by steroids. Furthermore, the steroid-sensitive mediators, such as prostaglandins, may be suppressed only moderately by topical steroids in burn injury [21], therefore resulting in a largely unaltered response to burn injury. Finally, the multiplicity of and synergy between the inflammatory mediators may explain the lack of effect of glucocorticoids in thermal injury.
BRITISH JOURNAL OF ANAESTHESIA
382
16.
17. 18. 19. 20.
corticoid hormone. Journal of Immunology 1988; 140: 1895-1902. Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of cndotoxin resistance. Science 1986; 232: 977-980. Hindson TC, Hazell M, Wickramasinghe L. Clobetasol propionate ointment as first-aid for burns. Lancet 1987; 8541: 1087-1088. Hindson TC, Spiro J, Scon LV. Clobetasol propionate ointment reduces inflammation after cryotherapy. British Journal of Dermatology 1985; 112: 599-602. Robson MR, Kucan JO, Paik KI, Eriksson E. Prevention of dermal ischemia after thermal injury. Archtves of Surgery 1978; 113: 621-625. Robson MR, Del Beccaro EJ, Heggers JP. The effect of
21.
22. 23. 24.
prostaglandins on the microcirculation after burning, and the inhibition of the effect by specific pharmacological agents. Plastic and Reconstructive Surgery 1979; 63: 781-787. Bronaugh RL, Roller RG, CargiU R. The evaluation of topical anti-inflammatory activity on rat ears subjected to thermal injury. Journal of Investigative Dermatology 1978; 71: 263-265. Godowski PJ, Picard D, Yamamoto KR. Signal transduction and transcriptional regulation by glucocorticoid receptorLexA fusion proteins. Science 1988; 241: 812-816. Schleimer RP, Lichtenstein LM, Gillcspie E. Inhibition of basophil histamine release by anti-inflammatory steroids. Nature 1981; 292: 454-455. Kupper TS. Immune and inflammatory processes in cutaneous tissues. Mechanisms and speculations. Journal of Clinical Investigation 1990; 86: 1783-1789.
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