Subcutaneous apomorphine in Parkinson’s disease

Over 40 years have passed since Schwab and colleagues reported the beneficial effect of apomorphine hydrochloride in Parkinson’s disease.¹ In 1979 Corsini et al reported the successful use of subcutaneous apomorphine in combination with domperidone,² and this was confirmed by a series of experiments by Hardie et al.³ More recently, in 1988, Stibe et al described the successful use of continuous subcutaneous infusion of apomorphine in overcoming refractory on-off oscillations in Parkinson’s disease.⁴ Since then at least 16 papers, mostly using open label designs (except two double blind placebo controlled studies), have been published confirming the efficacy of apomorphine given as subcutaneous “rescue” injection or continuous infusion using an automated syringe driver in Parkinson’s disease.⁶ Apomorphine received regulatory approval in Britain in 1993, but, despite its efficacy, it remains largely underused.

The motor response to apomorphine is indistinguishable from that to levodopa, and subcutaneous apomorphine is almost 100% bioavailable with a rapid onset of action (3-20 minutes) and duration of 20-40 minutes. It is indicated in Parkinson’s disease when levodopa responses become erratic and marred by fluctuations in motor responses, on-off oscillations, and dyskinesias.²,⁵

Counselling of patients and liaison with the general practitioner are important before prescribing apomorphine because there are commonly held misconceptions that it is addictive and a respiratory depressant. An apomorphine challenge is required for determining the right dose of the drug, dopaminergic responsiveness, and occasionally for diagnostic purposes as tremor-dominant Parkinson’s disease may mimic essential tremor. Apomorphine challenge should be carried out after pretreating the patient with domperidone for three days and after an electrocardiogram has ruled out serious cardiac arrhythmia. Young motivated patients with short (less than one hour) off periods may prefer to inject apomorphine up to 10 times a day with a penjet, while more disabled patients may need a subcutaneous infusion for 12-24 hours a day. Once the patient has been stabilised on apomorphine, the dose of levodopa can be reduced by 20%-80%.^2–6

Apomorphine has other benefits. It appears to have an antagonistic effect on side effects of levodopa such as dyskinesias and nausea. Colzi et al reported continuous subcutaneous apomorphine given as single therapy to severely dyskinetic patients resulted in a reduction of dyskinesia scores comparable to that produced by pallidotomy over a mean of 2.7 years of apomorphine therapy).⁷ Apomorphine has a low incidence of neuropsychiatric problems, and it has thus been used in patients with severe neuropsychiatric complications due to oral anti-Parkinsonian drugs.⁸ Timed injections of apomorphine may help specific symptoms such as off-period pain, belching, screaming, anismus, constipation, nocturia, restless legs syndrome, dystonias, erectile impotence, and post-surgical state in selected patients who may not otherwise be candidates for apomorphine.⁵,⁶ At a cellular level, recent evidence suggests that the combined D₁ and D₂ receptor agonist action of apomorphine may be more desirable for optimal anti-parkinsonian and anti-dyskinetic action than selective D₂ agonism.⁹

In 1970 Cotzias et al reported that the benefits of apomorphine may be limited by its short duration of action and peripheral side effects.¹⁰ Patients must be pretreated with the extracerebral dopamine antagonist domperidone before apomorphine is started, to prevent nausea and postural hypotension. Tachyphylaxis may develop to these peripheral side effects, allowing discontinuation of domperidone after a time. Subcutaneous nodules complicate therapy and may be avoided by good hygiene, changing injection sites, avoiding reuse of injection lines or needles, and local ultrasound therapy.^2–5 Rarely an autoimmune haemolytic anaemia may occur in patients on long term treatment.² Other modes of administration such as intranasal, rectal, buccal and transdermal iontophoresis and subcutaneous implants are being investigated.⁶ A prefilled variable dose pen injector has recently become available for self injection.

Neurologists’ reluctance to use apomorphine may be due to the need for parenteral delivery and dislike of prescribing a treatment perceived to be expensive. Cost benefit analysis, however, shows that successful apomorphine use helps to reduce “crisis” visits to surgeries and clinics and admissions to hospital as well as allowing reductions in the dose of levodopa.²,⁶ Neurologists, physicians, and general practitioners should now ensure that suitable patients are not denied apomorphine therapy.