MEPTAZINOL DIMINISHES THE JARISCH-HERXHEIMER REACTION OF RELAPSING FEVER

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Saturday 16 April 1983

MEPTAZINOL DIMINISHES THE JARISCH-HERXHEIMER REACTION OF RELAPSING FEVER BAYU TEKLU

Department of Medicine, Addis Ababa University, Ethiopia AKLOG HABTE-MICHAEL St Paul’s Hospital, Addis Ababa

DAVID A. WARRELL

some groups of patients. The reaction occurs about 1 h after intravenous tetracycline. There is a steep rise in temperature, blood pressure, and pulse and respiratory rates accompanying violent and distressing rigors. The peripheral leucocyte count falls and spirochaetes disappear from the blood. During the next 4-6 h the temperature falls and there is sustained hypotension associated with vasodilatation. The use of slow-release penicillin, corticosteroids, and antipyretics has had little or no effect on the intensity of the

in

reaction.4-6

NICHOLAS J. WHITE

Tropical Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford DAVID J. M. WRIGHT

Department of Microbiology, Charing Cross Hospital Medical School, London

Experiments with a mouse model of the J-HR indicated that two opioid antagonists, naloxone and meptazinol,7 could suppress certain features of this reaction.8,9 The present study tested, in a double-blind trial, the efficacy of these compounds and reinvestigated the use of high-dose corticosteroids in the J-HR of patients with louse-borne relapsing fever. Patients and Methods

and with

Naloxone, opioid antagonist, meptazinol, an opioid antagonist agonist properties, were tested in a double-blind placebocontrolled trial in 24 Ethiopian patients with louse-borne relapsing fever. The potentially fatal Jarisch-Herxheimer reaction (J-HR), which invariably follows tetracycline treatment of the disease, was unaffected by naloxone, 30-40 mg intravenously, but was diminished by meptazinol, 300-500 mg intravenously. Compared with naloxone and placebo, meptazinol reduced the clinical severity of the reaction, significantly delayed and shortened its chill phase, delayed the rise in temperature, and reduced peak temperature and changes in pulse and respiratory rates and leucocyte count. High-dose corticosteroids given before or at the time of tetracycline treatment failed to alter the reaction, which is thought to result from release of endotoxin-like substances. Meptazinol is the first effective treatment for the J-HR of louse-borne relapsing fever. This finding suggests a role for endogenous opioids in the pathogenesis of the J-HR.

Summary

an

Introduction 1B the present century, louse-borne relapsing fever (Borrelia recurrentis infection) has caused a number of pandemics in Africa, the Middle East, and Europe, with 50 million cases and 5 million deaths.’ The untreated mortality of between 30% and 70% is reduced to less than 407o by antimicrobial treatment,2 but elimination of spirochaetes is invariably associated with a severe Jarisch-Herxheimer reaction (J-HR), which may carry a mortality as high as 12%

At St Paul’s Hospital, Addis Ababa (altitude 2535 m, barometric pressure 550 mm Hg), in July, 1982, 33 patients aged between 15 and 45 years, who were in their initial episode of fever and in whom B. recurrentis spirochaetes had been found in the blood smear, were selected for study. All patients had negative Widal and Weil-Felix reactions with Proteus OX2 and OX 19. They gave informed consent to hospital admission, treatment, and investigation. After being deloused they were admitted to the hospital ward and examined. Rectal temperature was monitored with an electronic telethermometer (YSI model 432A), and blood pressure was measured with a sphygmomanometer. Temperature, blood pressure, pulse rate, and respiratory rate were recorded every 10 min for periods of up to 10 h until values were stable after the J-HR. All measurements and clinical observations were made by the authors and recorded on a standard form. The severity of J-HR was graded from 1 to 3 according to the patient’s discomfort and agitation and the severity of rigors (1=mild, 2=moderate, 3 = severe). All patients were treated with a

single 250 mg dose of tetracycline hydrochloride (’Achromycin’, Lederle) given by slow intravenous injection after baseline observations had been recorded for 30 min. 1-2 litres of 0-9% saline were infused during the 10 h after tetracycline treatment. If the patient’s temperature exceeded 41°C, dipyrone was given intramuscularly, and vigorous tepid sponging and fanning were instituted. Treatment

Regimens

placebo-controlled trial of naloxone and meptazinol.- There were three treatment groups of 8 patients each. 1.

1 ml

Double-blind

solutions, identical in appearance, of 10 mg naloxone, 100 mg

meptazinol, and placebo in batches of four ampoules were labelled with code numbers and randomised. A slow intravenous injection of 8329 ©

836 2. Continuous infusion of meptazinol. -After completion of th: double-blind trial 4 patients with spirochaetaemia and I when spirochaetes had disappeared spontaneously were given 100 fig meptazinol by slow intravenous injection simultaneously M: tetracycline. This was followed by continuous infusion of 150 rr meptazinol/h for 2 h.

TABLE I-COMPARABILITY OF THE THREE TRIAL GROUPS BEFORE TREATMENT

3. Infusion of high-dose corticosteroid.-In 1 patient, 3. 75 mg!ka body-weight of betamethasone disodium phosphate (’Celestone’. Schering) diluted in 100 ml of 09% saline was infused at a constar,; rate over 1 h, starting 30 min before tetracycline treatment. 4. Pre-treatment with

a large dose of oral prednisolone.-3 patienr: pre-treated with prednisolone, 3 mg/kg by mouth, 18 h befor: tetracycline treatment.

were

Results 1. Double-blind Placebo-controlled Trial of Naloxone and Meptazinol

All results are means± I SD, except the length of history and spirochaete count, for which the medians are given. Values in parentheses are ranges. All comparisons not significant at 5% level (by analysis of variance, Wilcoxon rank sum test, or Kruskal Wallis test) except systolic blood pressure, which is significantly lower in the meptazinol group than in either the placebo or the naloxone group. ’

the

test drug was given simultaneously with the tetracycline injection, again 30 min later, at the start of the chill phase of the reaction (signalled by the development of goose pimples and rigors), and during the flush phase of the reaction if the systolic blood pressure fell below 70 mm Hg. Comparability of patients in the three treatment groups was tested by measurement of height, weight, age, length of history, severity of clinical features, and pretreatment laboratory estimation of haematocrit, number of circulating borrelia, total and differential white-cell counts, serum fibrin/fibrinogen-related antigen, plasma fibrinogen, electrolytes, urea, creatinine, total protein, albumin, and bilirubin, and serum enzymes (aspartate and alanine transaminases, creatine kinase, and alkaline phosphatase).

Patients in the three treatment groups proved comparable before treatment (table I). There was a significant difference between plasma chloride concentrations in the meptazinol and naloxone groups (94±6-0 and 101±3’6mmolll [mean± 1 SD] respectively, p <0 05), but there were no other significant differences between the haematological or biochemical values of the three groups. The study code was not broken until the trial was completed, all measurements had been tabulated, and data extracted. All patients in the study had a recognisable J-HR. Severity was graded as 1 in all 8 patients treated with meptazinol, whereas 6 patients in the placebo group and 5 in the naloxone group had grade-3 (severe) reactions. The J-HR in the meptazinol group differed in several respects from that in the other two groups-the interval between tetracycline treatment and the start of rigors was significantly longer; the duration of the rigors was shorter (table II), the rise ic temperature was delayed; and the peak temperature was significantly lower (fig. la). The interval between

tetracycline treatment and peak systolic blood pressure was longer in the meptazinol group (119. 6::!:49 . 2 min versus 82. 9::!:35. 9 min for placebo and 81 · 9±42 ·min for naloxone; means--t 1 SD), but these differences did not reach 2

TABLE II-COMPARISON OF JARISCH-HERXHEIMER REACTIONS IN THE THREE TRIAL GROUPS

Results of spirochaete significant (p>O. 05).

count

and time after treatment

at ’

which

no

circulating spirochaetes

were seen are

medians. Other results

are

meansl SD, NS=ê,’

837

Hou rs

Fig. I-Physiological response in three groups of 8 patients with louse-borne relapsing fever treated with tetracycline at 0 h. (a) rectal temperature, (b) systolic blood pressure, (c) heart rate, (d) respiratory rate. Mean values and 1 SD 8----8 placebo group. 0"’""0 meptazmol-treated group. 8- - - -8 naloxone-treated group.

significance. The maximum systolic blood pressure recorded during the rigors was similar in the meptazinol and placebo groups (140 . 1::t 10’ 6 and t46’5±16’9mm Hg respectively) but was significantly lower (123’3±10’1mm Hg) in the naloxone group (p=O’006 and 0-005 respectively). The mean increase in pulse rate associated with the J-HR was significantly smaller (table 11), although maximum pulse rates were similar in the three groups (fig. lc). Maximum respiratory rates during the rigors were significantly lower in the meptazinol group (indeed, there was no change in this group), whereas it rose by about 20 breaths/min in the other two groups (fig. ld). The maximum fall in peripheral leucocyte count at the start of the reaction was significantly smaller (table II), although minimum counts were not significantly different. There was no significant difference in the intervals between tetracycline treatment and the lowest counts (116±65 min for placebo, 146±67 min for naloxone, 165±53 min for meptazinol). There were also no differences in the median spirochaete counts 30 min after treatment or the spirochaete clearance times (table n). The minimum systolic blood pressures reached during the statistical

min in the meptazinol group, 304±93 min in the group, and 288±59 min in the naloxone group (fig.

placebo lb).

Clinical effects of test drugs.-Meptazinol given at the start of rigors diminished or aborted the reaction in all 8 cases. It had a pronounced sedative and analgesic effect, although patients remained rousable. Meptazinol also produced pupillary constriction (3 patients), giddiness (2), nystagmus (1), and nausea (1). 4 of the meptazinol group vomited during the reaction, compared with 1 each in the other two groups. 2 patients in the meptazinol group were given the test drug when their systolic blood pressures fell below 70 mm Hg during the flush phase: there was no effect in either case. Naloxone had no obvious acute clinical effect on the reaction, and no side-effects were evident. 3 patients in the naloxone group were given the test drug when their systolic blood pressures fell below 70 mm Hg during the flush phase: in 1 there was no effect, but in the other 2 blood pressure rose by 24 and 14 mm Hg during the following 18-30 min.

flush phase of the reaction

Infusion of Meptazinol (Fig. 2) The patient whose spirochaetes had cleared spontaneously before treatment developed no J-HR after tetracycline

(meptazinol

treatment.

were similar in the three groups 77±11 mm Hg, placebo 77±14 mm Hg, naloxone 79±15 mm Hg). The intervals between tetracycline treatment and lowest systolic blood pressure were 291 ±79

2. Continuous

His temperature fell from a baseline value of 37’3°C during the 3 h study. This excluded a pyrogenic effect of the batch of tetracycline used in the study. 39-0°C

to

838

reaction, but the fall in blood pressure during the flush phase was significantly reduced.5 Our decision to test a very high dose of corticosteroid was based on the observation that in mice infected with B. duttoni the reaction provoked by

Hours

2-Rectal temperatures (mean and 1 SD) in 4 patients treated with a loading dose followed by continuous infusion of meptazinol, 3 patients pretreated with a high dose of oral prednisolone, and 1 patient given a high-dose infusion of betamethasone.

Fig.

The 5 patients given meptazinol infusions received an average of 8 - 14 (range 7 -14-9’76) mg/kg. In the 4 patients with spirochaetaemia, symptoms of the J-HR were extremely mild. All 5 patients were sedated, and 3 vomited. The patient given the highest dose (9’ 76 mg/kg) vomited repeatedly. In none of the patients did the systolic blood pressure fall below 70 mm Hg during the flush phase.

Infusion of a Large Dose of Betamethasone (Fig. 2) The patient showed a small initial drop in rectal temperature, but a severe J-HR started 68 min after tetracycline treatment. The duration of rigors, peak temperature, 3.

rise and fall in blood pressure, and all other measures of the severity of the reaction were similar to those of patients in the placebo group.

Pre-treatment with a LargeDose of Oral Prednisolone (Fig. 2) patients were febrile on the morning of treatment baseline temperatures 40-0, 40-6, and 39’5°C). (mean Moderate to severe J-HRs began 58 to 113 min after tetracycline treatment. Rigors persisted for 15 to 31 min. Peak rectal temperatures were 41’4 to 41’9°C. Systolic blood pressures fell to a mean of 65 mm Hg 5 h after treatment. The reactions in these patients were as severe in every respect as in the placebo group. 4.

All 3

Discussion The

J-HR of louse-borne relapsing fever poses a therapeutic dilemma. Clearly therapy cannot be withheld in an infection carrying such a high mortality, but the risks of the Jarisch-HerxheinSer reaction induced by severe

difficult

treatment are also

unacceptable. Previous attempts to reduce

severity of the reaction have included the use of antipyretics (paracetamol), hydrocortisone, and slow-release penicillins. Paracetamol (650 mg) given by mouth before and5 after erythromycin therapy failed to alter the reaction. Hydrocortisone given in a dose of 20 mg/kg/h for 4 h, starting an hour before tetracycline injection, decreased rectal temperature before and at the peak of the reaction but did not alter the clinical or physiological severity of the reaction.4 Hydrocortisone in a dose of 500 mg injected intravenously 2 h before and after erythromycin therapy failed to alter the the

ampicillin treatment was prevented by giving 2 mg hydrocortisone 2 h before antibiotic treatment, whereas lower doses (0’2mg and 0 02 mg) were not effective.’" Very large doses of methylprednisolone have proved necessary to protect animalsil and perhaps mant2 against the circulatory effects of endotoxaemia and haemorrhage. The dose of betamethasone used in the study, 3 75mg/kg, was equivalent to 30 mg/kg methylprednisolone or 106 mg/kg hydrocor tisone, but the reaction was not prevented or altered in any way. The febrile response and local reaction to penicillin treatment in early syphilis can be prevented by giving 60 mg prednisolone by mouth divided between the day before and the day of antibiotic treatment,13 but in the present study a dose of prednisolone approximately three times greater than this, given 18 h before tetracycline treatment, failed to prevent or alter the reaction. In particular, pretreatment with prednisolone did not prevent a fall in blood pressure during the flush phase. In view of the debate about the role of highdose corticosteroid in preventing endotoxin-mediated reactions, it is interesting that the pretreatment of these patients with massive doses of corticosteroid failed to prevent the subsequent reaction, which is thought to be caused by the release of an endotoxin-like substance. 10,14-16 Compared with tetracycline, slow-release penicillins, such as penicillin with aluminium monostearate, induce a J-HR which peaks later, is less often associated with rigors, and causes a smaller rise in temperature and a smaller fall in peripheral-leucocyte count. The fever is, however, protracted, and the spirochaetes are cleared from the blood more slowly. The reaction associated with slow-release penicillin appears to be no less stressful 6 physiologically than the one following tetracycline. The idea of exploring the use of opioid antagonists in relapsing fever was based on experiments with mice infected with B. duttoni.8,9 There is a predictable reaction consisting of tachypnoea, the development of ruflled fur, and a steep fall in leucocyte and platelet counts which occurs approximately an hour after ampicillin treatment and coincides with the disappearance of spirochaetes from the blood. Unlike patients with louse-borne relapsing fever, the mice show a fall in temperature during this reaction. Both naloxone and meptazinol prevented the reaction in mice,8,9 although meptazinol was some fifty times more potent on a weight-forweight basis. Naloxone also prevents endotoxin-induced hypotension in rats 17 and raises the blood pressure of patients with septic shock. 18 Meptazinol is a potent opioid antagonist with some agonist properties. It is comparable to naloxonein the treatment of experimental endotoxic shock in animals’s and is also highly effective in experimental and haemorrhagic shock.2O The pressor effects of opioid antagonists might be particularly valuable in the J-HR of louse-borne relapsing fever, for many of the fatalities occur during the period of profound hypotension in the flush phase.4In the present study 10 mg naloxone, a dose which has proved effective in septic shock,18 failed to prevent the reaction, but in 2 of3 patients whose systolic blood pressures fell below 70 mm Hg during the flush phase, naloxone exerted a definite pressor effect. In view of the relative potencies of naloxone and meptazinol in preventing the J-HR in mice, it remains possible that a much higher dose of naloxone might proveas effective as meptazinol in diminishing the J-HR in man. We in are not aware, however, that doses higher than those tested

839 i

:his study have been used in such patients. Alternatively, the beneficial effect of meptazinol may be unrelated to its opioid-

CONTROLLED TRIAL OF ADJUVANT CHEMOTHERAPY WITH MELPHALAN FOR BREAST CANCER

JI1tagonist properties. the reaction both in the patients treated with three or more intravenous injections of 100 mg in the double-blind trial and also in the later patients given a loading dose of 100 mg by injection followed by infusion of a further 300 mg over the next 2 h. Clinical manifestations of the reaction were reduced to mild transient shivering. The rise in temperature was delayed and reduced, tachypnoea was virtually abolished, and the maximum fall in peripheral leucocyte count at the start of the reaction was reduced. The sedative effect of meptazinol could possibly account for the attenuation of rigors and reduction in anxiety and tachypnoea during the chill phase of the reaction, but the delay in temperature rise (suppression of fever before the start of the reaction) and the effect on leucocyte count must represent an effect on the underlying mechanism of the J-HR. The most serious toxicity associated with the doses of meptazinol used in this study was vomiting. No adverse cardiovascular effects occurred. For clinical use it is suggested that a dose of 100 mg, given by slow intravenous injection at the same time as tetracycline treatment, will have a clinically useful effect in diminishing the J-HR. A further dose of 100 mg could be given at the start of the reaction. Despite its opioid agonist effects, the high doses ofmeptazinol used in the present study (up to 9 76 mglkg) did not cause a drop in blood pressure. This is the first effective treatment for the J-HR of lousebome relapsing fever. The findings are relevant to the pathophysiological mechanisms underlying the reaction and

Meptazinol diminished

are of

R. D. RUBENS R. K. KNIGHT I. S. FENTIMAN A. HOWELL D. CROWTHER W. D. GEORGE

J. L. HAYWARD R. D. BULBROOK M. CHAUDARY H. BUSH R. A. SELLWOOD J. M. T. HOWAT

Imperial Cancer Research Fund Breast Cancer Unit, Guy’s Hospital, London; and Departments of Medical Oncology and Surgery, University Hospital of South Manchester, Manchester 370 patients who had carcinoma of the breast with involved axillary lymph-nodes were randomised after total mastectomy and axillary clearance to receive either no additional treatment or melphalan 6 mg/m2 daily for 5 days every 6 weeks for sixteen cycles. There was a trend towards longer relapse-free survival (RFS) in patients treated with melphalan, but this was not significant either in the whole series or in sub-groups according to menopausal status or extent of nodal involvement. In patients receiving melphalan RFS was not significantly affected by either the occurrence of amenorrhoea or the dosage of melphalan received. Overall survival did not differ significantly between the two groups. The results of this trial suggest that there is no place for the use of melphalan as adjuvant therapy in the management of early breast cancer.

Summary

therapeutic importance.

We thank the director and the medical, nursing, and technical staff at St Paul’s Hospital, Addis Ababa, for their help in the study and the staff of Tikur knbessa Hospital and Arada and Teklehaimanot clinics for referring patients. The Central Laboratory, Addis Ababa, and the departments of biochemistry (Dr G. Doran), microbiology (Mr D. Frost), and haematology (Mr J. Owen) at Channg Cross Hospital Medical School kindly helped with laboratory measurements. Dupont supplied naloxone. We gratefully acknowledge the help of Wyeth Laboratories which provided meptazinol and funds for equipment and for the visit to Ethiopia of D. A. W., N. J. W., and D. J. M. W. We are grateful to Miss Eunice Berry for administrative and secretarial help. D. A. W. and N. J. W. were on leave of absence from the Wellcome-Mahidol University/Oxford tropical medicine research programme, which is supported bv the Wellcome Trust. ’

Correspondence should be addressed to D. A. W., Faculty of Tropical kiedicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400,

Introduction THE hypothesis that chemotherapy may be more effective when there is only a slight tumour burden has led to its use after mastectomy in patients at high risk of recurrence. The preliminary results of a trial ofmelphalan as adjuvant therapy carried out by the National Surgical Adjuvant Breast Project (NSABP),’ suggested that melphalan therapy could significantly prolong postoperative relapse-free survival The external reviewer was Dr J. W. Meakin, Ontario Cancer Treatment and Research Foundation, 7 Overlea Boulevard, Toronto, Ontario M4H 1A8, Canada.

Thailand. REFERENCES 1. Baltazard M Evaluation of the research

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and a reconsideration of the literature. QuartJ Med 1970; 39: 129-70. 3 Wolff BP Asiatic relapsing fever: a report of 134 cases treated with mapharsen. Ann Intern Med 1946; 24: 203-16. 4 Warrell DA, Perine PL, Krause DW, Bing DH, MacDougal SJ. Pathophysiology and immunology of the Jarisch-Herxheimer-like reaction in louse-borne relapsing fever: comparison of tetracycline and slow release penicillin. J Infect Dis (in press). 5 Butler T, Jones PK, Wallace CK. Borrelia recurrentis infection: single-dose antibiotic regimens and management of the Jarisch-Herxheimer reaction. J Infect Dis 1978; 131: 573-77 5. Warrell DA, Pope HM, Parry EHO, Perine PL, Bryceson ADM. Cardiorespiratory disturbances associated with infective fever in man: studies of Ethiopian louse-borne relapsing fever. Clin Sci 1970; 39: 123-45 Stephens RJ, Waterfall JF, Franklin RA. A review of the biological properties and metabolic disposition of the new analgesic agent meptazinol. Gen Pharmacol 1978; 9: 73-78.

8. Wright DJM. The fall in circulating leucocyte and platelet counts after endotoxin: an adrenergic opioid interaction. Neuropeptides 1981; 1: 181-202. i Wright DJM Opiate induced reduction of peripheral white blood cell and platelet counts in mice Br J Pharmacol 1982; 75: 127P.

Reaction following treatment of murine borreliosis and Shwartzman with borrelial sonicates. Parasite Immunol 1980; 2: 201-21. 11. Sheagren JN. Septic shock and corticosteroids. N Engl J Med 1981; 305: 456-57 12. Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg 1976; 184: 333-41. 13. Gudj6nsson H, Skog E. The effect of prednisolone on the Jarisch-Herxheimer reaction. Acta Derm Venereol 1968; 48: 15-18. 14. Bryceson ADM, Cooper KE, Warrell DA, Perine PL, Parry EHO. Studies of the mechanism of the Jarisch-Herxheimer reaction in louse-borne relapsing fever: evidence for the presence of circulating Borrelia endotoxm. Clin Sci 1972; 43: 343-54. 15. Butler T, Hazen P, Wallace CK, Awoke S, Habte-Michael A Infection with Borrelia recurrentis: pathogenesis of fever and petechiae. J Infect Dis 1979; 140: 665-75. 16. Butler T, Spagnuolo PJ, Goldsmith GH, Aikawa M. Interaction of Borrelia spirochetes with human mononuclear leukocytes causes production of leukocytic pyrogen and thromboplastin. J Lab Clin Med 1982; 99: 709-21. 17. Holaday JW, Faden AI. Naloxone reverses the pathophysiology of shock through an antagonism of endorphin system. In Martin JB, Reichlin S, Bick KL, eds. Neurosecretion and brain peptides. New York: Raven Press, 1981: 421-34. 18. Peters WP, Johnson MW, Friedman PA, Mitch WE. Pressor effect of naloxone in septic shock. Lancet 1981, i 529-32. 19. Chance E, Todd MH, Waterfall JF. A comparison of the cardiovascular effects of meptazinol, morphine and naloxone in septic shock in rats. Br J Pharmacol 1981; 74: 930-31P. 20. Paciorek PM, Todd MH, Wyllie MG. Restoration of mean arterial blood pressure in endotoxic shock by meptazinol. Contribution from lysomal membrane stabilisation, opiate antagonism and noradrenaline release. Biochem Pharmacol (in press). 10.

Wright DJM. type

reaction