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Supplements Implications of Early Treatment for Parkinson’s Disease [CME/CPE]

Early Pharmacologic Treatment in Parkinson's Disease

Robert A. Hauser, MD, MBA
Tocopherol, the biologically active component of vitamin E, is an antioxidant that has been studied for possible diseasemodifying properties in PD.2 The DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) study was a large clinical trial (n = 800) in which patients with early untreated PD were randomized to receive tocopherol, selegiline (deprenyl), a combination of both, or placebo.27,28 After a mean follow-up of 14 months, tocopherol was observed to provide no meaningful benefit in the delay of the onset of disability.27





Early Symptomatic Treatment of Parkinson's Disease

Levodopa

Although levodopa is the most efficacious medication for PD, its propensity to cause adverse effects, especially dyskinesia, is an important reason to consider delaying its use if alternative treatments are able to adequately control symptoms. This is a particularly important consideration in younger patients who are most prone to developing disabling dyskinesia. Levodopa is associated with a high rate of motor fluctuations and dyskinesia and some risk of nausea and vomiting.2,29 The Scottish Intercollegiate Guidelines Network (SIGN) states that levodopa can be considered in early PD, but that it should be given at the lowest effective dose and be accompanied by a DDI. Surveillance for dopamine dysregulation syndrome, somnolence and sudden-onset sleep, and impulse control disorders is also advised. The risk of adverse events notwithstanding, levodopa is the most effective medication for treating the signs and symptoms of PD. The effect of levodopa on progression of the underlying disease is uncertain; currently, there are no convincing data supporting neuroprotection or neurotoxicity.





Dopamine Agonists

The American Academy of Neurology (AAN) practice parameters for initiation of treatment in PD, published in 2002, found that while the dopaminergic therapies including levodopa, ropinirole, pramipexole, and cabergoline all improved motor disability and activities of daily living, levodopa was regarded as a generally superior therapy.30 The AAN guidelines support the use of levodopa for patients requiring an improvement in motor disability and recommend dopamine agonist therapy for reducing the development of motor complications.30





A 2008 Cochrane meta-analysis of dopamine agonists for early PD, which included 29 clinical trials and 5247 patients in total, found that compared with levodopa, early treatment with a dopamine agonist was significantly less likely to result in dyskinesia (P <.00001), dystonia (P = .0002), or motor fluctuations (P = .002).31 Nonmotor adverse effects, however, were more likely to occur with dopamine agonists, including edema (P <.00001), somnolence (P = .007), constipation (P = .01), dizziness (P = .01), hallucinations (P = .01), and nausea (P = .02).31 Discontinuation of treatment was also more likely with dopamine agonists (P <.00001).31





The 2010 SIGN guidelines state that dopamine agonists (either an oral or transdermal formulation) "may be considered" for use in patients with early PD and motor symptoms. The National Collaborating Centre for Chronic Conditions (NCCCC) guidelines for PD management (supported by the United Kingdom's National Health Service) recommend dopamine agonists for symptomatic treatment of early PD. They further recommend titrating to an effective dose and switching to another dopamine agonist, or drug from a different class, should tolerability issues emerge. Ergot dopamine agonists are generally no longer used because of the risk of cardiac valvulopathy.





Nonetheless, the value of early treatment with dopamine agonists remains a matter of debate. Although they clearly delay the onset of dyskinesia, the long-term value of this benefit is unclear.32,33 In addition, there is an increased awareness of potential side effects including somnolence and sudden-onset sleep, and impulse control disorders including gambling, shopping, and Internet use.34,35 The relative risk and benefit for individual patients must be considered.





Monoamine Oxidase Type B Inhibitors

As previously noted, the ADAGIO trial suggests that rasagiline 1 mg/day (but not the 2-mg/day dose) provides a disease-modifying effect in PD.21 There was also a secondary end point in the ADAGIO trial: change in UPDRS score from baseline to the last measurement in phase 1 (ie, after the first 36 weeks, prior to the delayed-start treatment group switching from placebo to rasagiline).21 In this case, both rasagiline 1 and 2 mg/day showed significant superiority to placebo in change of UPDRS score (P <.001 for both).21 These data unambiguously delineate the clinical benefit of rasagiline compared with placebo. In addition, the side-effect profile of rasagiline 1 or 2 mg/ day in the ADAGIO trial was not significantly different from placebo.21 Rasagiline 1 mg/day, but not the 2-mg/day dose, is approved by the FDA for the treatment of PD.





A 2004 Cochrane review examined the efficacy of MAO-B inhibitors in early PD, an analysis that comprised 17 clinical trials (13 involving selegiline, 3 with lazabemide, and 1 with rasagiline) and included 3525 patients.13 The data showed that MAO-B inhibitors were associated with a reduction in disability in early PD as well as a decreased need for levodopa and fewer motor fluctuations.13 The impact of these agents on mortality was negligible, while their side-effect profile was relatively mild.





A subsequent Cochrane review, from 2005, included 10 clinical trials (9 with selegiline and 1 with lazabemide) and 2422 patients.12 Within the rather narrow confines of this analysis, it was concluded that MAO-B inhibitors were associated with significant improvements in impairment and disability based on UPDRS scores, but that these improvements were not clinically significant.12





A Cochrane review from 2009 compared MAO-B inhibitors with levodopa and dopamine agonists in early PD, but found only 2 clinical trials (n = 593) worth considering (1 of which was not blinded).36 MAO-B inhibitors were associated with fewer motor fluctuations compared with levodopa (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.32-0.94) but not dopamine agonists (OR, 1.15; 95% CI, 0.65-2.05).36 One of the 3 studies, which included 317 patients, found that the time to addition of levodopa was half as long in the MAO-B inhibitor group compared with the dopamine agonist group (15 months vs 30 months, respectively). In the second study, which involved 92 patients, the MAO-B inhibitor group was associated with a marginally longer delay of levodopa than the dopamine agonist group (29.5 vs 26.4 months, respectively).36 There were fewer adverse event-related withdrawals with MAO-B inhibitors compared with dopamine agonists (OR, 0.11; 95% CI, 0.01-0.99; P = .05). The authors concluded that MAO-B inhibitors were more tolerable than the other drug classes but possessed weaker symptomatic efficacy.36





Because of the newness of some of the MAO-B inhibitor data, particularly from the ADAGIO trial, current available clinical guidelines lack consideration of key data that may otherwise influence their recommendations. That said, the AAN guidelines (from 2002) state that selegiline therapy may be considered prior to dopaminergic therapy for mild relief of symptoms.30 The NCCCC and SIGN guidelines both concur that MAO-B inhibitors may be used for early symptomatic treatment of PD.2,5





Other Agents

Anticholinergics

The SIGN guidelines recommend against the use of anticholinergic agents as first-line therapy in PD due to elevated risk for cognitive and neuropsychiatric adverse events.2 They should usually not be given to patients already exhibiting significant cognitive or neuropsychiatric comorbidities.





Amantadine

A lack of sufficient data regarding amantadine in the treatment of PD makes recommendations untenable, according to both the NCCCC and SIGN guidelines.2,5





Beta-Blockers

While there is insufficient evidence to offer recommendations for the use of beta-blockers in PD, the NCCCC guidelines noted that these drugs may be useful and safe in patients with PD suffering from postural tremor.5

 
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