Treatment of Raynaud’s Phenomenon with Calcium Channel Blockers

CRAIG Ft. SMITH, M.D. RICHARD J. RODEHEFFER, M.D. Baltimore, Maryland

Raynaud’s phenomenon may cause severe digital pain and func- tional disability, particularly in patients with underlying connective tissue diseases. The pathophysiology of Raynaud’s phenomenon is varied, but digital ischemia is an essential element. Because cal- cium channel blockers cause arteriolar vasodilation and an increase in peripheral blood flow, they have been used to treat patients with Raynaud’s phenomenon in several prospective, randomized, dou- ble-blind, placebo-controlled trials. Verapamil was ineffective in low doses, but both nifedipine and diltiazem produced subjective im- provement. In placebo-controlled studies with nifedipine, the fre- quency of vasospastic episodes per two weeks decreased from 14.7 episodes during placebo therapy to 10.8 during nifedipine therapy (p -C 0.05). This response was more pronounced in patients without underlying vascular disease. Moderate or marked subjective im- provement occurred in 80 percent of the patients receiving nifedi- pine and in only 13 percent of patients receiving placebo. Adverse effects were mild. It is concluded that nifedipine is an effective short-term therapy for most patients with Raynaud’s phenomenon.

Raynaud’s phenomenon is characterized by the sudden development of digital pallor or cyanosis in response to exposure to cold or stress [I ,2]. lschemic symptoms such as parasthesias and numbness usually last as long as the stimulus is present and are followed by hyperemia, pain, and throbbing of the digits. The color changes are usually well demarcated, involve one or more fingers, and may be asymmetric. Severe pain and functional disability may occur in association with digital atrophy, ulcera- tion, or gangrene, particularly in patients with underlying vascular dis- ease. Raynaud’s phenomenon may also be a generalized process, in- volving the feet, ear lobes, and visceral vessels.

From the Divisions of Internal Medicine and Cardi- ology, Johns Hopkins Hospital, Baltimore, Mary- land. Requests for reprints should be addressed to Dr. Craig R. Smith, Division of Internal Medicine, Johns Hopkins Hospital, Harvey Building, Room 402, 600 North Wolfe Street, Baltimore, Man/land 21205. there is no evidence of underlying disease.

Several diseases may be associated with Raynaud’s phenomenon (Table I) [3]. These include immunologic diseases, such as systemic sclerosis, SLE, and rheumatoid arthritis; obstructive arterial diseases, such as vasculitis, thoracic outlet syndrome, atherosclerosis of proximal vessels, and thromboangiitis obliterans; arterial trauma due to vibration and cold; and a variety of other etiologies, including cryoglobulinemia, hypothyroidism, vinyl chloride disease, chronic renal failure, and occult malignancy. Several drugs, including ergotamine, oral contraceptives, methysergide, beta blockers, and bleomycin, have also been implicated as causes of Raynaud’s phenomenon. The most common secondary causes are scleroderma, arterial trauma, and mixed connective tissue disease [3]. In most patients with Raynaud’s phenomenon, however,

February 22, 1985 The American Journal of Medlclne Volume 78 (suppl 28) 39

SYMPOSIUM ON CALCIUM CHANNEL BLOCKERS-SMITH and RODEHEFFER

TABLE I Diseases and Drugs Associated with Raynaud’s Phenomenon

lmmunologlc disorders Systemic sclerosis SLE Rheumatoid arthritis

Obstructive arterial disease Vasculitis Thoracic outlet syndrome Atherosclerosis Thromboangiitis obliterans

Arterlal trauma Vibration Cold

Other diseases Cryoglobulinemia Hypothyroidism Vinyl chloride disease Chronic renal failure Occult malignancy

Drugs Ergotamine Oral contraceptives Methysergide Beta blockers Bleomycin

PATHOPHYSIOLOGY

Decreased digital blood flow is an essential element in the pathophysiology of Raynaud’s phenomenon (Figure 1) [4]. Decreased digital blood flow may be caused by de- creased perfusion pressure, increased blood viscosity, or decreased luminal area of the digital artery [5]. Decreased perfusion pressure may be caused by hypotension or proximal vascular occlusions. Increased blood viscosity may be caused by increased plasma fibrinogen, in- creased platelet adhesion, or decreased red cell deforma- bility, all of which have been noted in patients with Ray- naud’s phenomenon [6-91.

Figure 1. The pathophysiology of Raynaud’s syndrome, characterited by a decrease in digital blood flow, which may be due to diverse causes. PGE, = prostaglandin El; PG12 = prostacyclin; TX& = thromboxane.

Most commonly, decreased digital blood flow is induced by decreased luminal area of the digital artery, which is caused either by anatomic vascular occlusion or vaso- spasm, or both. Anatomic luminal occlusion is the hall- mark of patients with scleroderma. These patients have intimal and adventitial fibrosis of the vessel wall, and they may also have diffuse small fibrin thrombi in the vessels, both of which may further impair digital flow [lo]. Vaso- spasm may be caused by enhanced adrenergic respon- siveness of the blood vessels, or by a local mediator ab- normality. Each one of these mechanisms has been implicated as a cause of Raynaud’s phenomenon. For example, exposure to cold increases the alpha-adrenergic responsiveness of the digital vessels by increasing norep inephrine release, decreasing norepinephrine degrada- tion, and (possibly) increasing receptor sensitivity [l 11. Local mediator abnormalities, including diminished pros- tacyclin or increased thromboxane production, have also been suggested, but conclusive evidence for these abnor- malities is lacking [12].

DRUGTHERAPY

The drug therapy of Raynaud’s phenomenon has been directed at reversing many of the previously discussed abnormalities. A variety of drugs have been used, includ- ing vasodilators, alpha-adrenergic blocking agents, ni- trates, griseofulvin, terbutaline, fibrinolytics, prostaglandin infusions, and the calcium channel blockers (Table II). Other than the calcium channel blockers, isoxsuprine, griseofulvin, and topical glyceryl trinitrate are the only drugs demonstrated to be effective in controlled double- blind clinical trials. Unfortunately, adverse effects or in- convenience of administration have limited the utility of all but the calcium channel blockers.

CALCIUM CHANNEL BLOCKERS

Both in vitro and in vivo physiologic experiments have demonstrated that calcium channel blockers cause vas- cular smooth muscle relaxation and relief of arterial vaso- spasm. Vasodilation induced by these drugs has been shown to cause a fall in peripheral vascular resistance and an increase in peripheral blood flow [13]. Calcium channel blockers have also been shown in vitro to inhibit norepinephrine-induced vasospasm of rabbit and human peripheral arteries and veins [14]. As a result of these findings, several investigators have studied the effective- ness of calcium channel blockers in patients with Ray- naud’s phenomenon.

Kinney et al [15] conducted a prospective double-blind crossover trial in 17 patients receiving verapamil (40 to 60 mg) four times a day for two weeks. These investigators assessed the effectiveness of therapy by means of diary tabulation of attack frequency, subjective evaluation of overall effectiveness, and digital systolic pressures. In this study, there was no significant difference between pla-

48 February 22.1888 The American Journal ol Medicine Volume 78 (suppl2B)

cebo- and verapamil-treated patients in the number or severity of attacks, the subjective evaluation of effective- ness, or mean digital systolic pressure during cold expo- sure.

Vayssairat [I 61 studied the effectiveness of diltiazem in 26 patients with Raynaud’s phenomenon. Diltiazem (60 mg three times a day) was given for two weeks in a pro- spective, double-blind, placebo-controlled trial. In this study, patients demonstrated improvement in their sub- jective assessment of disability and in the frequency of attacks. There was a 17 percent decrease in symptoms during placebo treatment and a 51 percent decrease dur- ing diltiazem treatment; the number of vasospastic attacks decreased by 6.5 percent and 64 percent, respectively (p < 0.05). Objective evidence of improvement in digital blood flow was not observed. Vayssairat concluded that diltiazem was effective therapy for patients with Ray- naud’s syndrome.

Nifedipine is the calcium channel blocker that has been most extensively studied in patients with Raynaud’s phe- nomenon. Kahan et al [17] first reported the results of a prospective controlled trial in 16 patients. Nifedipine (20 mg) was given as a single oral dose on two consecutive days. Vasospasm was provoked by hand immersion in cold water before and at the first and sixth hours after each drug administration. Nifedipine delayed the onset of digital vasospasm in 14 of the 16 patients. A long-term study of the effectiveness of nifedipine (20 mg three times a day) was then carried out in 10 patients during three winter months. The mean number of digital vasospastic attacks per week decreased from 29.5 to 4.3, and four of the 10 patients were entirely free from attacks. Kahan et al [18] subsequently published the results of a prospective, placebo-controlled, randomized, double-blind, crossover trial in 30 patients treated with nifedipine (20 mg three times a day) for two weeks. The number of vasospastic episodes decreased 90.1 percent for patients with idio- pathic Raynaud’s phenomenon, 78.6 percent for patients with SLE, and 64 percent for patients with scleroderma. These differences were statistically significant compared with placebo and suggest that nifedipine was effective therapy for most patients with Raynaud’s phenomenon.

Smith and McKendry (191 also conducted a prospective, double-blind, crossover trial comparing placebo to nifedi- pine (10 mg four times a day) in 17 women with Ray- naud’s phenomenon. Effectiveness was measured by dia- ries, subjective evaluation, and skin temperature recovery times. Severity and global effectiveness were each as- sessed with separate lo-cm visual analog scales, in which a score of 10 indicated either the greatest severity or the greatest effectiveness. The daily frequency of at- tacks decreased from 2.5 ? 0.4 during placebo therapy to 1.3 * 0.3 during nifedipine therapy. The severity of at- tacks decreased from 5.8 r 0.6 during placebo therapy to 3.4 f 0.5 during nifedipine therapy, and effectiveness

SYMWSIUM ON CALCIUM CHANNEL BLOCKERS-SMITH and RODEHEFFER

TABLE II Drugs Used in the Therapy of Raynaud’s Syndrome

Vasodilator lsoxsuprine

Alpha-adrenergic blockers Reserpine Prazosin Alpha-methyldopa Guanethidine Phentolamine Phenoxybenzamine

Fibrlnolytics Stanozolol Pit viper venom

Prostaglandlns PGE, PGEp

Calcium channel blockers Verapamil Diltiazem Nifedipine

Other Glyceryl trinitrate Griseofulvin Terbutaline

improved from 1.3 ? 0.6 to 5.3 f 0.8. No improvement was noted in skin temperature recovery times.

We have also conducted a placebo-controlled double- blind trial of nifedipine in the treatment of patients with Raynaud’s phenomenon [20]. We selected patients with symptomatic, cold-induced digital vasospasm. Patients with digital vasospasm due to thoracic outlet syndrome, vibratory trauma, large vessel atherosclerosis, thrombo- angiitis obliterans, and polyarteritis nodosa were excluded from the trial.

The trial consisted of four study periods. The first was a placebo run-in period that lasted two weeks and was fol- lowed by two treatment periods of two weeks’ duration each, separated by a one-week washout period. During the treatment periods, patients received either nifedipine or placebo. The dose of nifedipine was 10 mg three times a day for three days, then 20 mg three times a day for 11 days. Several measurements were made to determine the effectiveness of nifedipine, including the patient’s global assessment of drug effectiveness, diaries in which the patients tabulated the daily frequency and severity of their vasospastic episodes, and digital perfusion pressures while patients were lying on a thermal blanket at 30°C or 15°C.

The frequency of vasospastic episodes per two weeks decreased from 14.7 episodes during placebo therapy to 10.8 episodes during nifedipine therapy (p < 0.05). This response was more pronounced in patients who did not have underlying vascular disease. The patients’ overall assessment of the effectiveness of therapy was also sig-

February 22, 1995 The American Journal of Medicine Volume 78 (suppl2B) 41

SYMPOSIUM ON CALCIUM CHANNEL BLOCKERS-SMITH and RODEHEFFER

TABLE III Subjective Assessment of Therapeutic Efficacy* by Patients in a Controlled Study Using Nifedipine and Placebo

Subjective Assessment

Nifedipine Placebo

Number Percent Number Percent

Moderate or marked improvement

Minimal improvement, no change, or worse

9 60 2 13

6 40 13 87

l p = 0.02, Fisher exact test. Reproduced from [20].

nificantly different between nifedipine and placebo. Mod- erate or marked subjective improvement occurred in 60 percent of the patients receiving nifedipine and in only 13 percent receiving placebo (Table Ill). Despite the de- crease in the number of vasospastic episodes and marked improvement in the patients’ global assessment of therapy, no changes were noted in digital perfusion pressures when placebo was compared with nifedipine. The brachial index (the ratio of mean digital systolic pres- sure to the mean brachial systolic pressure) was 0.7 in both groups during 30°C exposure and 0.4 in both groups during 15°C exposure.

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COMMENTS

These results indicate that some patients had a decrease in the frequency of vasospastic attacks and a moderate or marked improvement in their symptoms during nifedipine treatment. However, there was variability in the response to therapy; in some patients, there was no response at all. In patients who did not have underlying vascular disease, the response appeared to be better than in patients with scleroderma. Kahan et al [18] and Smith and McKendry [19] also found that patients with scleroderma responded less well. The reasons for the difference in individual re- sponses to nifedipine cannot be determined from the data. They may have been due to variation in the severity of vasospasm, to the extent of anatomic narrowing of the digital arteries, or to other as yet uncharacterized factors associated with the presence of underlying vascular dis- ease. Four independent, double-blind, controlled clinical trials have shown that short-term treatment with nifedipine or diltiazem provides symptomatic relief in some patients with Raynaud’s phenomenon [16,18,20]. Nifedipine and diltiazem are conveniently administered and well-toler- ated. Further clinical studies will determine the dose-re- sponse relationship, the effectiveness of long-term ther- apy, and the predictors of clinical responsiveness.

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