Restless Legs Syndrome Linked to Higher CV Death in Women

Women with restless legs syndrome (RLS) appear to have a higher risk for cardiovascular death, according to a new analysis of data from the large-scale Nurses’ Health Study.

“This is further evidence that RLS can have major clinical implications and needs to be taken seriously. It is not just a benign nuisance condition,” lead author, Xiang Gao, MD, PhD, from Pennsylvania State University, State Park, told Medscape Medical News.

“There are things that can be done to treat RLS,” he added. “For example, we know that adopting healthy lifestyle reduces symptoms. In addition, about half of RLS patients are iron deficient, and correcting this may help. So clinicians need to be on the lookout for RLS. They should measure ferritin levels in these patients, and those with low levels should be prescribed iron supplements, and all patients should receive counseling on lifestyle.”

The study was published online in Neurology on December 15.

Dr Gao explained that this was the first time a study has looked at cause-specific deaths among women with RLS. “We published a paper in 2013 in a male cohort with RLS showing an increased risk of all-cause mortality, and now we are looking at the female population.”

Noting that a previous study has suggested a link between RLS and increased risk for coronary heart disease in women, also from the Nurses’ Health Study cohort, Dr Gao said the current study set out to answer two questions: Is all-cause mortality increased in women with RLS similar to the effect seen in men? And is there a specific link to increased cardiovascular death in women?

“From our results, we cannot say anything definite about all-cause mortality,” he said. “The primary analysis showed a marginally significant association, and after excluding women with chronic common morbidities associated with RLS, this became significant. But I would say this is still inconclusive.”

“But for cardiovascular death, our results were more informative,” he added. “We did find a significant association between RLS and increased cardiovascular death, and this became stronger after excluding patients with other associated comorbidities.”

Dr Gao explained that patients with RLS are more likely to have other conditions such as hypertension, obesity, cardiovascular disease, and sleep disorders. “Any mortality increase could be due to these. But after excluding patients with these conditions, the relationship between RLS and increased cardiovascular death was still strong,” he noted. “This suggests that RLS itself is a real risk factor. However, we would like to see another prospective study in a different patient cohort to confirm our findings.”

He said the mechanism is not known, but previous studies have suggested RLS increases dopaminergic and autonomic dysfunction, leading to increased sympathetic activation, which may play a role.

The current study included 57,417 women (mean age, 67 years) from the Nurses’ Health Study without cancer, renal failure, or cardiovascular disease at baseline (2002). The researchers used the Cox proportional hazards model to calculate hazard ratios for all-cause and cardiovascular mortality based on RLS status, adjusting for age, presence of major chronic diseases, and other potential confounders.

There were 6448 deaths during 10 years of follow-up. Results did not show a significant association between presence of physician-diagnosed RLS and increased risk for total mortality (adjusted hazard ratio [HR], 1.15; 95% confidence interval {CI], 0.98 – 1.34).

However, women with RLS had a significantly higher risk for cardiovascular mortality (adjusted HR, 1.43; 95% CI, 1.02 – 2.00) relative to those without RLS after adjustment for potential confounders.

Longer duration of RLS diagnosis was significantly associated with a higher risk for cardiovascular mortality (P for trend = .04).

Excluding participants with common RLS comorbidities strengthened the association between RLS and total mortality (adjusted HR, 1.43; 95% CI, 1.03 – 1.97) and cardiovascular mortality (adjusted HR, 2.27; 95% CI, 1.21 – 4.28).

The researchers say the strengths of this study included a large sample size, long follow-up duration, a large number of outcome events (6448 deaths vs from <55 to 2765 deaths in previous studies), and availability of cause-specific mortality data and detailed information on potential confounders.

There was no significant association between RLS and mortality resulting from cancer and other causes.

This study was supported by grants from the National Institutes of Health. One coauthor is a consultant for Merck, Flex Pharma, and Otsuka; has provided expert testimony for Cantor Colburn; receives royalties from UpToDate; and has received research grants from Xenoport, UCB Pharma, NeuroMetrix, National Institute of Mental Health, and Luitpold Pharmaceuticals. Another coauthor receives an RLS research grant from and was a consultant to Xenoport/Arbor Pharmaceuticals, MundiPharma, and UCB Pharma. Dr Gao and the remaining authors have disclosed no relevant financial relationships.

Continuous L-Dopa Enteric Infusion Relieves RLS Symptoms

Patients with restless legs syndrome (RLS) for whom conventional therapies are contraindicated may benefit from a treatment usually reserved for patients with advanced Parkinson’s disease and augmentation phenomena, a case report suggests.

In a presentation here at the 20th International Conference of Parkinson’s Disease and Movement Disorders, Jesús Pérez-Pérez, MD, of the Movement Disorders Unit at the Hospital de la Santa Creu i Sant Pau, in Barcelona, Spain, described the case of a 70-year-old man who had experienced RLS with augmentation for 3 years. The patient was successfully treated using a 24-hour infusion of carbidopa/levodopa enteral gel (Duopa, AbbVie Inc).

His condition had initially responded well to dopaminergic medication, but after 1 year of therapy with dopaminergic drugs, augmentation began, and RLS was present all day and was worse at night. Augmentation is a phenomenon of worsening symptoms after dopaminergic drug exposure.

The patient had severe, chronic obstructive pulmonary disease and had undergone several hospitalizations in less than a year because of respiratory decompensation. For these reasons, drugs such as benzodiazepines, opioids, gabapentin (multiple brands), and pregabalin (Lyrica, PF Prism CV) were contraindicated. Because of RLS, the patient was unable to use nocturnal continuous positive airway pressure, which led to hypercapnic respiratory failure.

The treating physicians then offered, and the patient accepted, 24-hour constant infusion with carbidopa/levodopa enteral gel delivered by pump directly into the small intestine through a tube with a jejunal extension introduced percutaneously into the stomach. Because of the continuous drug delivery, this system avoids the pulsatile dosing effect that leads to augmentation.

Three months after starting therapy with the enteral gel formulation, the patient’s RLS symptoms were greatly improved, as was his quality of life, Dr Pérez-Pérez reported.

Table. Results of Switching Patient From Oral to Enteral Infusion Medication

Intervention/Period RLS Rating Scale Score RLS Quality-of-Life Questionnaire
Oral/preintervention* 36 (very severe) 22
Enteric gel at 3 months 9 (mild) 74
Enteric gel at 1 year 4 (mild) 100
*Levodopa/carbidopa 150 mg 5x/day plus levodopa/carbidopa retard 200 mg at night.

Symptoms and quality-of-life scores continued to improve during the first year of treatment, as reflected in Clinical Global Impression–Improvement scale scores.
The patient has not experienced any adverse effects or complications from the medication or the implantation procedure and was hospitalized only once during the year.

Olga Klepitskaya, MD, associate professor of neurology at the University of Colorado, in Denver, who has a special interest in the use of deep brain stimulation to treat RLS, commented to Medscape Medical News that although the presentation involved a single case report, it was well done and is important. “They described very well why they did [it] and what they did and what are the implications of that,” she said.

“Just like in Parkinson’s disease, with RLS…pulsatile dopaminergic stimulation is not healthy for our dopamine receptors in the brain, and that’s why it causes all these problems of augmentation,” she said. The mainstream treatment of augmentation is to use longer-acting dopaminergic medications, such as rotigotine transdermal patches (Neupro, UCB Pharma, Inc), longer-acting pramipexole (Miraprex ER, Boehringer Ingelheim Pharmaceuticals, Inc), and ropinirole (Requip XL, GlaxoSmithKline).

The treatments that provide constant dopaminergic stimulation are better physiologically for the brain, “and Duopa is the ultimate long-acting medication,” she said. “It’s administered through the GI system, and I assume it can be used for very, very severe RLS with augmentation that cannot be treated by anything else.”

Calling delivery of the medication through a percutaneous indwelling tube “a little bit extreme,” she said the authors “really justified why they used this…for this particular patient, because he had a lot of comorbidities that can [lead to] a lot of side effects.”

For this patient, the choice of this continuous but somewhat invasive treatment, which led to significant improvement in quality of life, appeared correct, she said.

Dr Klepitskaya said she believes that treatments that provide continuous stimulation ― whether pharmacologic or electrical ― would be best.

“That’s why I have put my hopes in my study, deep brain stimulation for RLS,” she said, “and deep brain stimulation and Duopa now can be not completely interchangeable, but we are considering both as treatments available in the United States in patients with very advanced Parkinson’s disease and trying to find which of those treatments will fit that particular patient profile the best.”

The current case report and other reports on the use of deep brain stimulation suggest that difficult-to-treat RLS may be amendable to these treatments as well.

Opioids Prove Effective for Restless Legs Syndrome.

In a new, placebo-controlled study, prolonged-release opioid treatment with an oxycodone-naloxone combination product produced impressive relief of symptoms in patients with severe restless legs syndrome for whom other therapies had failed.

The study, published online October 18 in Lancet Neurology, was led by Claudia Trenkwalder, MD, Paracelsus-Elena Hospital, Kassel, Germany.

“We found an 8-point reduction in the mean International RLS Study Group rating scale sum score vs placebo,” Dr. Trenkwalder commented to Medscape Medical News. “This is the most effective treatment response ever seen in restless legs syndrome. A reduction of more than 3 points is thought to be clinically significant. While between-study comparisons are always difficult, dopaminergic drugs ― the main agents used ― are associated with reductions of about 4 to 6 points vs placebo. A reduction of 8 points has never been seen before.”

Professor Trenkwalder explained that there has been much interest in using opioids in restless legs syndrome for many years, after a small study conducted in 1993 showed a positive effect in 8 patients. This has been followed by other small case series and anecdotal reports, but there has never been a controlled clinical trial before.

“This trial is long overdue. It has taken us 20 years to get it done, largely because no one wanted to pay for it. But we eventually managed to get funding from MundiPharma and have now definitely proven that this opioid-based combination works and works very well in reducing all symptoms of restless legs syndrome ― sensory, restlessness, pain, and sleep,” she said.

She added that doctors have been using different opioids at different dosages over the years, but this study provides solid evidence in support of one combination product used at a low dosage and given twice a day.

Professor Trenkwalder noted that the inclusion of the opioid antagonist naloxone counters peripheral side effects of the oxycodone in the gastrointestinal system and so minimizes constipation, the major side effect of long-term opioid therapy. She also highlighted the importance of taking the drug combination twice a day ― morning and evening. “Some people just take medication for restless legs syndrome at night, but you then get high levels at night and a trough during the day. It is important to have stable levels of opiates in the brain to get good symptom improvement.”

In an accompanying commentary, Arthur S. Walters, MD, Vanderbilt University School of Medicine, Nashville, Tennessee, says that the data are “especially convincing because the study included patients who were refractory to other treatments. Such patients would normally be much more likely to fail an alternative treatment than patients who have not had previous treatment failure.”

Although he notes that no direct comparisons can be made between drugs, “the treatment difference between groups of 8.15 points is much greater than that for most approved drugs for restless legs syndrome.”

For the study, Professor Trenkwalder and colleagues randomly assigned 306 patients who had had symptoms for at least 6 months and whose International RLS Study Group severity rating scale sum score was at least 15 to study drug or placebo. Study drug was oxycodone 5 mg, naloxone 2.5 mg twice daily, up-titrated according to investigator’s opinion to a maximum of oxycodone 40 mg, naloxone 20 mg twice daily.

The primary outcome was mean change in severity of symptoms according to the International RLS Study Group severity rating scale sum score at the end of the 12-week double-blind phase.

Mean score at baseline was 31.6. This was reduced by 16.5 points in the oxycodone-naloxone group vs 9.4 points in the placebo group ― a difference of 8.15 points.

Primary Outcome: International RLS Study Group Severity Rating Scale Sum Score at 12 Weeks

Oxycodone-Naloxone Placebo Treatment Difference (95% CI) PValue
Mean sum score at 12 weeks 15.1 22.1 8.15 (5.46 – 10.85) <.0001

Restless Legs Syndrome Seems an Independent Predictor of Mortality in Men.

Relatively healthy men with restless legs syndrome have nearly twice the risk for death as those without RLS, according to a prospective study in Neurology.

Over 18,000 male health professionals in the U.S. answered questions about RLS symptoms and then were followed for roughly 8 years. Four percent had RLS at baseline (symptoms at least five times monthly). Overall, 15% died during follow-up.

After adjustment for confounders including age and lifestyle risk factors, men with RLS had a 30% increased likelihood of death. In a subgroup of men without major chronic conditions such as cancer and cardiovascular disease, RLS increased risk nearly twofold. The increase in mortality was primarily attributed to deaths from respiratory illnesses; blood diseases; and endocrine, metabolic, and immunity disorders.

The authors speculate that “the nocturnal blood pressure variations associated with RLS could be among potential underlying mechanisms for the observed association between RLS and mortality.”

Source: Neurology


FDA Warns of Possible Heart Failure Risk with Pramipexole .

The FDA is investigating the possibility that pramipexole (Mirapex) increases the risk for heart failure.

In a pooled analysis of randomized trials, the drug — used to treat Parkinson disease and restless legs syndrome — showed an increased incidence of heart failure relative to placebo, but the results weren’t statistically significant. Further review of two epidemiologic studies also found an increased risk, but confounding factors may have influenced the results, according to the FDA.

Until the agency completes its review, it is instructing clinicians to continue prescribing pramipexole according to the recommendations on the label. Patients should be counseled about the potential risk.

Source: FDA MedWatch safety alert.