Special Considerations for Treatment of Restless Legs Syndrome

By | July 1, 2012

Side Effects of Dopaminergic Treatments

Dopaminergic agents (dopamine agonists and levodopa) are usually considered first-line therapy in restless legs syndrome.

Common side effects of dopamine agonists include nausea, dizziness, orthostatic hypotension, and headache (). A very slow dose titration will help minimize side effects.

Hallucinations are another common side effects of dopaminergic therapy in Parkinson’s disease (Parkinson’s disease), but have not been reported in restless legs syndrome up to now. In fact, hallucinations may not be a problem in restless legs syndrome patients who do not have dopaminergic cell loss and are usually treated with very low doses.

Of specific interest for dopamine agonists is daytime sleepiness as a side effect. Falling asleep at the wheel has been reported first in Parkinson’s disease patients taking pramipexole and ropinirole, but later it became obvious that involuntary and even unnoticed napping and / or “sudden onset of sleep” (Sudden Onset of Sleep) were quite common in Parkinsonian patients, and dopamine agonist treatment was only one of several possible causes.

It has been argued that daytime sleepiness in restless legs syndrome is not a problem because of the very low doses used. However, unpublished data from our group and from others indicate that sleepiness as a side effect of dopaminergic therapy may also occur in a few patients with restless legs syndrome, and this was even proven in one patient by polysomnography (polysomnography) in a double-blind design. Bassetti and coworkers reported the occurrence of daytime sleepiness in an restless legs syndrome patient during reduction of pergolide and discussed this as a potential consequence of wake-promoting effects of higher doses of pergolide. Nevertheless, it seems that — apart from a few individual exceptions — for the average of restless legs syndrome patients, dopaminergic treatment seems to be protective regarding Sudden Onset of Sleep, and not a risk: Meller and coworkers investigated the frequency of Sudden Onset of Sleep in 156 patients with restless legs syndrome and 126 controls. A slightly higher frequency of Sudden Onset of Sleep in restless legs syndrome (33%) versus controls (20%) was found. The Epworth Sleepiness Scale score predicted Sudden Onset of Sleep, and patients on dopaminergic therapy had a lower risk of Sudden Onset of Sleep than untreated controls, which is in contrast to the findings in Parkinson’s disease.

Another specific side effect of dopaminergic therapy is cardiac valvulopathy. This has been reported as a long-term side effect of treatment in Parkinson’s disease, specifically with pergolide and cabergoline. Multivalvular insufficiency has been described in (ergot) bromocriptine, pergolide, and cabergoline. On the basis of this, a class effect of ergot-like dopamine agonists has been suggested. The pathogenesis of multivalvular heart disease is suspected to involve serotonin-mediated abnormal fibrogenesis by means of 5-HT2B receptors. In this context, it has been discussed that the 5-HT2B receptor agonist effect is responsible for cardiac valvulopathies, not the ergoline structure. In fact, it has been argued that no such side effects would occur with the isoergot derivatives, lisuride and terguride. A database and literature search comprising 360,000 patient years reported by a company on lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties, did not reveal a case of fibrotic cardiac valvulopathy and a very low incidence of any other fibrosis. In any case, it is important to remember that lack of reports do not mean nonexistence of a certain side effect.

In addition, Chaudhuri mentioned a fibrotic reaction in seven cases treated with ropinirole reported by the World Health Organization (WHO), and one case with pramipexole.

An echocardiographic study showed an increase of grade 2 or higher valvular regurgitation in 31% of pergolide-treated patients and 47% of cabergoline-treated patients, and a frequency in the normative range for patients treated with nonergot compounds.

On the basis of these data, pergolide is no longer considered first-line treatment for restless legs syndrome and, if other treatments fail, at least echocardiography before onset and every 6 to 12 months during treatment is warranted for patients on pergolide, possibly also on cabergoline treatment.

Because a cumulative dose-dependent risk for the occurrence of cardiac valvulopathies has been reported, this side effect might, as many others, again be less problematic in restless legs syndrome, but the precautions should be maintained (regular echocardiograms).

Lastly, restless legs syndrome patients prescribed dopaminergic agents should be warned of the development of compulsive behavior, including pathologic gambling and hypersexuality, which occurs infrequently in patients taking these medications.

Augmentation and Rebound

Augmentation is the most serious and specific side effect of dopaminergic treatment in restless legs syndrome. According to original criteria, augmentation requires a two-hour advance in the time of symptom onset during the day, or at least two of the following: an overall worsening of symptoms despite increasing dose and an overall improvement of symptoms when dose is decreased, an expansion of restless legs syndrome symptoms from legs to arms, a shorter latency to symptoms at rest, or a shorter duration of treatment effect. Augmentation has been reported with greatly varying frequencies between absent and higher than 80%, but the definitions of augmentation have not been uniform, and most studies have been retrospective, hampering a reliable comparison of frequencies. Nevertheless, the highest frequencies of augmentation have been reported with levodopa. Augmentation was reported in 48% of patients on different dopamine agonists, namely, ropinirole, pramipexole, and pergolide or 8% to 32% of cases with pramipexole, but in the latter study, quite mild worsening covered by a slight dosage increase was also defined as augmentation. Even with cabergoline, a dopamine agonist with a 65-hour plasma half-life, a 9% frequency of augmentation was reported. Of course, reported frequencies of augmentation depend very much on the fact, if this phenomenon has been recognized at all and / or systematically assessed.

Several risk factors for augmentation have been identified, namely, a high levodopa dose, previous augmentation or tolerance, albeit controversial, lack of neuropathy, familial restless legs syndrome, and secondary restless legs syndrome in another study.

A novel hypothesis, well based on experimental data, suggests that augmentation results from a treatment-induced imbalance between decreased analgesic D2 receptor activation and increased pain-enhancing D1 receptor activation, and that the clue to avoiding augmentation lies in administering very low doses of dopamine agonists to restless legs syndrome patients. Once augmentation has occurred, it is necessary to withdraw the patients from the causative agent (e.g., levodopa) and to switch to a dopamine agonist, opiate, or a combination of both; frequently it will be necessary to hospitalize the patient for a few days.

Similar symptoms like augmentation may be caused by tolerance, which has been viewed as a first step toward augmentation by several authors. However, tolerance should not necessarily include a time advance of symptoms, and symptoms should not be worse than baseline.

Frequently, a slight dose increase will sufficiently cover tolerance, but patients should be monitored closely in order not to miss the conversion into frank augmentation.

Rebound, specifically early morning rebound, is another related symptom. It refers to the reoccurrence of symptoms in the second half of the night or in the early morning and is a result of short-acting levodopa. In this case, one would consider adding a sustained release levodopa formulation or middle-of-night or morning dose, or switching to dopaminergic agonists.

The knowledge about augmentation and its risk factors will certainly increase when the new uniform criteria are used in prospective studies, and new instruments to assess the presence [Structured Interview for Diagnosis of Augmentation (SIDA)] or severity of augmentation [Augmentation Severity Rating Scale (ASRS)] are incorporated into clinical studies and routine practice. It might also occur that novel ways of drug delivery in restless legs syndrome, for example, transdermal systems, may change the appearance of augmentation. On the basis of experience gathered in the past few years since the publication of the first uniform criteria for augmentation in 2003, a new version with some slight adaptation and modification is currently being prepared.

Side Effects of Nondopaminergic Treatments

Nondopaminergic treatments in restless legs syndrome include opiates and some antiepileptics, for example, gabapentin. Constipation is among the most relevant side effects of opiates and may definitely be prohibitive for treatment specifically in elderly patients with comorbid diseases impairing bowel function (e.g., Parkinson’s disease) or a history of diverticulitis. Gabapentin has been used in high doses in restless legs syndrome, but side effects like sleepiness may limit its use. It has to be taken into account that gabapentin can only be used in very low doses (200-300 mg per day) in patients on dialysis.

Side Effects of Iron Treatment

Iron treatment is now being proposed not only in patients with iron deficiency but also in patients with low normal serum ferritin levels.

Oral iron is well known for its limited tolerability (nausea, diarrhea). Its absorption is good only from an empty stomach and an acidic environment. It may cause severe esophageal inflammation and focal erosion.

Intravenous (i.v.) iron may have severe, local, and generalized side effects, such as local tissue necrosis in case of paravascular injection, and anaphylactic and / or anaphylactoid reactions. Anaphylactic reactions have been described with various i.v. iron injections. They are observed more frequently with iron dextran.

A significant 0.6% rate of life-threatening complications has been reported with i.v. iron dextran treatment in 481 hemodialysis patients.

One hundred and ninety-six cases were published in the literature from 1976 to 1997. The incidence of complications was lower with iron saccharates between 1.5 and 6 permille (e.g., iron III saccharose complex), and between 1976 and 1997, 74 cases were published.

In addition, in contrast to dextrans (31 deaths), with iron saccharates no deaths were observed On the basis of the possibility of anaphylactic or anaphylactoid reactions, it has been recommended to use oral iron whenever possible and implement i.v. applications only when necessary.

Another iron preparation is sodium ferric gluconate complex, which is considered to be the safest option. However, an anaphylactoid or anaphylactic reaction to sodium gluconate complex administered in a pregnant woman has been reported. In another four-year study with repeated i.v. iron administration, iron sucrose and sodium ferric gluconate in 57 patients, no cases of anaphylactic reactions, two cases of flushing, and one hypotension case were reported.

Despite the impressive benefits of i.v. iron dextran reported in the past few years, these side effects will have to be carefully weighed against the risks mentioned above, and the least harmful preparation and administration method selected.

Age and Gender Effects of Treatment

It is well known that the frequency of restless legs syndrome is related to gender. In addition, the comorbidities of restless legs syndrome have been reported to be different in men and women, for example, higher rates of coexistent hypothyroidism were reported in women with restless legs syndrome. Women also had a higher frequency of multisymptomatic sleep disturbance from restless legs syndrome.

An increasing frequency of restless legs syndrome has been noted across decades in many studies, but it may be in the highest age group that a decline in prevalence is observed. However, restless legs syndrome may still be widely unrecognized in cognitively impaired persons, for example, demented elderly. New criteria for recognizing restless legs syndrome in this patient group have been defined, which include observation of behavior (e.g., rubbing the legs, moaning while holding the legs).

Specifically in these patient groups, interactions of restless legs syndrome exacerbations and restless legs syndrome treatment, concomitant medications (e.g., neuroleptics), or aggravation by comorbid conditions (e.g., untreated anemia) may be far more frequent than expected.

Possibly, dopamine agonists can be used safely for the treatment of restless legs syndrome in the highest age group, but no specific study is available to prove this possibility.

In contrast, treatment of restless legs syndrome in children has completely different caveats, for example, impaired osteogenesis by benserazide given together with levodopa in some preparations.

In an epidemiological study of restless legs syndrome, subtle, albeit nonsignificant, differences were found for the concentration of soluble transferrin receptors (sTfR) in plasma, which was elevated in individuals with restless legs syndrome (p < 0.ZZZZZ) compared with a nonaffected population. The association was particularly strong in men and somewhat less pronounced in women, even though from a statistical viewpoint gender was not a significant effect modifier. In men, high sTR was found in 22.7% of patients with restless legs syndrome and in 3.8% of nonaffected individuals, and in women, high sTR was found in 13.5% of patients with restless legs syndrome and in 8.3% of the nonaffected group.

In periadolescent rats, it has been reported that gender affects locomotor response to quinpirole.

Kompoliti and coworkers reported a greater bioavailability of levodopa in postmenopausal women compared to men, but an equivalent pharmacokinetics of pramipexole. Craig and coworkers investigated growth hormone response to subcutaneous apomorphine in postmenopausal women with and without estrogen therapy. The area under the curve was greater in estrogen-treated women, suggesting that estrogen therapy enhances dopaminergic responsivity in postmenopausal women. Gender has been reported to have no effect on the pharmacokinetics of ropinirole, but clearance was slower in women taking hormone replacement therapy compared to those without therapy.

Pregnancy is another gender-related condition very relevant for treatment of restless legs syndrome. Controlled studies are lacking. Many restless legs syndrome medications imply potential harm to the unborn (e. g., impairment of osteogenesis in levodopa-benserazide, inhibition of lactation in dopamine agonists) and controlled studies are lacking. Therefore, in pregnancy, most authors recommend to carefully weigh the need for treatment, and if possible, get along with iron supplementation, magnesium or physical measures such as cold showering, massages, etc. Folate supplementation might also be helpful, albeit the available evidence is not high. If pharmacological treatment cannot be avoided, opiates are considered to be least harmful by some (www.rls.org).

Driving Risks and Medicolegal Aspects

Although, as discussed above, levodopa or dopamine agonist-induced sleepiness may be infrequent in restless legs syndrome treatment, all patients should be clearly warned when a new restless legs syndrome medication is started, that sleepiness may occur in the beginning of (or during stable) treatment. Patients should also be educated on how to recognize sleepiness, and that chronic sleepiness may sometimes lead to habituation and misperception. It is important that patients understand how their driving abilities may be impaired by sleepiness. On the other hand, one should take into account that untreated restless legs syndrome may also severely disturb sleep and cause sleep deprivation-induced daytime sleepiness.