SNOWMASS, COLO. – Plenty of medication options exist for treatment of primary Raynaud’s phenomenon caused by reversible cutaneous arteriolar vasospasm. But actually, for most affected patients, no drug therapy is required, according to Dr. Fredrick M. Wigley.
“The environment – physical and emotional – has a huge impact on the severity of Raynaud’s phenomenon,” he emphasized at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Dr. Fredrick M. Wigley
“Whatever I tell you in terms of drugs, there’s nothing more potent than getting the patient out of a stressful, cold environment. So I tell patients who have digital ischemia to stop work, go home, get in bed, put the blanket up to your neck, keep warm, and often that’s more effective than the drug therapy that we try,” said Dr. Wigley , professor of medicine, associate head of rheumatology, and director of the scleroderma center at Johns Hopkins University, Baltimore.
Primary Raynaud’s phenomenon is typically reversible within 15-20 minutes after rewarming, he added.
Aggravators: Stress, trauma, smoking, certain drugs
Besides cold temperatures, another important aggravating factor in primary Raynaud’s phenomenon is emotional stress. Anxiety, like cold, increases sympathetic tone, triggering cutaneous vasoconstriction and rapid shunting of blood into the body core in vulnerable patients. Other major triggers of Raynaud’s are physical trauma – especially vibration – and smoking.
“I can tell you that in patients who have complicated Raynaud’s with digital lesions, if they continue to smoke, it doesn’t matter what drug you give them; you’re not going to get good control or fast healing of those digital lesions,” the rheumatologist continued.
Drugs known to aggravate Raynaud’s phenomenon include the serotonin agonists prescribed for migraine headaches, interferons, opiates, some cancer chemotherapy drugs, and medications used in treating attention-deficit/hyperactivity disorder.
“Thirty to forty percent of ADHD kids develop Raynaud’s phenomenon. Methylphenidate, dextroamphetamine, atomoxetine – those are definitely potent sympathomimetic drugs. And the vascular shunts in the skin are very sensitive to sympathomimetic agonists,” according to Dr. Wigley.
Poor evidence for behavioral therapies
The notion of biofeedback, acupuncture, herbals, autogenic training, and other nondrug treatments appeals to many, but in his view, there is no good supporting evidence. What clinical trials have been done have been negative.
“Those therapies have all sort of gone belly up. I wouldn’t be recommending behavioral therapies,” he continued.
When to use vasodilators
In the minority of patients with severe primary Raynaud’s phenomenon, which affects their quality of life and doesn’t sufficiently respond to strategies aimed at avoiding environmental triggers, calcium channel blocker monotherapy is king.
“Amlodipine is my favorite because it has less cardiac effects. I use the long-acting form rather than short-acting agents. I titrate the calcium channel blocker to the maximum tolerated dose before considering combining it with a second agent. It’s a rare patient that I don’t have good control with just a calcium channel blocker,” he said.
“Usually it’s at 15-20 mg/day of amlodipine when patients start getting edema and intolerance to the drug, so you’ve got a lot of room. You usually see about a 40% reduction in the severity of Raynaud’s with 5-10 mg/day. And understand that you’re not going to get rid of Raynaud’s phenomenon. But bringing it down to where you get improved quality of life, along with all the nondrug things that you do, can be all you need to do,” Dr. Wigley said.
When he needs to resort to a second vasodilator, it’s typically a phosphodiesterase-5 inhibitor.
“I use them,” the rheumatologist said. “The best benefit I’ve gotten is when I add it to a calcium channel blocker. If someone tolerates, say, 5 mg/day of amlodipine but not 10 mg, then I might add 10 mg of sildenafil t.i.d. [three times daily] to the calcium channel blocker.”
He was quick to add, however, that the supporting evidence base for the phosphodiesterase-5 inhibitors is weak. All of the studies to date have been small – too small, in fact, to persuade insurance companies to routinely authorize this use of the medications without a fight. For example, a recent double-blind, randomized, crossover trial showed udenafil and amlodipine had equal efficacy in reducing the frequency of Raynaud’s attacks and the phosphodiesterase-5 inhibitor achieved greater blood flow in the digital arteries ( Rheumatology 2014;53:658-64 ); however, there were only 29 subjects, and the drug is not approved in the United States.
“I’m just talking about my own experience. The studies aren’t there,” Dr. Wigley observed. “The fact of the matter is we need a large, well-controlled, double-blind study to exactly define the role of the phosphodiesterase inhibitors.”
Botox in need of supporting evidence
OnabotulinumtoxinA (Botox) has become very popular. On the plus side, it has no adverse impact upon blood pressure, and in case series, 75%-100% of treated patients report significant improvement. The negatives? It’s costly, the benefit doesn’t kick in until after about 48 hours, and the supporting evidence to date is weak, although Dr. Wigley and coinvestigators have an ongoing placebo-controlled trial .
“I have to say, in my own experience in patients with garden-variety primary Raynaud’s, [onabotulinumtoxinA] has not been very exciting, but in patients with critical ischemia, where they’re losing a finger, I’ve been very impressed. So I do think that it works. We need evidence to prove it,” he said.
Alternative vasodilator options with some demonstrated benefit in mild disease include the selective serotonin reuptake inhibitor fluoxetine, the angiotensin receptor blocker losartan, cilostazol, pentoxifylline, and topical nitrates, although the benefits of nitrates tend to wane over time and headaches are often a problem.
Dr. Wigley reported serving as a consultant to Novartis and United Therapeutics and receiving research grants from KineMed, MedImmune, and CSL Behring.