Treatment of severe or refractory Raynaud phenomenon

INTRODUCTION — Raynaud phenomenon (RP) is caused by vasospasm induced by cold temperature or emotional stress.

Most patients with RP have mild symptoms. Mild RP manifests clinically by discomfort and sharply demarcated color changes of the skin of the digits (eg, fingers, toes).

Some patients will develop severe RP, which is associated with severe pain and/or tissue damage. Severe or refractory disease is more common among patients who have developed RP in association with another disease, especially systemic sclerosis (SSc; scleroderma) (table 1). Whenever RP is associated with tissue damage, a secondary disease process needs to be considered.

The treatment of severe or refractory RP is reviewed here. The initial therapy of mild RP, including general measures, the use of calcium channel blockers, and lifestyle modifications, as well as the pathogenesis, clinical manifestations, and diagnosis of RP, are presented separately. (See "Treatment of Raynaud phenomenon: Initial management" and "Pathogenesis and pathophysiology of Raynaud phenomenon" and "Clinical manifestations and diagnosis of Raynaud phenomenon".)

DEFINITIONS — When discussing Raynaud phenomenon (RP), we use the following terminology:

●Acute ischemia – Acute ischemia refers to a rapid onset of reduced flow that compromises the integrity of the tissue (picture 1 and picture 2).

●Chronic ischemia – Chronic ischemia refers to tissue injury due to prolonged or progressive reduction in flow. Chronic ischemia commonly leads to digital ulcerations.

●Severe RP – RP is called severe when it causes severe pain and/or chronic ischemia. While RP is often associated with numbness or a pins and needle sensation of the involved digits, pain is an indication of ischemia that can threaten tissue viability. (See 'Treatment of severe Raynaud phenomenon' below.)

●Refractory RP – Refractory RP refers to severe RP that fails to respond adequately to initial therapies for severe disease. (See 'Treatment of refractory Raynaud phenomenon' below.).

PRETREATMENT CONSIDERATIONS

●Goals of therapy – In patients with severe or refractory Raynaud phenomenon (RP), the goal of therapy is to improve blood flow and prevent tissue injury. This goal improves quality of life and prevents chronic ischemia from causing recurrent digital ulcerations and/or digital necrosis. (See "Treatment of Raynaud phenomenon: Initial management", section on 'Goals of therapy'.)

●Education – All patients should be educated about the potential causes of a Raynaud attack as well as the nonpharmacologic measures (eg, cold avoidance, heated garments) to help prevent and terminate the episode. Initial therapy, patient education, and self-management issues are discussed in detail separately. (See "Treatment of Raynaud phenomenon: Initial management", section on 'Patient education and self-management'.)

●Evaluation for vasoocclusive disease – Vasoocclusive diseases (eg, vasculitis, embolism, atherosclerosis) can also cause tissue ischemia. However, unlike RP, these phenomena are not cold dependent and often present asymmetrically. Patients with vasoocclusive disease may require other approaches to restore blood flow. The approach to the diagnosis and the management of these conditions are reviewed elsewhere. (See "Overview of upper extremity ischemia", section on 'Incidence and etiologies'.)

SSc is associated with both RP and vasoocclusive disease. In addition to vasospasm, SSc induces immune-mediated endothelial injury and intimal proliferation, which leads to occlusion of the small arteries, arterioles, and capillaries. This impaired circulation leaves patients with SSc at particularly high risk of severe or refractory RP. Digital vasculopathy associated with SSc is reviewed elsewhere. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Digital vasculopathy'.)

TREATMENT OF SEVERE RAYNAUD PHENOMENON — Raynaud phenomenon (RP) is considered severe when it causes severe pain and/or tissue loss. (See 'Definitions' above.)

Pretreatment considerations and the initial management of milder forms of RP are discussed elsewhere. (See 'Pretreatment considerations' above and "Treatment of Raynaud phenomenon: Initial management".)

Initial care — Active treatment is important in patients who develop severe ischemia that threatens all or a portion of a digit. These patients present with sustained signs of severe ischemia, with painful digits demarcated by pallor and/or cyanosis and/or with areas of tissue gangrene or ulceration. For patients experiencing a severe ischemic event, we consider it a medical emergency and immediately institute the following:

●Hospitalization – We prefer to manage severe RP with ischemia that is threatening the digit(s) in an inpatient setting. Hospitalization is frequently necessary to achieve adequate pain control quickly. Hospitalization may also facilitate anticoagulation, nerve blocks, initiation of intravenous prostaglandins, and evaluation for secondary causes, if necessary. The patient should be kept warm and at rest. (See 'Initial management strategies' below.)

●Pain control – Pain due to severe ischemia may be intense, and adequate pain control may require the use of opioid analgesics. Pain induces vasospasm; therefore, achieving adequate pain control in the first one to two days is vital. A local or regional anesthetic block can be used in the acute setting (see below). (See "Pain control in the critically ill adult patient" and "Pharmacologic management of chronic non-cancer pain in adults", section on 'Opioids'.)

●Anticoagulation – We anticoagulate patients with severe RP who are at risk of associated arterial thrombosis for one to two days to minimize propagation of any possible thrombus [1]. We use intravenous unfractionated heparin for short-term therapy, but there are no data to support a specific form of anticoagulation as more efficacious in this setting. We continue anticoagulation past two days only if a thrombotic cause of severe ischemia is suspected. However, it must be emphasized that there is no evidence for the use of anticoagulation therapy for RP alone; anticoagulation is used should in those with a risk of vascular thrombosis. (See "Overview of upper extremity ischemia", section on 'Approach to treatment'.)

Pharmacologic interventions and procedures — Many of the vasodilatory agents used for milder forms of RP (eg, topical nitrates, angiotensin II receptor blocker, alpha 1 blocker, selective serotonin reuptake inhibitor) are unlikely to help patients with severe, refractory, or progressive ischemia. (See "Treatment of Raynaud phenomenon: Initial management", section on 'Unable to tolerate or receive preferred initial therapy'.)

Intravenous prostaglandins

General considerations — For patients with severe RP who are failing oral vasodilator therapy or who present with a severe ischemic event threatening tissue or digital loss, we initiate treatment with intravenous prostaglandins (eg, epoprostenol, iloprost, treprostinil).

●Administration – In patient with a severe ischemic event, treatment with intravenous prostaglandins leads, within the first hours of the infusion, to rapid reversal of symptoms whenever vasospasm alone is the underlying cause of the event. If there is associated occlusive vascular disease, signs of persistent ischemia may occur during the infusion therapy. Signs of improved tissue ischemia with resolution of pain and lack of progression of tissue loss should be seen within the first days after the infusion. Several weeks after the treatment session one can expect continued improvement in RP events and continued tissue healing. Intravenous prostaglandins may be readministered at regular intervals (eg, every 10 to 12 weeks) depending on the clinical response. The lack of response suggests that irreversible vascular occlusive disease is present.

Intravenous prostaglandins are often administered in an inpatient setting, but hospitalization may not be required in patients with an established diagnosis who are not otherwise acutely ill and if an outpatient infusion center with established monitoring is available. The latter approach is often used for administering iloprost outside of the United States.

●Precautions

•Avoid in patients with pulmonary hypertension – Prior to initiating therapy with an intravenous prostaglandin, all patients should be screened for pulmonary hypertension with an echocardiogram. In a patient with pulmonary hypertension, sudden interruption of a prostaglandin infusion may induce a life-threatening exacerbation in pulmonary hypertension. Therefore, we do not use intravenous prostaglandins for RP in patients with pulmonary hypertension. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Parenteral prostanoid'.)

•Temporarily hold other vasodilators – Calcium channel blockers and other vasodilatory agents, such as topical nitrates or phosphodiesterase (PDE) inhibitors, are briefly held while patients are receiving a treatment course of intravenous prostaglandins. Returning after the infusion treatment to the oral vasodilator therapy as tolerated is recommended.

•Side effects – Side effects of intravenous prostaglandin therapy include headache, flushing, nausea, jaw pain, and hypotension, which are usually reversible with a reduction in dose. The dose of intravenous prostaglandins should be adjusted to the level that is tolerated.

●Selection of agent – Comparative studies among these agents are not available. Therefore, the choice of parenteral prostaglandins and analogs for patients with severe RP is largely based on drug availability (eg, intravenous epoprostenol, but not iloprost, is available in the United States) as well as clinician preference and experience.

We use epoprostenol because of its availability in the United States. However, iloprost, treprostinil, and alprostadil may also be effective for severe RP.

Epoprostenol — Epoprostenol (prostaglandin I₂ [PGI₂]) is typically started at a dose of 2 ng/kg per minute and increased over a period of one to two days, as tolerated, to 4 to 8 ng/kg per minute for a duration of five hours [2,3].

A randomized trial including 14 patients with RP found that treatment with intravenous epoprostenol weekly was associated with a reduction in the frequency and duration of attacks compared with placebo, with a loss in clinical response observed between 8 and 10 weeks after the last infusion [3].

Another randomized trial of epoprostenol for pulmonary hypertension associated with systemic sclerosis (SSc; scleroderma) and related disorders showed a favorable but statistically nonsignificant difference in the severity of RP and fewer new digital ulcers in the epoprostenol-treated patients [4].

Epoprostenol has been most widely used for the treatment of idiopathic pulmonary hypertension as well as pulmonary hypertension associated with SSc. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis", section on 'Prostacyclin pathway agonists' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Iloprost — Iloprost (a PGI₂ analog) is typically administered for a course of three to five consecutive days at a (continuous) dose of 0.5 to 2 ng/kg per minute (titrated to the maximum dose tolerated by the patient). The infusion can be administered over eight hours, if done in the outpatient setting, or as a continuous infusion, if in the inpatient setting.

The largest meta-analysis of randomized trials to assess the efficacy of iloprost for the treatment of RP included 332 patients with RP secondary to SSc [5]. Intravenous iloprost appeared to decrease the frequency and severity of RP and, in some cases, increased digital ulcer healing. However, dosing regimens, outcome measures, and follow-up periods in the trials varied.

One of the higher-quality trials with 126 patients that was included in the meta-analysis found that a five-day infusion of iloprost compared with placebo was associated with a mean reduction in the number of weekly RP attacks (40 versus 22 percent, respectively) and an improvement in the global Raynaud severity score (35 versus 20 percent) during the nine-week follow-up period [6]. Also, at week 3, 14.6 percent more patients receiving iloprost had 50 percent or more lesions heal compared with those who received placebo (95% CI 0.9-30).

Longer-term follow-up data come from an observational study of 30 patients with RP secondary to SSc who received iloprost infusions every three weeks for a median of three years following an initial cycle of infusions over five days [7]. Healing of digital ulcers and a subjective decrease in RP were reported in this study. Larger observational studies support the long-term therapy in SSc patients with severe RP [8-11].

Other prostaglandins

●Treprostinil – Treprostinil (a PGI₂ analog) may be given intravenously, by subcutaneous injection, or inhaled [12]. Its use in the setting of RP is largely based on limited indirect evidence that it may have beneficial effects on digital ulcers or necrosis in patients with SSc [12,13].

Treprostinil is available for treatment of pulmonary hypertension, but its use in patients with severe symptoms of RP or acute or chronic digital ischemia by either the subcutaneous or intravenous route has not been investigated to provide specific treatment guidelines.

●Alprostadil – Alprostadil (PGE1) may be administered at a dose of 60 mcg intravenously once daily (20 mcg/hour) for a course of five or six consecutive days [14-16]. Although the ideal long-term regimen is not well defined, it has been repeated at six-week intervals [14].

●Oral prostacyclin analogs – The use of oral prostacyclin analogs has been studied in primary and secondary RP, but there is insufficient evidence to support their use in clinical practice. (See 'Treatments lacking efficacy or of uncertain benefit' below.)

Alternative therapies — For most patients presenting with severe RP, intravenous prostaglandins are faster and more effective than alternate agents. However, oral agents may be useful in the following scenarios:

●While making arrangements for intravenous prostaglandins

●Following treatment with intravenous prostaglandins, to mitigate future episodes

●When intravenous prostaglandins are not available

●Patient and/or clinician preference, depending on the specific clinical scenario

Outside of calcium channel blockers, most of these agents have been well studied only in patients with SSc. However, they may be effective for some patients presenting with severe RP.

Calcium channel blockers — Many patients presenting with severe RP have already failed to respond to treatment with calcium channel blockers, which are commonly initiated for the management of milder forms of RP. (See "Treatment of Raynaud phenomenon: Initial management", section on 'Calcium channel blocker'.)

If confronted with a patient with severe ischemia threatening the loss of a digit, we prefer using intravenous prostaglandin therapy as initial therapy. However, for patients not already treated with a calcium channel blocker, we suggest treating all patients with severe RP with a dihydropyridine calcium channel blocker (eg, amlodipine 5 mg daily or nifedipine extended-release 30 mg daily). The selected drug should be titrated daily to the maximum tolerable dose (e.g., amlodipine 10 mg daily, nifedipine extended-release 90 mg daily). The onset of action of the calcium channel blocker is rapid, with onset within hours. For example, amlodipine reaches peak concentrations within 6 to 12 hours. Coupled with warmth, rest, and good pain control, there may be rapid benefit for the acute event. However, formal studies for severe ischemic events have not been done. Clinical trials with calcium channel blockers have reported improvement over several weeks of follow-up.

There are no data supporting the use of a specific calcium channel blocker. However, we avoid immediate-release calcium channel agents (eg, short-acting nifedipine), which may increase sympathetic tone, leading to vasospasm [17]. We also avoid non-dihydropyridine calcium channel blockers (eg, verapamil, diltiazem), which are less effective vasodilators.

Calcium channel blockers are generally considered first line in the initial management of RP and may reduce the frequency or intensity of future RP attacks. The evidence supporting their use is discussed in detail separately [18,19]. (See "Treatment of Raynaud phenomenon: Initial management", section on 'Calcium channel blocker'.)

Interventions for patients with systemic sclerosis — For patients with SSc who have severe RP that fails to respond to calcium channel blockers at maximum dose, we suggest adding a PDE type 5 (PDE-5) inhibitor to their regimen. Patients with recurrent digital ulcers who fail to respond to calcium channel blockers and PDE-5 inhibitors may benefit from adding bosentan to their regimen [20-23].

Patients without SSc may also benefit from these drugs, although there are minimal data supporting their use in the absence of SSc.

Phosphodiesterase type 5 inhibitors — In patients with SSc associated with severe RP refractory to calcium channel blockers, we suggest adding a PDE-5 inhibitor, which promotes vasodilation by increasing the concentration of cyclic guanosine monophosphate [24].

●Administration – We use oral sildenafil 100 mg daily or in divided dose (commencing in a lower dose of 25 mg twice daily can be considered), although other PDE-5 inhibitors may also be effective. For example, tadalafil at 20 mg daily is an option. PDE-5 inhibitors may be combined with calcium channel blockers and may be used in patients who have received intravenous prostaglandins to prevent recurrent disease. The limiting factors in combination therapy are primarily low blood pressure and fluid retention. Dose reduction or slow titration of sildenafil is an alternative. For example, we recommend a starting dose of 20 to 40 mg of sildenafil in these cases. Some expert use dosing at 20 to 40 mg three times daily. (See 'Prevention' below.).

●Rationale – There are limited data suggesting that PDE-5 inhibitors ameliorates severe RP in patients with SSc [25-28].

•In a trial of 41 patients with RP secondary to SSc, patients were randomly assigned to receive oral sildenafil 100 mg daily (21 patients, mean age 47.2 years) or placebo (20 patients, mean age 41.6 years) [26]. After eight weeks of treatment, sildenafil improved digital blood flow and RP symptoms.

•A meta-analysis found that PDE-5 inhibitors were beneficial in digital ulcer healing in patients with SSc compared with placebo (relative risk 3.28, 95% CI 1.32-8.13) [27]. Based on a low-certainty of evidence, a second meta-analysis also reported benefit of PDE-5 inhibitors in treating secondary RP [29].

PDE-5 inhibitors are commonly used for the treatment of erectile dysfunction. These agents discussed in greater detail elsewhere. (See "Treatment of male sexual dysfunction", section on 'Initial therapy: PDE5 inhibitors'.)

Bosentan — In patients with SSc associated with severe RP refractory to calcium channel blockers plus PDE-5 inhibitors and who have recurrent digital ulcers, we suggest adding bosentan, an orally administered inhibitor of the vasoconstrictor endothelin 1.

●Administration – Treatment with bosentan is initiated at a dose of 62.5 mg twice daily for four weeks. The dose should be increased to 125 mg twice daily in patients who do not benefit from the initial dose.

●Precautions – Liver function tests should be obtained monthly in patients receiving the medication to monitor for hepatic toxicity.

In the clinical trials, approximately 15 percent of patients discontinued therapy due to side effects. Commonly reported side effects are headache, flushing, edema (18 percent), hypotension, liver enzyme elevation (12 percent), and fatigue.

Less common but more serious reactions include liver failure, bone marrow suppression, and angioedema.

●Rationale – Data from clinical trials suggest that bosentan may help reduce the number of new digital ulcers in patients with SSc, but it has not been shown to improve the healing of existing ulcers or to reduce the frequency of Raynaud attacks:

•A randomized trial of 122 patients with SSc reported a 50 percent reduction in new ulcers among those who had ulceration at baseline; however, there was no reduction in frequency or intensity of attacks of RP and no improvement in ulcer healing in patients with digital ulcers at baseline.

•A subsequent trial in 188 patients with SSc with digital ulcers at trial entry found a statistically significant 30 percent reduction in new digital ulcers compared with placebo (1.9 versus 2.7) but also observed no differences in the healing rate of the cardinal ulcer [30,31]. Peripheral edema and elevated aminotransferases were associated with bosentan use. A randomized controlled trial found bosentan to superior to nifedipine alone in reducing to number of new digital ulcers in patients with SSc [32].

In patients with SSc, bosentan has been used primarily for the treatment of pulmonary hypertension. Bosentan is discussed in greater detail elsewhere. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis", section on 'Endothelin-1 receptor antagonists' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Local or regional nerve block for refractory pain — For patients with severe RP associated with pain refractory to standard management strategies, we suggest digital or regional nerve block.

A digital or regional (eg, at the wrist or ankle) nerve block is usually performed with local infiltration of lidocaine or bupivacaine (without epinephrine) [33,34].

This intervention may be thought of as a temporizing measure. A digital block may achieve rapid control of pain while arrangements for other therapies are underway. In addition to pain relief, local or regional nerve blocks interrupt the sympathetic pathways, which promote vasodilation that may also alleviate pain [35,36]. Rarely, this vasodilation may result in orthostatic hypotension.

Nerve blocks for RP have not been systematically evaluated in clinical trials, and their use in this setting is largely based on clinical experience and extrapolation from other clinical settings. Also, there are also no formal studies to define the impact on complications of RP, such as recurrent digital ulcers.

More proximal nerve blocks, such as cervical or lumbar injections, are rarely used unless other approaches have failed.

The use of local or regional nerve blocks are discussed in detail elsewhere:

●(See "Overview of peripheral nerve blocks".)

●(See "Upper extremity nerve blocks: Techniques", section on 'Wrist blocks'.)

●(See "Upper extremity nerve blocks: Techniques", section on 'Digital nerve block (finger)'.)

●(See "Lower extremity nerve blocks: Techniques", section on 'Ankle block'.)

●(See "Lower extremity nerve blocks: Techniques", section on 'Digital nerve block (toe)'.)

TREATMENT OF REFRACTORY RAYNAUD PHENOMENON — Severe Raynaud phenomenon (RP) is considered refractory when it fails to respond adequately to the measures described above, including intravenous prostaglandins. (See 'Treatment of severe Raynaud phenomenon' above.)

We treat refractory RP with digital sympathetectomy and antiplatelet agents (eg, aspirin). Patients with refractory RP not associated with systemic sclerosis (SSc; scleroderma) may also benefit from agents used to manage severe RP in patients with SSc. (See 'Interventions for patients with systemic sclerosis' above.)

Initial management strategies

●Local care of tissue loss – Surgical debridement of areas of necrosis and occasionally amputation may be needed for areas of irreversible ischemia. Ischemic tissue may cause ongoing, severe pain, and necrotic tissue may serve as a nidus for infection.

Digital ulcers due to refractory RP occur in up to half of patients with SSc. Among 1459 patients with SSc and digital ulcers, ulcers were recurrent in 46.2 percent and chronic in 11.2 percent [37]. Amputation occurred in 7.6 and 15.9 percent of these patients, respectively. Most amputations are minor, involving the distal digit.

When proper care is given to digital ulcers, healing typically occurs within 6 to 12 weeks. Treatment of digital ulceration or gangrene is reviewed separately. (See "Basic principles of wound management" and "Overview of treatment of chronic wounds", section on 'Ischemic ulcers and gangrene'.)

●Reevaluation for secondary causes – Given the efficacy of the strategies described above, refractory RP is becoming increasingly uncommon. Therefore, patients with refractory RP should be carefully re-examined for a secondary reversible process that is causing or aggravating the ischemia. This includes a careful evaluation for arterial occlusive disease, hypercoagulable states, certain neurologic conditions, and environmental or toxic exposures (table 1). (See "Overview of upper extremity ischemia", section on 'Incidence and etiologies'.)

Digital sympathectomy for most patients — We suggest digital sympathectomy for most patients with refractory RP.

Digital sympathectomy is a microsurgical technique that isolates the terminal branches of the sympathetic nerves that travel with the peripheral nerves, dividing these branches, and stripping the adventitia of the digital arteries [38-40]. It is important that the procedure is done before irreversible deep tissue damage occurs [41]. It is a highly specialized procedure, performed only in specialist centers.

Although some cases have reported successful results and few complications following digital sympathectomy or periarterial sympathectomy [42-49], their exact role for refractory RP has not been well defined. One review noted that differences in surgical technique, causes of digital ischemia, and outcome measures made comparisons of reported series difficult [50]. Digital amputation and recurrent ulceration following digital sympathectomy were frequent (14 and 18 percent, respectively). Among patients with RP and SSc with digital ischemia, the perioperative complication rate was 37 percent.

Antiplatelet agents for most patients

●Aspirin – We use low-dose aspirin (75 or 81 mg daily) in patients with refractory RP. However, the benefit of antiplatelet therapy with aspirin is overall uncertain because of the lack of evidence overall for its use in patients with RP.

There has been only one small trial with treatment using aspirin plus dipyridamole, aspirin alone, or dipyridamole alone in patients with RP [51]. Antiplatelet agents appeared to have no effect on symptoms of RP. However, the study did not examine the effect of antiplatelet agents on patients with severe RP.

Aspirin should be avoided in selected patients such as those with SSc who are at a higher risk of gastrointestinal bleeding from underlying gastric antral vascular ectasia. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity" and "Gastrointestinal manifestations of systemic sclerosis (scleroderma)", section on 'Gastric antral vascular ectasia'.)

●Dipyridamole – Some clinicians have used dipyridamole because of its antiplatelet, vasodilating, and antioxidant properties, which may improve vascular tone. However, there is no evidence to support the use of dipyridamole alone or with another antiplatelet agent (eg, aspirin or clopidogrel) for RP with digital ischemia.

Limited role for other interventions

●Botulinum toxin A – We use intradigital and palmar botulinum toxin A for patients with severe RP who are not responding to or tolerating vasodilator therapy due to hypotension and have poor quality of life due to RP. Botulinum toxin injection may also be used in conjunction with vasoactive drugs or as a trial prior to surgical intervention. (See 'Digital sympathectomy for most patients' above.)

Botulinum toxin reduces release of vasoactive mediators, but its onset of action is not immediate. The use of botulinum toxin is generally limited by cost, access to surgical hand specialists with specialized training in these injections, and the need for retreatment.

The role of injections of botulinum toxin in the treatment of RP is not well defined. Evidence from mostly small observational studies of patients with primary and secondary RP have been favorable, suggesting that intradigital and palmar injection of botulinum toxin A inhibits vasoconstriction, relieves clinical symptoms, improves skin blood flow, and promotes healing of digital ulcers [52-64]. However, a metanalysis found a great deal of variation in multiple parameters, including the dose, injection site, and primary endpoint [65]. The only two randomized placebo-controlled trials performed in patients with RP associated with SSc failed to demonstrate significant clinical benefit [66,67].

●Proximal sympathectomy – We do not routinely use more proximal sympathectomy (eg, cervicothoracic, thoracic, lumbar) in patients with RP. However, some patients with refractory or progressive ischemia may elect to proceed with this procedure.

•Rationale – Sympathectomy disrupts the efferent autonomic pain pathways and attenuates vasoconstriction. The resulting vasodilation increases distal perfusion.

•Technique – The sympathetic ganglia can be divided or ablated using radiofrequency or surgery [68]. Surgical sympathectomy can be approached using open or minimally invasive techniques.

Minimally invasive approaches have replaced open surgical approaches because of fewer perioperative complications compared with open surgery [69]. As an example, in one study of 28 patients treated using a minimally invasive approach, no major complications occurred, and there were no perioperative deaths [70]. However, a minimally invasive technique and open surgical techniques do not appear to differ in terms of recurrent symptoms [70,71]. (See "Overview of minimally invasive thoracic surgery", section on 'Sympathectomy'.)

In the upper extremity, resection of the upper thoracic sympathetic chain can be performed via a supraclavicular or axillary incision or by using a thoracoscopic approach. In the lower extremity, the lumbar sympathetic chain can be accessed via an anterior abdominal or retroperitoneal incision or a laparoscopic or retroperitoneoscopic approach.

•Efficacy – Several reports have suggested that sympathectomy is helpful in primary RP but not in secondary forms [69,72-76]. Patients with refractory secondary RP may have some immediate improvements in blood flow following sympathectomy, but the degree and duration of improvement are quite variable [77,78].

In a systematic review of thoracic sympathectomy (open or thoracoscopic) that included a total of 580 patients with digital ischemia, an initial positive response was reported in 92 percent of primary RP and 89 percent of secondary RP patients. A long-term benefit was seen in 58 percent of primary RP and 89 percent of secondary RP patients. Ulcer improvement or healing occurred in 95 percent of patients [69]. However, in a survey of 140 patients with RP who had undergone sympathectomy, 66 percent noted no benefit after one year, and only 19 percent of patients reported lasting benefit [77].

TREATMENTS LACKING EFFICACY OR OF UNCERTAIN BENEFIT

●Oral prostaglandins and analogs – The role of oral prostacyclin and analogs (which are available in Japan, Europe, and the United States) for the treatment of severe or refractory Raynaud phenomenon (RP) is unclear. Studies of several agents, including misoprostol [79], limaprost [80], cisaprost [81], beraprost [82,83], iloprost [84-86], and treprostinil, have yielded mixed results regarding their efficacy for the treatment of RP [87,88].

Several small observational studies and one small randomized trial suggested benefit of alprostadil for symptoms related to RP as well as improvement in ulcer healing [14-16,89,90]; however, these findings were not substantiated in another small randomized trial [91].

For example, a study of 147 patients with severe RP associated with systemic sclerosis (SSc; scleroderma) failed to demonstrate that treprostinil impacted digital ulcer frequency, healing of digital ulcerations, RP severity, or quality of life [87]. However, other studies have demonstrated that treprostinil improved digital blood flow among patients with severe RP in patients with SSc, and stopping treprostinil increases the number of digital ulcerations [88,92].

●Other endothelin 1 antagonists – Endothelin 1 antagonists other than bosentan (which, as stated above, has been shown to prevent SSc-related digital ulcers) have not been shown to be beneficial in patients with severe or refractory RP:

•Macitentan, another nonselective endothelin 1 antagonist that is also used to treat pulmonary hypertension, failed to reduce the frequency of new ischemic digital ulcers over 16 weeks, compared with placebo, in two randomized trials involving a total of 554 patients with SSc and active digital ulcers at baseline [93].

•Likewise, a pilot study of ambrisentan did not prevent the development of new digital ulcers in patients with SSc [94].

●Long-term anticoagulation – We do not use long-term anticoagulation in patients with chronic ischemia due to RP. The only study to evaluate anticoagulation in the setting of RP was a small placebo-controlled study in which low-molecular weight heparin (LMWH) was associated with a reduction in the severity of RP attacks after 4 and 20 weeks [95]. However, this study only included 30 patients and has never been repeated.

ONGOING MANAGEMENT

Prevention — All patients should receive education regarding nonpharmacologic strategies to prevent Raynaud phenomenon (RP). (See 'Pretreatment considerations' above.)

However, most patients with severe RP will also require chronic therapy with calcium channel blockers to prevent additional attacks.

For patients with systemic sclerosis (SSc; scleroderma) who continue to experience episodes of severe ischemia despite maximal therapy with a calcium channel blocker, we suggest if tolerated, the addition of a phosphodiesterase type 5 (PDE-5) inhibitor (eg, sildenafil at 20 mg orally three times daily or tadalafil 20 mg daily). As an alternative for patients not tolerating combination vasodilators or not responding to therapy, we suggest a trial of statin therapy. A small trial of 84 patents with SSc found that patients assigned to receive atorvastatin 40 mg daily for four months developed fewer RP-associated digital ulcers than patients in the placebo group (mean of 1.6 versus 2.6 ulcers, respectively) [96]. There were also improvements in other patient-reported outcomes including pain and Raynaud attack severity. Another small open-label trial also reported long-term favorable effects [97]. Statins exert multiple effects on the vasculature that preserve circulation and prevent vascular events [98]. However, more studies are needed to define their role in the treatment RP.

Patients with SSc who continue to develop recurrent digital ulcerations despite combination therapy with a calcium channel blocker and a PDE-5 inhibitors and/or statin therapy may benefit from bosentan or repeat infusions of intravenous prostaglandins, [99]. Some prefer to use bosentan therapy early in SSc patients with recurrent digital ulcers.

The combination of bosentan and intravenous prostaglandins may be more effective at preventing severe RP than intravenous prostaglandins alone [100]. However, there are no studies indicating which of these strategies may be most effective for a given patient. (See 'Interventions for patients with systemic sclerosis' above and 'Intravenous prostaglandins' above.)

The efficacy of these interventions in patients without SSc is unclear, although they may also benefit.

Routine follow-up — Patients should be evaluated periodically, ideally every three months if the patient has fluctuating symptoms or up to six months if the scenario is less complex. At each evaluation, the patient and clinician should consider the need for continued therapy. Deciding whether to halt or taper interventions depends on the risk of the intervention, the clinical evidence for its effectiveness, and the need for continued therapy at the time of the evaluation, and the severity of the digital ischemia

Long-term outcomes — There are no clinical trials to clearly define long-term outcomes of the intravenous prostaglandins. Most reported clinical trials are short term, reporting data based on three months of follow-up.

However, there is evidence in patients with SSc that chronic therapy is well tolerated and reduces risk of digital ulcers [8,9,11]. One study treated patients with SSc with iloprost during winter months or if a severe event occurred [23]. After a mean follow-up time of 6.9±4.0 years of treatment (range 0.06 to 22), 36 patients (60 percent) were still receiving active treatment; 24 patients (40 percent) stopped the therapy, 14 (58.3 percent) due to clinical improvement.

Likewise, careful long-term studies of the outcome following surgical intervention are not adequate to provide guidance. Our experience is that the RP recurs following surgical digital sympathectomy but is usually not as severe as prior to surgery.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Raynaud phenomenon".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Raynaud phenomenon (The Basics)")

●Beyond the Basics topic (see "Patient education: Raynaud phenomenon (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Goals of therapy – In patients with Raynaud phenomenon (RP), the goals of therapy are to improve quality of life and to prevent ischemic tissue injury. All patients should be educated about the potential causes of a Raynaud attack as well as the nonpharmacologic measures to help prevent and terminate the episode. (See 'Pretreatment considerations' above.)

●Initial measures for severe Raynaud phenomenon – For patients with RP who are experiencing a severe ischemic event, we immediately institute the following (see 'Initial care' above):

•Short-term anticoagulation – During a severe ischemic event that is threatening digit loss, we initiate anticoagulation (Grade 1C). We anticoagulate patients for one to two days. We continue anticoagulation past two days only if a thrombotic cause of severe ischemia is suspected.

•Pain control – Pain due to severe ischemia may be intense and may induce further vasospasm. Adequate pain control may require the use of opioid analgesics.

●Treatment of severe Raynaud phenomenon

•Intravenous prostaglandins – For patients with acute or prolonged digital ischemia related to RP, we suggest treatment with a prostaglandin (Grade 2C).

We use an intravenous prostacyclin (PGI₂, epoprostenol). Epoprostenol is administered through a peripheral line, started at a dose of 2 ng/kg per minute, and increased over a period of one to two days, as tolerated, to 4 to 8 ng/kg per minute for a duration of five hours. Iloprost or treprostinil are reasonable alternatives to epoprostenol. (See 'Intravenous prostaglandins' above.)

•Local or regional nerve block – Some patients with refractory pain may benefit from a local or regional nerve block. In addition to pain relief, the nerve block inhibits sympathetic pathways, which promotes vasodilation. (See 'Local or regional nerve block for refractory pain' above.)

•Alternative therapies – Oral agents may be effective for some patients with severe RP and may help mitigate the intensity or severity of future RP attacks. (See 'Alternative therapies' above.)

●Treatment of refractory Raynaud phenomenon – In patients with RP associated with tissue loss or severe pain that fails to respond to standard therapies including intravenous prostaglandins, we suggest digital sympathectomy (Grade 2C). We also suggest the addition of low-dose aspirin (eg, 75 to 81 mg daily) (Grade 2C).

Surgical debridement and amputation of necrotic tissue may be necessary. We also reevaluate patients carefully for reversible processes that may be contributing to the patient’s refractory disease. (See 'Treatment of refractory Raynaud phenomenon' above.)

●Limited role for other interventions

•Botulinum toxin – We use botulinum toxin in patients with severe digital ischemia unresponsive to (or intolerant of) other interventions. Botulinum toxin may be used in conjunction with other interventions or as a trial before proximal sympathectomy. However, use of botulinum toxin is generally limited by cost, access to surgical hand specialists with specialized training in these injections, and the need for retreatment.

•Digital sympathectomy – We prefer using distal or digital sympathectomy over proximal sympathectomy in cases of severe, refractory digital ischemia, although the degree and duration of improvement are variable. (See 'Treatments lacking efficacy or of uncertain benefit' above.).

●Therapies with uncertain benefit – There is no strong evidence to support long-term anticoagulation of patients with chronic ischemia due to RP.

Similarly, oral prostaglandins and analogs have been studied for severe RP, with mixed results. (See 'Treatments lacking efficacy or of uncertain benefit' above.)

●Prevention – All patients should undergo education regarding nonpharmacologic strategies to prevent severe RP. Most patients will also require long-term therapy with a calcium channel blocker to prevent further episodes of severe RP. Some cases will need combination therapy, such as the addition of a PDE-5 inhibitor to the calcium channel blocker. (See 'Prevention' above.)

●Monitoring – We reevaluate patients every three to six months to monitor the effectiveness of the interventions. However, there are no clear data to guide the duration of therapy. Deciding whether to halt or taper interventions depends on the risk of the intervention, the clinical evidence for its effectiveness, and the need for continued therapy at the time of the evaluation, and the severity of the digital ischemia. (See 'Routine follow-up' above and 'Long-term outcomes' above.)