Intermittent Apomorphine Use for off Period Rescue in Parkinson's Disease: A Pragmatic Review of over Three Decades of Clinical Experience

Abstract

Background: Although proven very efficacious as treatment for Parkinson's disease by Schwab as far back as the 1950s, and later confirmed by Cotzias and colleagues in the early 1970s, use of intermittent subcutaneous injections of the dopamine agonist apomorphine remains limited worldwide.

Objectives: To review evidence regarding use of intermittent, on-demand apomorphine as a treatment for off-period disability in Parkinson's disease.

Methods: A PRISMA-compliant structured literature search was carried out with a focus on clinical effect (motor improvement, daily off time decrease; latency, duration), antiemetic prophylaxis, and adverse events.

Results: Fifty-eight studies were evaluated. Apomorphine administration route was subcutaneous in 29 (50%), sublingual in 14 (24.1%), intranasal in 6 (10.3%), inhaled in 5 (8.6%), rectal in 3 (5.2%) and transdermal in 1 (1.7%). Irrespective of the route, motor disability improved 19% to 74% and daily off time decreased 3% to 68%, with subcutaneous having the fastest onset of action ranging from 6 to 24 minutes and lasting 28 to 96 minutes. Antiemetic prophylaxis was used in almost all studies. Systemic side effects like nausea and yawning were mild and well tolerated, but sedation led to discontinuation of subcutaneous apomorphine in 5.5%. Local side effects to subcutaneous administration did not result in discontinuation. Stomatitis with the early sublingual formulations led to discontinuation in nearly half of patients and was reduced to 16.7% with novel film strips.

Conclusions: Intermittent subcutaneous injections remain the most reliable and safest route of apomorphine administration, with an efficacy for off period treatment supported by nearly four decades of clinical experience.

Keywords: Parkinson's disease; apomorphine; motor fluctuations; off period.

FIG. 1

Flow diagram. Flow diagram of structured literature search, according to the preferred reporting items for systematic reviews and meta‐analyses (PRISMA). Taken from: Page MJ, McKenzie JE, Bossuyt PM, et al. the PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021;372:n71. DOI: 10.1136/bmj.n7

FIG. 2

Dose finding protocol. Dose finding through increasing doses. Besides from finding the optimal dose to rescue an off period or morning akinesia, it also represents an opportunity to educate the patient and/or caregiver on the rescue modality treatment, management of pre‐filled syringes and adequate injection technique. As well as instructing to check injection sites regularly and giving strategies to manage local reactions.* The dose titration test could be performed at any time of the day at the outpatient clinic. However, Following the procedures for acute LDOPA challenge, many centers use overnight drugs withdrawal to ensure a practically defined off. and fasting state to minimize nausea and vomiting.

FIG. 3

Follow‐up. Suggested follow‐up flowchart based on the evaluation of the effect of the rescue therapy through on–off charts, clinical and patient global impression and side effects evaluation.