Patient education is important in RP management. The whole body should be kept as warm as possible. This includes wearing several layers of loose fitting clothing, mittens, stockings, and headwear in cold temperatures. RP attacks are likely to be precipitated by damp windy weather or rapid shifts in ambient temperature. Even in the summer months, air-conditioning may trigger a RP attack. Emotional stress can aggravate RP and lower the threshold for temperature-induced attacks. Therefore, stress control and relaxation techniques are helpful in preventing RP attacks.
Vasoconstrictor medications such as sympathomimetic drugs (decongestants, diet pills, ephedra) and serotonin agonists (such as sumatriptan) should be avoided because they can vasoconstrict peripheral arteries and precipitate RP attacks. In addition, certain chemotherapeutic agents (bleomycin, cisplatin, carboplatin, and vinblastine) may cause vascular occlusion and RP attacks. RP patients should be counseled on smoking avoidance because nicotine reduces cutaneous and digital blood flow. Opioids can also cause cutaneous vessel vasoconstriction and should be used with caution.
If nonpharmacologic treatments are not successful, medications are indicated for the treatment of RP. Vasodilator therapy is the usual first-line medication therapy, particularly if digital ulcerations have developed or quality of life is affected. Calcium channel blockers are the most widely used vasodilators; however, other agents including sympatholytic agents, phosphodiesterase inhibitors, and prostaglandins are also therapeutic options. No medication has proved to be more effective or safer than the calcium channel blockers.
Calcium channel blockers are the most frequently used therapy for primary and secondary RP. They have been shown to decrease both the frequency and severity of attacks. The benefit is more robust in patients with primary RP compared to those with secondary RP. The use of calcium channel blockers appears to reduce the frequency of RP by up to five attacks per week.
Calcium channel blockers differ in their peripheral vasodilatory properties. Nifedipine, amlodipine, felodipine, nisoldipine, and isradipine have more vasodilatory effect than diltiazem and verapamil in the treatment of RP. The most significant side effects from calcium channel blockers are headache, hypotension, tachycardia, aggravation of gastroesophageal reflux, and lower extremity edema. Gum hypertrophy may also occur with long-term use of calcium channel blockers.
Slow-release preparations of calcium channel blockers are preferred because they are safer than rapid-release preparations. Oral amlodipine at doses of 5–20 mg/d is effective in RP and exerts less negative cardiac inotropy. If one calcium channel blocker is not effective, patients may be switched to another; individual responses to medications may vary. Combination therapy with calcium channel blockers and other vasodilators are often used, but this approach has not been studied rigorously.
Nitroglycerin ointment is frequently used alone or in combination with other vasodilator therapy. Improvement in RP has been noted with topical nitroglycerin with 0.25–0.5 inch of 2% nitroglycerin ointment applied daily. The medication is absorbed systemically and patients often have side effects of headaches or hypotension. One can attempt to avoid the systemic effect by placing very small amounts of the ointment directly on the fingers of affected hands.
Autonomic Nervous System Blockade
The sympathetic nervous system is important in cutaneous blood vessel thermoregulation and mediates vasoconstriction, particularly α2c-adrenergic receptors on the digital arteries. In severe RP, another treatment option is to block sympathetic tone with the goal of inducing vasodilatation of digital vessels. In the absence of α2c-adrenergic receptor antagonist, prazosin, an α1-adrenergic receptor blocker, is used. In two controlled trials, prazosin was more effective than placebo in primary and secondary RP. However, patients became resistant to prazosin after prolonged use. Intravascular administration of sympatholytic agents has been advocated for treatment of refractory ischemia in RP; however, there is little clinical data demonstrating benefit.
Prostacyclin is a potent vasodilator with inhibitory effects on platelet aggregation and antiproliferative properties on smooth muscle cells. Iloprost, a prostacyclin analogue, is beneficial in the treatment of RP secondary to scleroderma. Therapy with iloprost (0.5–2 ng/kg/min intravenous infusion for 5 days) can provide relief for several weeks with significant improvement on number and duration of vasospastic RP attacks. However, in the United States, iloprost is only available as an inhaled medication for the treatment of pulmonary hypertension. Epoprostenol and alprostadil have also been reported as helpful for severe RP and digital ulcerations secondary to scleroderma. The oral form of these agents has poor bioavailability. Thus, intravenous administration is required.
Phosphodiesterases are enzymes that regulate intracellular cyclic nucleotide levels such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). In turn, these cyclic nucleotides mediate intracellular responses to prostacyclin and nitrous oxide. Selective phosphodiesterase type 5 inhibitors (eg, sildenafil, tadalafil, vardenafil) have been successfully used for the treatment of erectile dysfunction and pulmonary hypertension. Sildenafil has been reported to reduce the severity and number of RP attacks in patients with SSc. Tadalafil has also shown variable success in the treatment of RP. However, these studies with phosphodiesterase type 5 inhibitors are limited and demonstrate varied responses. Therefore, the benefit of these agents has yet to be proven, and they should not be used if the patient is taking nitrates.
Rho-kinases are implicated in cold-induced vasoconstriction by inducing α2c-adrenoreceptors on smooth muscle cells of blood vessels. While agents that block this pathway in theory could be helpful, they are not yet tested or available.
Angiotensin-Converting Enzyme (ACE) Inhibitors
Although controversial, some studies suggest that ACE inhibitors may be helpful in RP by increasing blood flow through increased kinin release. Captopril, a traditional ACE inhibitor, improved RP attacks in primary RP, but not RP secondary to SSc. A recent 3-year study of quinapril, however, did not demonstrate any benefit compared to placebo, strongly suggesting that ACE inhibitors are not useful for the treatment of RP. However, losartan, an angiotensin II receptor blocker, decreased the number and severity of RP attacks in both primary and secondary RP.
Selective Serotonin Reuptake Inhibitors
Serotonin is a potent circulating vasoconstrictor. Its role in RP is not clearly defined; however, several reports have noted improvement in RP in patients treated with selective serotonin reuptake inhibitors. While the evidence is still preliminary, the use of selective serotonin reuptake inhibitors can be considered in complex cases, particularly if the patient’s baseline blood pressure is low.
Anticoagulation therapy with aspirin (81 mg/d) is recommended in selected patients with severe secondary RP who are at risk for digital ulceration or larger-artery thrombotic events. Heparin may be used during an acute ischemic crisis to prevent further digital vessel thrombosis, but long-term anticoagulation with heparin or warfarin is not recommended unless there is evidence of a hypercoagulable disorder (eg, antiphospholipid syndrome, malignancy).
Surgical sympathectomy may be used to ligate the sympathetic nerves that cause vasoconstriction. A chemical sympathectomy with a digital or wrist block using lidocaine or bupivacaine without epinephrine can rapidly reverse digital artery vasospasm. The risk of cervical sympathectomy, including neuralgia, decreased localized sweating, and Horner syndrome, is reduced by new scope-directed procedures. No controlled studies of surgical sympathectomy versus a control procedure exist and benefit of the procedure may be short-lived.
Botulinium toxin type A has also been shown to be effective in a small study of five patients with RP. There was a trend toward faster rewarming of the digits following cold provocation, but little change in final temperature after 20 minutes.
Case reports of a localized procedure of digital sympathectomy for RP demonstrate success. Among SSc patients, the complication rate is about 37% and amputation and recurrent ulceration still occurs during follow-up in up to 18% of patients. Sympathectomy can be very helpful in an acute digital ischemic crisis and it is best reserved for patients who have not responded to medical therapy and continue to have severe RP or ischemia threatening the digits. Most of the available evidence shows that RP attacks recur, often less severe, several weeks to months following either proximal or digital sympathectomy.