Treating Raynaud phenomenon: Beyond staying warm
ABSTRACT
Raynaud phenomenon is an overactive vascular response to cold and emotional stress that results in cutaneous color changes and sensory symptoms in the digits. It can be idiopathic (primary) or secondary to another condition; the latter can be more severe and more apt to lead to ischemic complications such as digital ulceration and even loss of digits. If nonpharmacologic interventions prove inadequate, then vasodilator agents are used.
KEY POINTS
- Primary Raynaud phenomenon occurs in the absence of any underlying disease process. Secondary Raynaud phenomenon occurs in concert with another disease, frequently rheumatic.
- Young patients with mild Raynaud phenomenon, normal nailfold capillaries, and no additional symptoms or signs to suggest a rheumatic or other underlying disease can be followed carefully by the primary care doctor and do not require further serologic workup or referral to a specialist.
- Nonpharmacologic interventions, ie, cold avoidance and stress management, are first-line for all patients.
- Calcium channel blockers are first-line drugs and should be titrated to the maximum tolerated dose before adding or switching to other agents.
- The goal of treatment should not be to eliminate Raynaud attacks completely but to improve quality of life and prevent ischemic complications.
Phosphodiesterase type 5 inhibitors
When calcium channel blockers do not adequately control symptoms, phosphodiesterase type 5 (PDE5) inhibitors can be added or substituted. These medications work by preventing breakdown of cyclic guanosine monophosphate, which induces relaxation in vascular smooth muscle and vasodilation.
Sildenafil can be started at a low dose (20 mg daily) and up-titrated to the maximum dose (20 mg 3 times daily) as tolerated.
A 2014 meta-analysis of 6 randomized controlled trials included 244 patients with secondary Raynaud phenomenon treated with sildenafil, tadalafil, or vardenafil.13 These drugs decreased the daily frequency of attacks by about 0.5 per day vs placebo (–0.49, 95% CI –0.71 to –0.28, P < .0001). PDE5 inhibitors also decreased the severity of attacks (based on the Raynaud’s Condition Score, a popular scoring system) and the duration of attacks by a statistically significant amount.
Almost all patients in these 6 trials were on PDE5 monotherapy. Data on the cumulative benefit of calcium channel blocker and PDE5 inhibitor combination therapy are not yet available. Not all patients tolerate combination therapy, as it can cause symptomatic hypotension, but it can be a successful option in some.
There are also no data showing that either calcium channel blockers or PDE5 inhibitors are superior, though the former are less expensive. A small double-blind, randomized, crossover study of udenafil vs amlodipine in the treatment of secondary Raynaud phenomenon showed that both medications significantly decreased the frequency of attacks and had comparable efficacy.14
Cost and insurance coverage. We have generally been successful in obtaining coverage for this off-label use of PDE5 inhibitors, though additional effort may be required. No drug (not even a calcium channel blocker) is approved by the US Food and Drug Administration for use in Raynaud phenomenon. In our experience, a letter of appeal outlining the rationale for use and citing supporting publications can lead to successful coverage of a medication. If the drug is still not approved, the patient either pays for it out of pocket or another agent is selected. In certain circumstances, pharmaceutical companies may provide prescription assistance for compassionate use of these drugs in Raynaud phenomenon, although this also takes letter-writing, phone calls, or both on the part of the physician.
Topical nitrates
Patients who have an unsatisfactory response to calcium channel blockers with or without PDE5 inhibitors can try topical nitrates, available as sustained-release transdermal patches, tapes, creams, gels, and ointments.
Small trials have noted slight improvement in the Raynaud Condition Score15 and finger temperature16 with these therapies. Another trial noted decreased frequency of attacks and symptoms with the use of sustained-release glyceryl trinitrate patches, but use was limited by intolerable headache.17
In our experience, topical nitrates are most helpful for patients who have 1 or a few digits that are more severely affected than the others, and we reserve these drugs for this indication. Localized vasodilation can provide targeted rapid relief of more ischemic areas.
Topical nitroglycerin can be applied to the base of the ischemic digit for 6 to 12 hours. Preparations vary, and patients should be closely monitored for dose response and tolerance.
Combining a topical nitrate with a calcium channel blocker is safe, but the use of a nitrate with a PDE5 inhibitor is contraindicated due to the risk of hypotension. The use of topical nitrates may be limited by systemic side effects such as headache and flushing and a lack of benefit over time.
Other therapies
If the aforementioned agents are not tolerated or not effective, there is limited evidence that other therapies reduce the frequency and sometimes the severity of attacks. These are not first-line agents but may be tried when other options have been exhausted and symptoms persist. There are no data to support combining these therapies, but in our experience doing so may help some patients in whom drug-drug interactions are not prohibitive.
Prazosin, an alpha-1-adrenergic receptor antagonist, was reported to improve Raynaud phenomenon in 2 small studies in the 1980s, but we do not use it since better options are available. In addition, the vasoactive blood vessels involved do not have alpha-1 receptors, so there is no theoretical basis for using prazosin.18,19
Fluoxetine, a selective serotonin reuptake inhibitor, reduced the frequency and severity of attacks in a 6-week crossover study with nifedipine.20
Losartan, an angiotensin II receptor blocker, also reduced the severity and frequency of attacks when compared with nifedipine.21
Pentoxifylline, a nonselective phosphodiesterase inhibitor, showed some benefit in a trial in 11 patients with primary Raynaud.22
Atorvastatin, a lipid-lowering drug, reduced the number of digital ulcers in patients with secondary Raynaud already on first-line vasodilatory therapy, and might be added in this situation.23
Botulinum toxin A injections have some data to support their use, but evidence is based on uncontrolled case series.24 A controlled trial in scleroderma patients with severe Raynaud phenomenon found botulinum toxin to be no better than placebo.25
Prostacyclin preparations are available. Intermittent intravenous doses of prostacyclin analogues over several days can be used in resistant cases. Oral prostacyclin agents have not shown consistent benefit. New prostacyclin receptor agonists are under investigation.
Overall, we move to other options only in patients with persistent symptoms that impair quality of life, or in patients with recurrent digital ischemic lesions that have not responded to calcium channel blockers and PDE5 inhibitors or nitrates, either alone or in combination.
DIGITAL ULCERATION AND ACUTE DIGITAL ISCHEMIC CRISIS
Patients with secondary Raynaud phenomenon may be at risk of recurrent digital ulceration and acute digital ischemia with gangrene. These patients should be comanaged with a rheumatologist so that the underlying disease process is fully addressed. Digital ulcers should be inspected closely for signs of infection, which may require treatment with antibiotics.
Acute digital ischemia is a medical emergency and should prompt inpatient admission with warming, emotional regulation, and pain control (often with narcotics) to decrease sympathetic vasoconstriction. These patients require aggressive vasodilatory therapy to reverse the ischemic event.
A short-acting calcium channel blocker or combination therapy with a calcium channel blocker and a PDE5 inhibitor or topical nitrate should be started. If there is no benefit, then transient intravenous vasodilatory therapy with a prostacyclin (epoprostenol) or localized digital sympathectomy is used to prevent digital loss.
The endothelin receptor inhibitor bosentan has been shown to decrease recurrent digital ulcers in patients with scleroderma, and while bosentan does not decrease the frequency of Raynaud attacks, it can be used in this select group to prevent new digital ulcers.
Treatment options may be limited by insurance coverage or access to intravenous infusions.
TAKE-HOME RECOMMENDATIONS
For many patients with primary or secondary Raynaud phenomenon, nonpharmacologic interventions are all that are required to decrease the frequency of attacks and improve quality of life. The goal should not be to eliminate attacks completely, as aggressive drug treatment may cause more harm than benefit. From our perspective, the goals of treatment should be to improve quality of life and prevent ischemic complications.
Pharmacologic therapies should be added only if attacks remain poorly controlled with incapacitating symptoms, or if the patient has digital ischemic ulcers. Calcium channel blockers are first-line therapy, given proven efficacy and low cost, and should be titrated to the maximum tolerated dose before adding or substituting other agents.
