Parkinsons disease Wearing off Phenomena

Long-term levodopa use in Parkinson's disease can result in "wearing off" motor fluctuations. Strategies include dietary changes, dose adjustments, long-acting formulations, and adjunctive therapies like dopamine agonists, MAOB inhibitors, COMT inhibitors, and istradefylline. Rescue options are also available.

Overview of Strategies to Mitigate "Wearing Off" in Parkinson's Disease:

Levodopa provides the greatest benefit to control motor symptoms in Parkinson disease. However, its long- term use is associated with the development of motor fluctuations “wearing off” effect. The majority of patients experience "wearing off" after five years of therapy with levodopa. A variety of strategies can help to mitigate “wearing off”. They include the following;

Dietary Adjustment:

Protein- rich meals impair the absorption of levodopa and should be avoided at the time of drug administration. Also, studies suggested that eradication of Helicobacter might help to improve Levodopa absorption. (1)

Adjusting Levodopa:

Increasing the dose or small and more frequent doses of Levodopa might help to decrease wearing off. The time to “wearing off” determines which appropriate interdose interval is needed. Also, an additional levodopa dose at the end of the day might be required. (2, 3) Long acting oral levodopa formula with controlled- release (CR) at an initial dose of 50/200 mg orally twice a day, or extended release capsules (ER) at a starting dose of 23.75/ 95 mg orally three times daily for 3 days with a possible increase to 36.25/145 mg may be considered. Controlled release tablet (CR) However, one of the major limitations of extended- release formula is the high cost of the drug. Liquid levodopa as a solution and its dose can be titrated and administered every hour is the most recent approach to decrease “wearing off”. (4, 5)

Adjunctive Therapy:

If levodopa adjustment is not adequate, the addition of an adjunctive therapy, such as, oral dopamine agonist, monoamine oxidase type B (MAOB) inhibitor, catechol-O-methyl transferase [COMT] inhibitor or istradefylline) can help to reduce “wearing off". Oral dopamine agonists, such as ropinirole IR at 0.125 mg three times daily, rotigotine IR at 0.25 mg three times daily, can help to reduce "wearing off". (6) Monoamine oxidase type B (MAOB) inhibitor, such as, rasagiline at 0.5- 1.0 mg once daily, selegiline (5 mg twice daily), along with levodopa may prolong the half- life of dopamine in the brain and thereby decrease "wearing off" phenomena. (7) Catechol -O - methyl transferase (COMT) inhibitor, such as, entacapone at 200 mg tablet taken along with each dose of levodopa, opicapone 50 mg once daily can potentiate the effect of levodopa and thereby reduce wearing "off". (8) Istradefylline (20 mg daily) is an oral adenosine A2A receptor antagonist which was approved in August 2019 as an adjunctive to levodopa for the treatment of "wearing off" effect. (9) Other rescue strategies include the use of subcutaneous at a usual dose of 2mg or sublingual apomorphine or inhaled levodopa at 84 mg. Either approach can help for sudden and unpredictable “wearing off" periods. (10, 11) For patients who failed medical therapies, other modalities; such as, device- assisted surgical options could be considered. (12)

References

1- Rees K, Stowe R, Patel S, et al. Helicobacter pylori eradication for Parkinson's disease. Cochrane Database Syst Rev 2011; :CD008453.

2- Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA 2014; 311:1670.

3-Nyholm D, Stepien V. Levodopa fractionation in Parkinson's disease. J Parkinsons Dis 2014; 4:89.

4- Mittur A, Gupta S, Modi NB. Pharmacokinetics of Rytary®, An Extended-Release Capsule Formulation of Carbidopa-Levodopa. Clin Pharmacokinet 2017; 56:999.

5-Hauser RA, Hsu A, Kell S, et al. Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial. Lancet Neurol 2013; 12:346.

6- Pahwa R, Stacy MA, Factor SA, et al. Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease. Neurology 2007; 68:1108.

7- Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005; 365:947.

8- Ferreira JJ, Lees A, Rocha JF, et al. Long-term efficacy of opicapone in fluctuating Parkinson's disease patients: a pooled analysis of data from two phase 3 clinical trials and their open-label extensions. Eur J Neurol 2019; 26:953.

9- Kondo T, Mizuno Y, Japanese Istradefylline Study Group. A long-term study of istradefylline safety and efficacy in patients with Parkinson disease. Clin Neuropharmacol 2015; 38:41.

10- Olanow CW, Factor SA, Espay AJ, et al. Apomorphine sublingual film for off episodes in Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 study. Lancet Neurol 2020; 19:135.

11-LeWitt PA, Hauser RA, Pahwa R, et al. Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol 2019; 18:145.

12-Williams DR, Evans AH, Fung VSC, et al. Practical approaches to commencing device-assisted therapies for Parkinson disease in Australia. Intern Med J 2017; 47:1107.