British Journa! of Dermatology (1992) 127. 292-294.
Verapamil-induced secondary erythermalgia J.P.H.DRENTH.*§ J.J.MICHIELS.* T.VAN JOOSTt AND V.D.VUZEVSKI^: Departments of*Haemato!ot}y. -[Dermatology, and tCHnica! Patho!ogy. University Hospital Erasmus University Rotterdam. The Netherlands Accepted for publication 15 April 1992
Summary
A 59-year-old man developed red. swollen and warm feet accompanied by intermittent burning pain during treatment for cardiac failure and arrbytbmias witb several drugs including verapamil. Tbe condition gradually worsened until tbere was persistent disabling burning pain and severe erytbema and swelling of tbe feet. Aspirin and other analgesics were ineffective in relieving the discomfort. Histopathology of punch biopsies sbowed a mild perivascular mononuciear infiltrate and moderate perivascular oedema. Within 2 weeks of stopping verapamil tbe burning pain, erythema, and swelling of tbe feet had resolved. The clinical features and subsequent course are consistent witb a diagnosis of erythermalgia secondary to verapamil.
Recurrent attacks of severe burning pain, erythema, warmtb and swelling of tbe extremities are designated either as erythromclalgia. or as primary or secondary erytbermalgia.' Erythromelalgia is invariably associated with thrombocytbaemia. The clinical features are the result of platelet-mediated arteriolar inflammation and thrombosis. Aspirin alleviates the symptoms by irreversibly inbibiting platelet cycio-oxygenase activity and platelet aggregation."^ The idiopathic variant of burning and painful extremities is designated primary erytbermalgia. It occurs spontaneously in childhood or adolescence in the absence of any detectable underlying disorder.^'' It typically presents as hilateral. symmetrical burning pain associated with erytbema of tbe feet, ankles and legs. Tbe symptoms are exacerbated by beat and exercise, and usually deteriorate to such a degree tbat the patient is compelled to lead a sedentary life-style and continuously attempts to find a means of cooling tbe feet. Secondary erytbermalgia is defined as an acquired, persistent, but potentially curable, symmetrical, painful erytbema of the extremities."* "^ It occurs as an adverse effect of several drugs, including the ergot derivatives pergolide and bromocriptine.'' '" and the vasodilating calcium antagonists nifedipine and nicardipine.""''' In this report we present a typical case of acquired secondCorrespondence: Dr J.).Micbiels. University Hospital Dijkzigt. lX:partment of Haematology. Dr Molenwaterplein 40. 3015 GD Rotterdam. Tbe Netherlands, § Present address: University Hospital St Radboud, Department of Medicine, Division of Cieneral Internal Medicine, P.O. Box 9101, 6500 HB Nijmegen, Tbe Netherlands.
292
ary erythermalgia occurring in a patient receiving longterm treatment with verapamil.
Case report A 59-year-old man had a bistory of myocardial infarction in 1984 and a coronary artery bypass operation, witb resection ofa left ventricular aneurysm. in 1987. Since March 1990 be bad been treated for atrial fibrillation and cardiac failure with a number of drugs including daily digoxin ()-2S mg. frusemide 80 mg. spironolactone 25 mg. captopril 2 5 mg. verapamii 120 mg and a coumarin derivative. A few months after starting this treatment be complained of intermittent redness, warmth and swelling ofthe feet, together witb burning pain, occurring more often during warm weatber and in tbe evening. The symptoms gradually worsened and were eventually present constantly throughout tbe day and nigbt. Tbe unbearable burning pain could only be relieved by immersing bis feet in icecold water. Aspirin and many otber analgesics provided no relief. When we saw bim in February 1991 tbe feet and ankles were symmetrically swollen and erytbematous. and were extremely tender (Fig. 1). The peripheral pulses were palpable. A full blood count, electrolytes and urea, and liver function tests were normal. Antinuclear antibodies, rbeumatoid factor and an autoantibody screen were negative. Histology of punch biopsies from tbe affected areas sbowed sligbt to moderate perivascular oedema, and a mild inflammatory infiltrate around capillaries in the upper dermis. Tbe capillary walls appeared to be
VERAPAMIL-INDUCED SECONDARY ERYTHERMALGIA
29i
Figure 1. Bilateral, syiiiiiicu and swelling ofthe feet and ankles.
Figure 2, Photomicrograpb showing a mild pericapillary inflammatory iniiltrate and oedema, in tbe upper dermis. Tbere is mild to moderate swelling of endotbelial cells (hatmatoxylin and cosin x 1 20),
sligbtly thickened, and tbere was mild to moderate swelling of endotbelial cells (Fig. 2). Because calcium antagonists arc known to cause secondary erytherma!gia.""'"" treatment with verapamil was stopped. His symptoms gradually resolved over the course of 1-2 weeks. The temporal relation with verapamil. and tbe absence of otber causes, make tbis drug tbe most probable cause ofthe erythermalgia. The patient refused recballenge witb verapamil.
Discussion Drug-induced secondary erytbermalgia bas been described in association witb tbe long-term use of ergot
derivatives and calcium antagonists (Tahle 1). Bromocriptine bas been reported to induce erytbermalgia-like cbanges, and in two large studies of patients witb parkinsonism 1 S of 202 patients developed red. tender, warm, ocdematous feet, ankles and lower legs. Some discomfort, described as a burning sensation, was noted in most cases.'•'^ Tbe ergot derivative pergolide. a drug used to control the tremor of Parkinson's disease, bas also been reported as causing an erythermalgia-like eruption in two cases.'"Botb patients suffered from a bilateral symmetrical erythema of tbe skin. Biopsy in one patient showed marked focal capillary proliferation in tbe upper dermis and a minimal intlammatory infiltrate. Three studies report a connection between the calcium antagonist nifedipine and incapacitating secondary erytbermalgia.'' ' * Tbe patients complained of burning pain, and bad symmetrical erytbema ofthe feet and lower legs wbicb subsided within 2 days of withdrawal of tbe drug. Resumption of tbe drug resulted in recurrence of tbe symptoms. Tbe calcium antagonist nicardipine bas been reported as causing intermittent redness, warmtb and pain in tbe fingers of one patient.'^ These cbanges rapidly resolved after discontinuation of tbe drug. As we observed in our case, erytbermalgia secondary to drugs develops insidiously after long-term treatment, and disappears 1-14 days after tbe responsible drug is stopped. Our patient presented with typical erythermalgia of both feet and lower legs. Tbe regression of the crytber-
294
J.P.H.DRENTH et aJ.
Drug
Dose (mg/day)
Table 1. Drug-induced secondary erythermalgia
n 7/92 11/110 1
Tl 10 months 15 months 24 months
Bromocriptine Bromocriptine Bromocriptine
115 101 120
Pergolide Pergolide
NS NS
12 months 18 months
Nifedipine Nifedipine
60 40
8 weeks
Nicardipine
60
1 year
Verapami!
120
NS
1 -9 months
T2 1 week 10 days NS NS NS
Reference Calne ft al.^ Eisler et at.^ Dupont et al.'^ Monk era/,'" Monk et a/,'"
2 days Immediate
Fisher el «/," Brodmerkel' ^
Rapid
Levesque et a!.
1 -2 weeks
Present case
fl. number of patients; T 1, time lapse between lirst dose and occurrence of erythermalgia: T2. time from discontinuation to resolution of erythermalgia; NS, not stated.
malgia after stopping verapamil strongly suggests that it was responsible for the problem. Unfortunately, the patient refused rechailenge with verapamil and absolute confirmation was therefore not possible. However, the temporal relationship witb verapamil makes this drug the most likely cause ofthe erytbermalgia. Verapamil is a phenylalkylamine derivative able to inhibit the slow inward current of calcium ions across the cell membrane of cardiac and vascular smooth muscle. It thereby causes coronary and peripheral vasodilatation and decreases myocardial contractility. It also infiuences the sinus and atrioventricuiar nodes. Verapamil is indicated for the treatment of hypertension, cardiac arrhythmias and angina."' A common sideeffect of verapamil is facial flushing and this is regarded as an extension ofthe vasodilator action."' To our knowledge, our case is the tirst report of verapamil-induced secondary erythermalgia. The pathophysiology of primary and secondary erythermalgia and the mechanism of drug-induced erythermalgia are unknown and remain to be elucidated.^
References 1 Drenth JPH, Michiels JJ, Tbree types of erythromelalgia. Br Med / 1990; 501:454-5. 2 Michiels J|, Abels |, Steketee J et at, Hrytbromelalgia caused by platelet-mediated arteriolar inilammation and thrombosis in thrombocytbaemia. Ann Intern Med 1985; 102: 4f>6-7l.
i Michiels )|, VanloostTh, Krythromelalgiaandthrotnbocythaemia; A causal relation. / Am Acad Dermalot 1990; 22: 107-1 1. 4 Michiels |), Ten Kale FW). hirythromelalgia in thrombocythaemia of various myeloproliferative disorders. Am } Hemtito! 1992: 39: 131-6, 5 Michiels J]. Van Joost Th, Vuzevski VD. Idiopathic erythermalgia. a congenital disorder, / Am Acad Dermatol 1989; 2 1 : 1128-30. fl Michiels)]. Van |oost Th, Primary and secondary erythermalgia, a critical review. Nelh / Med 1988; 33: 205-8. 7 Catne D, Plotkin C. Williams A el a!. Long-term treatment of parkinsonism with bromocriplinc. !Mncet 1978; i: 735, H Eisier T, Hall RP, Kalavar KAR, Calne DB. Krythromelalgia-like eruptions in parkinsonian patients treated with bromocriptine, Neuro!ogy 1981; 31: 1368-70, 9 Dupont E, Ilium F. Olivarius B. Bromocriptine and erythromelalgia-like eruptions. Netiro!ogy 1987; 10: 670, 10 Monk BE. Parkes ID, Du Vivier A. Rrythromeialgia following pergolide administration. Br j Dermato! 1984: 111: 97-9. I I Fisher ]R. Padnick MH, Olstein S, Nifedipine and erythromelalgia, Ann !ntern Med 1985; 98: 671-2. 12 Brodmerkel C
Verapamil-induced secondary erythermalgia J.P.H.DRENTH.*§ J.J.MICHIELS.* T.VAN JOOSTt AND V.D.VUZEVSKI^: Departments of*Haemato!ot}y. -[Dermatology, and tCHnica! Patho!ogy. University Hospital Erasmus University Rotterdam. The Netherlands Accepted for publication 15 April 1992
Summary
A 59-year-old man developed red. swollen and warm feet accompanied by intermittent burning pain during treatment for cardiac failure and arrbytbmias witb several drugs including verapamil. Tbe condition gradually worsened until tbere was persistent disabling burning pain and severe erytbema and swelling of tbe feet. Aspirin and other analgesics were ineffective in relieving the discomfort. Histopathology of punch biopsies sbowed a mild perivascular mononuciear infiltrate and moderate perivascular oedema. Within 2 weeks of stopping verapamil tbe burning pain, erythema, and swelling of tbe feet had resolved. The clinical features and subsequent course are consistent witb a diagnosis of erythermalgia secondary to verapamil.
Recurrent attacks of severe burning pain, erythema, warmtb and swelling of tbe extremities are designated either as erythromclalgia. or as primary or secondary erytbermalgia.' Erythromelalgia is invariably associated with thrombocytbaemia. The clinical features are the result of platelet-mediated arteriolar inflammation and thrombosis. Aspirin alleviates the symptoms by irreversibly inbibiting platelet cycio-oxygenase activity and platelet aggregation."^ The idiopathic variant of burning and painful extremities is designated primary erytbermalgia. It occurs spontaneously in childhood or adolescence in the absence of any detectable underlying disorder.^'' It typically presents as hilateral. symmetrical burning pain associated with erytbema of tbe feet, ankles and legs. Tbe symptoms are exacerbated by beat and exercise, and usually deteriorate to such a degree tbat the patient is compelled to lead a sedentary life-style and continuously attempts to find a means of cooling tbe feet. Secondary erytbermalgia is defined as an acquired, persistent, but potentially curable, symmetrical, painful erytbema of the extremities."* "^ It occurs as an adverse effect of several drugs, including the ergot derivatives pergolide and bromocriptine.'' '" and the vasodilating calcium antagonists nifedipine and nicardipine.""''' In this report we present a typical case of acquired secondCorrespondence: Dr J.).Micbiels. University Hospital Dijkzigt. lX:partment of Haematology. Dr Molenwaterplein 40. 3015 GD Rotterdam. Tbe Netherlands, § Present address: University Hospital St Radboud, Department of Medicine, Division of Cieneral Internal Medicine, P.O. Box 9101, 6500 HB Nijmegen, Tbe Netherlands.
292
ary erythermalgia occurring in a patient receiving longterm treatment with verapamil.
Case report A 59-year-old man had a bistory of myocardial infarction in 1984 and a coronary artery bypass operation, witb resection ofa left ventricular aneurysm. in 1987. Since March 1990 be bad been treated for atrial fibrillation and cardiac failure with a number of drugs including daily digoxin ()-2S mg. frusemide 80 mg. spironolactone 25 mg. captopril 2 5 mg. verapamii 120 mg and a coumarin derivative. A few months after starting this treatment be complained of intermittent redness, warmth and swelling ofthe feet, together witb burning pain, occurring more often during warm weatber and in tbe evening. The symptoms gradually worsened and were eventually present constantly throughout tbe day and nigbt. Tbe unbearable burning pain could only be relieved by immersing bis feet in icecold water. Aspirin and many otber analgesics provided no relief. When we saw bim in February 1991 tbe feet and ankles were symmetrically swollen and erytbematous. and were extremely tender (Fig. 1). The peripheral pulses were palpable. A full blood count, electrolytes and urea, and liver function tests were normal. Antinuclear antibodies, rbeumatoid factor and an autoantibody screen were negative. Histology of punch biopsies from tbe affected areas sbowed sligbt to moderate perivascular oedema, and a mild inflammatory infiltrate around capillaries in the upper dermis. Tbe capillary walls appeared to be
VERAPAMIL-INDUCED SECONDARY ERYTHERMALGIA
29i
Figure 1. Bilateral, syiiiiiicu and swelling ofthe feet and ankles.
Figure 2, Photomicrograpb showing a mild pericapillary inflammatory iniiltrate and oedema, in tbe upper dermis. Tbere is mild to moderate swelling of endotbelial cells (hatmatoxylin and cosin x 1 20),
sligbtly thickened, and tbere was mild to moderate swelling of endotbelial cells (Fig. 2). Because calcium antagonists arc known to cause secondary erytherma!gia.""'"" treatment with verapamil was stopped. His symptoms gradually resolved over the course of 1-2 weeks. The temporal relation with verapamil. and tbe absence of otber causes, make tbis drug tbe most probable cause ofthe erythermalgia. The patient refused recballenge witb verapamil.
Discussion Drug-induced secondary erytbermalgia bas been described in association witb tbe long-term use of ergot
derivatives and calcium antagonists (Tahle 1). Bromocriptine bas been reported to induce erytbermalgia-like cbanges, and in two large studies of patients witb parkinsonism 1 S of 202 patients developed red. tender, warm, ocdematous feet, ankles and lower legs. Some discomfort, described as a burning sensation, was noted in most cases.'•'^ Tbe ergot derivative pergolide. a drug used to control the tremor of Parkinson's disease, bas also been reported as causing an erythermalgia-like eruption in two cases.'"Botb patients suffered from a bilateral symmetrical erythema of tbe skin. Biopsy in one patient showed marked focal capillary proliferation in tbe upper dermis and a minimal intlammatory infiltrate. Three studies report a connection between the calcium antagonist nifedipine and incapacitating secondary erytbermalgia.'' ' * Tbe patients complained of burning pain, and bad symmetrical erytbema ofthe feet and lower legs wbicb subsided within 2 days of withdrawal of tbe drug. Resumption of tbe drug resulted in recurrence of tbe symptoms. Tbe calcium antagonist nicardipine bas been reported as causing intermittent redness, warmtb and pain in tbe fingers of one patient.'^ These cbanges rapidly resolved after discontinuation of tbe drug. As we observed in our case, erytbermalgia secondary to drugs develops insidiously after long-term treatment, and disappears 1-14 days after tbe responsible drug is stopped. Our patient presented with typical erythermalgia of both feet and lower legs. Tbe regression of the crytber-
294
J.P.H.DRENTH et aJ.
Drug
Dose (mg/day)
Table 1. Drug-induced secondary erythermalgia
n 7/92 11/110 1
Tl 10 months 15 months 24 months
Bromocriptine Bromocriptine Bromocriptine
115 101 120
Pergolide Pergolide
NS NS
12 months 18 months
Nifedipine Nifedipine
60 40
8 weeks
Nicardipine
60
1 year
Verapami!
120
NS
1 -9 months
T2 1 week 10 days NS NS NS
Reference Calne ft al.^ Eisler et at.^ Dupont et al.'^ Monk era/,'" Monk et a/,'"
2 days Immediate
Fisher el «/," Brodmerkel' ^
Rapid
Levesque et a!.
1 -2 weeks
Present case
fl. number of patients; T 1, time lapse between lirst dose and occurrence of erythermalgia: T2. time from discontinuation to resolution of erythermalgia; NS, not stated.
malgia after stopping verapamil strongly suggests that it was responsible for the problem. Unfortunately, the patient refused rechailenge with verapamil and absolute confirmation was therefore not possible. However, the temporal relationship witb verapamil makes this drug the most likely cause ofthe erytbermalgia. Verapamil is a phenylalkylamine derivative able to inhibit the slow inward current of calcium ions across the cell membrane of cardiac and vascular smooth muscle. It thereby causes coronary and peripheral vasodilatation and decreases myocardial contractility. It also infiuences the sinus and atrioventricuiar nodes. Verapamil is indicated for the treatment of hypertension, cardiac arrhythmias and angina."' A common sideeffect of verapamil is facial flushing and this is regarded as an extension ofthe vasodilator action."' To our knowledge, our case is the tirst report of verapamil-induced secondary erythermalgia. The pathophysiology of primary and secondary erythermalgia and the mechanism of drug-induced erythermalgia are unknown and remain to be elucidated.^
References 1 Drenth JPH, Michiels JJ, Tbree types of erythromelalgia. Br Med / 1990; 501:454-5. 2 Michiels J|, Abels |, Steketee J et at, Hrytbromelalgia caused by platelet-mediated arteriolar inilammation and thrombosis in thrombocytbaemia. Ann Intern Med 1985; 102: 4f>6-7l.
i Michiels )|, VanloostTh, Krythromelalgiaandthrotnbocythaemia; A causal relation. / Am Acad Dermalot 1990; 22: 107-1 1. 4 Michiels |), Ten Kale FW). hirythromelalgia in thrombocythaemia of various myeloproliferative disorders. Am } Hemtito! 1992: 39: 131-6, 5 Michiels J]. Van Joost Th, Vuzevski VD. Idiopathic erythermalgia. a congenital disorder, / Am Acad Dermatol 1989; 2 1 : 1128-30. fl Michiels)]. Van |oost Th, Primary and secondary erythermalgia, a critical review. Nelh / Med 1988; 33: 205-8. 7 Catne D, Plotkin C. Williams A el a!. Long-term treatment of parkinsonism with bromocriplinc. !Mncet 1978; i: 735, H Eisier T, Hall RP, Kalavar KAR, Calne DB. Krythromelalgia-like eruptions in parkinsonian patients treated with bromocriptine, Neuro!ogy 1981; 31: 1368-70, 9 Dupont E, Ilium F. Olivarius B. Bromocriptine and erythromelalgia-like eruptions. Netiro!ogy 1987; 10: 670, 10 Monk BE. Parkes ID, Du Vivier A. Rrythromeialgia following pergolide administration. Br j Dermato! 1984: 111: 97-9. I I Fisher ]R. Padnick MH, Olstein S, Nifedipine and erythromelalgia, Ann !ntern Med 1985; 98: 671-2. 12 Brodmerkel C
