Appropriate Use of Dopamine Agonists and Levodopa in Restless Legs Syndrome in an Ambulatory Care Setting

Ogochukwu Chidozie Molokwu, PharmD

Disclosures

The Annals of Pharmacotherapy. 2008;42(5):627-632. 

In This Article

Discussion

To date, no other study has evaluated the use of dopamine agonists and levodopa for treatment of RLS or their appropriate use in patients diagnosed with RLS. This study examined the utilization and appropriateness of use of these drugs in patients with RLS. Ropinirole and pramipexole, both dopamine agonists, are the only FDA-approved agents for the treatment of moderate-to-severe primary RLS with daily symptoms. Clinically, moderate-to-severe RLS can be defined as nightly symptoms severe enough to affect sleep quality and quality of life negatively. However, there are several scales that may be useful in determining the severity of a person's RLS. The International RLS Rating Scale is a validated scale commonly used in clinical trials and may have a role in determining RLS severity in clinical practice.[21] Other commonly used scales include the Johns Hopkins RLS Severity Scale, RLS-6 severity scale, and the Clinical Global Impressions scale.[21] Although these scales have been widely used in clinical trials, they have several limitations and their role in clinical practice is not yet clear. In our study, only 2 patients had documented RLS severity, described as nightly symptoms, and the majority (82%) of patients with RLS were receiving levodopa compared with the others (18%) who were receiving ropinirole. The mean doses of ropinirole and levodopa ( Table 1 ) in this study were within the dose ranges used in other studies.[22,23,24] The starting dose of ropinirole used in other studies was 0.25 mg daily, given 1-3 hours before bedtime, and could be titrated up as needed and tolerated over several weeks to a maximum dose of 4 mg daily.[22,23]

The starting dose of levodopa/carbidopa that had been used in various studies was 100 mg/25 mg, with the maintenance dose ranging from 100 mg/25 mg to 200 mg/50 mg approximately one hour before bedtime.[24] All patients on levodopa were instructed to take levodopa daily rather than intermittently. Such daily dosing has been associated with augmentation characterized by worsening of RLS symptoms and earlier onset with chronic use. Augmentation will occur in up to 80% and in 15-48% of patients taking daily levodopa and dopamine agonists, respectively.[8,25,26] Also, rebound characterized by reemergence of symptoms in the early morning hours has been associated with daily dosing of levodopa.[25] In our study, there was no documentation of augmentation or rebound, but levodopa was discontinued in one patient who developed left-sided twitching. The lack of documentation is not a proof of lack of adverse effects. It is not clear why there was high use of levodopa among patients in the Community Medical Centers, but unawareness among prescribers of the current role of dopamine agonists in management of RLS and the lack of knowledge of the complications associated with daily dosing of levodopa might have played a role.

Determining severity of RLS may help in choosing the most appropriate therapy for a patient. Dopamine agonists are not first-line agents for mild or intermittent RLS and should be reserved for patients who are nonresponsive to alternative treatments (Figure 1). Levodopa is likely to be beneficial when used intermittently for mild or intermittent RLS symptoms.

Iron has been shown to play an important role in both dopamine synthesis and functioning of the dopaminergic system.[25,27,28,29] It has also been shown that low ferritin levels (<50 ng/mL) are correlated with the development of RLS symptoms, and iron replacement to achieve ferritin levels above 50 ng/mL has been effective in treatment of RLS.[18] The expert panel of the Medical Advisory Board of Restless Legs Syndrome Foundation recommended determining the serum ferritin level in all patients with RLS.[7] The serum ferritin level is a reliable way of determining an individual's iron storage. In addition, the serum ferritin level is an acute-phase reactant; therefore, it is important to determine transferrin saturation as well. Transferrin saturation may also be necessary in screening for individuals with coexisting hemochromatosis. Iron replacement should not be attempted in anyone with a Tsat percentage greater than 45% to avoid exacerbation of underlying hemochromatosis. In this study, the serum ferritin level was obtained in only 33% of the patients. Iron replacement should be attempted for patients with a low serum ferritin level before dopaminergic agents are considered, as long as no contraindication exists. A suggested dose of 50-60 mg of elemental iron 1-3 times daily is deemed appropriate, with the goal of achieving a serum ferritin level greater than 50 ng/mL. Iron studies should be repeated every 3-4 months during therapy. A recent retrospective study has also shown that augmentation symptoms are associated with lower levels of serum ferritin.[30]

Several drugs have been associated with induction or exacerbation of RLS symptoms including antidepressants, antidopaminergics, and sedatives.[11,12,13,14] More than half of the patients in this study were on antidepressants, mainly SSRIs and TCAs. Efforts should be made to determine whether such drugs are contributing to a patient's symptoms and whether discontinuation is possible without causing harm to the patient. It is also important to inquire as to a patient's use of over-the-counter sedating antihistamines, alcohol, caffeine, and tobacco.

Interestingly, more than a year after FDA approval of the first dopamine agonist for treatment of RLS, levodopa continues to be the most prescribed drug for RLS in the ambulatory care setting described here. It is possible that many of these patients were initiated on levodopa before FDA approval of ropinirole. It is also possible that many of these patients failed or were intolerant to dopamine agonists or other non-dopaminergic agents, although there was no such documentation. Many of the patients were on other drugs used for RLS symptom management, such as benzodiazepines, opioids, and anticonvulsants, but were taking them for indications other than RLS. Drug cost might have played a role, since levodopa is significantly less expensive than dopamine agonists.

It is not clear what effect increasing media reporting on RLS and direct-to-consumer advertising will have on the prescribing pattern of physicians. In this study, 96% of dopaminergic agents were prescribed by primary care providers. This finding shows that there is a need to educate these providers on the current scientific evidence regarding management of RLS. There is also a need for better assessment and documentation of RLS severity and presence of pain, as this would help in determining a more appropriate therapy for an individual.

Dopamine agonists, although considered the first-line agents in management of moderate-to-severe RLS, are not without adverse effects, the most common being nausea, dizziness, fatigue, insomnia, hallucinations, and peripheral edema. Drugs such as benzodiazepines, gabapentin, and opioids have been shown to be effective in the management of RLS symptoms and should be appropriately considered based on a patient's RLS severity and accompanying symptoms. Nonpharmacologic interventions are also recommended for all patients with RLS (Figure 1).

The retrospective nature of this study poses some limitations. Some of the data collected for analysis depend on the accuracy of documentation by the treating providers. Another limitation is that study patients were identified using the institution's outpatient pharmacy database rather than the ICD-9 coding system; therefore, patients eligible for the study who did not use the outpatient pharmacy may have been excluded. In addition, this study did not evaluate the use of non-dopaminergic agents for management of patients with RLS. All patients on dopamine agonists were receiving ropinirole since it is the preferred agent at this institution.

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