Short-Term Effects of Bedtime Levodopa Regimens on Subjective Sleep Quality in Parkinson's Disease: A Randomized Crossover Study

Abstract

Objective: To compare the short-term effects of levodopa-benserazide prolonged-release and levodopa-carbidopa-entacapone on subjective sleep quality in patients with idiopathic Parkinson's disease and nocturnal hypokinesia.
Methods: In this prospective, randomized, open-label, two-period crossover study conducted in a tertiary hospital movement disorders unit, thirty patients with idiopathic Parkinson's disease, daily levodopa dose ≥1000 mg, and nocturnal hypokinesia received levodopa-carbidopa-entacapone (100/25/200 mg) and levodopa-benserazide prolonged-release (125 mg) on two consecutive nights in randomized order, about one hour before bedtime. Subjective sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) at baseline and by structured telephone interview the following mornings. Scores were compared across assessments and sequences using the Friedman test, with Wilcoxon signed-rank tests and Bonferroni correction for pairwise comparisons.
Results: Median PSQI scores decreased from eight at baseline to six after the first treatment night and 6.5 after the second treatment night. No statistically significant difference was observed across the three assessment periods in the overall cohort (p=0.157). A significant overall difference across assessments was observed only in the levodopa-benserazide prolonged-release-first sequence (p=0.001); however, none of the pairwise comparisons remained statistically significant after Bonferroni correction (p<0.016).
Conclusions: In this study, PSQI scores decreased following short-term bedtime dopaminergic therapy in patients with Parkinson's disease. Although the reduction was more pronounced when levodopa-benserazide prolonged-release was administered first, the difference did not reach statistical significance. This finding may have been influenced by the imbalance in concomitant long-acting dopaminergic medication use between treatment sequences and the relatively small sample size.

Keywords

• Parkinson's disease
• Sleep quality
• Levodopa
• Nocturnal hypokinesia
• Crossover study
• Dopaminergic therapy

Ethical Statement

This study was approved by the Ethics Committee of Ankara Atatürk Sanatoryum Training and Research Hospital (Approval No: 2024-KAEK-24/12). All procedures were conducted in accordance with the Declaration of Helsinki and relevant institutional guidelines.

References

1. Taximaimaiti R, Luo X, Wang XP. Pharmacological and non-pharmacological treatments of sleep disorders in Parkinson's disease. Curr Neuropharmacol. 2021;19(12):2233-49. doi:10.2174/1570159X19666210517115706.
2. Stefani A, Högl B. Sleep in Parkinson's disease. Neuropsychopharmacology. 2020;45(1):121-8. doi:10.1038/s41386-019-0448-y.
3. Stocchi F, Barbato L, Nordera G, Berardelli A, Ruggieri S. Sleep disorders in Parkinson's disease. J Neurol. 1998;245(Suppl 1):S15-8. doi:10.1007/PL00007731.
4. Schütz L, Sixel-Döring F, Hermann W. Management of sleep disturbances in Parkinson's disease. J Parkinsons Dis. 2022;12(7):2029-58. doi:10.3233/JPD-212749.
5. Iranzo AC, Cochen De Cock V, Fantini ML, Pérez-Carbonell L, Trotti LM. Sleep and sleep disorders in people with Parkinson's disease. Lancet Neurol. 2024;23(9):925-37. doi:10.1016/S1474-4422(24)00170-4.
6. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines. Neurology. 2001;56(11 Suppl 5):S1-S88. doi:10.1212/wnl.56.suppl_5.s1.
7. Nyholm D. Pharmacokinetic optimisation in the treatment of Parkinson's disease. Clin Pharmacokinet. 2006;45(2):109-36. doi:10.2165/00003088-200645020-00001.
8. Nyholm D, Lewander T, Gomes-Trolin C, Bäckström T, Panagiotidis G, Ehrnebo M, et al. Pharmacokinetics of levodopa/carbidopa microtablets versus levodopa/benserazide and levodopa/carbidopa in healthy volunteers. Clin Neuropharmacol 2012;35(3):111-7. doi:10.1097/WNF.0b013e31825645d1.

9. Torti M, Alessandroni J, Bravi D, Casali M, Grassini P, Fossati C, et al. Clinical and pharmacokinetic equivalence of multiple doses of levodopa-benserazide generic formulation vs the originator (Madopar). Br J Clin Pharmacol. 2019;85(11):2605-13. doi:10.1111/bcp.14086.
10. Schaeffer E, Vaterrodt T, Zaunbrecher L, Liepelt-Scarfone I, Emmert K, Roeben B, et al. Effects of levodopa on quality of sleep and nocturnal movements in Parkinson's disease. J Neurol. 2021;268(7):2506-14. doi:10.1007/s00415-021-10419-7.
11. Scanga A, Lafontaine AL, Kaminska M. An overview of the effects of levodopa and dopaminergic agonists on sleep disorders in Parkinson's disease. J Clin Sleep Med. 2023;19(6):1133-44. doi:10.5664/jcsm.10450.
12. Jampolska M, Kaczyńska K. The effect of dopaminergic therapies in Parkinson's disease on non-motor symptoms. Int J Mol Sci. 2025;26(24):11996. doi:10.3390/ijms262411996.
13. Amara AW, Wood KH, Joop A, Memon RA, Pilkington J, Tuggle SC, et al. Randomized controlled trial of exercise on objective and subjective sleep in Parkinson's disease. Mov Disord. 2020;35(6):947-58. doi:10.1002/mds.28009.