Safety review of current pharmacotherapies for levodopa-treated patients with Parkinson’s disease

ABSTRACT

Introduction

Levodopa remains the gold standard for treatment of Parkinson’s disease (PD). Patients develop complications with disease progression, necessitating adjunctive therapy to control fluctuations in motor and non-motor symptoms and dyskinesia. Knowledge of medication safety and tolerability is critical to ascertain the benefit-risk ratio and select an adjunctive therapy that provides the highest chance for medication adherence. Posing a challenge are the sheer abundance of options, stemming from the development of several new drugs in recent years, as well as differences in commercial drug availability worldwide.

Areas covered

This review evaluates the efficacy, safety, and tolerability of current US FDA-approved pharmacotherapies for levodopa-treated PD patients, including dopamine agonists, monoamine oxidase type-B inhibitors, catechol-O-methyltransferase inhibitors, the N-methyl-D-aspartate receptor antagonist amantadine, and the adenosine receptor antagonist istradefylline. Data were taken from pivotal phase III randomized controlled and post-surveillance studies, when available, that directly led to FDA-approval.

Expert opinion

No strong evidence exists to support use of a specific adjunctive treatment for improving Off time. Only one medication has demonstrated improvement in dyskinesia in levodopa-treated PD patients; however, every patient cannot tolerate it and therefore adjunctive therapy should be tailored to an individual’s symptoms and risk for specific adverse effects.

KEYWORDS:

• Adjunctive
• Amantadine
• COMT inhibitor
• Dopamine agonist
• Dyskinesia
• Istradefylline
• MAO-B inhibitor
• Motor fluctuations

Article highlights

• Although levodopa remains the gold standard for treatment of Parkinson’s disease (PD), adjunctive medications are often required to treat complications such as Off time and levodopa-induced dyskinesia (LID) as the disease progresses.

• Long-acting formulations of pramipexole and ropinirole, as well as transdermal rotigotine, provide more stable plasma drug concentrations than available standard oral formulations and may improve medication adherence.

• Common side effects of dopamine agonists include dyskinesia, hallucinations, somnolence, sleep attacks, dizziness, nausea, peripheral edema, and impulse control disorder behavior.

• Subcutaneous (SC) apomorphine injections and sublingual (SL) apomorphine are effective on-demand therapy options but are associated with dopaminergic effects and yawning, as well as skin issues (SC injection) and oropharyngeal complications (SL film).

• Monoamine oxidase-B inhibitors are efficacious, safe, and generally well-tolerated adjunctive treatment options that carry potential risks for the development of serotonin syndrome when used concomitantly with certain medications or at doses higher than recommended, and severe, uncontrolled hypertension when taken with high amounts of dietary tyramine.

• Catechol-O-methyltransferase inhibitors are efficacious adjunctive treatment options for Off time in PD, but tolcapone requires routine liver monitoring due to increased risk for severe hepatic dysfunction.

• Nighttime administration of amantadine delayed release/extended-release leads to stable plasma drug concentrations during the day that improve Off time and LID, but some patients, especially those with renal impairment, can experience side effects such as hallucinations, dizziness/postural hypotension, dry mouth, peripheral edema, and constipation.

• Istradefylline is an efficacious non-dopaminergic adjunctive therapy that is safe and well-tolerated for the treatment of Off periods.

• Choice of adjunctive treatment for levodopa-treated patients with PD and Off periods and/or dyskinesia should be tailored to individual’s symptoms and risk for specific side effects.

Declaration of Interest

AM Richmond serves as a consultant for Acadia. R Pahwa serves as a consultant for Abbott, AbbVie, Acadia, Acorda, Allevion, Amneal, Artemida, BioVie, CalaHealth, Convatec, Fasikl, Global Kinetics, Inbeeo, Insightec, Jazz, Kyowa, Lundbeck, Merz, Neurocrine, Neuroderm, Ono, Photo Pharmics, Regenxbio, Sage, Sunovion, Supernus, UCB and Wren. He receives research support from Abbott, AbbVie, Alexza, Annovis, Biogen, Bluerock, Bukwang, Cerevel, Global Kinetics, Jazz, Michael J Fox Foundation, Neuroderm, Neuraly, Parkinson’s Foundation, Praxis, Roche, Sage, Scion, Sun Pharma, UCB, and Voyager. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One reviewer has attended advisory boards by Stada, AbbVie Pharma, Merz and Bial during the past year. They received travel grants and educational support from Boehringer Ingelheim, AOP Pharma as well as lecturing honoraria from GE, UCB, Bial, Stada, AOP Orphan, AbbVie, Medtronic and Merz Pharma.

Author contribution statement

The authors confirm contribution to the paper as follows: paper conception and design: AM Richmond, R Pahwa; data collection: AM Richmond, R Pahwa; analysis and interpretation of results: AM Richmond, K Lyons, R Pahwa; draft manuscript preparation: AM Richmond, K Lyons, R Pahwa. All authors reviewed the results and approved the final version of the manuscript. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Data availability statement

The data that support the findings in this review are openly available in PubMed at https://pubmed.ncbi.nlm.nih.gov/. Additional data that support the findings of this review are available and readily accessible by search of individual drug names on the US FDA website at https://www.fda.gov/drugs/development-approval-process-drugs/drug-approvals-and-databases. No new data were created or analyzed in this study.

Additional information

Funding

This paper was not funded.