Add-On Parkinson's Drugs Effective Against Levodopa Motor Complications

Megan Brooks

July 15, 2010

July 15, 2010 — A meta-analysis of published studies confirms the efficacy of adjuvant therapy, including dopamine agonists, catechol-O-methyl transferase inhibitors (COMTIs), or monoamine oxidase type B inhibitors (MAOBIs), in patients with Parkinson's disease (PD) who develop motor complications on levodopa therapy.

"However, this is at the expense of increased dyskinesia and numerous other side-effects," the study team reported online July 7 in the Cochrane Database of Systematic Reviews.

Indirect comparisons suggest that dopamine agonist therapy may be more effective than a COMTI or MAOBI, which have comparable efficacy, Carl E. Clarke, MD, professor of clinical neurology at City Hospital and University of Birmingham, United Kingdom, and colleagues note in their report.

In particular, the meta-analysis suggests that "dopamine agonists and [the COMTI] tolcapone appear better than the MAOB inhibitors and [the COMTI] entacapone," Dr. Clarke said in an email to Medscape Medical News. "However, this needs to be confirmed in head-to-head trials. We have one ongoing in the UK called PD MED," he added.

Patients with Parkinson's who are receiving long-term levodopa therapy often develop motor complications, requiring adjuvant therapy with dopamine agonists, COMTIs, or MAOBIs. However, it remains unclear which is best.

First Umbrella Meta-Analysis of Add-On PD Drugs

Dr. Clarke's team performed the first "umbrella" meta-analysis to compare the 3 drug classes used as adjuvant therapy for patients with PD who develop motor complications on levodopa. Their analysis included 44 randomized controlled trials that compared an orally administered dopamine agonist, COMTI, or MAOBI vs placebo in a total of 8436 levodopa-treated patients with PD experiencing motor complications.

They report that compared with placebo, any adjuvant therapy significantly reduced off time and required levodopa dose and improved United PD Rating Scale (UPDRS) Activities of Daily Living score, motor score, and total score.

Change From Baseline With Adjuvant Treatment vs Placebo

Endpoint Change From Baseline 95% Confidence Interval (CI) P
Off time (hours/day) −1.05 −1.19 to −0.90 <.00001
Required levodopa dose (mg/day) −55.65 −62.67 to −48.62 <.00001
UPDRS Activities of Daily Living score (points) −1.31 −1.62 to −0.99 <.00001
UPDRS Motor Score (points) −2.84 −3.36 to −2.32 <.00001
UPDRS Total Score (points) −3.26 −4.52 to −2.00 <.00001

Adjuvant Therapy May Come at a Price

Although all of the add-on therapies improved functional motor skills, they also were associated with a number of adverse effects, namely:

  • dyskinesia (odds ratio [OR], 2.50; 95% CI, 2.21 - 2.84; P < .00001),

  • constipation (OR, 3.19; 95% CI, 2.17 - 4.68; P < .00001),

  • dizziness (OR, 1.57; 95% CI, 1.30 - 1.90; P < .00001),

  • dry mouth (OR, 2.33; 95% CI, 1.22 - 4.47; P = .01),

  • hallucinations (OR, 2.16; 95% CI, 1.70 - 2.74; P < .00001),

  • hypotension (OR, 1.47; 95% CI, 1.18 - 1.83; P = .0007),

  • insomnia (OR, 1.38; 95% CI, 1.09 - 1.74; P = .007),

  • nausea (OR, 1.78; 95% CI, 1.53 - 2.07; P < .00001),

  • somnolence (OR, 1.87; 95% CI, 1.40 - 2.51; P < .0001), and

  • vomiting (OR, 2.56; 95% CI, 1.67 - 3.93; P < .0001).

"It is unclear from the publications how severe or prolonged these side-effects were (most studies were of short duration), although there was a trend towards increased patient withdrawal due to adverse events in patients on adjuvant therapy," the authors note.

Dopamine Agonist Most Effective but With More Adverse Effects

Indirect comparisons of the 3 drug classes suggest that dopamine agonists may provide more effective symptomatic control than COMTI and MAOBI inhibitors, the authors note, and COMTIs and MAOBIs have comparable efficacy.

Dopamine agonists reduced off time by 1.54 hours/day compared with a reduction of 0.83 and 0.93 hours/day with COMTI and MAOBI inhibitors, respectively (P = .0003). Levodopa dose was reduced by 116 mg/day with dopamine agonists vs 52 and 29 mg/day with COMTI and MAOBI, respectively (P < .00001). Similarly, UPDRS total scores improved more with a dopamine agonist than with a COMTI or MAOBI (−10.01 points vs −1.46 and −2.20 points, respectively: P < .00001).

"There was no significant evidence of differences in efficacy between individual drugs within the drug classes, other than tolcapone appearing more effective than entacapone," the authors note. They emphasize, however, that these observations are based on indirect comparisons between trials, and therefore could be caused by other factors.

When compared with placebo, there was a greater incidence of dyskinesia with dopamine agonists and COMTIs, but no increase with MAOBIs (OR, 2.70, 2.50, and 0.94, respectively: P = .009). "Although the increase in the overall incidence of side-effects was generally more marked with dopamine agonists (OR 1.52) and COMTI (OR 2.0) than with MAOBI (OR 1.32), heterogeneity between drug classes was only of borderline significance (P = .07)," the authors note.

Adjunctive PD Drugs Useful in a "Limited Way"

In a telephone interview with Medscape Medical News, William J. Weiner, MD, who was not involved in the research, acknowledged the "tremendous amount of work" that went into reviewing the published literature.

"Basically, the authors found that the adjunctive medicines to levodopa are useful — but in a limited sort of way," said Dr. Weiner, who is director of the Maryland Parkinson's Disease and Movement Disorders Center at the University of Maryland Medical Center in Baltimore.

"The researchers," he added, "tried to sort of rank them in usefulness, finding that the agonists are the most powerful and that the COMT inhibitors and the MAO inhibitors are about the same, which is certainly in agreement with my clinical experience. I think most people who treat a lot of Parkinson's patients won't be surprised by the findings."

Limitations and Caveats

Dr. Clarke and colleagues point out in their report that most of the included trials were designed by the pharmaceutical industry and had narrow inclusion criteria, with patients being predominantly white and relatively young (early 60s) compared with the typical clinical population of patients with PD. Another shortcoming is that most trials lasted 6 months or less, only 3 studies included a patient-related quality-of-life assessment, and no studies reported data on health outcomes.

Furthermore, both Dr. Clarke and Dr. Weiner caution that the studies reviewed compared each class of drugs against placebo; these were not head-to-head comparisons of the different agents. "It is not really fair to make comparisons this way, but everybody does it," Dr. Weiner noted.

"Direct head-to-head randomized trials assessing the impact of these different drug classes on overall patient-rated quality of life are needed," Dr. Clarke and colleagues conclude in their report.

Dr. Clarke has received payments for consulting, lectures and travel from Boehringer-Ingelheim, GlaxoSmithKline, Lundbeck, Orion, Teva, UCB, and Valeant. Dr. Weiner has disclosed no relevant financial relationships.

Cochrane Database Syst Rev. Published online July 7, 2010. Abstract