eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease
Raynaud Phenomenon: Treatment & Medication
Updated: Jun 3, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
- General measures: These include education, warming of local body part, and cessation of vasoconstricting agents such as nicotine.
- Primary Raynaud phenomenon
- Use calcium channel blockers, especially those that cause vasodilation. The most commonly used drug is nifedipine. Use the lowest dose of a long-acting preparation and titrate up as tolerated. If adverse effects occur, decrease dosage or use another agent such as nicardipine, amlodipine, or diltiazem.
- ACE inhibitors and intravenous prostaglandins have been advocated, and clinical trials have indicated some benefit. The selective serotonin uptake inhibitor (SSRI) fluoxetine has also been shown effective in at least one study.
- Therapy with antiplatelet agents has been attempted but has not been proven effective, and anticoagulation is not indicated. The angiotensin-receptor antagonist losartan at 50 mg/d has been found effective in patients with primary Raynaud phenomenon and scleroderma.
- Topical nitroglycerin (1% or 2%) has been found to help if applied locally based on a limited number of controlled studies.18
- Secondary Raynaud phenomenon
- Therapy must be tailored to the underlying disorder.
- If associated with occupational or toxic exposure, the patient should avoid the inciting environment.
- Patients with hyperviscosity syndromes and cryoglobulinemia improve with treatments that decrease the viscosity and improve the rheologic properties of their blood (eg, plasmapheresis).
- Unfortunately, patients with autoimmune disorders and associated Raynaud phenomenon do not usually respond well to therapy.
- Hepatitis B, hepatitis C, and Mycoplasma infections need to be addressed, if present.
- In older patients with newly onset Raynaud phenomenon and no obvious underlying cause, malignancy must be considered.
Surgical Care
- Cervical sympathectomy is still considered controversial and may offer only temporary relief.
- Digital sympathectomy has been gaining support for severe or tissue-threatening disease. This may be used in patients with either primary or secondary Raynaud phenomenon, but it is more commonly necessary with the secondary forms.
Consultations
- Typically, primary Raynaud phenomenon does not require any consultations.
- Secondary Raynaud phenomenon may require consultations.
- Consult a rheumatologist or hematologist to delineate associated syndromes.
- Fixed (nonreversible) lesions are not Raynaud phenomenon and may require referral to a rheumatologist, vascular surgeon, orthopedist, or other specialist.
Diet
Fish oils containing omega-3-fatty acids may be beneficial in some patients with primary Raynaud phenomenon.
Activity
- Nondrug therapy may be all that is required for mild cases of primary Raynaud phenomenon. Therapies can include the following:
- Biofeedback and relaxation
- Avoiding inciting environmental factors such as direct contact with frozen foods or cold drinks
- Insulation against cold and local warming, including electric and chemical warming devices
- Removing any drugs from the medical regimen that may provoke vasospasm
- Avoiding smoking
- With time, most patients learn to incorporate these therapies on their own.
Medication
Drugs should be used to vasodilate the affected circulation, as long as other tissues and systemic blood pressure are not compromised.
Calcium channel blockers
These agents are used for vasodilation and possible antiplatelet effects. The dihydropyridine class of agents contains potent vasodilators and is the first line of treatment after nondrug therapy.
Nifedipine (Adalat, Procardia)
Start with lowest dose available and titrate upward as tolerated. Result should be a diminution in the frequency or severity of attacks. Usually preparations that are not strong negative inotropes are preferred. ER dosage form is most commonly used. If this drug cannot be used, the alternative preparations (nicardipine, amlodipine, diltiazem) are worth considering.
On average, moderate reduction of up to 35% improvement can be expected.
Nifedipine among the dihydropyridines has been extensively studied; however, in the same category, felodipine, amlodipine, and isradipine seem to be equally effective.
Adult
30 mg XL PO qd
Pediatric
Not recommended
Caution with coadministration of any agent that can lower BP, including beta-blockers and opioids; H2 blockers (cimetidine) may increase toxicity
Documented hypersensitivity; systemic hypotension; possibly, esophageal reflux; aortic stenosis
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Teratogenic in rats and rabbits; blood pressure should be monitored; PT in patients on warfarin may be prolonged; may cause lower extremity edema; allergic hepatitis has occurred but is rare; possible increased cardiovascular risks with short acting preparations; may cause headache and reflex tachycardia, edema, and flushing
Nicardipine (Cardene, Cardene SR)
Used for vasodilatation and possible antiplatelet effects. Start with lowest dose available. Extended dose preparations and agents with fewer negative inotropic effects are preferred.
Adult
20-30 mg PO tid or 30-60 mg PO bid (extended dose)
Pediatric
Not recommended
Interactions with other agents that lower blood pressure
Documented hypersensitivity; systemic hypotension; possibly, gastroesophageal reflux; aortic stenosis
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Causes vasodilatation; may cause headache, tachycardia, edema, and flushing; possible increased cardiovascular risks with short-acting agents; used with caution in patients with intracerebral hemorrhage and hepatic metabolism, so caution should be used when using it in patients with impaired liver function
Amlodipine (Norvasc)
Relaxes coronary smooth muscle and produces coronary vasodilation, which in turn improves myocardial oxygen delivery. Benefits nonpregnant patients with systolic dysfunction, hypertension, or arrhythmias. Can be used during pregnancy if clinically indicated.
Adult
2.5-5 mg/d PO; not to exceed 10 mg/d PO
Pediatric
Not recommended
Fentanyl may increase hypotensive effects; may increase cyclosporin levels; H2 blockers (cimetidine) may increase toxicity
Documented hypersensitivity; systemic hypotension; aortic stenosis
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Adjust dose in renal/hepatic impairment; may cause lower extremity edema; allergic hepatitis has occurred but is rare
Diltiazem (Cardizem CD, Cardizem SR, Dilacor, Tiamate, Tiazac)
During depolarization, inhibits calcium ions from entering the slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium. Causes some vasodilatation but not as potently as nifedipine.
Adult
Cardizem SR: 60-120 mg PO bid
Pediatric
Not established
May increase carbamazepine, digoxin, cyclosporine, and theophylline levels; when administered with amiodarone, may cause bradycardia and a decrease in cardiac output; when administered with beta-blockers may increase cardiac depression; cimetidine may increase diltiazem levels
Documented hypersensitivity; severe CHF, sick sinus syndrome, second- or third-degree AV block, and hypotension (<90 mm Hg systolic)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in impaired renal or hepatic function; may increase LFT levels, and hepatic injury may occur
Angiotensin-converting enzyme inhibitors
These agents are used for vasodilation and possible antifibrotic and anti-inflammatory properties.
Benazepril (Lotensin)
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. Should be used once a day. Should be started at the lowest possible dose and titrated upwards as tolerated. Desired effects include a decrease in frequency and severity of attacks of Raynaud phenomenon.
Adult
10 mg PO qd
Pediatric
Not recommended
May increase digoxin, lithium, and allopurinol levels; probenecid may increase benazepril levels; coadministration with diuretics increase hypotensive effects; the hypotensive effects of benazepril may be enhanced when administered concurrently with diuretics and NSAIDs
Documented hypersensitivity; chronic cough; systemic hypotension; hyperkalemia; NSAIDs
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Use lowest effective dose and monitor serum potassium level; caution in renal impairment, valvular stenosis, or severe congestive heart failure
Angiotensin II receptor antagonists
Used for vasodilation and for their possible antifibrotic and anti-inflammatory effects.
Losartan (Cozaar)
Nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors. Does not affect the response to bradykinin and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors. Less effective in patients with scleroderma than with primary Raynaud phenomenon. May modify some serum markers of vascular damage and possibly modulate some of the underlying tissue damage in scleroderma.
Adult
50 mg PO qd
Pediatric
Not recommended
Ketoconazole, sulfaphenazole, and phenobarbital may decrease effects; cimetidine may increase effects of losartan; may interact with other drugs that increase potassium concentrations and produce hyperkalemia
Documented hypersensitivity to angiotensin II preceptor antagonists
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in patients with unilateral or bilateral renal artery stenosis; may cause hyperkalemia
Endothelin inhibitors
These agents inhibit vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 (ET-1) receptors ETA and ETB in endothelium and vascular smooth muscle.
Bosentan (Tracleer)
Endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension in patients with WHO class III or IV symptoms to improve exercise ability and to decrease rate of clinical worsening. This leads to significant increase in cardiac index (CI) associated with significant reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP).
Recently, prevention of digital ulcers was demonstrated in a randomized prospective, placebo-controlled trial that involved 122 patients with scleroderma.
Case series also reported complete cessation of Raynaud symptoms in 4 patients.
Adult
<40 kg: 62.5 mg PO bid; not to exceed 125 mg/d
>40 kg: 62.5 mg PO bid for 4 wk initially, then increase to 125 mg PO bid
Pediatric
Not established; 62.5 mg PO bid recommended if <40 kg, or >12 years; not to exceed 125 mg/d
Toxicity may increase when administered concomitantly with inhibitors of isoenzymes CYP450 2C9 and CYP450 3A4 (eg, ketoconazole, erythromycin, fluoxetine, sertraline, amiodarone, and cyclosporine A); induces isoenzymes CYP450 2C9 and CYP450 3A4, causing decrease in plasma concentrations of drugs metabolized by these enzymes, including glyburide and other hypoglycemics, cyclosporine A, hormonal contraceptives, simvastatin, and, possibly, other statins; hepatotoxicity increases with concomitant administration of glyburide
Documented hypersensitivity; coadministration with cyclosporine A or glyburide
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Causes at least 3-fold elevation of liver aminotransferases (ie, ALT, AST) levels in about 11% of patients; may elevate levels of bilirubin (serum aminotransferase levels must be measured prior to initiation of treatment and then monthly); caution in patients with mildly impaired liver function (avoid in patients with moderate or severe liver impairment); not recommended while breastfeeding; monitor hemoglobin levels after 1 and 3 mo of treatment and every 3 mo thereafter; exclude pregnancy before initiating treatment and prevent thereafter with use of reliable contraception; headache and nasopharyngitis may occur
Serotonin reuptake inhibitors
Serotonin is a potent vasoconstrictor that is released from nerve endings and during platelet activation, explaining why SSRIs are believed to be helpful in the treatment of Raynaud phenomenon. Fluoxetine (20 mg) versus nifedipine (40 mg) in patients with primary and secondary Raynaud phenomenon showed that fluoxetine statistically improved the frequency and severity of Raynaud attacks, while nifedipine did not reach statistical significance. A better response was seen in patients with Raynaud disease versus patients with Raynaud phenomenon.
Fluoxetine (Prozac)
Selectively inhibits presynaptic serotonin reuptake with minimal or no effect in the reuptake of norepinephrine or dopamine.
May cause more gastrointestinal adverse effects than other SSRIs now currently available, which is the reason it is not recommended as a first choice. May be given as a liquid or a capsule.
May give as 1 dose or divided doses. Presence of food does not appreciably alter levels of the medication. May take up to 4-6 weeks to achieve steady state levels of the medication, as it has longest half-life (72 h).
Long half-life is both an advantage and a drawback. If it works well, an occasional missed dose is not a problem; if problems occur, eliminating all active metabolites takes a long time. The choice depends on adverse effects and drug interactions. Adverse effects of SSRIs seem to be quite idiosyncratic; thus, relatively few reasons exist to prefer one over another at this point if dosing is started at a conservative level and advanced as tolerated.
Adult
10 mg PO upon waking; can be increased q2wk; not to exceed 60 mg/d
Pediatric
Not established
Increases toxicity of diazepam and trazodone by decreasing clearance; also increases toxicity of MAOIs and highly protein-bound drugs; serotonin syndrome (ie, myoclonus, rigidity, confusion, nausea, hyperthermia, autonomic instability, coma, eventual death) occurs with simultaneous use of other serotonergic agents (eg, anorectic agents, tramadol, buspirone, trazodone, clomipramine, nefazodone, tryptophan; discontinue other serotonergic agents at least 2 wk prior to SSRIs)
Documented hypersensitivity; concurrent or recent (within 2 wk) use of MAOIs; coadministration with thioridazine
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in hepatic impairment and history of seizures; MAOIs should be discontinued at least 14 d before initiating fluoxetine therapy
Prostaglandins
Agents in this class have potent vasodilatory effects.
Epoprostenol (Flolan)
Analogue of PGI2 has potent vasodilatory properties, immediate onset of action, and half-life of approximately 5 min. In addition to vasodilator properties, also contributes to inhibition of platelet aggregation and plays role in inhibition of smooth muscle proliferation.
Continuous chronic infusion should be administered through central venous catheter.
Adult
Acute dose: 2 ng/kg/min continuous IV; increase by 2 ng/kg/min q15min or longer until dose-limiting effects are elicited (eg, chest pain, anxiety, dizziness, changes in heart rate, dyspnea, nausea, vomiting, headache, hypotension, flushing)
Continuous chronic infusion: Initial: 4 ng/kg/min IV less than maximum-tolerated infusion rate determined during acute dose
If maximum-tolerated infusion rate is <5 ng/kg/min IV, chronic infusion rate should be half maximum-tolerated acute infusion rate
Dosage adjustments: Dose adjustments in chronic infusion rate should be based on persistence, recurrence, or worsening of patient symptoms of pulmonary hypertension; if symptoms persist or reoccur after improving, infusion rate should be increased by 1-2 ng/kg/min q15min or more; following establishment of new chronic infusion rate, patient should be observed and vital signs monitored
Studies used dosing regimens of 6-10 ng/kg/min for 72 h
Pediatric
Coadministration with anticoagulants may increase bleeding risk because of shared effects on platelet aggregation
Documented hypersensitivity to epoprostenol or structurally related compounds; chronic use in patients with CHF due to severe left ventricular systolic dysfunction
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Coadminister whenever possible with anticoagulants to reduce risk of thromboembolism; sudden discontinuation or reduction in therapy may result in rebound pulmonary hypertension
Iloprost (Ventavis)
Synthetic analogue of prostacyclin PGI2 that dilates systemic and pulmonary arterial vascular beds. Indicated for pulmonary arterial hypertension (WHO Group I) in patients with NYHA class III or IV symptoms to improve exercise tolerance and symptoms and to delay deterioration.
Adult
Inhalation: Initial: 2.5 mcg/dose; if tolerated, increase to 5 mcg/dose; administer 6-9 times/d (dose at intervals 2 h while awake); 5 mcg/dose for maintenance dose; 45 mcg maximum daily dose
Pediatric
May increase hypotensive effect of vasodilators and antihypertensives; may increase bleeding risk when coadministered with anticoagulants
Documented hypersensitivity to iloprost or any component of formulation
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Intended for inhalation administration using Prodose ADD drug-delivery system; monitor vital signs during initiation; avoid use in patients with hypotension (systolic BP <85 mm Hg); use caution with concurrent conditions or medications that may increase risk of syncope; dosage or therapy adjustment may be required if exertional syncope occurs; may reflect therapeutic gap or insufficient efficacy; if pulmonary edema occurs during administration, discontinue therapy; use caution in hepatic dysfunction; safety not established in patients with other concurrent pulmonary diseases (eg, COPD, severe asthma, acute infections); safety and efficacy not established in pediatric patients
Phosphodiesterase type 5 enzyme inhibitors
Agents in this class have potent vasodilatory effects.
Sildenafil (Revatio)
Phosphodiesterases are a complex group of enzymes that help to tightly regulate the degradation of intracellular cyclic nucleotides. Intracellular responses to both NO and prostacyclin are mediated by the cyclic nucleotides cGMP and cyclic-AMP (cAMP) respectively. So, by bolstering the vasodilatory effect of both NO and prostacyclin, these agents may be useful in the treatment of Raynaud phenomenon.
Adult
50 mg PO bid
Pediatric
Not established
Potentiates vasodilatory effect of NO, resulting in potentially fatal drop in blood pressure; coadministration with ketoconazole, erythromycin, or cimetidine increases plasma sildenafil concentrations; coadministration with rifampin decreases plasma levels of sildenafil; coadministration with bosentan increases bosentan levels by 50% and reduces sildenafil levels by 63%
Documented hypersensitivity; concurrent or intermittent using of organic nitrates in any form
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Adverse effects include headaches (16%), flushing (10%), upset stomach (7%), nasal congestion (4%), and a blue haze at the periphery of vision (3%); adverse effects occur more often in men taking the 100-mg dose; serious adverse effects occur in patients with severe heart disease and those who are taking nitrates; rates of MI were 1.7 and 1.4 per 100 man-years for sildenafil and placebo groups; sudden vision loss caused by nonarteritic anterior ischemic optic neuropathy (NAION) has been associated with PDE-5 inhibitors following use for ED, analysis is ongoing to determine causality; sudden decreases or loss of hearing has been reported
Vasodilators
These agents are used for their local vasodilatory effects.
Nitroglycerin (Nitro-Bid)
Decreases coronary vasospasm, which increases coronary blood flow. Also induces vessel dilatation, decreasing cardiac workload.
Adult
0.5 inch (1%-2%) applied locally upon rising and 0.5 inch 6 h later; may double dose as needed
Pediatric
Not established
Aspirin may increase nitrate serum concentrations; marked symptomatic orthostatic hypotension may occur with coadministration of calcium channel blockers (dose adjustment of either agent may be necessary)
Documented hypersensitivity; severe anemia, shock, postural hypotension, head trauma closed angle glaucoma, or cerebral hemorrhage
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in coronary artery disease, and low systolic blood pressure
More on Raynaud Phenomenon |
| Overview: Raynaud Phenomenon |
| Differential Diagnoses & Workup: Raynaud Phenomenon |
 Treatment & Medication: Raynaud Phenomenon |
| Follow-up: Raynaud Phenomenon |
| Multimedia: Raynaud Phenomenon |
| References |
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Further Reading
Keywords
Raynaud's phenomenon, Raynaud phenomenon, vasospasm, Raynaud disease, Raynaud’s disease, reversible ischemia of peripheral arterioles, exposure to cold, stress-related ischemia, systemic sclerosis, scleroderma, secondary Raynaud, secondary Raynaud's, vasospasm, pallor, white finger disease
