Causalgia

BASICS

Introduction

Raynaud's disease (RD) is idiopathic, paroxysmal bilateral cyanosis of the digits due to arterial or arteriolar contraction. First described by Maurice Raynaud in 1883, it remains a medical mystery to this day.' Raynaud's phenomenon (RP) is a syndrome manifested by attacks of pallor (paleness of the skin) and cyanosis (bluish discoloration of the skin) of the digits in response to cold or emotion; when the attack subsides, redness replaces the paleness and bluish discoloration of the digits.2 RD is idiopathic and can only be diagnosed when secondary causes have been excluded;1 whereas RP is due to secondary causes. RD is the most common cause of RP, accounting for 60% of such cases.2 Although RD can begin at any age, it is most common between the ages of 20 and 40 years and is more common among women than men.

Etiology

Raynaud believed that RD was caused by increased sympathetic nerve activity. However, it has been reported that sympathetic nerve traffic in the median nerve is no different in patients with RD than in normal individuals and that attacks of RP could be induced after interruption of the sympathetic nerves.2 It has also been concluded that the cause of the disorder is a fault in the arterial wall that renders the vessels hyperresponsive to the vaso constrictive effects of cold.2 It has been proposed that accelerated destruction of platelets and release of agents such as serotonin or thromboxane A^sub 2^ are the cause of vasoconstriction in some patients with RP.2 However, it is not known whether platelet destruction is the cause of spasms in patients or a consequence of them. In one study,2 26% of patients with angina pectoris were found to have migraine; and 24% were found to have RP. Some patients with RP may have a generalized defect that predisposes arteries in many regions to vasospasm. An association of RP with idiopathic pulmonary hypertension has also been suggested. This association may reflect a very high level of peripheral vascular tone secondary to the severe reduction in cardiac output.

RP is observed frequently and may be caused by:

* Occlusive arterial disease

Note: Occlusive arterial disease may be caused by arteriosclerosis obliterans, Buerger's disease, arterial embolism vasculitis or arterial thrombosis.

* Connective-tissue diseases

Note: Connective-tissue diseases may be caused by scleroderma (almost all patients with scleroderma develop RP during the course of their illness2).

* Vascular injury

* Neurogenic causes

Note: Included in neurogenic causes are carpal tunnel syndrome, sympathetic causalgia and spinal-cord diseases.

* Drugs

* Exposure to chemicals, or intravascular coagulation or aggregation

* Rheumatoid arthritis

* Systemic lupus erythematosus

RP may be the presenting manifestation in connective-tissue diseases and may precede the appearance of other manifestations by several years.2 Smoking, beta-adrenergic blocking agents, ergots, sympathomimetics, imipramine or clonidine exposure may precipitate an RP attack. The most common chemical precipitating factors are smoking and the use of betablockers. Trauma to the digital areas, frequent use of the hands or use of heavy, vibrating machinery are other commonly associated conditions or contributing factors to RP.1

Pathophysiology

The pallor of the skin during an attack of RP is explained by intense vasoconstriction or spasm of the digital arteries. This vasoconstriction or spasm results in severe reduction in blood flow. In a later stage of the attack, the vasoconstriction becomes less severe, the capillaries and veins are partially filled with blood and hemoglobin becomes markedly deoxygenated. This accounts for the cyanosis. Upon rewarming of the skin, cyanosis is replaced by an intense red color, which is associated with reactive hyperemia. Between attacks, blood flow to the digits is usually reduced, especially in patients who have trophic changes (a result of the interruption of nerve supply), but blood flow may be normal in some patients. In those patients without trophic changes, blood flow to the hand during maximum vasodilation is the same as in normal individuals but is severely reduced in those with trophic changes, which is a reflection of structural changes in the blood vessels.2 In the early stages of RP, the digital vessels are histologically normal. In long-standing cases, the intima becomes thickened; and the media may be hypertrophied. In severe progressive cases, complete obstruction from thrombosis may occur; and gangrene of the tips of the digits may ensue.

Clinical Manifestations

The onset of RD is usually gradual. The patient notices an occasional mild, short-lasting attack during the winter months. Over succeeding years, the severity and duration of the attacks may increase. A wide variation in severity is present. Most commonly, the attacks are provoked by exposure to cold. In some patients, attacks are also precipitated by emotion. The attacks may be terminated by rewarming, or they may abate spontaneously. Between attacks, in a warm environment, the patient is asymptomatic; and physical examination shows no abnormalities. However, some patients complain of chronically cold hands and feet; and they may have cold fingers with cyanosis on examination. In a typical attack of RP, the digits become pale. Usually, all digits are affected symmetrically. The pallor is sharply demarcated at the level of the metacarpophalangeal joints, which is a reflection of spasm of the digital arteries. At a later stage during the attack, pallor is replaced by cyanosis. The patient may have feelings of coldness; numbness; and, occasionally, pain. Upon rewarming of the skin, the cyanosis is replaced by intense redness, and the patient may feel tingling or throbbing. Most commonly, only the hands are affected. Frequently, both the hands and the feet are affected. Rarely are the nose, cheeks, chin or ears affected.

Diagnosis

RP can usually be diagnosed on the basis of the history of vasospastic attacks in the digits, precipitated by cold and relieved by warming. Pharmacists may wish to ask their patients a few screening questions, such as:

* Are your fingers unusually sensitive to cold?

* Do your fingers change color when they are exposed to cold temperatures?

* Do your fingers turn white, or blue or both white and blue? The diagnosis of RP is confirmed by a positive response to all three questions.3

Differentiating RD from RP is based mainly on the exclusion of disorders known to cause RP. Pharmacists may wish to review the patient's medication profile to exclude the use of chemotherapeutic agents, interferon, estrogen, nicotine, narcotics, sympathomimetic agents, cyclosporine, cocaine, polyvinyl chloride, ergotamine derivatives or clonidine.3 The patient should also be questioned about environmental exposure and possible injury such as frostbite, repetitive occupational stress (hand-arm vibration syndrome) and carpal tunnel syndrome. Patients who have normal findings on review of their medical history and physical examination, no digital lesions or gangrene and normal nail-fold capillaries do not need to undergo specialized studies and can be diagnosed with RD.3 Other patients should be referred to their physician for further studies and subsequent diagnosis.

Prognosis

The prognosis of patients with RD is good. There is no mortality associated with the disease, and morbidity is low; it is generally limited to the loss of portions of digits as a result of ulcerations. In approximately 50% of patients with RD, the disorder improves and may disappear completely after several years.2 In fewer than 1% of patients diagnosed with RD, an amputation is necessary.2 Approximately 15% of patients diagnosed with RP eventually develop a connective-tissue disorder, particularly scleroderma.

Treatment

The management of patients with RP must be tailored to the individual needs of the patient, and the frequency and severity of the attacks should be taken into consideration. These patients should be taught to recognize and terminate attacks. All patients benefit from protective measures against exposure to cold. RP patients should:

* Limit the duration of exposure to cold as much as possible.

* Wear heavy clothing to protect not only the hands and feet but also the face and trunk, especially when there is a cold wind. This is important because exposure to cold of other portions of the body may induce vasoconstriction in the digits and precipitate RP.

When prolonged exposure to cold is unavoidable, the use of electrically powered or solid fuel-powered hand and foot warmers is advisable. If the patient has been unavoidably exposed to cold temperatures, he or she should:

* Return promptly to a warm environment.

* Place the hands in warm water (110 deg F), which will induce vasodilation and has been reported to raise skin temperature and minimize the severity of attacks of RP, or use a hair dryer to warm the hands rapidly.

These simple measures will usually suffice for patients with infrequent or mild attacks. However, when RP is more frequent or more severe, and when the disease has resulted in trophic changes or ulcerations, these measures need to be supplemented by drug therapy. The goal of drug therapy is to induce vascular smooth-muscle relaxation, which should relieve spasms, raise resting blood flow and limit the degree of ischemia during attacks. For most patients, the drug of choice is a calcium antagonist. Table 1 lists the drugs of choice for the treatment of RD and/or RP and furnishes comments and preferred dosages. Reserpine, guanethidine and methyldopa are among the group of drugs that interfere with the function of the adrenergic nervous system. Reserpine is the best studied (see Table 1). This group of drugs causes significant side effects, including nasal congestion, postural hypotension and fatigue.

It is uncertain whether niacin is beneficial in the treatment of RD and/or RP, as the benefits are dependent upon the patient's concomitant disease state. For example, a patient who is being treated for hypercholesterolemia and RP will likely have dual benefit from the addition of the vasodilating effects of niacin. In contrast, a patient with diabetes mellitus may not benefit from niacin treatment due to the risk of losing glucose control. Topical prostaglandin E^sub 2^ (PGE^sub 2^) has been found to be effective in RP.2 The topical application is advantageous because the local relaxant action is not counteracted by reflex vasoconstriction, secondary to changes in blood pressure that may occur when PGE^sub 2^ is given systemically.2

Nutritional supplementation may play a safe and important role in reducing the severity and frequency of RD and/or RP attacks. Table 2 provides a list of the nutritional supplementations that may be more beneficial. Other nutritional supplementation that may be taken to reduce the severity and frequency of RD and/or RP attacks are dimethylglycine, flaxseed oil, inositol and vitamin B complex.4 Table 3 provides sample formulations for the treatment of RD.

Recommendations

There are no formal guidelines for the evaluation and treatment of patients with RP. However, any patient who presents with RP should be assessed for signs and symptoms suggestive of a secondary cause.2 Patients presenting before the age of 20 years who have no symptoms or signs of a secondary cause can be followed without undergoing other specialized tests. Initial management should include the avoidance of cold temperatures. Drug therapy should be added only if the attacks are poorly controlled and disabling. Calcium-channel blockers are the first line of therapy. Nifedipine is the drug of choice and may be given orally or transdermal JV.2 Doses should be increased until benefit is noted or until a maximal tolerated dose is reached. Treatment of any underlying autoimmune disease may reduce the frequency and severity of attacks of RP, although the pattern or pace of attacks is often independent of overall disease activity.

References

1. Lawrence D, Weart C. Peripheral vascular disorders. In: Young L, Koda-Kimble MA, eds. Applied Therapeutics: The Clinical Use of Drugs. 6th ed. Vancouver, WA:Applied Therapeutics, Inc.; 1995:(11-2)-(11-7).

2. Kontos H. Vascular diseases of the limbs. In: Wyngaarden J, Smith L, eds. Cecil's Textbook of Medicine. 18th ed. Philadelphia:WB Saunders Co.:1988;1:375-377, 382, 601, 1561-1565, 2015, 2018-2037.

3. Wigley FM. Clinical practice. Raynaud's phenomenon. N Engl J Med 2002;347:1001-1003.

4. Balch JF, Balch PA. Prescription for Nutritional Healing. 2nd ed. Garden City Park, NY:Avery Publishing Group; 1998:458.

Andrew Glasnapp, BS, PharmD, FIACP

Professional Compounding Centers of America Houston, Texas

Address correspondence to: Andrew Glasnapp, BS, PharmD, FIACP, Professional Compounding Centers of America, 9901 South Wilcrest, Houston, TX 77099. E-mail: glasnapp@pccarx.com

Copyright International Journal of Pharmaceutical Compounding Jul/Aug 2003
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