What makes UpToDate so powerful?

  • over 10000 topics
  • 22 specialties
  • 5,700 physician authors
  • evidence-based recommendations
See more sample topics
Find Patient Print
0 Find synonyms

Find synonyms Find exact match

Initial treatment of the Raynaud phenomenon
UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
Initial treatment of the Raynaud phenomenon
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Nov 07, 2016.

INTRODUCTION — The 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 skin of the digits. Treatment includes patient education and general measures taken by the patient to prevent and treat attacks and, in severe cases, may include pharmacologic interventions and/or surgical sympathetic blockade to prevent and treat digital ischemia.

The initial treatment of the Raynaud phenomenon is reviewed here. The treatment of patients resistant to initial therapy, as well as the pathogenesis, clinical manifestations, and diagnosis of RP, is presented separately. (See "Treatment of the Raynaud phenomenon resistant to initial therapy" and "Pathogenesis of the Raynaud phenomenon" and "Clinical manifestations and diagnosis of the Raynaud phenomenon".)

PRIMARY AND SECONDARY RP — The Raynaud phenomenon (RP) is considered primary if the symptoms occur alone without any associated disorder; secondary RP refers to the presence of the disorder in association with a related illness, such as systemic lupus erythematosus or systemic sclerosis (scleroderma). Primary RP is sometimes also referred to as idiopathic RP or Raynaud disease. (See "Clinical manifestations and diagnosis of the Raynaud phenomenon".)

Patients with primary RP are generally not significantly disabled by the attacks, although the quality of life may be affected by the need for cold avoidance and by the lack of normal finger sensation. A survey of 443 subjects with self-reported RP from 15 countries found that 64 percent of subjects reported a poor or very poor current ability to prevent/control RP attacks [1]. An initially conservative, nonpharmacologic approach is therefore most important for these patients, although pharmacologic therapy may ultimately be necessary. By comparison, patients with secondary RP are more likely to have severe attacks, and disease management is more likely to be based upon pharmacologic agents while continuing nonpharmacologic measures.

GOALS AND OVERVIEW OF THERAPY — The goals of therapy are to improve quality of life and to prevent ischemic tissue injury. At least a moderate reduction in the intensity of attacks and the prevention of digital ulcers or tissue injury 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 "Pathogenesis of the Raynaud phenomenon".)

The efficacy of the treatment depends upon the severity of disease and upon the presence or absence of an underlying disorder; this is particularly important in patients with an underlying systemic rheumatic disease related to systemic sclerosis, as such patients can have a structural component to their vascular disease in addition to the vasospastic component seen in all patients with RP. The symptoms of RP can be highly variable; emotional stress and ambient temperature may also influence symptoms, in addition to the specific medical therapy. The initial treatment of patients with the Raynaud phenomenon includes:

Patient education (see 'Patient education' below)

General measures to maintain body warmth and to avoid other triggers of RP (see 'General measures' below)

Pharmacotherapy with calcium channel blockers for vasodilation, if general nonpharmacologic measures are inadequate (see 'General measures insufficient' below and 'Calcium channel blockers' below)

Behavioral therapies, the use of which depends upon patient preference and cost to the individual patient (see 'Behavioral therapy' below)

In patients who do not respond to initial therapies, further steps include the addition or substitution of other pharmacologic agents, such as topical nitrates or phosphodiesterase 5 inhibitors. Patients with digital ischemia that has not responded to oral or topical vasodilators may require hospitalization and/or treatment with anticoagulants, intravenous prostanoids, and/or sympathectomy or other interventions. (See "Treatment of the Raynaud phenomenon resistant to initial therapy".)

Assessment of the response to therapy — In clinical practice, a practical approach to assessing the response to therapy is to ask the patient a question similar to that used for the Raynaud Condition Score (RCS), a validated assessment tool used in clinical trials, which 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 [2,3]. The RCS uses a visual scale of 0 to 100; a change of about 15 is the minimum change considered clinically important [4].

Measures such as the RCS and other patient-reported outcomes are the gold standard 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.

PATIENT EDUCATION — We advise that all patients should be educated regarding both the potential causes of a Raynaud attack and the general measures to help prevent and terminate an episode. (See "Clinical manifestations and diagnosis of the Raynaud phenomenon", section on 'Provoking factors' and 'General measures' below.)

Clinical trials have demonstrated a 10 to 40 percent reduction in the frequency and severity of Raynaud attacks among placebo-treated patients with either primary or secondary Raynaud phenomenon (RP) [5-7]. These findings suggest that a positive attitude, attention to the patient, and general education may be important factors in controlling attacks, and they emphasize the importance of placebo-controlled trials in evaluating the efficacy of a specific therapy.

We also reassure patients with primary RP about the excellent prognosis in most patients, and we try to eliminate fears or unfounded misconceptions about RP and its management. Sympathetic tone and sensitivity to sympathetic mediators are enhanced in the patient with RP, and higher levels of anxiety correlate with more frequent attacks at temperatures over 60ºF (16ºC) and with more severe attacks at all ambient temperatures [8].

GENERAL MEASURES — We counsel all patients with Raynaud phenomenon (RP) to undertake a series of general measures that help to prevent or diminish the severity of attacks of RP, including changes in lifestyle and drug use [9-11]. Such measures are often sufficient for control of symptoms in patients with primary RP, while most patients with secondary RP will also require treatment with medications or correction of the underlying condition. In our experience, these precautions include:

Avoidance of cold exposure, especially sudden changes such as walking into the frozen food section of a grocery store.

Use of strategies to keep the whole body warm, including dressing warmly (eg, with thermal underwear, layered clothing, and a heat-conserving hat).

Use of strategies to keep the digits of the hands and feet warm (eg, winter gloves, chemical hand warmers, and heavy wool stockings).

Knowledge of 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. Rubbing the hands together can help.

Avoidance of rapidly changing temperatures, such as occurs when quickly moving from a hot environment (90ºF) into an air-conditioned room (70ºF). Avoiding sitting motionless in cool breezes or in humid cold air is also recommended.

Avoidance of smoking is advised since regular smokers are sensitized to the vasoconstrictive properties of cigarettes. The response in patients with RP does not appear to be different from that in normal individuals [12]. A large study including over 600 patients with systemic sclerosis (SSc) found that smoking was associated with substantially worse RP symptoms among patients with SSc [13]. Avoiding secondhand smoke is also prudent.

Avoidance of sympathomimetic drugs (such as decongestants, amphetamines, diet pills, herbs containing ephedra), which is generally recommended, although studies evaluating the degree of the impact of over-the-counter preparations (such as cold medications) have not been performed [11].

Avoidance of agents used to treat attention deficit hyperactivity disorder (methylphenidate and dextroamphetamine) is recommended. A case-control study found a significant association between the presence of RP and past or current use these stimulants [11].

Avoidance of some of the medications used for migraine headaches, including serotonin agonists (eg, sumatriptan) or caffeine plus ergotamine.

Avoidance of repeated trauma to the fingertips by all patients with RP and avoidance of vibrating tools by patients with vibration-induced RP [14].

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 [15].

An aggravating role of estrogen use is suggested by the finding that postmenopausal women using unopposed estrogens have a higher prevalence of RP [16]. However, the exact impact of estrogens is not fully defined.

We do not routinely stop caffeine-containing drinks in patients with RP, 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 [17,18]. Coffee consumption has been associated with vasoconstrictive effects, which transiently increase blood pressure. However, coffee contains many biological active compounds in addition to caffeine and overall may have vascular benefit [19]. 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.

GENERAL MEASURES INSUFFICIENT — We initiate pharmacotherapy in patients in whom general nonpharmacologic treatment measures alone are insufficient to adequately reduce the frequency and severity of attacks. We prefer to use one of the calcium channel blockers that have proven effective for primary and secondary Raynaud phenomenon (RP) as the initial choice for drug therapy. (See 'Calcium channel blockers' below.)

Additional oral and parenteral agents of benefit for RP and digital ischemia related to RP include other vasodilators, sympatholytic agents, prostaglandins, and an endothelin-1 receptor antagonist [20,21]. These therapies are discussed separately. (See "Treatment of the Raynaud phenomenon resistant to initial therapy".)

Pharmacotherapy

Calcium channel blockers — We recommend use of the slow-release or long-acting preparations of the dihydropyridine calcium channel blockers (CCBs), such as nifedipine or amlodipine, in the nonurgent management of RP that has not responded adequately to general measures. Other dihydropyridine CCBs that may be beneficial include isradipine and felodipine. The efficacy and safety of these medications have been documented in systematic reviews and in meta-analyses of randomized trials. (See 'CCBs: Efficacy and safety' below.)

Effective doses of nifedipine range from 30 to 180 mg/day, and effective doses of amlodipine range from 5 to 20 mg/day. We start with the lowest dose and gradually increase, if needed, depending upon the response. Some experts feel that amlodipine may be better tolerated in patients with low blood pressure at baseline or with problematic lowering of blood pressure with use of nifedipine, but this has not been systematically evaluated. The duration of a drug trial at a given dose is determined by the frequency of attacks, which dictates how long of a period of observation is 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.

We generally titrate the dose slowly in nonurgent situations, usually adjusting the dose every four weeks and no more frequently than every 7 to 10 days. In more urgent situations, a short-acting agent (eg, nifedipine rapid release) is preferred to allow more rapid dose adjustment in more severely affected patients. In hospitalized patients under close observation, the dose of nifedipine may be increased in 10 mg increments over four- to six-hour periods as required.

The major side effects associated with the dihydropyridines include headache, dizziness, flushing, tachycardia, and edema. Maximal doses of the calcium channel blocker (eg, amlodipine 15 to 20 mg/day) may lead to significant edema.

We generally discontinue CCBs and other vasodilators during pregnancy if possible, as RP often improves during pregnancy in association with increased blood volume. We prefer to use CCBs for digital ischemia during pregnancy, if required. If beta blockers are needed for blood pressure control, the selective agents are preferred, as some studies suggest that nonselective beta blockers sometimes worsen the symptoms of RP.

In addition, the relative benefits and tolerance of long-acting compared with short-acting preparations have assumed increasing importance with the suggestion that short-acting dihydropyridine preparations may increase cardiovascular risk. We thus prefer to use long-acting rather than short-acting formulations of CCBs for the treatment of RP. (See 'CCBs: Efficacy and safety' below and "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 of the potentially effective calcium channel blockers may be substituted, such as felodipine, nisoldipine, and isradipine of the dihydropyridine group or such as diltiazem, a nondihydropyridine [5,22-31].

CCBs: Efficacy and safety — The efficacy and safety of many of the CCBs in the treatment of both primary and secondary RP have been documented in meta-analyses of randomized trials and in systematic reviews [20,32-35].

As examples:

A 2016 meta-analysis of seven randomized trials with 296 patients evaluated the effects of oral CCBs, specifically nifedipine or nicardipine, for the treatment of primary RP [35]. A decrease in the frequency of attacks was reported for patients on a CCB (standardized mean difference of 0.23; 95% CI 0.08 to 0.38, p = 0.003). This translates to 1.72 (95% CI 0.60 to 2.84) fewer attacks per week on a CCB compared with placebo. This review provides moderate-quality evidence that oral CCBs are minimally effective in the treatment of primary RP, as measured by the frequency of attacks, and high-quality evidence that they have little effect on severity.

A 2005 meta-analysis of randomized trials involving 361 patients with primary RP showed benefit from the use of CCBs overall and of nifedipine in particular [33]. The frequency of attacks was reduced by an average of 2.8 to 5 per week, and the severity of attacks was reduced by one-third. Relatively low doses of CCBs were employed in some of the trials.

Much variability in the response to CCBs is observed in clinical trials, although approximately 60 percent of patients experience less intense and fewer attacks at doses of 10 to 20 mg three to four times daily of short-acting nifedipine [32]. This variability occurs, in part, because the trials often include both primary and secondary RP, and patients with secondary RP (particularly scleroderma) are less likely to benefit from nifedipine (and other CCBs) than are those with primary RP. (See "Treatment of the Raynaud phenomenon resistant to initial therapy", section on 'Recurrent digital ulcers in scleroderma'.)

CCBs differ in their vasodilating potency, and responses in individuals vary. Nifedipine, amlodipine, felodipine, nisoldipine, and isradipine of the dihydropyridine group, as well as diltiazem (a nondihydropyridine), are effective in RP [5,22-31]. However, not all CCBs appear to be beneficial. In one report, verapamil, a nondihydropyridine CCB, was ineffective at doses of 40 to 80 mg four times daily in a group of patients with severe RP [36]. In addition, nicardipine was not effective in one study [37] and was only minimally different from placebo in another [38].

Many published studies have used short-acting preparations of the CCBs in the treatment of acute digital ischemia due to RP. However, we prefer to use extended-release formulations for management of RP, given the ease of administration and the safety of the extended-release agents. (See "Major side effects and safety of calcium channel blockers".)

A large clinical experience suggests that long-acting nifedipine is effective in managing patients with RP and has fewer adverse reactions than rapid-acting preparations. The frequency of adverse events with the long-acting form of nifedipine is illustrated in the following trial:

In this trial, 313 patients with primary RP were randomly assigned to receive sustained-release nifedipine, placebo, or two different forms of biofeedback therapy [5]. The majority of patients receiving nifedipine were taking 60 mg daily, and others received 30 mg daily. The patients were evaluated during one winter month approximately one year after initiation of treatment. Nifedipine-treated subjects had a 66 percent reduction in attacks compared with the placebo group, a significant improvement. Adverse results were few, resulting in discontinuation of therapy in only 14 percent of patients receiving nifedipine and in 9 percent of those receiving placebo.

The most common adverse effects present significantly more often in patients receiving nifedipine compared with placebo and biofeedback were edema and flushing (24 and 8 percent, respectively, versus 0 percent). Headache was reported by 17 percent of those receiving nifedipine, by 11 percent receiving placebo, and by one patient being treated with biofeedback. The frequency of dizziness was comparable between groups (7 to 8 percent), and tachycardia was experienced by 2 of the 77 patients taking nifedipine.

Objective improvement in digital blood flow following treatment with a CCB has been difficult to substantiate. In one study, nifedipine caused a decrease in skin temperature recovery time following cold provocation [39]. CCBs may have additional biological properties that are beneficial in RP, including inhibition of platelet activation [40].

There is also some concern that nonselective systemic vasodilators may cause acute worsening of digital ischemia as a result of a decrease in systemic blood pressure and, consequently, digital perfusion [41]. While this is a theoretical concern, it is rarely seen as a complication in our experience.

Unable to use CCBs — Alternative therapies may be required in patients in whom CCBs are contraindicated or are poorly tolerated at low doses (eg, patients with severe gastrointestinal dysmotility, severe pulmonary artery hypertension, significant cardiac disease with edema, and low blood pressure). The treatment alternatives, which are discussed in detail elsewhere, include:

A phosphodiesterase-5 inhibitor, such as sildenafil (see "Treatment of the Raynaud phenomenon resistant to initial therapy", section on 'Phosphodiesterase type 5 inhibitors')

Topical nitrates (see "Treatment of the Raynaud phenomenon resistant to initial therapy", section on 'Topical nitrates')

An alternative oral agent, such as losartan or fluoxetine (see "Treatment of the Raynaud phenomenon resistant to initial therapy", section on 'Other alternatives to CCBs')

Local injection of botulinum toxin type A is also an option (see "Treatment of the Raynaud phenomenon resistant to initial therapy", section on 'Chemical sympathectomy')

Behavioral therapy — We do not recommend the use of behavioral therapy given the lack of robust studies showing benefit and the significant expense. Some techniques that have been studied include biofeedback training, autogenic training, and classical conditioning.

Higher levels of anxiety correlate with Raynaud attack frequency [8]. While treatments for anxiety in patients with RP could potentially improve RP symptoms, behavioral treatments have not directly addressed mental health conditions such as anxiety disorders.

OTHER INTERVENTIONS — Other treatments have been proposed and have been subjected to limited study; sufficient evidence is lacking at present to support their use in place of other interventions.

Acupuncture has been reported to improve primary Raynaud phenomenon (RP), but there is not enough evidence to determine effectiveness [42].

Therapeutic gloves [43] and low-level laser therapy [44,45] are reported to improve RP, but the data are limited. Spinal cord stimulation has been used for treatment in RP, but no controlled study is available [46].

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 [47].

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 [48,49]. However, many patients with primary RP have 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. 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. (See "Clinical manifestations and diagnosis of the Raynaud phenomenon".)

Clinical trials have demonstrated a 10 to 40 percent reduction in the frequency and severity of Raynaud attacks among placebo-treated patients with either primary or secondary RP. A significant component of this placebo response may be due to reinforcement of the importance of general nonpharmacologic measures that the patient can take to prevent and treat attacks. (See 'Patient education' above and 'General measures' above.)

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 5th to 6th 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 10th to 12th 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 disease (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

The goals of therapy in patients with the Raynaud phenomenon (RP) are to improve quality of life and to prevent ischemic tissue injury. At least a moderate reduction in the intensity of attacks and the prevention of digital ulcers or tissue injury 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 RP. (See 'Goals and overview of therapy' above.)

We advise that all patients should be educated regarding both the potential causes of a Raynaud attack and the general measures to help prevent and terminate an episode. Patients with primary RP are unlikely to develop damaging digital ischemia and thus are considered good candidates for nonpharmacologic therapies. (See 'Patient education' above.)

General measures that help to prevent or diminish the severity of attacks of RP include avoiding cold exposure, maintaining warmth of the whole body, smoking cessation, and avoiding sympathomimetic medications and emotional stress. (See 'General measures' above.)

We recommend use of the slow-release or long-acting preparations of the dihydropyridine calcium channel blockers (CCB), nifedipine (30 to 180 mg/day) or amlodipine (5 to 20 mg/day), in the nonurgent management of RP that has not responded adequately to general measures (Grade 1A). We start with the lowest dose and gradually increase as needed depending upon the response. (See 'Calcium channel blockers' above.)

We do not recommend the use of behavioral therapy given the lack of robust studies showing benefit. Their use would depend upon patient preference and upon the cost to the individual patient. (See 'Behavioral therapy' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

  1. Hughes M, Snapir A, Wilkinson J, et al. Prediction and impact of attacks of Raynaud's phenomenon, as judged by patient perception. Rheumatology (Oxford) 2015; 54:1443.
  2. Khanna D, Merkel PA. Outcome measures in systemic sclerosis: an update on instruments and current research. Curr Rheumatol Rep 2007; 9:151.
  3. Merkel PA, Herlyn K, Martin RW, et al. Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon. Arthritis Rheum 2002; 46:2410.
  4. Khanna PP, Maranian P, Gregory J, Khanna D. The minimally important difference and patient acceptable symptom state for the Raynaud's condition score in patients with Raynaud's phenomenon in a large randomised controlled clinical trial. Ann Rheum Dis 2010; 69:588.
  5. Comparison of sustained-release nifedipine and temperature biofeedback for treatment of primary Raynaud phenomenon. Results from a randomized clinical trial with 1-year follow-up. Arch Intern Med 2000; 160:1101.
  6. Wigley FM, Wise RA, Seibold JR, et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann Intern Med 1994; 120:199.
  7. Pope J, Fenlon D, Thompson A, et al. Iloprost and cisaprost for Raynaud's phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev 2000; :CD000953.
  8. Brown KM, Middaugh SJ, Haythornthwaite JA, Bielory L. The effects of stress, anxiety, and outdoor temperature on the frequency and severity of Raynaud's attacks: the Raynaud's Treatment Study. J Behav Med 2001; 24:137.
  9. Wigley FM. Clinical practice. Raynaud's Phenomenon. N Engl J Med 2002; 347:1001.
  10. Bowling JC, Dowd PM. Raynaud's disease. Lancet 2003; 361:2078.
  11. Goldman W, Seltzer R, Reuman P. Association between treatment with central nervous system stimulants and Raynaud's syndrome in children: a retrospective case-control study of rheumatology patients. Arthritis Rheum 2008; 58:563.
  12. Goodfield MJ, Hume A, Rowell NR. The acute effects of cigarette smoking on cutaneous blood flow in smoking and non-smoking subjects with and without Raynaud's phenomenon. Br J Rheumatol 1990; 29:89.
  13. Hudson M, Lo E, Lu Y, et al. Cigarette smoking in patients with systemic sclerosis. Arthritis Rheum 2011; 63:230.
  14. Falkiner S. Diagnosis and treatment of hand-arm vibration syndrome and its relationship to carpal tunnel syndrome. Aust Fam Physician 2003; 32:530.
  15. Freedman RR, Ianni P. Role of cold and emotional stress in Raynaud's disease and scleroderma. Br Med J (Clin Res Ed) 1983; 287:1499.
  16. Fraenkel L, Zhang Y, Chaisson CE, et al. The association of estrogen replacement therapy and the Raynaud phenomenon in postmenopausal women. Ann Intern Med 1998; 129:208.
  17. Umemura T, Ueda K, Nishioka K, et al. Effects of acute administration of caffeine on vascular function. Am J Cardiol 2006; 98:1538.
  18. Echeverri D, Montes FR, Cabrera M, et al. Caffeine's Vascular Mechanisms of Action. Int J Vasc Med 2010; 2010:834060.
  19. O'Keefe JH, Bhatti SK, Patil HR, et al. Effects of habitual coffee consumption on cardiometabolic disease, cardiovascular health, and all-cause mortality. J Am Coll Cardiol 2013; 62:1043.
  20. Henness S, Wigley FM. Current drug therapy for scleroderma and secondary Raynaud's phenomenon: evidence-based review. Curr Opin Rheumatol 2007; 19:611.
  21. Herrick AL. Contemporary management of Raynaud's phenomenon and digital ischaemic complications. Curr Opin Rheumatol 2011; 23:555.
  22. Rodeheffer RJ, Rommer JA, Wigley F, Smith CR. Controlled double-blind trial of nifedipine in the treatment of Raynaud's phenomenon. N Engl J Med 1983; 308:880.
  23. Smith CD, McKendry RJ. Controlled trial of nifedipine in the treatment of Raynaud's phenomenon. Lancet 1982; 2:1299.
  24. Sauza J, Kraus A, González-Amaro R, Alarcón-Segovia D. Effect of the calcium channel blocker nifedipine on Raynaud's phenomenon. A controlled double blind trial. J Rheumatol 1984; 11:362.
  25. Kallenberg CG, Wouda AA, Kuitert JJ, et al. Nifedipine in Raynaud's phenomenon: relationship between immediate, short term and longterm effects. J Rheumatol 1987; 14:284.
  26. Sarkozi J, Bookman AA, Mahon W, et al. Nifedipine in the treatment of idiopathic Raynaud's syndrome. J Rheumatol 1986; 13:331.
  27. Kahan A, Amor B, Menkes CJ. A randomised double-blind trial of diltiazem in the treatment of Raynaud's phenomenon. Ann Rheum Dis 1985; 44:30.
  28. Gjørup T, Hartling OJ, Kelbaek H, Nielsen SL. Controlled double blind trial of nisoldipine in the treatment of idiopathic Raynaud's phenomenon. Eur J Clin Pharmacol 1986; 31:387.
  29. Leppert J, Jonasson T, Nilsson H, Ringqvist I. The effect of isradipine, a new calcium-channel antagonist, in patients with primary Raynaud's phenomenon: a single-blind dose-response study. Cardiovasc Drugs Ther 1989; 3:397.
  30. La Civita L, Pitaro N, Rossi M, et al. Amlodipine in the treatment of Raynaud's phenomenon. Br J Rheumatol 1993; 32:524.
  31. Kallenberg CG, Wouda AA, Meems L, Wesseling H. Once daily felodipine in patients with primary Raynaud's phenomenon. Eur J Clin Pharmacol 1991; 40:313.
  32. Thompson AE, Shea B, Welch V, et al. Calcium-channel blockers for Raynaud's phenomenon in systemic sclerosis. Arthritis Rheum 2001; 44:1841.
  33. Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud's phenomenon: a meta-analysis. Rheumatology (Oxford) 2005; 44:145.
  34. Huisstede BM, Hoogvliet P, Paulis WD, et al. Effectiveness of interventions for secondary Raynaud's phenomenon: a systematic review. Arch Phys Med Rehabil 2011; 92:1166.
  35. Ennis H, Hughes M, Anderson ME, et al. Calcium channel blockers for primary Raynaud's phenomenon. Cochrane Database Syst Rev 2016; 2:CD002069.
  36. Kinney EL, Nicholas GG, Gallo J, et al. The treatment of severe Raynaud's phenomenon with verapamil. J Clin Pharmacol 1982; 22:74.
  37. Wigley FM, Wise RA, Malamet R, Scott TE. Nicardipine in the treatment of Raynaud's phenomenon. Dissociation of platelet activation from vasospasm. Arthritis Rheum 1987; 30:281.
  38. Kahan A, Amor B, Menkès CJ, et al. Nicardipine in the treatment of Raynaud's phenomenon: a randomized double-blind trial. Angiology 1987; 38:333.
  39. White CJ, Phillips WA, Abrahams LA, et al. Objective benefit of nifedipine in the treatment of Raynaud's phenomenon. Double-blind controlled study. Am J Med 1986; 80:623.
  40. Takahara K, Kuroiwa A, Matsushima T, et al. Effects of nifedipine on platelet function. Am Heart J 1985; 109:4.
  41. Wise RA, Malamet R, Wigley FM. Acute effects of nifedipine on digital blood flow in human subjects with Raynaud's phenomenon: a double blind placebo controlled trial. J Rheumatol 1987; 14:278.
  42. Appiah R, Hiller S, Caspary L, et al. Treatment of primary Raynaud's syndrome with traditional Chinese acupuncture. J Intern Med 1997; 241:119.
  43. Ko GD, Berbrayer D. Effect of ceramic-impregnated "thermoflow" gloves on patients with Raynaud's syndrome: randomized, placebo-controlled study. Altern Med Rev 2002; 7:328.
  44. Hirschl M, Katzenschlager R, Ammer K, et al. Double-blind, randomised, placebo controlled low level laser therapy study in patients with primary Raynaud's phenomenon. Vasa 2002; 31:91.
  45. Hirschl M, Katzenschlager R, Francesconi C, Kundi M. Low level laser therapy in primary Raynaud's phenomenon--results of a placebo controlled, double blind intervention study. J Rheumatol 2004; 31:2408.
  46. Neuhauser B, Perkmann R, Klingler PJ, et al. Clinical and objective data on spinal cord stimulation for the treatment of severe Raynaud's phenomenon. Am Surg 2001; 67:1096.
  47. Malenfant D, Catton M, Pope JE. The efficacy of complementary and alternative medicine in the treatment of Raynaud's phenomenon: a literature review and meta-analysis. Rheumatology (Oxford) 2009; 48:791.
  48. Carpentier PH, Satger B, Poensin D, Maricq HR. Incidence and natural history of Raynaud phenomenon: A long-term follow-up (14 years) of a random sample from the general population. J Vasc Surg 2006; 44:1023.
  49. Suter LG, Murabito JM, Felson DT, Fraenkel L. The incidence and natural history of Raynaud's phenomenon in the community. Arthritis Rheum 2005; 52:1259.
Topic 7540 Version 13.0

All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.