Apomorphine in Parkinson's Disease-The Questions Raised.

Sir,

We read with great interest the study by Prashanth et al. titled “Apomorphine: The initial Indian experience in relation to response tests and pumps” published in this journal.[1] We have the following observations:

Motor fluctuations are a common complication of treatment in Parkinson's disease (PD).[2] It is known that 40% of patients with PD will develop these after four to six years of therapy. This usually signifies a crucial landmark in the disease course, because patients report an increase in impairment in activities of daily living as well as disability. Motor fluctuations are challenging to manage as oral medications become less predictable with disease progression. Apomorphine, a potent dopaminergic agonist at D1, D2, and D3 receptors, is an effective therapy for unpredictable 'off' periods.[3] Apomorphine is the oldest dopaminergic drug available for PD and has an efficacy comparable to levodopa. It has a long historical timeline for its use in various medical conditions including PD. It is a short-acting dopamine agonist with the onset of action in seven to ten minutes and effect of 60–90 min only. It is being used in many developed countries for motor fluctuation in advanced PD both as intermittent subcutaneous injections and continuous subcutaneous infusion by the pump. It was approved in Europe in 1995 for both intermittent injections as well pump and the US FDA approved it as rescue therapy by subcutaneous intermittent injection in sudden offs in PD patients in 2004. However, Apomorphine has been introduced in India only recently and made headlines and controversies due to inappropriate claims in the media.

The study by Prasanth et al. is a retrospective analysis of Apomorphine Response Test (ART) in 29 patients. It is a preliminary description which does not assess efficacy or clinical outcomes of long-term Apomorphine usage in Indian PD patients which would have been very useful. However, it is a welcome initial observation. Apomorphine (long-term use) experience from India has also been previously reported in five patients.[4]

Clinical efficacy and outcomes can only be studied once patients are placed on the drug and then followed up on an objective quantitative scale (such as UPDRS) serially over a timeline (at least 12 weeks) with a reduction in quantified off-time before and after therapy, increase in on-time or improvement in nonmotor symptoms. ART is done to determine response to Apomorphine and also to titrate its dose if the patient is responsive. In this paper, the authors do not mention how many patients were placed on long-term subcutaneous intermittent Apomorphine therapy after ART and what their outcomes were. Such information would have been of additional clinical utility.

Although the authors state that all 29 subjects were confirmed PD patients, the results show that some of these patients had other parkinsonian syndromes (as indicated in [Figure 3]). Apomorphine is not indicated for Parkinson-plus syndromes since one of the pre-requisites is levodopa responsive parkinsonism,[5] other than negative Coomb's test, ECG, etc. Apomorphine has to be given in selected patients of advanced PD with motor fluctuation under strict medical supervision, preferably supported by a PD nurse trained for Apomorphine usage. It is best used as rescue therapy as an intermittent injection in unpredictable “offs” or patients waiting for deep-brain stimulation. Patient's selection, as well as monitoring and other practical limitations, have been well described in the literature by expert groups and guidelines.[6]

Another interesting finding in this paper was a subset analysis on the impact of administration of domperidone (20 mg for three days) compared to one dose of domperidone (20 mg) did find any difference. Further details of this subset analysis in terms of a number of patients and side-effect profile on the two different doses would have been of great help. We would like to point out that the premedication recommended for ART is 20 mg of domperidone thrice daily for three days prior to testing with one dose one hour prior to the first subcutaneous injection.[7] This is the protocol being used in various centres worldwide for premedication. The findings in the above study are contrary to the usual practice, and a larger study on the same is needed to answer this question raised.

Patients on Apomorphine pump had a drastic reduction of levodopa equivalent dose (e.g. from 2000 mg to 300 mg, 660 mg to 150 mg, 1000 mg to 150 mg over 8–10 weeks). Rapid reduction of levodopa therapy is not desirable in PD patients due to the risk of the neuroleptic malignant syndrome. Did the authors experience this in the reported series of patients?

Despite these limitations, the study highlights the role of Apomorphine in the management of selected patients with advanced PD by pen or pump though continuous infusion by pump is still not approved by the US FDA. Our own experience with Apomorphine in many patients with advanced PD has been promising with a favourable response, but challenging in view of financial and compliance issues as well as patient's reluctance to shift to pump. Patient education and training of Apomorphine use and lack of concordance between patients and treating clinicians have been major barriers as experienced in many other resource-poor countries.

Since it is an invasive therapy with definite indications as well as limitations, its acceptance by PD patients as well as neurologists in India for routine use in these patients will be known only in the years to come.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.