|Year : 2021 | Volume
| Issue : 1 | Page : 137--139
The Great Indian Apomorphine Story: Challenges and Its Usage in Parkinson's Disease in the Indian Context
Rajinder K Dhamija, Divyani Garg
Department of Neurology, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India
Rajinder K Dhamija
Department of Neurology, Lady Hardinge Medical College, New Delhi
|How to cite this article:|
Dhamija RK, Garg D. The Great Indian Apomorphine Story: Challenges and Its Usage in Parkinson's Disease in the Indian Context.Neurol India 2021;69:137-139
|How to cite this URL:|
Dhamija RK, Garg D. The Great Indian Apomorphine Story: Challenges and Its Usage in Parkinson's Disease in the Indian Context. Neurol India [serial online] 2021 [cited 2021 Dec 6 ];69:137-139
Available from: https://www.neurologyindia.com/text.asp?2021/69/1/137/310088
Optimum management of advanced Parkinson's disease (PD) is a challenge for neurologists. It is estimated that 40% of PD patients will experience motor fluctuations between four and six years of onset of disease. This represents not only a difficult therapeutic task as the impact of oral medications used to manage motor fluctuations attenuates with advancing disease but also significantly impairs quality of life and activities of daily living. Although motor fluctuations are common complications of advanced PD treatment, these patients also have nonmotor “OFFs” in addition to wearing off, motor fluctuations, unpredictable and sudden “OFFs,” and delayed on. They may also have gastrointestinal and other autonomic disturbances, making oral absorption of levodopa erratic. In addition, many have peak dose or biphasic troublesome dyskinesias thereby making reasonable on time difficult despite adequate pharmacotherapy.
Apomorphine, a morphine derivative, is among the oldest dopaminergic agents used for PD, predating levodopa use by at least a decade., Matthiessen and Wright synthesized it in 1869. It has been used as a sedative, antiepileptic, antipsychotic, and for alcohol dependence as well as sexual dysfunction. However, its utility in PD was demonstrated only in 1951. It is a potent albeit short-acting nonergot dopaminergic agonist. Due to structural similarity to dopamine, it acts directly and strongly at all dopaminergic receptors, both D1-like (D1, D5) and D2-like (D2, D3, and D4) types.
Despite its potent dopaminergic properties, apomorphine did not find widespread use initially due to the firm establishment of levodopa and oral dopaminergic agonists as the pillars of PD management. However, over time, with the increasing recognition of constraints associated with levodopa use in advanced PD, apomorphine has found a stronghold in the management of wearing-off and sudden off when oral drugs are not as effective. The pulsatile nature of levodopa action leading to various motor fluctuations can be circumvented by continuous dopaminergic therapy, which may be provided by a slew of alternatives such as deep brain stimulation, levodopa pumps, dopaminergic patches as well as apomorphine pumps. It has been found to be extremely useful as a rescue therapy in patients experiencing a sudden unexpected and resistant “off” periods. In India, however, apomorphine has been introduced very recently. With its introduction in India, controversial claims of outstanding efficacy in the media led to much debate and discussion. In this report, we explore the potential utility and possible limitations of apomorphine in an Indian context.
Apomorphine has very limited oral bioavailability (<4%) because of almost complete first-pass hepatic metabolism. The highly lipophilic quality permits its rapid transit to the brain. On subcutaneous administration, the peak plasma life of apomorphine is achieved in 10–20 min and peak cerebrospinal fluid level in 30 min. It has rapid onset of action after intermittent injection (7–10 min) making it ideal for unpredictable of sudden offs as a rescue agent. It also has a short elimination half-life of 45–60 min.
Apomorphine initiation requires shared decision making between the treating neurologist, ideally a Movement Disorders specialist, and the patient and his family. There are clear cut indications and protocols along with expert consensus recommendations from Movement Disorders Society to guide neurologists in patient selection as well as initiation and monitoring of apomorphine therapy. Parenteral apomorphine is suitable for PD patients with troublesome and significant “OFF” periods despite optimum oral and transdermal dopaminergic therapy.
Apomorphine initiation requires a validated apomorphine challenge test (also known as apomorphine response test (ART)) to determine responsiveness as well as the optimum starting dose of subcutaneous injections or the hourly dose in case the patient is initiated on pump therapy. Baseline ECG, Coomb's test, and blood counts are mandatory, as well as premedication with domperidone for 1–3 days. The apomorphine challenge test should ideally be done in an inpatient setting in the “OFF” stage under the supervision of a Movement Disorders specialist with documentation of quantified and unequivocal improvement in “OFF” periods.
Apomorphine is being used in several countries, either in the form of intermittent subcutaneous injections or continuous subcutaneous pumps for the management of motor fluctuations in PD. In Europe, it was approved in the form of intermittent subcutaneous therapy as well as subcutaneous pump infusion in 1995. The Food and Drug Administration, USA, approved it as rescue therapy for the management of sudden “OFF” periods in PD patients in 2004. It is well established that apomorphine is as effective and equipotent as levodopa. Despite these approvals, it has been underutilized in PD. It has been evaluated in more than 25 studies involving hundreds of patients with consistent benefits in “OFF” time reduction as well as reduction in dyskinesias. It has also been shown that chronic subcutaneous infusion therapy with apomorphine in advanced PD also leads to profound improvement in nonmotor symptoms compared to conventional therapy. It has also been suggested that apomorphine may be a potential modifier of amyloid deposits in patients with advanced PD. Initial apomorphine trials were limited to small sample size and many were open-label studies. However, in a recent and large multicentric European TOLEDO double-blinded randomized controlled trial, the effect of subcutaneous apomorphine in 106 PD patients with motor fluctuations not controlled on medical therapy was assessed over a period of 12 weeks. Significant reduction in “OFF” time occurred in the apomorphine arm compared to placebo, with a mean final dose of 4.68 mg/h [SD 1.50] and mean difference of -1.89 h per day [95% C.I -3.16 to -0.62; P = 0.0025).
In a comparative study of subthalamic nucleus-deep brain stimulation, Duodopa and apomorphine, it was shown that apomorphine improved mood/cognition and perceptual problems.
Apomorphine use in India has been reported in literature to a limited extent. A recent study by Prashanth et al. summarized the results of the ART in 29 patients with parkinsonism. In this retrospective study, patients with PD with motor fluctuations underwent ART, and among these, six further underwent apomorphine pump placement. Among those who underwent ART, half of them developed nausea, which was the most common side effect. One patient developed sudden deep sleep with 6 mg of apomorphine and another developed postural hypotension with 1 mg. Among the patients who underwent pump placement, two discontinued due to financial constraints. Most patients used the pump in a suboptimal fashion to reduce cost. Since these were preliminary observation, numbers were small. However, even so, cost was identified as a prohibitive feature. In another small study in 2007 from India, five patients with PD and motor fluctuations were administered long-term subcutaneous apomorphine therapy. In three of these patients, levodopa could be withdrawn, and in two patients, it led to a reduction in levodopa dose. In a meta-analysis of randomized controlled trials (RCT) to assess the efficacy and safety of subcutaneous apomorphine versus placebo, seven RCTs with 312 participants with PD were identified. In this pooled meta-analysis, no effect of subcutaneous apomorphine was observed on the primary outcome, i.e., change in total Unified Parkinson's Disease Rating Scale (UPDRS) score although the authors reported significant effect on sensitivity analysis. No effect was observed on the motor subpart of UPDRS (part III) or quality of life. It is apparent that there is an urgent need for not only larger but also long-term studies on Indian patients that comprehensively describe apomorphine use in our scenario.
More recently, apomorphine has been studied in other routes of administration in PD patients. In a small open-label proof of concept trial of sublingual apomorphine, it was shown to rapidly and predictably convert a PD patient from the practically defined “OFF” state to a full ON state. In a recent study published earlier this year, apomorphine sublingual film provided an efficacious, on-demand treatment for “OFF” episodes for most patients with PD. However, one-third of the patients discontinued treatment due to oropharyngeal side effects. Other modes of apomorphine delivery as well as long-term safety and efficacy are being studied. These include oral apomorhine in oil lipid-based formulation, which has been evaluated in animal studies. Another promising route is pulmonary delivery of aomorphine, which has been found to be safe and feasible without any major adverse pulmonary side effects.
In spite of its very strong dopaminergic actions, apomorphine is still infrequently used in Asian countries including India. This is due to the fact that it also has many adverse effects that are mainly due to its potent emetic action, variable degree of somnolence, and skin as well as erythema at the injection sites. Needle phobia is also an important factor for many patients making them reluctant to switch to apomorphine injections or infusions. Moreover, it should preferably be given in Movement Disorders setups with PD specialist nurse support. Our initial experience of subcutaneous intermittent apomorphine injections in our hospital in patients with advanced PD has been rewarding but with major barriers of financial and compliance issues. Most of our patients have also been reluctant to consider pump therapy. This probably suggests the need for more patient education and training.
We still believe that apomorphine has a distinct place in the management of selected patients who have advanced PD. With its availability in India, our patients should also be more frequently and emphatically offered its benefits. However, since it is an invasive therapy, and still has forbidding cost factors, only time will reveal its acceptance, not only by Indian PD patients but also by neurologists in India.
|1||Weiner WJ. Motor fluctuations in Parkinson's disease. Rev Neurol Dis 2006;3:101-8.|
|2||Perez-Lloret S, Negre-Pages L, Damier P, Delval A, Derkinderen P, Destée A, et al. L-DOPA-induced dyskinesias, motor fluctuations and health-related quality of life: The COPARK survey. Eur J Neurol 2017;24:1532-8.|
|3||Stibe CM, Lees AJ, Kempster PA, Stern GM. Subcutaneous apomorphine in parkinsonian on-off oscillations. Lancet 1988;1:403-6.|
|4||Frankel JP, Lees AJ, Kempster PA, Stern GM. Subcutaneous apomorphine in the treatment of Parkinson's disease. J Neurol Neurosurg Psychiatry 1990;53:96-101.|
|5||Lees AJ. Dopamine agonists in Parkinson's disease: A look at apomorphine. Fundam Clin Pharmacol 1993;7:121-8.|
|6||Schwab RS, Amador LV, Lettvin JY. Apomorphine in Parkinson's disease. Trans Am Neurol Assoc 1951;56:251-3.|
|7||Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence-based medical review update: Pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004. Mov Disord 2005;20:523-39.|
|8||Gancher ST, Nutt JG, Woodward WR. Absorption of apomorphine by various routes in parkinsonism. Mov Disord 1991;6:212-6.|
|9||Trenkwalder C, Chaudhuri KR, García Ruiz PJ, LeWitt P, Katzenschlager R, Sixel-Döring F, et al. Expert consensus group report on the use of apomorphine in the treatment of Parkinson's disease--Clinical practice recommendations. Parkinsonism Relat Disord 2015;21:1023-30.|
|10||Titova N, Chaudhuri KR. Apomorphine therapy in Parkinson's and future directions. Parkinsonism Relat Disord 2016;33:S56-60.|
|11||Martinez-Martin P, Reddy P, Antonini A, Henriksen T, Katzenschlager R, Odin P, et al. Chronic subcutaneous infusion therapy with apomorphine in advanced Parkinson's disease compared to conventional therapy: A real life study of non motor effect. J Parkinsons Dis 2011;1:197-203.|
|12||Katzenschlager R, Poewe W, Rascol O, Trenkwalder C, Deuschl G, Chaudhuri KR, et al. Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): A multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2018;17:749-59.|
|13||Dafsari HS, Martinez-Martin P, Rizos A, Trost M, Santos Ghilardi MGD, Reddy P, et al. EuroInf 2: Subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson's disease. Mov Disord 2019;34:353-65.|
|14||Prashanth LK, Jaychandran R, Seetharam R, Iyer RB. Apomorphine: The initial Indian experience in relation to response tests and pumps. Ann Indian Acad Neurol 2020;23:20-4.|
|15||Surya N. Parkinson's disease and apomorphine-An Indian experience. Mov Disord 2007;22:S1-295.|
|16||Azharuddin M, Adil M, Ghosh P, Sharma M. The efficacy and safety of subcutaneous apomorphine in patients with Parkinson's disease: A meta-analysis of randomised controlled trials. Mov Disord 2019;34:S1-930.|
|17||Hauser RA, Olanow CW, Dzyngel B, Bilbault T, Shill H, Isaacson S, et al. Sublingual apomorphine (APL-130277) for the acute conversion of OFF to ON in Parkinson's disease. Mov Disord 2016;31:1366-72.|
|18||Olanow CW, Factor SA, Espay AJ, Hauser RA, Shill HA, Isaacson S, et al. Apomorphine sublingual film for off episodes in Parkinson's disease: A randomised, double-blind, placebo-controlled phase 3 study. Lancet Neurol 2020;19:135-44.|