Apomorphine subcutaneous titration in Parkinson’s disease - the effectiveness and safety of apomorphine challenges: A Literature Review

Apomorphine is a specialised therapy for Parkinson’s disease, where initiation and titration vary between hospital, health care professional and states. Clinicians perform apomorphine challenges to estimate starting doses and rates for patients. However, there is no literature about the efficacy or accuracy of this practice and how well it helps to predict starting doses or what doses side effects occur. The purpose of this literature review is to analyse the efficacy and safety of performing an apomorphine challenge on a person with Parkinson’s disease and whether the process of the challenge is the most efficacious way to determine the starting dose for commencing of apomorphine therapy.

This review will help ensure clinicians are using the best evidence to guide patient care and ensure the best clinical outcomes for patients. Its primary objective is to identify the rates and intermittent doses of the most common adverse events, involved with apomorphine challenges. The secondary objective is to determine whether this procedure is warranted prior to commencing Apomorphine therapy or if a slow titration is more efficacious.

This Literature review protocol has been developed in accordance with the process set out in the Cochrane handbook of systematic reviews. As this is a literature review, formal ethics approval was not required.

Eligibility for materials included in the review include textbooks and journal articles. Editorials, opinion pieces, newspaper articles, materials not based on scientific method, and not written in English were excluded. Studies included randomised controlled trials, observational, cohort and qualitative studies, case studies, systematic reviews and guidelines. The studies had to be specific to people with idiopathic Parkinson’s disease and specific to Apomorphine subcutaneous injections, apomorphine therapy, “apomorphine challenge” or “Apomorphine Challenge test”.

Participants in the studies had to be diagnosed with idiopathic Parkinson’s disease. Studies were excluded where participants were described as Parkinson’s syndrome or atypical Parkinson’s disease. No restrictions regarding age, disease stage or sex were applied.

Types of interventions were specific to subcutaneous apomorphine therapy including continuous infusion and injector pens. Nasal, rectal and oral forms of apomorphine were excluded.

Outcome measures included:

Safety: the types and frequency of adverse events including cardiac arrhythmias, orthostatic hypotension, cardiac arrest, hallucinations, skin nodules, dyskinesia, somnolence, nausea and vomiting. As well as identify apomorphine dose most likely to cause adverse events.

Effectiveness measures: included Hoehn and Yahr score, UPDRS part III and discontinuation rates, ECG, postural blood pressures.

The review was conducted using published literature from Pub Med/ MEDLINE and CI-NAHL databases from 1970-2019. Truncated key words were used to identify key words and synonyms (See appendix 1 for key words). The results were refined using and Boolean operators see appendix 1. Reference lists of relevant articles were searched to identify relevant articles.

Two reviewers independently reviewed the studies using validated appraisal tools specific to the research design. Disagreements of appraisal were resolved by discussion. Eligible studies were assessed for homogeneity of population, intervention, and validated measurements.

Results were abstracted into a literature matrix by the authors, checked for accuracy, amalgamated and analysed. The extracted information included data on methods, participants, interventions, outcomes and results.

Once studies were appraised, the body of evidence was graded using the National Health and Medical Research Council (NHMRC) grades of evidence. The grading was used to make recommendations on apomorphine titrations and intervention efficacy. The key outcomes in ’Summary of findings’ table as recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Using the Group Reading Assessment and Diagnostic Evaluation (GRADE) approach (Guyatt, 2011), The following was assessed for each outcome: • estimate of the treatment effect; • quantity of supporting evidence; • quality of evidence assessed.

This literature review highlights the lack of evidence that apomorphine challenges accurately predict the initiation or continuing doses for apomorphine therapy. The review shows that most studies regarding the use of apomorphine challenge in initiating and titrating this therapy is anecdotal and based on clinician experience. Studies inadequately controlled for reporter and rater bias, have small sample sizes and high-level evidence is currently lacking. This review found that performing an apomorphine challenge does not equate to that patient staying on that dose and often further titration to correct the dose is required for months after performing the challenge.

An apomorphine challenge needs to be structured around the drug’s pharmacokinetics and patient safety parameters; in particular, ensuring cardiac arrhythmias are screened and controlled for. It’s noteworthy that there are no qualitative studies that investigate the patient’s experience of the apomorphine challenge and how this experience impacts on the patient’s confidence in commencing and continuing the therapy. It’s also interesting to note that 1 in ten people commenced on apomorphine usually discontinue within the first year (Sesar. 2017). Commonly cited reason’s for discontinuing include lack of drug efficacy at relieving symptoms but also include high rates of orthostatic hypotension, nausea, skin nodules and hallucinations (Sesar. 2017). What studies don’t comment on is whether discontinuation rates are higher when patients are not in regular contact with a Parkinson’s specialist nurse or movement disorder specialist and how the types of support impact discontinuation rates.

This literature review highlights that most patients have a continuous flow rate between 2-4mg/hr (Deleu, 2004). During pharmacodynamic studies, 60% of patients achieved a clinically significant improvement (20%) with subcutaneous apomorphine 2mg, which increased to 75% after subcutaneous apomorphine 4mg (Deleu, 2004). Similar results were produced by Ondo (2012); who showed patients who are on continuous doses higher than this are more likely to experience side effects, which may encourage therapy discontinuation.

This review also found that nausea is more likely a complication when patients are on intermittent apomorphine rather than continuous apomorphine, which is likely due to a down regulation of medullary dopamine receptor sensitivity with continuous dopaminergic stimulation (Bhidayasiri, Garcia Ruiz et al. 2016). Domperidone is superior to trimetho-benzamide for preventing nausea for people with PD. Of note, trimethobenzamide is not available for use in Australia (Bhidayasiri, Garcia Ruiz et al. 2016). Nausea symptoms tend to reduce after a week of being on apomorphine therapy (Bhidayasiri, Garcia Ruiz et al. 2016), unless a patient is on less than four intermittent injections per day, where nausea is likely to persist (Bhidayasiri, Garcia Ruiz et al. 2016). Theoretically, domperidone could be discontinued one week post commencement of apomorphine infusion, if there have been no problems with nausea to that point. Studies indicate that a positive result for an apomorphine challenge is when MDS-UPDRS part III improves by 20% from baseline (Albanese, Bonuccelli et al. 2001, Deleu, Hanssens et al. 2004). This is usually achieved at doses between 2-4 mg, negating the need to continue the challenge to higher doses beyond the 20% MDS-UPDRS score improvement (Deleu et al. 2004).

It is not uncommon for clinicians to give doses greater than 7mg during an apomorphine challenge (Ondo et al. 2012). However, given that most side effects occur when patients are given >4mg, it’s questionable whether doses higher than 5mg are really necessary within the challenge structure. In the past apomorphine challenges have been used to help diagnose those who may have an undifferentiated diagnosis such as PSP, MSA or CBS (Muguet, Broussolle et al. 1995). However. The NICE guidelines from 2018 state that apomorphine challenges are not useful as diagnostic tools (NICE, 2018), showing that apomorphine challenges need not exceed 5mg as other diagnostic tools, such as fluorodopa pet scans, are more accurate for diagnosing atypical parkinsonism syndromes (Brown et al., 1999).

While cardiac arrest is extremely uncommon (Attanasio, Capria et al. 1990, Muguet, Broussolle et al. 1995), it is still a risk and therefore all first apomorphine doses should be given in a clinical setting and a bed should be allocated to the patient, to help manage the patient in situations where orthostatic hypotension or cardiac arrest occur.

QT interval prolongation is linked with both apomorphine and domperidone use (Trenkwalder, Chaudhuri et al. 2015). It’s interesting to note that within the apomorphine challenge structure most ECGs are performed before commencing apomorphine, but not before commencing domperidone.

Further studies are required to determine whether domperidone is more likely to induce QT prolongation than apomorphine and whether an ECG is necessary both prior to commencing domperidone and the apomorphine challenge.

Lastly, Tomlinson (2010) investigates the levodopa equivalent dose (LED) conversion formulae which can be used to compare the dose intensities of different PD treatment regimens. Tomlinson’s conversion formulae help to convert different does of antiparkinsonian medications into a standard levodopa dose equivalent helping clinicians convert oral medications into an apomorphine equivalent and calculate the average dose a person would require each hour to maintain motor control.

Tomlinson calculated the arithmetic mean and mode for each drug (Tomlinson. 2010). A limitation of this review is the paucity of direct randomized comparisons between different agents. Therefore, Tomlinson’s LED estimates are approximations and not absolute. Tomlinson (2010) states that their review must be seen as a consensus document rather than a quantitative data synthesis.

The Tomlinson levodopa conversion chart offers a theoretical way to titrate patients by calculating the apomorphine equivalent dose. However, a straight conversion of levodopa to apomorphine, where dose would be higher than 4mg are likely to induce side effects as shown by Ondo (Et al 2014). A sensible approach is to convert the oral parkinsonian medications that are being down titrated as apomorphine is up titrated.

This review found there is a lack of evidence that apomorphine challenges accurately predict the initiation or continuing doses for apomorphine therapy. Adverse events predict the maximum rate or dose a patient can tolerate and further studies are required to determine whether domperidone is more likely to induce QT prolongation than apomorphine and whether an ECG is necessary both prior to commencing domperidone and the apomorphine challenge. On this basis, we conclude that further research and investigatory studies are required to determine the above recommendations and in particular defining the clinical circumstances where a slow titration may be warranted or more efficacious. Based on this literature review the investigators make several recommendations for practice based on the literature review findings: Domperidone can be used 2-3 days before apo challenge to control nausea. Grade A (Bhidayasiri, Garcia Ruiz et al. 2016, Deleu, Hanssens et al. 2004)

There is one study where domperidone was administered as one initial 10mg initial dose pre apomorphine challenge and when requested thereafter, with only a minimal number of patients having problems with nausea. Therefore, it may be useful for some patient to only have domperidone on initiation of apomorphine challenge and as requested; grade D (Bhidayasiri, Garcia Ruiz et al. 2016). Domperidone is most useful for intermittent apomorphine injections. Can be discontinued after 3–6-week post apomorphine initiation but will vary depended on patient reactions and should be regularly reviewed; Grade D. (Deleu, Hanssens et al. 2004)

Patients who do not experience nausea on oral dopamine agonists are less likely to experiences nausea with apomorphine, therefore could have an initial dose of domperidone for the apomorphine challenge. Grade D (Bhidayasiri, Garcia Ruiz et al. 2016) Apomorphine flow rates more than 4mg/hr are likely to induce side effects. Grade C (Deleu, 2004, Pahwa et al 2007)

An apomorphine challenge should only be continued until the part III of the MDS-UPDRS shows a 20% improvement and should be stopped if side effects are experiences i.e., orthostatic hypotension, nausea, arrhythmia, hallucinations. Grade C (Albanese, Bonuccelli et al. 2001, Deleu, Hanssens et al. 2004)

When commencing an apomorphine infusion, 50% of the maximum cumulative dose reached in the apomorphine challenge should be used as the continuous infusion hourly flow rate. Grade C (Deleu, 2004, Pahwa et al 2007)

The order to down titrating antiparkinsonian medications are dopamine agonists, monoamine oxidase type B (MAO-Bs), COMT-Inhibitor, amantadine, levodopa. Grade C (Trenkwalder, Chaudhuri et al. 2015).

The Tomlinson conversion can be used to assist in calculating the levodopa equivalent of the ceased antiparkinsonian medications and help determine the apomorphine dose which will fill in the gaps. Grade B (Tomlinson. 2010).

Key search words: “Apomorphine”, “Apomorphine Challenge” “Apomorphine challenge test’ “Apomorphine titration”, “24-hour continuous apomorphine therapy”, Safety and Efficacy of Apomorphine, “intermittent subcutaneous apomorphine injection”, “Apomorphine rescue dose”.