Treatment of Raynaud phenomenon: Initial management

INTRODUCTION — Raynaud phenomenon (RP) is an exaggerated vascular response to cold temperature or to emotional stress, which is manifested clinically by sharply demarcated color changes of the distal skin of the digits as well as toes, nose, and earlobes. Initial treatment includes patient education and general measures taken by the patient to prevent and treat attacks. In severe cases, treatment may include pharmacologic interventions and/or sympathetic blockade to prevent and treat digital ischemia.

The initial treatment of patients with uncomplicated RP is reviewed here. The treatment of patients who are refractory to initial therapy or with severe attacks or digital ischemic lesions is discussed separately (see "Treatment of Raynaud phenomenon: Refractory or progressive ischemia"). The pathogenesis, clinical manifestations, and diagnosis of RP can also be found elsewhere. (See "Treatment of Raynaud phenomenon: Refractory or progressive ischemia" and "Pathogenesis and pathophysiology of Raynaud phenomenon" and "Clinical manifestations and diagnosis of Raynaud phenomenon".)

GENERAL PRINCIPLES

Goals of therapy — The goals of therapy are to improve quality of life and to prevent tissue loss (ie, ulceration, gangrene). At least a moderate reduction in the intensity of attacks and the prevention of tissue loss are achievable in most patients. However, abolishing cold sensitivity and eliminating all Raynaud events is not likely with available treatment options, particularly in patients with secondary Raynaud phenomenon (RP), due to the complexity and sensitivity of the regulation of thermoregulatory vessels in the skin. (See "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Primary versus secondary Raynaud phenomenon' and "Pathogenesis and pathophysiology of Raynaud phenomenon".)

Patient education and self-management — All patients should be educated about the potential causes of a Raynaud attack as well as the nonpharmacologic measures to help prevent and terminate an episode. These nonpharmacologic measures include avoidance of provoking factors such as cold temperature and vasoconstricting drugs, smoking cessation (when applicable), and other measures discussed further below. (See 'Nonpharmacologic measures' below.)

It is also important to explain to patients that the response to treatment can vary depending upon the presence or absence of an underlying disease; this is particularly important in patients with systemic sclerosis (SSc, scleroderma), as such patients can have a structural component to their vascular disease in addition to the vasospastic component seen in all patients with RP. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Digital vasculopathy'.)

Measures of disease severity and impact — A Raynaud Condition Score (RCS) is a validated outcome measure that assesses the level of difficultly due to RP and captures broader aspects of the patient experience [1]. The RCS asks the patient to consider the impact of the condition on their life, taking into account the frequency of attacks, the duration of attacks, the disability it is causing, and the effect on daily quality of life [1,2]. The RCS uses a visual scale of 0 to 100; a change of approximately 15 is the minimum change considered clinically important [3]. It has been used in clinical trials as a semiquantitative tool to assess outcome. However, there has been concern that the RCS does not capture the complexity of patient perceptions. A survey found that RCS diary entries could be influenced by factors including seasonal variation in weather, efforts made by patients to avoid or ameliorate attacks of RP, habituation to RP symptoms, and patient coping strategies [4].

Measures such as the RCS and other patient-reported outcomes are tools typically used for assessment in clinical trials. Other such measures include a paper or electronic record of the number of daily attacks and of the duration of typical attacks. These data are then averaged over some defined period, usually weekly. A number of laboratory-based measures (eg, laser Doppler, thermography, cold challenges) have been used, but none has become a standard measure for clinical trials or daily patient care. Ambulatory monitoring of skin temperature has been proposed as a potential outcome measure but has not been studied.

INITIAL MANAGEMENT — Most patients presenting with Raynaud phenomenon (RP) will respond to the typical measures described below with or without the addition of pharmacologic therapy (algorithm 1). A subset of patients, particularly those with secondary RP, can have severe digital ischemia requiring more advanced treatments or intervention. In addition, it is important to distinguish patients with acute hand ischemia due to etiologies that might mimic RP since some conditions may actually be worsened by the administration of pharmacologic agents typically useful for RP (eg, calcium channel blockers [CCBs]) [5]. The treatment of severe RP characterized by refractory or progressive digital ischemia (ie, threatening digit loss) is discussed separately. (See "Overview of upper extremity ischemia" and "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Differential diagnosis' and "Treatment of Raynaud phenomenon: Refractory or progressive ischemia".)

The initial treatment of RP in most patients includes patient education and lifestyle modifications to maintain body warmth and avoid other triggers for RP. Pharmacotherapy is initiated if nonpharmacologic therapy is inadequate, with dihydropyridine CCBs being the preferred first-line agents. However, for patients who have contraindications to or do not tolerate CCBs, monotherapy with a phosphodiesterase (PDE) type 5 inhibitor, a topical nitrate, an angiotensin receptor blocker, or a serotonin reuptake inhibitor are alternative options.

Nonpharmacologic measures — We counsel all patients with RP to undertake a series of nonpharmacologic measures to help prevent attacks or reduce their severity.

General measures

●Avoidance of cold exposure – Avoidance of cold exposure and sudden temperature changes (when possible) is a key component of the management of RP. Patients should be made aware of circumstances that can trigger an attack such as putting one's hand in a refrigerator or freezer, holding an ice-cold drink, and entering an air conditioned environment such as the frozen food section of the supermarket or swimming in cold water. Modest seasonal changes such as cool rainy days can aggravate RP.

There are no randomized trials that have investigated the effect of cold avoidance on symptoms of RP. This approach of avoiding a known trigger is based on our understanding of the mechanism of the disease along with common sense and anecdotal reports that taking measures to reduce cold exposure will limit the number of attacks.

●Strategies to maintain whole body and digital warmth – It is important to understand that one must keep the whole body warm and not just the hands and feet. We therefore advise that patients with RP use strategies that not only keep the digits warm (eg, hand warmers, warm socks), but also the whole body. Strategies to maintain body warmth include dressing warmly with thermal underwear, layered clothing, and a hat when going outside and arranging to have appropriate heating in both the home and working environment. This also includes measures to avoid whole body cold exposure such as not sitting still in cold breezes from air conditioning and avoiding situations that involve rapid changes from a warm to cold ambient temperature. Keeping the digits of the hands and feet warm with winter gloves, chemical hand warmers, and heavy wool socks may also help. Heating up clothing in a dryer and putting them on while they are still warm before entering a cold environment is suggested as helpful.

Limited evidence from two small observational studies of patients with systemic sclerosis (SSc, scleroderma) have suggested that warming the hands can reduce cold-induced symptoms [6,7]. A number of different types of gloves have been proposed for patients with RP to reduce the likelihood of attacks, including battery-heated gloves and gloves knotted with silver thread. The only randomized trial to evaluate specialized gloves, specifically ceramic-impregnated gloves, had significant methodologic issues, making it difficult to interpret the findings [8].

Patients should also be taught methods to help terminate an attack of RP. These include placing the hands under warm water or in a warm place (such as the axilla) or rotating arms in a whirling or windmill pattern. A maneuver similar to throwing a Frisbee can also be used [9]. Rubbing the hands together can also help warm the hands and restore blood flow. A typical attack lasts approximately 15 to 20 minutes after rewarming.

●Other general measures:

•Avoidance of repeated trauma to the fingertips by all patients with RP and avoidance of vibrating tools by patients with vibration-induced RP [10].

•We do not routinely counsel patients with RP to stop consuming caffeine-containing drinks, although some experts have recommended doing so. The impact of caffeine on RP has not been defined, and its xanthine-related properties may result in systemic vasodilation [11,12]. Coffee consumption has been associated with vasoconstrictive effects, which transiently increase blood pressure (BP). However, coffee contains many biologically active compounds in addition to caffeine and overall may have vascular benefit [13]. Thus, the decision to stop caffeine-containing drinks should be based on the patient's experience.

•In patients with RP undergoing surgery, the risk of attacks from increased cold exposure in the operating room can be reduced by keeping patients warm. The choice of medications in patients undergoing an attack in this setting should be individualized based upon the specific clinical circumstances.

•Control or limitation of emotional stress because the thermoregulatory vessels are constricted by increased sympathetic tone. Stress plus cold exposure is an especially potent trigger for RP [14].The exact impact of stress and anxiety has been challenging to define due to the lack of studies accounting for the influence of ambient temperature and differences between laboratory-based studies and real life experiences. In a laboratory study of patients with primary RP, finger temperature decreased when subjects viewed a cold-related stress situation [15]. An ambulatory study in over 300 patients with primary RP found a relationship between the trait of anxiety and severity of RP [16]. Most interventions have focused on managing stress situations rather than treating any defined mental health condition. To date, clinical trial evidence does not support behavioral therapy (eg, biofeedback, relaxation therapy) in the treatment of RP. The management of anxiety and stress in the treatment of RP is primarily based on clinical and patient-related experiences, and attention to depression and anxiety disorders should be provided. (See 'Therapies lacking efficacy or of uncertain benefit' below.)

Avoidance of vasoconstricting drugs — Patients should be advised to avoid medications known to worsen vasospasm, when possible. There are almost no formal studies that have evaluated the effects of various drugs on RP; however, since the therapeutic mechanism of some drugs is known to cause vasospasm, we advise that these medications be avoided. Several classes of drugs known to be associated with vasospasm include the following:

●Over-the-counter nasal decongestants (eg, phenylephrine, pseudoephedrine)

●Amphetamines, diet pills, and herbs with ephedra

●Agents used to treat attention deficit hyperactivity disorder (ADHD) (methylphenidate and dextroamphetamine)

●Some medications used for migraine headaches, including serotonin agonists (eg, sumatriptan) or ergotamine

The only study that investigated the relationship between a medication and RP was a small case-control study including 64 pediatric rheumatology patents, half of whom had RP [17]. The presence of RP was associated with past or current use of stimulants for ADHD (methylphenidate and dextroamphetamine).

An aggravating role of estrogen use is suggested by the finding that postmenopausal women using unopposed estrogens have a higher prevalence of RP [18]. However, while the exact impact of estrogens is not fully defined, most experts avoid estrogen replacement in patients with severe RP.

Smoking cessation — The vascular effects of smoking do not appear to be any different in patients with RP [19]. Thus, avoidance of smoking is advised since smokers are sensitized to the vasoconstrictive properties of cigarettes. Avoiding secondhand smoke and electronic cigarettes is also prudent. (See "Benefits and consequences of smoking cessation" and "Overview of smoking cessation management in adults" and "Pharmacotherapy for smoking cessation in adults".).

The detrimental effects of smoking are multifactorial, with mechanisms that include vasoconstriction and alterations in wound healing [19,20]. A large study including over 600 patients with SSc found that smoking was associated with substantially worse RP symptoms and that symptom severity decreased after smoking cessation [21].

Pharmacologic measures

Initial pharmacologic therapy — The decision to either initiate or assess treatment for RP is ultimately going to be based on clinician-patient discussions considering reported symptom severity, impact on their quality of life, drug tolerability, and the perceived effectiveness of existing and/or planned interventions. (See 'Measures of disease severity and impact' above.)

A review of therapy for primary RP noted that apart from calcium channel blockers (CCBs), which are considered to be the drugs of choice, evidence of the effects of alternative pharmacologic treatments is limited by studies of small sample sizes, limited data, and variability in outcome reporting yielding evidence of very low to moderate certainty [22].

Calcium channel blocker — In patients with uncomplicated RP who have not responded adequately to nonpharmacologic measures, we suggest the use of long-acting dihydropyridine CCBs. There are no clear data to support the use of one dihydropyridine CCB over another. Amlodipine is preferred by the author. Others may prefer nifedipine because it is the CCB that has been the most studied for RP. There are no studies that have directly compared CCBs for RP. Generally, long- rather than short-acting formulations of CCBs should be used given the ease of administration and better safety profile of longer-acting CCBs.

Effective doses of amlodipine range from 5 to 20 mg/day, and effective doses of long-acting nifedipine range from 30 to 120 mg/day. We start with the lowest dose and gradually increase, depending upon the response. The duration of a drug trial at a given dose should be determined by the period of observation needed to assess whether there has been a clinically meaningful reduction in the frequency and severity of acute attacks, and by the degree to which the drug is tolerated. In most nonurgent situations, the dose is adjusted every four weeks and no more frequently than every 7 to 10 days. Systemic BP measurements should be followed serially during the titration of the CCB. When possible, we advise patients to obtain a BP cuff to monitor their BP daily until dosing is stable and then weekly thereafter, as well as when symptoms of hypotension occur. The major side effects associated with the CCBs include hypotension, headache, dizziness, flushing, tachycardia, and peripheral edema [23]. (See "Major side effects and safety of calcium channel blockers".)

Individual responses to the CCBs may vary. If nifedipine or amlodipine is ineffective at the highest tolerated dose, then another dihydropyridine CCB may be substituted, such as nicardipine, felodipine, lacidipine, nisoldipine, nimodipine, and isradipine [23-32]. The nondihydropyridine CCBs are generally avoided because they have not been shown to be consistently effective [33-35].

The duration of benefit from drug intervention in RP has not been formally studied. Most reported clinical trials are short term, typically four to six weeks in duration. In our experience, there is sustained benefit from treatment with a CCB. This impression is based upon the consistent occurrence of relapses of severe Raynaud events if a CCB is discontinued. However, there are little objective data to define the duration of benefit of single or combination drug therapy.

The efficacy of various CCBs compared with placebo in reducing the frequency and severity of Raynaud attacks has been demonstrated in randomized trials and meta-analyses [36-41]. However, the overall effects of CCBs on RP attacks generally appear to be small. It is important to note that clinical trials differ in the various measures to define whether or not there was a response to therapy, making it difficult to compare studies. The most commonly reported outcome is self-recorded frequency and severity of attacks and the Raynaud Condition Score (RCS). Duration of attacks and patient and physician global assessments are also used but have poor reliability. Placebo response rates are high and laboratory measures (thermography, laser Doppler flow) differ from subjective data collected in an ambulatory setting. Thus, much of the variability in findings is related to small sample sizes, mixed populations (with primary versus secondary RP), different outcome measures, and differences in the type and dose of CCB. (See 'Measures of disease severity and impact' above.)

The largest systematic review and meta-analysis to examine the effects of dihydropyridine CCBs on primary and secondary RP using data from 23 trials with 528 participants found that CCBs were superior to placebo in reducing the frequency of attacks [41]. CCBs reduced the average number of attacks per week by six (weighted mean difference [WMD] -6.13, 95% CI -6.60 to -5.67) compared with 13.7 attacks per week with placebo. When one of the studies with the largest reduction in frequency of attacks was excluded [42], CCBs reduced attack frequency by 2.93 per week (95% CI -3.44 to -2.43). Although CCBs were also found to reduce attack severity, it is uncertain whether the reductions are clinically meaningful. Improvements in pain and disability also favored CCBs, but the effect estimates were likely underpowered. Subgroup analyses from the same meta-analysis also suggested that CCBs in higher doses may be more effective for primary RP than for secondary RP [41].

Unable to tolerate or receive preferred initial therapy — Alternative therapies may be required in patients in whom CCBs are contraindicated or poorly tolerated (eg, patients with severe gastrointestinal dysmotility, severe pulmonary artery hypertension, significant cardiac disease with edema, and/or low BP). The decision to use one agent over another depends largely on the side effect profile and whether there are additional benefits for other comorbidities. As an example, a PDE type 5 inhibitor may be preferable to a CCB in a patient with RP secondary to SSc, particularly in a patient with concomitant pulmonary hypertension. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis".)

Phosphodiesterase type 5 inhibitor — We use a low-dose PDE type 5 inhibitor in patients with uncomplicated RP in whom CCBs are contraindicated or not tolerated. We typically start with sildenafil 20 mg once or twice daily and increase the dose to 20 mg three times daily if no benefit is achieved. The dose may be further increased to 40 mg three times daily in patients who do not respond and can tolerate the higher dosing. This dose is similar to that used in patients with pulmonary hypertension. Sildenafil is also available as 25 mg and may be titrated up to 50 mg twice or three times daily as tolerated in a similar manner to that of the 20 mg formulation. As with CCBs, we advise that patients obtain a BP cuff to monitor their BP serially while titrating the dose. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis", section on 'Phosphodiesterase type 5 inhibitors'.)

A PDE inhibitor should not be used together with topical nitrates due to the increased risk of hypotension. Other adverse effects that may occur include peripheral edema, palpitations, tachycardia, hearing loss, and visual disturbances.

A meta-analysis of six randomized trials including 244 patients with secondary RP found that there was a modest benefit of PDE inhibitors (sildenafil, tadalafil, and vardenafil) on the RCS, as well as on the frequency and duration of RP attacks [43]. PDE inhibitors reduced the frequency of RP attacks by approximately 0.5/day compared with placebo, which is comparable to the reduction reported in another meta-analysis assessing the efficacy of CCBs in SSc-related RP (0.6/day) [37]. The RCS represents the level of difficulty experienced by the patient each day that is attributed to RP, and is assessed using a visual analog scale. Although the improvement in the RCS was statistically significant, it was not a clinically meaningful difference [3].

A study using n-of-1 trials in 38 patients with RP did not demonstrate clinically relevant effects for on-demand sildenafil use before or during exposure to cold [44]. Although the analysis reported a high probability that sildenafil was superior to placebo, there was substantial heterogeneity among the patient responses, with a clinically relevant benefit in just a few patients. The strength of the n-of-1 study design is that it allows the estimation of therapeutic effect in each patient and permits correlation of individual outcomes and patient preference.

The benefits of PDE inhibitors for patients with recurrent digital ulcers and RP due to SSc is discussed separately. (See "Treatment of Raynaud phenomenon: Refractory or progressive ischemia", section on 'Phosphodiesterase type 5 inhibitors'.)

Topical nitrate — In our experience, the topical nitrates are more useful for patients with a single or small number of severely affected digits and for short-term (days to weeks) use, compared with patients with more diffuse involvement and with the need for chronic use (months to years). In patients with low BP, dehydration, acute or chronic heart failure, pulmonary hypertension, or ongoing use of a PDE inhibitor, topical nitrates should be avoided. Topical nitrates should be avoided in patients in using PDE inhibitors due to the increased risk of hypotension.

Topical nitrate should be applied to a single more severely affected or ischemic digit for 6 to 12 hours. Starting at a low dose of 0.5 inch (or 1 to 2 cm) is recommended to define tolerance before increasing dose if no improvement. The dose of topical nitrate may vary depending upon the preparation and should be adjusted with close monitoring of tolerance and the clinical response. The nitroglycerin 2% ointment can be titrated as needed up to a full 2 inches (approximately 5 cm) every 4 to 6 hours with a 12-hour nitrate-free period each day. However, the higher dose is often not well tolerated, and patients stop usage. The dose may be divided between several digits, although absorption with most preparations results in systemic effects. Side effects include headache, flushing, lightheadedness, decreased BP, tachycardia, and aggravation of gastroesophageal reflux.

Several small observational studies and randomized trials of different topical nitrates suggest benefit in patients with RP [45-50]. A systematic review and meta-analysis of seven randomized trials with 346 patients with either primary or secondary RP reported a treatment benefit (standardized mean difference 0.7, 95% CI 0.35-1.05), which was a pooled measure of clinical and blood flow outcomes [50]. Subgroup analyses showed a larger treatment effect for secondary compared with primary RP. Important limitations to the study include the use of multiple topical nitrate preparations and the integration of different outcome measurements.

Angiotensin II receptor blocker — Angiotensin II receptor blockers (ARBs) may be used for patients with uncomplicated RP who cannot tolerate CCBs or who may benefit from the use of an ARB for other indications (eg, hypertension, heart failure, proteinuric chronic kidney disease). There is limited evidence supporting the use of ARBs as being effective for RP. In a small 12-week trial in patients with primary and secondary (SSc-related) RP, patients receiving losartan (50 mg/day) experienced a greater reduction in the severity and frequency of attacks compared with nifedipine (40 mg/day) [51]. The evidence for the use of angiotensin-converting enzyme (ACE) inhibitors is much less favorable. (See 'Therapies lacking efficacy or of uncertain benefit' below.)

Selective serotonin reuptake inhibitor — Fluoxetine may be used in patients with uncomplicated RP who cannot tolerate CCBs or the systemic vasodilatory effects of some of the other alternative agents. Limited evidence from preliminary observations and only one small open-label crossover study suggest that fluoxetine may be of benefit for RP [52,53]. In a small study including 53 patients with primary or secondary RP, the use of fluoxetine (20 mg daily) or nifedipine (40 mg daily) for six weeks resulted in a reduction in attack frequency and severity of RP; the effect was only statistically significant for the fluoxetine group [53]. It is advised that patients start at a dose of 10 mg daily for approximately one week for tolerability before increasing to 20 mg daily.

Inadequate response to calcium channel blocker or alternative agent — Prior to a trial of combination therapy of a CCB with another agent for patients who do not respond to initial therapy, we take the following measures:

●Review and reinforce the importance of continuing the general nonpharmacologic measures for prevention and treatment. (See 'Nonpharmacologic measures' above.)

●Revisit the underlying cause for RP to readdress reversible causes or treatable aggravating or comorbid conditions. (See "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Clinical features' and "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Differential diagnosis'.)

Combination of calcium channel blocker with another agent — In patients who do not respond adequately to a CCB alone, we typically add or substitute either a PDE type 5 inhibitor or a topical nitrate. As discussed above, fluoxetine can be added for patients who cannot tolerate the systemic vasodilatory effects of some of the other alternative agents, but whether or not it is beneficial needs to be carefully defined by follow-up assessment. There are no randomized trials that address the efficacy of combination therapy of a CCB plus another vasodilatory agent, and the rationale behind this approach is based on the benefits observed with the individual agents. The combination of PDE type 5 inhibitors and topical nitrates should be avoided due to the increased risk of hypotension. (See 'Phosphodiesterase type 5 inhibitor' above and 'Topical nitrate' above.)

Monitoring response to therapy

Routine follow-up — Patients should be evaluated periodically, ideally every three to six months, to identify the need for ongoing or additional treatments. It is important to take into account the risk of the treatment, the clinical evidence for its effectiveness, and the need for continued therapy at the time of the evaluation, balancing the risks of therapy and the level of severity of the RP.

In clinical practice, a practical approach to assessing the response to therapy is to ask the patient questions similar to those used for the RCS. This includes asking the patient to consider the impact of the condition on their life, taking into account the frequency of attacks, the duration of attacks, the disability it is causing, and the effect on daily quality of life. (See 'Measures of disease severity and impact' above.)

However, it is difficult to determine the full impact of a drug intervention in that the severity and frequency is influenced by many factors including seasonal temperature changes, lifestyle adjustments, and patient acclimation. In one survey, most subjects (78 percent) reported making at least one adjustment to their life due to RP, more so for secondary RP than primary RP (87 versus 71 percent) [54]. Another study found attack frequency and duration was not prioritized by patients as factors that would lead them to consider treatment escalation [55]. They reported the inability to use their hands properly due to RP as the highest ranked factor that might prompt change of treatment or initiation of drug therapy. (See 'Measures of disease severity and impact' above.)

Refractory or progressive ischemia — The management of severe RP resistant to initial therapy or severe events with digital ulcers or ischemic lesions (ie, tissue loss) is discussed in detail separately. (See "Treatment of Raynaud phenomenon: Refractory or progressive ischemia".)

THERAPIES LACKING EFFICACY OR OF UNCERTAIN BENEFIT — Other treatments have been proposed and have been subjected to limited study; sufficient evidence is lacking at present to support the routine use of any of the therapies discussed below in place of other interventions.

●Behavioral therapy – There are no robust trials showing benefit of behavioral therapy for reducing the number or severity of attacks in Raynaud phenomenon (RP). Some techniques that have been studied include biofeedback training, autogenic training, and classical conditioning. Most studies have used temperature biofeedback for RP, where finger temperature data are provided to patients to help them learn to relax by monitoring their internal states and changing temperature. However, the majority of biofeedback trials are generally low quality and have used small numbers of patients [16,56-59]. The best data come from a trial including 313 patients with primary RP that randomized patients to sustained-release nifedipine, placebo, temperature biofeedback, and sham biofeedback and found that patients who received temperature biofeedback did not reduce RP attacks compared with sham biofeedback at one-year follow-up [23].

●Complementary and alternative medicine – A literature review and meta-analysis of the efficacy of complementary and alternative medicine in the treatment of RP found that most studies were inconclusive and that there is a need for well-designed studies in this area of treatment for RP [60].

•Antioxidant agents – Antioxidant agents such as zinc gluconate (50 to 150 mg/day) have also been utilized based upon the rationale that they may reduce tissue damage that may occur during ischemia-reperfusion from superoxide production [61-63]. In one study, intravenous (IV) N-acetylcysteine reduced the frequency and severity of RP attacks compared with baseline and, in another uncontrolled study, reduced digital ulcers and severity of RP in systemic sclerosis (SSc, scleroderma) patients [64,65]. Probucol, a synthetic antioxidant, improved RP compared with a control group [66].

•Ginkgo biloba – Ginkgo biloba is an herbal medication that we do not use because the preponderance of evidence has not shown it to be beneficial [67,68].

•Acupuncture – Acupuncture has been reported to improve primary RP, but there is not enough evidence to determine effectiveness [69].

•Laser irradiation – Therapeutic gloves [8] and low-level laser therapy [70,71] are reported to improve RP, but the data are limited.

•Spinal cord stimulation – Spinal cord stimulation has been used for treatment in RP, but no controlled study is available [72].

●Angiotensin-converting enzyme inhibitors – There is little evidence to suggest that angiotensin-converting enzyme (ACE) inhibitors are effective for RP. Despite an open-label study that suggested some benefit from use of captopril in patients with primary (but not secondary) RP, a subsequent randomized trial involving 210 patients with secondary RP did not support the use of an ACE inhibitor for this indication [73,74]. The trial found no evidence of benefit for quinapril, an ACE inhibitor, in the incidence of digital ulcers or in the frequency or severity of attacks of RP [73].

●Prazosin – Because of the lack of robust studies and the availability of alternative agents, we no longer use prazosin in the treatment of RP. In our experience, patients eventually become refractory to this agent after prolonged usage. Prazosin, an alpha-1-adrenergic receptor antagonist, was found to be beneficial in two small randomized trials [75,76]. In one study, a blinded crossover study of 14 patients with primary and secondary RP, nine patients reported fewer episodes of RP during the two-week study period [75]. Only one of five patients with SSc reported improvement with prazosin. A dose of 1 mg three times daily was reported to improve RP compared with placebo and was tolerated with fewer side effects compared with higher doses [76,77].

●Other medications – Several other medications that have been used for which there are limited data to define clinical utility include the sympatholytic drugs methyldopa and reserpine (which has been given intra-arterially) [78-85]. However, none of these agents is a specific inhibitor of the alpha-2C-adrenergic receptor that is thought to be the major pathway through which cold-induced digital artery vasoconstriction is triggered. A laboratory-based study using a specific alpha-2C adrenergic receptor antagonist demonstrated improvement in cold-induced skin temperature, suggesting that similar agents may be helpful in the treatment of RP, but a specific alpha-2C agent is not available [86]. Pentoxifylline has been found to provide some benefit in a study of 11 patients with primary RP (including increased blood flow) [87].

A number of other agents have been studied but failed to show adequate benefit or acceptable levels of safety compared with other available medications, including ketanserin, L-arginine, calcitonin gene-related peptide, and a thromboxane A2 inhibitor [88-91]. Other such agents include direct vasodilators, such as nitroprusside; hydralazine; papaverine; minoxidil; niacin; and topical agents, including nitric-oxide (via a generating system), hexyl nicotinate, and ethyl nicotinate [46,92]. Sarpogrelate hydrochloride, a 5-hydroxytryptamine 2A serotonin receptor (5-HT2A) inhibitor available in Japan, has been reported to improve RP and to reduce digital ulcers [93-95]. A review of Chinese herbal medicine for the treatment of primary RP suggested they may have a positive effect [96]. However, these findings are inconclusive given weak methodology.

PROGNOSIS — Primary Raynaud phenomenon (RP) is a benign condition; it is often transient in nature and may improve or disappear with time in one-third or more of patients over 7 to 14 years of follow-up [97,98]. However, many patients with primary RP report that it has significant impact on their quality of life due to cold and uncomfortable fingers and hands. This is particularly true in individuals who have occupations that do not allow effective cold avoidance. An international survey of the self-reported impact of RP found over 25 percent of patients included reduced quality of life, describing feelings of embarrassment and alterations in physical and social function [99]. By comparison, patients with secondary RP are more likely to have severe attacks and sustained or progressive disease. Patients with associated systemic rheumatic disease, particularly systemic sclerosis (SSc, scleroderma), may develop persistent digital ischemia requiring aggressive intervention, which is not always effective. It is notable that a survey of 443 patients with self-reported primary or secondary RP from 15 countries found that 64 percent reported a poor or very poor current ability to prevent/control RP attacks despite lifestyle changes and prescribed medications [54]. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)

Spontaneous remission of primary RP may occur. This was illustrated in a prospective study that surveyed a middle-aged White American population over a seven-year period [98]. For those who had, or who developed, primary RP during that time frame, remissions occurred in 64 percent of both females and males. However, some symptoms suggestive of RP continued in about 20 percent of the cases that were classified as in "remission."

By comparison, remission is uncommon in patients with secondary RP.

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 topics (see "Patient education: Raynaud phenomenon (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

●General principles – The goals of therapy of Raynaud phenomenon (RP) are to improve quality of life and to prevent ischemic tissue injury. All patients should also be educated about the potential causes of a Raynaud attack as well as the nonpharmacologic measures to help prevent and terminate an episode. (See 'General principles' above.)

●Initial management – The initial treatment approach varies depending on the severity of Raynaud events and whether or not the patient has experienced complications (eg, digital ulcers, critical ischemia). For patients who have uncomplicated RP (ie, the absence of irreversible ischemic tissue loss), nonpharmacologic therapies alone or in combination with a pharmacologic agent are usually adequate to provide control of symptoms (algorithm 1). Nonpharmacologic interventions alone are typically insufficient to control RP events in patients who develop severe disease resulting in irreversible ischemic lesions. Such patients typically require pharmacologic intervention. (See 'Initial management' above.)

•General measures – We counsel all patients with uncomplicated RP to undertake a series of nonpharmacologic measures to help prevent attacks or reduce their severity. These measures include avoiding cold exposure, implementing strategies to maintain body and digital warmth, avoiding vasoconstricting drugs, and smoking cessation. Management of emotional stress is also advised. (See 'Nonpharmacologic measures' above.)

•Initial pharmacologic therapy – For patients with uncomplicated RP who have not responded adequately to nonpharmacologic measures, we suggest the use of long-acting dihydropyridine calcium channel blockers (CCBs) (Grade 2B). There is good evidence of the efficacy of CCBs compared with placebo, and there is more experience with their use compared with alternative oral agents. We start with the lowest dose and gradually increase as needed depending on the response. (See 'Calcium channel blocker' above.)

•Unable to tolerate or receive preferred initial therapy – For patients with uncomplicated RP in whom CCBs cannot be administered, alternative options include phosphodiesterase (PDE) type 5 inhibitors, topical nitrates, losartan, or fluoxetine. Each of these agents has limited evidence of efficacy, with few direct comparisons. The choice of one agent over another depends largely on the side effect profile and whether there are additional benefits for other comorbidities. (See 'Unable to tolerate or receive preferred initial therapy' above.)

●Subsequent management – For patients who do not respond adequately to a CCB alone, we typically add or substitute either a PDE type 5 inhibitor or a topical nitrate. The combination of PDE type 5 inhibitors and topical nitrates should be avoided due to the increased risk of hypotension. (See 'Combination of calcium channel blocker with another agent' above.)

●Monitoring response to therapy – Patients should be evaluated periodically, ideally every three to six months, for the need for a particular intervention. It is important to take into account the risk of the intervention, the clinical evidence for its effectiveness, and the need for continued therapy at the time of the evaluation, balancing the risks of therapy and the level of severity of the RP. (See 'Monitoring response to therapy' above.)

●Therapies lacking efficacy or of uncertain benefit – A variety of other treatments have been proposed and have been subjected to limited study, and sufficient evidence is lacking at present to support the routine use of any of these therapies. Some examples include behavioral therapy, complementary and alternative medicine, angiotensin converting enzyme (ACE) inhibitors, and prazosin. (See 'Therapies lacking efficacy or of uncertain benefit' above.)

●Prognosis – Primary RP is a benign condition; it is often transient in nature and may improve or disappear with time in one-third or more of patients over 7 to 14 years of follow-up. By comparison, patients with secondary RP are more likely to have severe attacks and sustained or progressive disease. (See 'Prognosis' above.)