Evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson´s disease patients with motor complications

Background One of the complications of long‐term treatment of Parkinson's disease (PD) with levodopa is the development of motor complications. Generally, when motor complications develop, clinicians add in an additional drug (to the levodopa regimen) from one of three other classes of anti‐Parkinsonian treatments (dopamine agonists, catechol‐O‐methyl transferase inhibitors (COMTIs) or monoamine oxidase type B inhibitors (MAOBIs)). However, despite trials having shown that these drugs are beneficial compared to placebo, it remains unclear as to the best way to treat patients experiencing motor complications and whether one class of drug is more effective than another. Objectives This meta‐analysis aims to assess more reliably the benefits and risks of the three classes of drugs (dopamine agonists, COMTIs and MAOBIs) currently used as adjuvant treatment to levodopa in PD patients suffering from motor complications. The three drug classes were compared with the aim of determining whether one class of drug provides better symptomatic control than another. Search methods We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, PubMed, LILACS and Web of Science, plus major journals in the field, abstract books, conference proceedings and reference lists of retrieved publications. Selection criteria Randomised trials comparing an orally administered dopamine agonist, COMTI or MAOBI versus placebo, both on a background of levodopa therapy, in PD patients experiencing motor complications. Data collection and analysis Two authors independently extracted data on off‐time, levodopa dose, motor complications, side‐effects, treatment concordance, clinician‐rated disability, mortality, quality of life and health economic data. Main results Forty‐four eligible trials, involving 8436 participants were identified. Compared to placebo, adjuvant therapy significantly reduced off‐time (‐1.05 hours/day, 95% confidence interval (CI) ‐1.19 to ‐0.90; P<0.00001), the required levodopa dose (‐55.65 mg/day, CI ‐62.67 to ‐48.62; P<0.00001) and improved UPDRS scores (UPDRS ADL score: ‐1.31 points, CI ‐1.62 to ‐0.99; P<0.00001; UPDRS motor score: ‐2.84 points, CI ‐3.36 to ‐2.32; P<0.00001; UPDRS total score: ‐3.26 points, CI ‐4.52 to ‐2.00; P<0.00001). However, dyskinesia (odds ratio (OR) 2.50, CI 2.21 to 2.84; P<0.00001) and side‐effects including constipation (OR 3.19, CI 2.17 to 4.68; P<0.00001), dizziness (OR 1.57, CI 1.30 to 1.90; P<0.00001), dry mouth (OR 2.33, CI 1.22 to 4.47; P=0.01), hallucinations (OR 2.16, CI 1.70 to 2.74; P<0.00001), hypotension (OR 1.47, CI 1.18 to 1.83; P=0.0007), insomnia (OR 1.38, CI 1.09 to 1.74; P=0.007), nausea (OR 1.78, CI 1.53 to 2.07; P<0.00001), somnolence (OR 1.87, CI 1.40 to 2.51; P<0.0001) and vomiting (OR 2.56, CI 1.67 to 3.93; P<0.0001) were all increased with adjuvant therapy. Indirect comparisons of the three drug classes suggested that dopamine agonists were more efficacious in reducing off‐time (dopamine agonist: ‐1.54 hours/day; COMTI: ‐0.83 hours/day; MAOBI: ‐0.93 hours/day; test for heterogeneity between drug classes P=0.0003) and levodopa dose (dopamine agonist: ‐116 mg/day; COMTI: ‐52 mg/day; MAOBI: ‐29 mg/day; test for heterogeneity between drug classes P<0.00001). UPDRS scores also improved more with dopamine agonists than with COMTI or MAOBI (UPDRS total scores ‐ dopamine agonist: ‐10.01 points versus COMTI: ‐1.46 points versus MAOBI: ‐2.20 points; test for heterogeneity between drug classes P<0.00001), although more dyskinesia were seen with dopamine agonists (OR 2.70) and COMTI (OR 2.50) than with MAOBI (OR 0.94) (test for heterogeneity between drug classes P=0.009). 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=0.07). Authors' conclusions Compared to placebo, adjuvant therapy reduces off‐time, levodopa dose, and improves UPDRS scores in PD patients who develop motor complications on levodopa therapy. However, this is at the expense of increased dyskinesia and numerous other side‐effects. Indirect comparisons suggest that dopamine agonist therapy may be more effective than COMTI and MAOBI therapy, which have comparable efficacy. However, as indirect comparisons should be interpreted with caution, direct head‐to‐head randomised trials assessing the impact of these different drug classes on overall patient‐rated quality of life are needed.