Raynaud's Phenomenon

Raynaud's Phenomenon

1 Overview

Summary and Quick Facts

  • Raynaud’s Phenomenon is when blood flow to the fingers or toes (and sometimes other extremities) is temporarily restricted. The reduction in blood flow causes fingers or toes to become pale, blue or red. Sometimes these color changes are accompanied by tingling or pain. Raynaud’s Phenomenon is usually triggered by cold temperatures or stress.
  • This protocol will help you understand the causes of Raynaud’s Phenomenon and how it is treated. Learn the differences between primary and secondary Raynaud’s Phenomenon and lifestyle considerations and supplements to support healthy blood flow throughout the body.
  • Ginkgo biloba extract has been shown to reduce the frequency of Raynaud’s Phenomenon episodes more than placebo in a clinical trial, and pre-clinical studies have shown it helps lessen blood vessel contraction.

What is Raynaud’s Phenomenon?

Raynaud’s phenomenon is a disorder in which blood vessels overreact to cold temperature or stress. Generally, blood vessels in fingers or toes are most affected. The blood vessels constrict, causing reduced blood flow to the affected extremity. Primary Raynaud’s phenomenon has no identified underlying cause and is generally not permanently damaging. Secondary Raynaud’s phenomenon, however, is related to an underlying cause and may be more damaging to the affected tissue.

With primary Raynaud’s phenomenon, minor lifestyle changes may be enough to reduce symptoms. However, with secondary Raynaud’s phenomenon, medical treatment is likely necessary to address the underlying cause.

Natural integrative therapies such as magnesium and N-acetylcysteine may help manage symptoms of Raynaud’s phenomenon.

What are the Risk Factors for Raynaud’s Phenomenon?

  • Excessive alcohol consumption
  • Smoking
  • Underlying medical conditions such as systemic sclerosis, scleroderma, and hypothyroidism
  • Certain medications, including beta-blockers and some chemotherapy drugs

What are the Signs and Symptoms of Raynaud’s Phenomenon?

  • “Triphasic” skin color change—the affected limb or digit generally turns white (decreased blood flow, sometimes accompanied by numbness or tingling), then blue (poor oxygenation), then red (blood flow is restored, sometimes accompanied with feeling warmth and pain).
  • In severe cases of secondary Raynaud’s phenomenon, ulcers and gangrene may occur in the affected extremity.

What are Conventional Treatments for Raynaud’s Phenomenon?

Note: Most cases of primary Raynaud’s phenomenon can be treated with moderate lifestyle changes. Secondary Raynaud’s phenomenon requires managing the underlying condition, as well as lifestyle changes.

  • Lifestyle changes include:
    • Dressing warmly
      • Keeping extremities warm (eg, gloves and socks)
    • Avoiding touching anything that vibrates
    • Quitting smoking
    • Avoiding caffeine
    • Avoiding emotional stress
  • Medications used to treat (usually secondary) Raynaud’s phenomenon and associated complications:
    • Calcium channel blockers (eg, nifedipine)
    • Phosphodiesterase-5 inhibitors (eg, sildenafil)
    • Serotonin reuptake inhibitors (eg, fluoxetine)
    • Other drugs such as statins, prostacyclin, and angiotensin-converting enzyme inhibitors

What are Emerging Therapies for Raynaud’s Phenomenon?

  • Topical nitrate therapy
  • Botulinum toxin (Botox)
  • Endothelin receptor A inhibitors

What Natural Interventions May Be Beneficial for Raynaud’s Phenomenon?

  • Magnesium. Low magnesium levels can increase contractility in blood vessels, and constriction of blood vessels is an important contributor to Raynaud’s phenomenon.
  • N-acetylcysteine. N-acetylcysteine (NAC) supports production of glutathione, which in turn prevents damage to blood vessel lining. Several studies indicate that NAC infusions reduced the severity and frequency of attacks.
  • Yohimbine. Yohimbine, an indole alkaloid derived from the bark of the yohimbe tree, can block alpha-2 receptors involved in vasoconstriction.
  • Vitamin C. Vitamin C promoted vasodilation and improved blood flow in people with coronary artery atherosclerosis, a condition that shares some risk factors with secondary Raynaud’s phenomenon.
  • Essential fatty acids. Fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and gamma-linolenic acid (GLA) have blood thinning effects and may help relieve symptoms of Raynaud’s phenomenon.
  • L-arginine. The amino acid L-arginine is important for synthesizing nitric oxide, a vasodilator.
  • Ginkgo biloba. Ginkgo biloba extract may decrease vasoconstriction. A study showed that treatment with the extract reduced the number of attacks of Raynaud’s phenomenon.
  • Other natural interventions such as vitamin D,vitamin E,niacin and inositol hexanicotinate, and selenium may help to improve the symptoms of Raynaud’s phenomenon.

2 Introduction

Raynaud’s phenomenon is a complex vascular disorder in which blood vessels, particularly those in the fingers and toes, or rarely the tongue, nose, ears, lips, or nipples, overreact to cold temperature or emotional stress (Mayo Clinic 2011c; Herrick 2012; Martínez 2011). The blood vessels constrict (ie, vasoconstriction), reducing blood flow to the affected extremity. This results in numbness while blood flow is reduced and tingling and/or pain as blood flow returns to the affected area (Herrick 2012; Martínez 2011). These attacks may last from minutes to hours, and the intensity of discomfort may vary from mild to severe (Malenfant 2011; NCBI 2011; Martínez 2011).

The hallmark of Raynaud's phenomenon is the transitioning of the affected extremities from white to blue to red over the course of an “attack”, representing lack of oxygen, cyanosis (a consequence of lack of oxygen), and restoration of blood flow, respectively. This classic “tricolor phenomenon” represents a key diagnostic criterion in the clinical management of Raynaud’s (Herrick 2012; Martínez 2011).

There are two types of Raynaud’s phenomenon: primary and secondary.

  • Primary Raynaud’s phenomenon (Raynaud disease) in which no underlying cause can be identified, is the result of a spasm (constriction) of the blood vessels; it generally does not lead to permanent tissue injury. Some medications or occupational exposures can cause the condition as well (Malenfant 2011). Most people with Raynaud’s phenomenon have the primary form (Herrick 2012).
  • Secondary Raynaud’s phenomenon is related to an underlying cause (Martínez 2011). Autoimmune diseases such as lupus or, especially, scleroderma are often associated with secondary Raynaud’s phenomenon (Malenfant 2011; Herrick 2012). The secondary form is usually more serious and may severely compromise the affected tissue, potentially leading to ulceration, gangrene, and loss of affected digit(s)(Mayo Clinic 2011c; Herrick 2012; Pauling 2012; Stewart 2012).

The primary form of Raynaud’s phenomenon is often controllable with lifestyle changes, such as avoiding cold temperatures and wearing gloves, but the secondary form generally requires medical treatment to address the underlying cause (Malenfant 2011; Herrick 2012).

In many cases, individuals who experience Raynaud’s phenomenon do not discuss their symptoms with their doctor, considering them just a periodic nuisance (Stewart 2012). This is unfortunate, because some people initially thought to have primary Raynaud’s phenomenon (Raynaud disease) go on to develop a systemic autoimmune disease, and early recognition can help improve management and outcomes (Herrick 2012). Those who experience episodes of Raynaud’s phenomenon should mention their symptoms to their physician, since simple blood tests and clinical examinations can help rule out a potentially serious underlying disease (Herrick 2012).

Unfortunately, many available medications provide only partial relief. However, topical nitroglycerin, which was originally investigated decades ago for Raynaud’s phenomenon, has received renewed interest after some recent trials demonstrated efficacy. The re-emergence of topical nitroglycerin therapy holds promise for patients with both primary and secondary Raynaud’s phenomenon, and has low potential for systemic side effects, since it is administered topically only to the affected body parts (Hummers 2012; Mediquest 2012; Chung 2009; Herrick 2012).

In this protocol you will learn about the primary and secondary forms of Raynaud’s phenomenon, and what causes them. Conventional treatment strategies will be outlined, and several promising emerging therapies will be discussed. In addition, the potential therapeutic role of several natural interventions will be examined.

3 Biology of Raynaud’s Phenomenon

Primary Raynaud’s Phenomenon

Although the causes(s) of primary Raynaud’s phenomenon are not entirely understood, a significant underlying feature appears to be an abnormal response of alpha-2 adrenergic receptors, which are proteins on cell surfaces that bind to hormones like norepinephrine and epinephrine and help control the stress response, regulate blood pressure, and control heart rate. Alpha-2 adrenergic receptors are particularly abundant within the blood vessels in the fingers, and their abnormal response can cause vasoconstriction (Herrick 2012). This process occurs in response to cold or emotional stress, and may be driven in part by free radicals, which cause oxidative stress (Boin 2005; Herrick 2012).

Oxidative stress is implicated not only in the pathogenesis of Raynaud’s phenomenon, but can be a significant consequence of the ischemia-reperfusion characteristic of both the primary and secondary forms of this disease as well. Lack of blood flow (ischemia), and its subsequent return (reperfusion), generates free radicals, which can damage the delicate interior lining of the blood vessels, called the endothelium, in the affected tissues; in severe cases this may lead to ulcers and tissue death. Therefore, antioxidants, which neutralize free radicals, have received significant attention among researchers studying Raynaud’s phenomenon (Herrick 2012).

Secondary Raynaud’s Phenomenon

Other biologic and chemical pathways are thought to be involved in secondary, and possibly also primary, Raynaud’s phenomenon. These include (Cooke 2005; Herrick 2012):

Vascular abnormalities. A key feature of secondary Raynaud’s phenomenon is a disruption of the vasodilation/vasoconstriction equilibrium, resulting in decreased vasodilation and increased vasoconstriction (Roustit 2011; Herrick 2012). This appears to be a consequence of decreased production of chemicals that dilate blood vessels, combined with the increased production of chemicals that constrict them (Herrick 2012).

In primary Raynaud’s phenomenon, structural abnormalities are thought to be subtle, and the vascular defect is mostly functional (Herrick 2005). On the other hand, in secondary Raynaud’s phenomenon blood vessels have several structural and functional abnormalities (Herrick 2011).

Various blood vessel abnormalities observed in secondary Raynaud’s phenomenon occur as a consequence of an underlying connective tissue disease, such as systemic sclerosis. These include enlarged, widened capillaries through which blood flow is sluggish. One of the most significant changes appears to be the increased thickness of the endothelium. Other contributors to vascular damage include the apoptosis, or programmed cell death, of endothelial cells; abnormal expression of transcription factors, which are proteins required for normal genetic processes; aberrant production of inflammatory cytokines; and irregularities in angiogenesis, which is the production and growth of blood vessels (Herrick 2012).

The endothelium, or the inner lining of the blood vessels, is a very dynamic structure that not only produces vasoactive chemicals, but also reacts to their presence. Some of these chemicals dilate, while others constrict the blood vessels (Herrick 2005). One aspect of Raynaud’s phenomenon that is not yet completely understood is whether the production of these vasoactive chemicals is impaired, or the endothelium does not respond to them properly (Herrick 2012).

One such vasoactive chemical that has received intense scrutiny in the context of Raynaud’s phenomenon is nitric oxide (NO). There are several forms of nitric oxide synthase (NOS), the enzyme that produces nitric oxide; in secondary Raynaud’s, some forms are overexpressed and others are underexpressed, complicating a clear understanding of nitric oxide’s role in the condition. Both increased and decreased nitric oxide production were reported in various studies, and the overall effect of NO in this condition was referred to as “paradoxical”, because it has positive as well as negative components (Matucci Cerinic 2002). Nonetheless, studies show that applying topical nitroglycerin, a compound that increases nitric oxide generation, provokes vasodilation in both primary and secondary Raynaud’s phenomenon and may relieve symptoms (Herrick 2012).

Additional contributing factors. Aside from factors directly related to the structure or function of the blood vessels, several intravascular factors have also been implicated in the pathogenesis of secondary Raynaud’s phenomenon (Herrick 2005). These include increased white blood cell and platelet activation, defective blood clotting, and increased blood viscosity (Herrick 2005, 2012). Neural abnormalities may be implicated as well. Nerve endings in the skin release chemicals called neuropeptides in response to various stimuli from the environment. The biological cascade they trigger can also result in the constriction or dilation of the blood vessels (Herrick 2012).

The Potential Role of Hormones in Raynaud’s Phenomenon Among Women

Hormonal factors, particularly estrogen, may also play a role in the etiology of Raynaud’s phenomenon among women. The relationship appears to be complex, however, as some studies suggest estrogens promote vasodilation in Raynaud’s phenomenon, whereas others point to a vasoconstrictive effect (Herrick 2012).

There is some evidence that estrogen replacement therapy (without progesterone) may be associated with Raynaud’s phenomenon. In a study that enrolled 49 women, Raynaud’s phenomenon was present in 19.1% of women receiving estrogen, 9.8% of women receiving estrogen together with progesterone, and 8.4% of women not receiving any estrogen (Fraenkel 1998). These observations are supported by the finding that estrogen increases the production of alpha 2C-adrenergic receptors, which play a role in vasoconstriction (Kleinert 1998; Eid 2007). On the other hand, progesterone has been shown to mitigate vasoconstriction and promote vasodilation, suggesting the observed vasoconstrictive tendencies of estrogen in Raynaud’s phenomenon may be offset if levels of the two hormones are balanced (Thomas 2013).

Although more studies are needed to firmly establish the role of estrogen and progesterone in Raynaud’s phenomenon, women affected by Raynaud’s are encouraged to have a blood test to assess their sex hormone levels. If an imbalance is detected, then women can work with a physician experienced in bioidentical hormone replacement therapy to naturally restore hormonal balance. More information is available in the Female Hormone Restoration protocol.

4 Triggers and Risk Factors

Raynaud’s phenomenon attacks are usually triggered by cold temperatures or emotional stress (Herrick 2012). However, it is important to know that Raynaud’s phenomenon can be triggered not simply by exposure to cold, but also by a temperature change – for example, moving from a warm environment to an air conditioned room, and sometimes even holding a cold bottle, can trigger the events. Therefore, vasoconstriction attacks may occur at any time of the year, not only during the cold season (Goundry 2012).

Alcohol consumption and smoking may influence Raynaud’s risk. One study that included middle-aged participants found an increased risk in women with high alcohol consumption. On the other hand, moderate alcohol consumption was associated with a reduced risk in men, but it appeared that smoking could attenuate this effect. However, moderate red wine consumption reduced the risk in both men and women (Suter 2007). This may be because red wine contains phytochemicals (namely resveratrol) that support blood vessel health; although some researchers suggest this compound may be of benefit for individuals with Raynaud’s, studies have yet to evaluate its effectiveness (Simonini 2000).

Secondary Raynaud’s phenomenon appears when there is an underlying condition, and in these situations, it is always necessary to identify the causative disease. The diseases most frequently associated with Raynaud’s phenomenon are systemic sclerosis and scleroderma; Raynaud’s phenomenon may be the first indication of the primary disease in up to 90% of these cases (Devulder 2011; Harding 1998). Other conditions that can cause secondary Raynaud’s phenomenon include systemic lupus erythematosus (SLE), inflammatory muscle disease, Sjögren’s syndrome, Buerger’s disease, and vasculitis (Herrick 2012).

Raynaud’s phenomenon may also occur as a side effect of certain medications, including beta-blockers, ergotamines (used for migraines), interferon alpha, cyclosporine (a drug that suppresses the immune system), and certain chemotherapy drugs, such as vinblastine, bleomycin, and cisplatin (Vogelzang 1981; Stewart 2012). In addition, gemcitabine, a drug used to treat several cancers, was associated with ischemia in the fingers, and the authors of a 2010 study recommended caution when using this drug in patients who previously had Raynaud’s phenomenon or are known to have peripheral arterial disease (Kuhar 2010).

Other causes of Raynaud’s phenomenon include hypothyroidism (low thyroid hormone levels), carpal tunnel syndrome, certain cancers (which may increase the viscosity of the blood and make blood flow more difficult), thoracic outlet syndrome (in which nerves and blood vessels of the upper extremities are compressed between the collar bone and the first rib), atherosclerosis, frostbite, and hand-arm vibrations from operating certain machines or tools (Herrick 2012; Stewart 2012; Thompson 2012).

5 Signs and Symptoms

The manifestation of an episode of Raynaud’s phenomenon typically comprises changes in skin color that occur in a characteristic “triphasic” pattern: white, blue, and red (Baumhakel 2010; Cooke 2005; Herrick 2012; Stewart 2012). In the initial phase, decreased blood flow as a result of vasoconstriction (known as ischemia) causes the skin to turn white (Goundry 2012). This is followed by a blue phase (known as the cyanotic phase), which is caused by poor oxygenation of the area (Goundry 2012). The third phase is characterized by redness, as blood flow to the area is restored (Cooke 2005; Goundry 2012; Herrick 2012). When the area becomes white, a sensation of numbness occurs, frequently accompanied by tingling. When the skin becomes red, the area becomes warm and painful (Stewart 2012). All three phases are not required for a diagnosis to be made (Goundry 2012). Raynaud’s phenomenon attacks sometimes affect only one or two fingers or toes, and they do not have to involve the same fingers or toes at every attack (Mayo Clinic 2011c).

Primary Raynaud’s Phenomenon

In most people with primary Raynaud’s phenomenon, signs and symptoms develop between ages 15 and 40 (Planchon 1994; NIAMS 2009; Stewart 2012). A study that enrolled over 3000 patients with primary Raynaud’s phenomenon reported that its appearance before age 40 was not significantly associated with connective tissue disorders, while its appearance after age 40 was significantly associated with connective tissue disorders. In addition, patients whose primary Raynaud’s phenomenon worsened over time were at higher risk for later developing connective tissue disorders (Pavlov-Dolijanovic 2012).

Although relatively rare in primary Raynaud’s phenomenon, ulcers may develop in the affected area due to lack of blood flow. The development of ulcers, scarring, and gangrene is more common in secondary Raynaud’s phenomenon (Cooke 2005; Stewart 2012).

Secondary Raynaud’s Phenomenon

Secondary Raynaud’s phenomenon usually starts after age 35–40 (NIAMS 2009). This form, in which an underlying disease exists, can result in more serious signs and symptoms, including painful ulcers and dead tissue (gangrene) in the affected extremity; this can lead to loss of the affected digit in severe cases (Stewart 2012).

6 Diagnosis and Conventional Treatment

Diagnosis

Raynaud’s phenomenon can be a difficult condition to diagnose because it has a complex set of causes, which may act by various different mechanisms, and signs and symptoms can vary. The primary goal of diagnosis is to determine if any underlying medical condition is contributing to the clinical signs and symptoms, as this allows the physician to distinguish primary from secondary Raynaud’s phenomenon (Baumhakel 2010).

Primary Raynaud’s phenomenon is diagnosed based on several criteria (Stewart 2012):

  • A history of attacks, triggered by cold or stress, involving both hands. Keeping a diary of the attacks and taking photographs of the affected areas are helpful. History also can reveal factors, such as drugs or activities (eg, smoking) that initiate or aggravate the attacks (Goundry 2012). Clinicians may also conduct an “ice test,” in which the patient’s hands are submerged in ice or ice water to observe any color changes (Delp 1986).
  • Lack of necrosis (tissue death) or other signs of tissue damage.
  • No history of physical signs or symptoms of any underlying condition.
  • Normal blood vessels in the nail fold, the area around the nail, based on capillaroscopy. Capillaroscopy is a noninvasive test in which the physician examines the nail fold under a special microscope. A positive test (eg, giant capillaries and tiny hemorrhages) rules out primary Raynaud’s in favor of secondary Raynaud’s, and may be a sign of early systemic sclerosis (Herrick 2012; Cutolo 2008). After Raynaud’s phenomenon is diagnosed, follow-up capillaroscopy is suggested approximately every 6 months (Cutolo 2008).

Diagnostic lab tests include complete blood count, erythrocyte sedimentation rate (ESR), and anti-nuclear antibody screening (ANA). The physician may also assess thyroid hormone levels and perform an X-ray to confirm there is no cervical rib, a condition in which an extra rib sometimes develops in conjunction with a vertebra in the neck. This can affect blood flow, especially to the arms (Herrick 2012).

Some specialists use an imaging technique called thermography. In this approach, the reaction of the fingers to a moderately cold temperature exposure is monitored using specialized equipment designed to assess temperature change. This test is expensive and rarely used in the primary care setting (Ammer 1996; Herrick 2012).

Additional tests are conducted to differentiate secondary from primary Raynaud’s phenomenon (Herrick 2012):

  • Autoantibody levels that might signify the presence of an underlying autoimmune disease. Autoantibodies can cause the immune system to attack the body’s own tissue.
  • Arterial Doppler and/or large vessel imaging if atherosclerosis in the large arteries is suspected.
  • Dermatoscopy or ophthalmoscopy, in addition to capillaroscopy, to identify capillary abnormalities.

The presence of ulcerations of the fingers or toes is usually a sign of secondary Raynaud’s phenomenon, and suggests the cause (eg, an existing connective tissue disorder) has to be examined (Goundry 2012).

Conventional Treatment

Primary Raynaud’s phenomenon. Most people with primary Raynaud’s phenomenon can be treated conservatively with lifestyle approaches. (Baumhakel 2010). Important lifestyle considerations include:

  • Dressing warmly, in layers (Mayo Clinic 2011c).
  • Keeping the extremities warm (wearing warm socks, gloves, or mittens) (Mayo Clinic 2011c).
  • Avoiding touching anything that vibrates (Stewart 2012).
  • Quitting smoking, since smoking is a well-known vasoconstrictor (Levien 2010).
  • Avoiding caffeine, which is a vasoconstrictor (Levien 2010).  
  • Avoiding emotional stress (Levien 2010).

However, if symptoms are frequent and last for a long time, medication may be needed (see Table 1). Most drugs used to treat primary and secondary Raynaud’s phenomenon either promote vasodilation or suppress vasoconstriction. Although several drugs have been investigated, few are approved by the Food and Drug Administration (FDA) for the treatment of Raynaud’s phenomenon (Stewart 2012; Levien 2010).

Calcium channel blockers are typically the first line of treatment for primary Raynaud’s, and of these, nifedipine (eg, Adalat®, Afeditab®, Procardia®) has been the most widely used (Herrick 2011, 2012).

Secondary Raynaud’s phenomenon. The most important approach in the management of secondary Raynaud’s phenomenon is to treat the underlying condition (Herrick 2011). Patients also need to follow the same lifestyle approaches as those with primary Raynaud’s, and calcium channel blockers are also the first-line medical treatment for the Raynaud’s symptoms. However, individuals with secondary Raynaud’s phenomenon who do not respond to calcium channel blockers may need other medications, which are listed in Table 1 and described below (Baumhakel 2010).

Patients with ulcers, necrosis, or gangrene may be hospitalized and receive intravenous prostaglandins and/or phosphodiesterase-5 (PDE-5) inhibitors. Those with underlying systemic sclerosis may also be treated with the dual endothelin receptor antagonist bosentan (Tracleer®) to prevent the development of new ulcers (Baumhakel 2010). Bosentan is approved to treat pulmonary arterial hypertension (Gabbay 2007). It works by interfering with the interaction between the protein endothelin-1 and cellular receptors. The binding between these two causes vasoconstriction, and interfering with this process prevents it (Clozel 1994; Channick 2001).

Calcium channel blockers (CCB). These drugs represent the first-line treatment for primary and secondary uncomplicated Raynaud’s phenomenon that does not respond to lifestyle changes; nifedipine (eg, Procardia®) is a commonly used and well-studied drug in this class (Lambova 2009; Herrick 2011, 2012). An important aspect of the treatment is to start with the lowest dose, and then gradually increase it until symptoms improve. Extended-release formulations often cause fewer side effects and are usually well tolerated (Herrick 2012). A comprehensive review of 18 randomized, placebo-controlled, double-blind trials of calcium channel blockers in patients with primary Raynaud’s phenomenon found these drugs led to significant reductions in severity (approximately 33% reduction) and frequency of attacks (Thompson 2005).

Phosphodiesterase-5 (PDE-5) inhibitors. These drugs work, in part, by enhancing nitric oxide-dependent vasodilation. Studies on their efficacy are mixed, and they are usually used when other vasodilator drugs are not effective (Herrick 2012). One small study of sildenafil (Viagra®) in patients with systemic sclerosis reported that the drug improved blood flow to the fingers, with maximum benefit being reached after a few months of treatment; it also helped heal ulcers on the fingers. However, during the study, many participants developed new ulcers while receiving treatment, indicating that the drug does not prevent new ulcers from forming (Herrick 2012; Brueckner 2010).

Two new PDE5 inhibitors are being studied for Raynaud’s phenomenon. Udenafil (Zydena®) is a newer PDE5 inhibitor that is more selective for PDE5 than previous compounds, which inhibit other types of phosphodiesterases as well (Paick 2008; Sung 2012). A clinical trial that analyzed 52 participants compared udenafil with the calcium channel blocker amlodipine (Norvasc®) for the treatment of secondary Raynaud’s phenomenon; no differences in the mean number of attacks per day between the 2 groups were observed (clinicaltrials.gov (a) 2012). Another clinical trial, evaluating the investigational compound PF-00489791, was completed in 2011, but no results were available as of early 2013 (clinicaltrials.gov (b) 2012).

Angiotensin-converting enzyme (ACE) inhibitors. A comprehensive review of 3 studies on the effectiveness of captopril (Capoten®) or enalapril (Vasotec®) compared to placebo in patients with primary Raynaud’s phenomenon found non-significant differences between captopril and placebo on the average number of attacks per week and a small increase in the frequency of attacks with enalapril (Stewart 2012). Nonetheless, the drugs are still prescribed sometimes since individual patients may receive some benefit.

Angiotensin II receptor antagonists. These drugs are sometimes used alone or in addition with calcium channel blockers to treat Raynaud’s phenomenon. However, there is little evidence to support their effectiveness, and these drugs may be less effective in patients with Raynaud’s secondary to scleroderma than in those with the primary form of the disease (Gliddon 2007; Herrick 2012).

Serotonin reuptake inhibitors. Serotonin acts as a vasoconstrictor and enhances blood clotting; therefore, serotonin reuptake inhibitors have the potential to ease Raynaud’s symptoms in some patients (Herrick 2012). Much of the evidence for their use stems from case studies or very small clinical studies, primarily with fluoxetine (Prozac®). A study that enrolled 26 patients with primary Raynaud’s phenomenon and 27 patients with secondary Raynaud’s phenomenon compared 6-week treatments with fluoxetine and nifedipine, and reported a decreased frequency and severity of the attacks in both treatment groups, but statistical significance was seen only for patients treated with fluoxetine. Additionally, comparisons among subgroups of patients revealed that women and those with primary Raynaud’s phenomenon showed the best response (Coleiro 2001). Importantly, some studies reported that symptoms get worse with serotonin reuptake inhibitors, while others reported that the effects are not different than what can be observed with placebo (Lambova 2009; Levien 2010).

Statins. Several studies suggest that statin therapy for patients with Raynaud’s phenomenon secondary to systemic sclerosis can reduce the number of new ulcers on the fingers or toes. Statins have several effects, which include suppressing inflammation, improving blood vessel function, and inhibiting smooth muscle proliferation, all of which can reduce damage to the lining of blood vessels associated with Raynaud’s phenomenon. Some studies showed that statins can delay vascular damage, but insufficient evidence exists to recommend them as a standard drug (Kuwana 2006; Abou-Raya 2008; Herrick 2012).

Prostacyclins. Intravenous infusion of the prostacylins epoprostenol (Flolan®, Veletri®), treprostinil (Remodulin®), and iloprost is a treatment of choice in patients with severe secondary Raynaud’s phenomenon who develop ulcers on their fingers or toes. Studies found that these medications reduce the severity and frequency of Raynaud’s phenomenon attacks and help the healing of finger and toe ulcers, while iloprost also decreases the inflammation associated with the disease. Although there is an oral form of iloprost, studies are mixed regarding its effectiveness (Lambova 2009). A study presented at the 2011 annual meeting of the American College of Rheumatology/ Association of Rheumatology Health Professionals found that the oral prostacyclin treprostinil diethanolamine, which is a salt form of the prostacyclin analog treprostinil, improved the patients’ perception of their change in hand ulcerations and of the Raynaud’s phenomenon symptoms (Selbold 2011). This drug is investigational only as of the time of this writing.

Individuals with ulceration of their fingers or toes due to lack of blood flow require immediate medical attention. These patients are typically treated with intravenous prostaglandin therapy, pain medication, and antibiotics. Patients may also receive antiplatelet and anticoagulant therapies, despite the lack of evidence for their efficacy. Endothelin-1 receptor antagonists such as bosentan may also be used to suppress vasoconstriction. Two clinical trials of bosentan found the drug reduced the number of new finger or toe ulcers, but it did not heal existing ulcers (Herrick 2012).

Table 1:  Medications Used to Treat Raynaud’s Phenomenon

(Sources: Stewart 2012; Baumhakel 2010, unless otherwise noted)

Class

Generic/Brand Name

Potential Side Effects

Vasodilator antihypertensive drugs, including prostacyclin analogues

Bosentan (Tracleer®), hydralazine (Apresoline®), iloprost

Headache, flushing, itching, runny nose, sore throat, other cold symptoms, heartburn (Medline Plus 2010)

Alpha-adrenergic blockers

Doxazosin (Cardura®), indoramin, prazosin (Minipress®), terazosin (Hytrin®)

Low blood pressure, dizziness, headache, pounding heartbeat, nausea, weakness, weight gain, changes in blood cholesterol (Mayo Clinic 2010a).

Angiotensin-converting enzyme (ACE) inhibitors

Captopril (Capoten®), cilazapril, enalapril (Vasotec®), fosinopril (Monopril®), lisinopril (Prinivil®, Zestril®), moexipril (Univasc®), perindopril (Aceon®), quinapril (Accupril®), ramipril (Altace®), trandolapril (Mavik®)

Dry cough, increased blood-potassium level (hyperkalemia), fatigue, rash, dizziness, headaches, sleep problems, rapid heartbeat (Mayo Clinic 2010b)

Angiotensin-II receptor antagonists

Candesartan (Atacand®), eprosartan (Teveten®), losartan (Cozaar®), olmesartan (Benicar®), telmisartan (Micardis®), valsartan (Diovan®)

Headache, dizziness, lightheadedness, nasal congestion, back and leg pain, diarrhea (Mayo Clinic 2011a)

Calcium channel blockers

Nifedipine (Adalat®, Afeditab®, Procardia®), amlodipine (Norvasc®), felodipine (Plendil®)

Constipation, headache, rapid heartbeat, dizziness, rash, drowsiness, flushing, nausea, swelling of the feet and lower legs (Mayo Clinic 2010c)

Nitrates

Glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate

Headache, dizziness, skin irritation (Chung 2009)

Peripheral vasodilators and related drugs

Cilostazol (Pletal®), pentoxifylline (Pentoxil®, Pentopak®, Trental®)

Fever, fast or irregular heartbeat,  chest pain, abnormal bleeding (rarely), stomach pain  (less common) (Mayo Clinic 2011b; Mayo Clinic 2012a)

Serotonin reuptake inhibitors

Citalopram (Celexa®), escitalopram (Lexapro®), fluoxetine (Prozac®), fluvoxamine (Luvox®), paroxetine (Paxil®, Pexeva®), sertraline (Zoloft®)

Nausea, drowsiness, dry mouth, rash, headache, diarrhea, nervousness, agitation or restlessness, insomnia, reduced sexual desire or difficulty reaching orgasm, inability to maintain an erection (erectile dysfunction), increased sweating, weight gain  (Mayo Clinic 2010d)

Phosphodiesterase type-5 inhibitors

Sildenafil (Viagra®), tadalafil (Cialis®), vardenafil (Levitra®, Staxyn®)

Indigestion, heartburn, runny nose, muscle aches and stiffness (with Cialis®), headache, temporary vision changes (including blurred vision), cold sweats (with Viagra® and Levitra®) (Mayo Clinic 2012b; Mayo Clinic 2012c; Mayo Clinic 2012d)

Statins

Atorvastatin (Lipitor®)

Headache, hoarseness, pain or tenderness around the eyes and cheekbones, lower back or side pain, painful or difficult urination, stuffy or runny nose (Mayo Clinic 2012e)

7 Novel and Emerging Medical Therapies and/or Drug Strategies

Topical Nitrate Therapy

One contribution to Raynaud’s phenomenon appears to stem from changes in the expression of various chemicals produced by the endothelium, particularly the potent vasodilator nitric oxide (NO) (Cooke 2005; Herrick 2011; Herrick 2012). Investigational studies found that applying a topical preparation of nitroglycerin, which enhances nitric oxide signaling, triggers vasodilation (Herrick 2012).

One compound, called Vascana® (MQX-503), combines the proprietary drug-delivery formulation AmphiMatrix (TAM™), which allows drugs to penetrate the skin, with nitroglycerin. As of the time of this writing, the manufacturer is conducting a Phase III trial for final FDA consideration (MediQuest 2008, 2012). Published data demonstrate that this therapy is safe and effective in patients with either primary or secondary Raynaud’s phenomenon (Chung 2009; Hummers 2012). In a 2009 study that enrolled 219 patients with primary and secondary Raynaud’s phenomenon, 212 of whom completed the study, participants applied Vascana® or a placebo just before or up to 5 minutes after a Raynaud’s phenomenon attack. Those receiving the drug (applied as a 0.9% gel) demonstrated an average reduction in the Raynaud’s Condition Score (a standardized assessment) of 14.3%, significantly larger than the 1.3% in the placebo group, but the frequency and duration of the attacks was not statistically different between the two groups. In addition, based on the mean Raynaud’s Condition Score values, patients with systemic sclerosis and secondary Raynaud’s phenomenon improved less (12.3% and 15% improvement, respectively) than those with primary Raynaud’s phenomenon (21.3% improvement). Side effects were similar in the MQX-503 and placebo group (Chung 2009).

Another study on Vascana®, published in December 2012, involved 37 participants with Raynaud’s phenomenon who were treated with 0.5% or 1.25% nitroglycerin gels or with a placebo gel. Both active treatment groups had a greater improvement in blood flow in the fingers than participants receiving placebo (Hummers 2012).

Botulinum Toxin (Botox®)

Used medically to treat muscle spasticity, migraine, and excessive sweating, botulinum toxin is also being evaluated for Raynaud’s phenomenon and other disorders characterized by vasoconstriction. At least 5 studies have been conducted since 2004 in which botulinum toxin A was injected into the fingers and hands. While the studies had multiple limitations, they all demonstrated some improvement in pain and decreased ulceration of the soft tissues. Botulinum toxin A appears to work by multiple mechanisms: it decreases muscular tone, inhibits the release of norepinephrine (a chemical that causes vasoconstriction), and blocks specific receptors involved in cold-induced blood vessel constriction and pain (Iorio 2012). Botox® is available for other indications and may be used “off label” for Raynaud’s phenomenon is some cases under physician supervision.

Endothelin Receptor A Inhibitors

Ambrisentan (Letairis®), FDA-approved to treat pulmonary hypertension, is being evaluated as a vasodilator in patients with scleroderma and Raynaud’s phenomenon. Although a small study that evaluated 18 systemic sclerosis patients did not find any improvements in blood flow to the fingers over 12 weeks, pain and health-related quality of life scores improved (Bena 2011). Other studies have shown some benefit on functional outcomes using the endotelin receptor antagonist bosentan (Tracleer®), but results have been inconsistent (Nguyen 2010; Selenko-Gebauer 2006; Rosato 2010).

8 Targeted Natural Interventions

Magnesium. Magnesium is required to maintain smooth muscle relaxation in blood vessels (D’Angelo 1992). The requirement for magnesium increases with physical and emotional stress, both of which are known to trigger episodes of Raynaud’s phenomenon, and there is some evidence that levels of magnesium in the red blood cells from women with Raynaud’s phenomenon drop in the winter compared to healthy controls (Seelig 1994; Herrick 2012; Leppert 1994a). Low magnesium levels can increase smooth muscle contractility in blood vessels, which is important because blood vessel constriction is an important aspect of Raynaud’s phenomenon (Leppert 1994b). One study found that decreased serum magnesium levels were more common in women who experience Raynaud’s phenomenon when exposed to cold than in healthy women (82% and 45%, respectively) (Leppert 1990). Studies evaluating magnesium infusion in women with primary Raynaud’s phenomenon found that it helped normalize levels of magnesium as well as levels of certain hormones, proteins, and enzymes associated with the condition (Myrdal 1994; Leppert 1994a,b; Leppert 1995).

N-Acetylcysteine (NAC). This powerful antioxidant supports the production of glutathione, which in turn helps prevent damage to the blood vessel lining. A small study in 22 patients with Raynaud’s phenomenon secondary to systemic sclerosis found that those receiving a continuous, 5-day intravenous infusion of NAC had fewer and less-severe attacks (Sambo 2001). In another study, for two years, patients received 15 mg/kg per hour intravenous NAC infusions for 5 consecutive hours every 2 weeks. Researchers found that this treatment enhanced blood flow in the hands, reduced the severity and frequency of Raynaud’s phenomenon attacks, and increased vasodilation (Salsano 2005). Another study, in which 50 patients with systemic sclerosis received NAC infusions every 2 weeks for a median duration of 3 years, reported that the therapy was beneficial for Raynaud’s phenomenon and finger ulcers related to insufficient blood flow; reductions in frequency of attacks, finger ulcers, and pain were observed (Rosato 2009).

Yohimbine. Yohimbine, derived from the bark of the yohimbie tree, is a chemical that blocks alpha-2 receptors, which are involved in vasoconstriction. The use of this compound in Raynaud’s phenomenon stems from the observation that patients with primary Raynaud’s phenomenon show abnormal alpha-adrenergic responses. In a laboratory study on blood vessels from 50 subjects who underwent hand surgery for reasons not related to vascular disease, it was noted that yohimbine reversed cold-induced blood vessel contraction (Bodelsson 1990). Another study enrolled 23 patients, and after cold-induced primary Raynaud’s phenomenon was triggered, participants were randomly assigned to receive one of the following three treatments: an intra-arterial infusion of yohimbine, the alpha-1 receptor blocker prazosin, or the 2 treatments combined. The authors reported that fewer fingers, overall, developed attacks in the yohimbine group and combined treatment group than in the prazosin group (Freedman 1995). It should be noted that yohimbine may cause a fast heartbeat or elevated blood pressure in some individuals.

Vitamin C. Vitamin C, also known as ascorbic acid, is important for the synthesis of collagen, a key component of blood vessel walls (Nusgens 2001). In addition, studies suggest vitamin C supplementation improves blood flow (Kirby 2009). There is also evidence that people with Raynaud’s phenomenon have low levels of ascorbic acid. In one study, researchers found that median plasma levels of vitamin C were 4.8 mg/L in patients with primary Raynaud’s phenomenon, 2.5 mg/L in those with limited cutaneous systemic sclerosis, and 6.8 mg/L in those with diffuse systemic sclerosis; all values were significantly lower than 10.6 mg/L, which was observed in healthy control subjects (Herrick 1994). Another study found that 500 mg per day of vitamin C for 30 days promoted vasodilation and improved blood flow in people with coronary artery atherosclerosis, a condition that shares some risk factors with secondary Raynaud’s phenomenon (Gokce 1999; NCBI 2011).

Essential fatty acids. Omega-3 fatty acids such as eicosapentaenoic acid (EPA) and decosahexaenoic aicd (DHA) found in fish oil, and gamma-linolenic acid (GLA), a healthy omega-6 fatty acid found in evening primrose oil and borage oil, have blood-thinning effects that may help relieve symptoms of Raynaud’s phenomenon. One study found that 12 capsules per day for 8 weeks of evening primrose oil significantly reduced the number and severity of primary Raynaud’s phenomenon attacks (Belch 1985). Another study on fish oil supplementation found that 12 fish-oil capsules daily containing a total of 3.96 g EPA and 2.64 g DHA taken for 12 weeks increased the time before symptoms appeared after cold exposure compared to placebo in primary Raynaud’s phenomenon. This treatment also significantly increased blood flow in the fingers in participants with primary Raynaud’s phenomenon, as compared to a control group that received olive-oil capsules (DiGiacomo 1989).

L-Arginine. The amino acid L-arginine is important for the synthesis of nitric oxide, a potent vasodilator (Rembold 2003; Cooke 2005). In 2003, a case report described 2 patients with severe Raynaud’s phenomenon in whom oral L-arginine supplementation reversed necrosis of tissue in the fingers or toes (Rembold 2003). In another study that included individuals with Raynaud’s phenomenon secondary to systemic sclerosis, the authors reported that warming patients’ fingers after L-arginine treatment led to an increase in blood flow. In addition, another study showed that L-arginine (administered orally; 4 g twice daily) modulated blood vessel response to cool temperatures in the fingers of individuals with systemic sclerosis (Agostoni 1991).

Vitamin D. A study on 42 people with low vitamin D blood levels (average 20.9 ng/mL) and Raynaud’s phenomenon reported that subjects receiving 600 000 IU of oral vitamin D3 per month for 2 months not only achieved higher blood levels of vitamin D than those receiving placebo (32.9 ng/mL versus 23.2 ng/mL), but also reported their Raynaud’s became less severe. Researchers speculated that vitamin D may function as a vasodilator in individuals with Raynaud’s phenomenon (Helou 2012). Although more studies need to evaluate the role of vitamin D in Raynaud’s phenomenon, individuals with this condition are encouraged to have a blood test to assess their levels of 25-hydroxyvitamin D, and use a daily vitamin D3 supplement to maintain their levels between 50 and 80 ng/mL.

Vitamin E. Vitamin E is an antioxidant that protects fatty acids and other cellular molecules from oxidative damage (Brigelius-Flohe 1999). Some reports indicate that low levels of vitamin E are associated with Raynaud’s phenomenon (Simonini 2000). One study on individuals experiencing Raynaud’s as a consequence of working with vibrating machinery found that supplementation with 600 mg of alpha-tocopherol nicotinate daily for 6 weeks improved subjective symptoms such as numbness and cold sensation; clinical examinations also indicated improvement (Matoba 1977).

Gingko biloba. A study exploring the effectiveness of 120 mg Gingko biloba extract taken 3 times per day (for a total of 360 mg/day) for 10 weeks found that treatment reduced the number of Raynaud’s phenomenon attacks per week by 56%, compared to 27% in the placebo group (Muir 2002). In addition, a study on mice found that intravenous administration of a Gingko biloba extract inhibited vasoconstriction induced by platelet activation, suggesting ginkgo may also attenuate the vasoconstriction that occurs during an attack of Raynaud’s phenomenon (Stücker 1997).

Niacin and inositol hexanicotinate. Niacin, or vitamin B3, improves peripheral vasodilation, helps prevent formation of blood clots, and modulates lipid metabolism (Rosenson 2003; Kamanna 2009). Inositol hexanicotinate is a compound containing inositol bound to six molecules of niacin; within the body, niacin is released from the inositol (Milton 2013). An 84-day study evaluated the effectiveness of 4 g/day inositol hexanicotinate in 23 patients with primary Raynaud’s phenomenon. The inositol hexanicotinate group reported feeling better, and their attacks were shorter and fewer compared to placebo (Sunderland 1988). Another study using inositol hexanicotinate in 30 patients with primary or secondary Raynaud’s phenomenon reported that severity of vasoconstriction attacks decreased in most participants; non-smokers responded faster to therapy than smokers. In addition, elderly participants with longstanding vasospastic disease showed improved blood flow as a result of treatment. No side effects were reported (Holti 1979).

Selenium. The mineral selenium is an important component of several enzymes involved in intrinsic antioxidant defense mechanisms within the body; low selenium levels can compromise the body’s ability to combat free radical damage (Tikly 2006). Studies report low levels of selenium in people with Raynaud’s phenomenon and particularly those with systemic sclerosis, suggesting that supplementation may be of benefit in this population (Herrick 1994). These findings are particularly important in the context of Raynaud’s phenomenon secondary to systemic sclerosis, since oxidative stress is a significant contributor to the endothelial dysfunction that underlies this condition (Simonini 2000).

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