Current research has shown that the drug apomorphine is effective for the treatment of Parkinson’s disease, however there are advantages and disadvantages to its use. While apomorphine has a rapid onset of action and benefits patients in reducing motor fluctuations and the number of daily ‘off’ periods, side-effects are also associated with its administration. However, with the introduction of new and improved methods of delivery and drugs for the control of side effects, such adverse drug reactions are now more easily managed and apomorphine is now a better tolerated medication. 

This review focuses on studies ranging from the 1980s to present day, evaluating the advantages and disadvantages of apomorphine treatment for Parkinson’s disease, including the methods of administration. Also discussed in this review are more recent studies on apomorphine’s benefits as a potential drug in the reduction of amyloid deposition in Parkinson’s disease. 

Introduction

Parkinson’s disease is a progressive degenerative disease of the nervous system, which can have a combination of motor and non-motor symptoms including tremor, slowness of movement (bradykinesia) and muscular rigidity. These primarily arise from a lack of the neurotransmitter dopamine in the substantia nigra. Current treatments for Parkinson’s disease aim to reduce these symptoms by temporarily replacing dopamine.

Apomorphine was the first dopaminergic drug used to treat Parkinson’s disease symptoms. The first documented use for apomorphine was in 1884. Clinical trials conducted in the 1950s reached the conclusion that oral apomorphine was a poor treatment due to its short duration of action and high level of ‘first pass’ hepatic metabolism.¹ When levodopa (L-dopa) was then introduced, apomorphine was relegated to a minor therapeutic option for several more decades.¹ Currently, continuous subcutaneous infusions, and intermittent subcutaneous injections are widely used, with other novel preparations in development.¹

Apomorphine has a similar chemical structure to dopamine, giving it dopamine agonist properties. It is a drug composed of two parts, the dopamine like moiety or catechol radical that binds to the dopamine receptor and the 2-amino-tetralein structure that determines the dopaminergic agonist property¹ (see Figure 1). Its distinct feature is that it is very lipophilic in nature and passively crosses the blood brain barrier, resulting in a high concentration of apomorphine in the brain. Apomorphine is a non-selective dopamine receptor agonist, due to its binding affinities for all five DA receptors, D1-like receptors – D1 and D5, and D2-like receptors – D2S, D2L, D3 and D41.

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Apomorphine: pros

Apomorphine has a rapid onset of action due to its lipophilic nature.¹ Of potential clinical interest, apomorphine is partially metabolised by catecholamine-O-methyl transferase (COMT). COMT can be inhibited by administering drugs such as tolcapone and entacapone, increasing plasma levels of apomorphine. Tolcapone increased the serum area under the curve and duration of clinical improvement with an oral preparation of apomorphine.^1,2,3,4

In 1988, Stibe et al first reported the beneficial effects of intermittent subcutaneous bolus injections of apomorphine.⁵ Total daily off time was reduced by in excess of 50%. More recently, three main trials led to the approval of apomorphine subcutaneous injections for the treatment of motor fluctuations in Parkinson’s disease in the US. Recently several randomised trials in the US established the efficacy of apomorphine in Parkinson’s disease.⁶ These trials investigated the use of 10mg/mL subcutaneous apomorphine as an acute treatment for ‘off’ periods in patients with Parkinson’s disease and employed the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score from pre-dose to post-dose to assess the effect of apomorphine. They consistently found significant improvement in UPDRS scores after a mean time of 20 minutes versus placebo.^1,3 This study came to the conclusion that the use of subcutaneous apomorphine for Parkinson’s disease treatment was safe. 

Grosset et al also describes such a reduction in UPDRS scores with subcutaneous administration, stating in one of the most recent studies, apomorphine single injections significantly reduced motor UPDRS scores at 10 and 20 minutes after administration as compared with placebo. Such effects were present six months after initial evaluation.^4,7

A recent study published in 2016 assesses the advantages of administering subcutaneous apomorphine injections to reduce time-to-‘on’ in Parkinson’s disease patients with morning akinesia, versus the use of L-dopa. It was concluded that following treatment with apomorphine, patients suffering morning akinesia experienced rapid improvement of time-to-‘on’. The mean ± SD time-to-‘on’ reduced from 60.86 ± 18.11 minutes at baseline with L-dopa therapy to 23.72 ±14.55 minutes at the end of the treatment period (reduction of 37.14 ± 20.51 minutes; p < 0.0001 versus baseline).⁸ This is a clinically relevant advantage of subcutaneous apomorphine treatment, as evidenced by significant improvements in patient-driven scales of quality of life.⁸

Timed injections of apomorphine may help specific symptoms such as off-period pain, belching, screaming, anismus, constipation, nocturia, restless legs syndrome, dystonias, erectile dysfunction and may be helpful for patients temporarily unable to take oral medication, who may not otherwise be candidates for apomorphine.⁹ Antidyskinetic effects were also observed in several patients treated with continuous subcutaneous apomorphine by Pietz et al.¹⁰ These antidyskinetic effects more than likely result from the fact that continuous subcutaneous apomorphine treatment is a continuous method of administration which can help in the reduction of dyskinesias – erratic and intermittent striatal dopamine receptor changes that occur with intermittent pulsed levodopa therapy.^5,10 Rapid onset of action with apomorphine administration is another significant advantage. With subcutaneous administration this is extremely rapid, providing relief, on average, between seven and 14 minutes post injection.¹ Grosset et al also describes this advantage of subcutaneous apomorphine treatment, stating that after injection, absorption is rapid and complete, the mean latency to motor response is about 11-13 minutes, and the duration of action is about 56-62 minutes.^4,7

Regarding subcutaneous infusions of apomorphine, there is currently data on the results of long-term continuous subcutaneous apomorphine infusions from one to eight years. Pietz discusses some of these findings, the most significantly advantageous being a reduction of the daily time spent in ‘off’ from 50% to 25% in the infusion group.¹⁰ Another advantage of apomorphine resulting from these studies was that some patients in these trials could be weaned off levodopa completely and handled by apomorphine monotherapy,⁵ which is a clear indication of a beneficial and advantageous medication for Parkinson’s disease. Some studies also show that continuous apomorphine infusion/monotherapy can reset the peak-dose dyskinesia threshold in L-dopa-treated patients, thus further decreasing fluctuations.¹

A paper from 1989 suggested sublingual administration as beneficial to patients with Parkinson’s disease. These authors suggested that sublingual apomorphine is likely to provide a viable alternative to intermittent injections of apomorphine in the treatment of ‘off’ period disabilities in Parkinson’s disease.¹¹ Since then, more studies have been carried out and now a new sublingual formulation of apomorphine studied in several papers has shown many benefits. Data from 1996 shows that a new formulation of a sublingual tablet with 10mg apomorphine was effective in 56% of nine patients with Parkinson’s disease. This study demonstrated that only one sublingual tablet with 10mg apomorphine is clinically effective; the reduced number of tablets in this study is a clear advantage over the large number used sublingually in other reports.^12,13,14 However, the newest studies on sublingual administration were set to undergo clinical trials in 2015. In this formulation, based on Listerine breath strips, a thin film delivery system is utilised incorporating active solid apomorphine in a stabilising buffer that allows for less acidity.¹ This strip will dissolve easily in saliva, allowing quicker absorption and less mucosal irritation as a result of the buffering solution. There are many potential advantages to sublingual administration, including less of a need for manual dexterity as is needed with subcutaneous IV administration, no need for needle, no potential skin irritation and pain.^1,3

Non-motor symptoms of Parkinson’s disease include gastrointestinal symptoms, disturbances of sleep, pain, urinary symptoms and impulse control disorders. While there have been no focused studies on the use of apomorphine for control of non-motor symptoms, trials which have focused on motor symptoms of Parkinson’s disease suggest a beneficial effect of continuous infusion of apomorphine on several neuroleptic malignancy syndromes (NMS) in patients with Parkinson’s disease.¹ Such benefits were also suggested in Chaudhuri and Clough’s paper entitled ‘Subcutaneous apomorphine in Parkinson’s disease: effective yet underused’.⁹

There has been some evidence from both clinical and pathological studies that beta-amyloid plaques play a role in Parkinson’s disease dementia (PDD). An exploratory study was carried out in 2015 investigating whether antemortem exposure to apomorphine was associated with lower levels of amyloid-beta in brain tissue.¹⁵ Findings showed that those who were cognitively normal and treated with apomorphine generally had lower levels of beta-amyloid (Aβ) plaques. It is possible that apomorphine treatment may have a modifying effect on Aβ peptide deposition in non-demented Parkinson’s disease cases, with results demonstrating decreased diffuse and total plaque load in the Apo+ compared to the Apo- group, reduced Aβ accumulation in subjects who had received greater earlier and maximum apomorphine doses.¹⁵ The fact that apomorphine may also serve as a novel therapeutic agent to reduce cognitive impairment in Parkinson’s disease may be another advantage of the drug. 

Apomorphine: Cons

The oral bioavailability of apomorphine is very poor; around 4% and the drug has a brief duration of effect.¹ Due to its low oral bioavailability and the high ‘first pass’ effect, parenteral administration is needed, which is an important disadvantage.¹¹ Domperidone is also frequently administered with apomorphine to reduce the associated peripheral side effects.^1,16 This need for concomitant administration of a second drug is another significant side effect of apomorphine. 

In earlier clinical trials, apomorphine’s use was considered limited due to marked side effects, mostly consisting of syncope and vomiting.¹ Specific preparations have unique side effects but the drug itself has several consistent problems. The most common issues are nausea and vomiting, and hypotension including syncope.¹ Q-T interval prolongation and cardiac events can also be observed as an effect of apomorphine.

Continuous subcutaneous infusions

While this is a major use of apomorphine, this method of administration has been complicated by the development of skin nodules with prolonged therapy.¹ In fact, granulomas or subcutaneous nodules at the injection site can be observed in up to 10% of patients after long-term use.⁴ This means injection sites have to be rotated in order to avoid reactions. As a result of these adverse reactions, compliance can also be an issue when administering this drug to patients and therefore its long-term use can be limited. As well as this, it commonly requires concomitant administration of oral L-dopa, resulting in limited dyskinesia improvement.¹⁷

Intravenous administration

While studies show that patients do have a decrease in ‘off’ periods with IV administration of apomorphine, use is limited by severe adverse effects, including hypotension, syncope and skin infections. The development of intravascular thrombosis is a more severe adverse drug reaction. This is thought to be due to the crystallisation of apomorphine in the catheter.^1,18

Sublingual administration

In the past, sublingual formulations were limited by mucosal irritation.¹ A 1996 paper on sublingual administration of apomorphine reported no severe adverse effects, stating blood pressure and heart rate remained stable in all patients involved.¹¹ However, there was no mention of mucosal irritation in this same paper and it is difficult to deduce whether this was considered a ‘severe adverse effect’. 

Other papers do discuss this as a significant side effect, with Poewe and Wenning stating that apomorphine is severely limited by the development of stomatitis.⁵ This review also mentions other adverse effects associated with sublingual administration of apomorphine. Using sublingual application of apomorphine tablets, patients switch on after longer latencies compared with the subcutaneous roots. The standard dose required with sublingual treatment is approximately tenfold higher.⁵

Conclusion

Apomorphine, one of the longest standing drugs for the treatment of Parkinson’s disease, is indeed an effective medication. Its rapid onset of action, various routes of administration and, more recently, its proposed benefits in Aβ plaque degradation make it a most useful drug. However, it is a treatment that appears to remain underutilised. Like most medications, it is not without its side effects and these must be taken into consideration when optimising treatment for patients with Parkinson’s disease. 

References

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