|Year : 2020 | Volume
| Issue : 3 | Page : 145-155
Subcutaneous apomorphine in advanced Parkinson’s disease and its use in Indian population
Vinod Metta, Rupam Borgohain, Prashanth L Kukkle, Rukmini Mridula, Pankaj Agarwal, Asha Kishore, Vinay Goyal, Ray Chaudhuri
Department of Movement Disorders, National Parkinson Centre of Excellence, Kings College Hospital London, London, United Kingdom
|Date of Submission||01-Apr-2020|
|Date of Decision||17-Apr-2020|
|Date of Acceptance||22-May-2020|
|Date of Web Publication||07-Nov-2020|
Dr. Vinod Metta
Department of Movement Disorders, National Parkinson’s Centre of Excellence, Kings College Hospital, Denmark Hill, London SE5 9RS
Source of Support: None, Conflict of Interest: None
Although subcutaneously administered apomorphine is widely used as an effective adjunct therapy for Parkinson’s disease (PD), it was approved for use in India only in 2019. This review summarizes the history, pharmacology, clinical spectrum, indications, efficacy, and side effects of subcutaneous apomorphine use in patients with PD along with clinical recommendations for its use in Indian context. Intermittent subcutaneous apomorphine injection or continuous subcutaneous apomorphine infusion is effective adjunctive treatments for patients with advanced PD with levodopa-related refractory motor complications and some specific nonmotor symptoms (NMS) as growing evidence shows apomorphine also improves aspects of NMS of PD. Common side effects of subcutaneous apomorphine are skin nodules, nausea, and somnolence with incidence being higher with infusion than that with injection. Impulse control disorders and neuropsychiatric complications common to most dopamine agonists can also occur. As per National Institute for Health and Care Excellence (NICE), United Kingdom, apomorphine, as intermittent injection or continuous subcutaneous infusion, is one of the best medical therapies and may be considered before using deep brain stimulation (DBS) or levodopa/carbidopa intestinal gel (LCIG). Head-to-head open-label comparative multicenter data suggest that apomorphine is at least as effective as DBS or LCIG in relation to nonmotor and motor benefit. More studies are needed to reduce the paucity of apomorphine data in Indian population. We also discuss criteria to select one device therapy over another and newer apomorphine delivery strategies in the pipeline.
Keywords: Apomorphine, dopamine agonists, levodopa, Parkinson’s disease
|How to cite this article:|
Metta V, Borgohain R, L Kukkle P, Mridula R, Agarwal P, Kishore A, Goyal V, Chaudhuri R. Subcutaneous apomorphine in advanced Parkinson’s disease and its use in Indian population. Ann Mov Disord 2020;3:145-55
|How to cite this URL:|
Metta V, Borgohain R, L Kukkle P, Mridula R, Agarwal P, Kishore A, Goyal V, Chaudhuri R. Subcutaneous apomorphine in advanced Parkinson’s disease and its use in Indian population. Ann Mov Disord [serial online] 2020 [cited 2021 Jan 18];3:145-55. Available from: https://www.aomd.in/text.asp?2020/3/3/145/300254
| Introduction|| |
Till recently, only two options were available in India for Parkinson’s disease (PD): oral dopamine replacement therapies dominated by levodopa for early PD and deep brain stimulation (DBS) for advanced PD. Subjects with PD who were not keen for surgical therapies or contraindicated for surgical procedures had no access to conventional infusion therapies available elsewhere. Younger subjects were offered DBS as first-line advanced treatment. Subcutaneous apomorphine injection and infusion recently entered Indian market. We summarize the history, pharmacology, clinical spectrum, indications, efficacy, and side effects of subcutaneous apomorphine use in PD and discuss clinical practice recommendations, with a special focus on its use in India.
| Apomorphine: History and Molecular Structure|| |
Ancient Mayans and Egyptians used naturally occurring analog, aporphine, found in water lilies as an emetic, aphrodisiac, or hallucinogen. In 1845, Adolf Edvard Arppe synthesized apomorphine from morphine and sulfuric acid. In 1851, Thomas Anderson also synthesized apomorphine by heating codeine with sulfuric acid. It gained interest in medicine in 1868, when Matthiessen and Wright heated morphine with concentrated hydrochloric acid and synthesized apomorphine hydrochloride. [Figure 1] shows the history and evolution of apomorphine as a treatment for PD.,,,
|Figure 1: Discovery and evolution of apomorphine for use in Parkinson’s disease.,,, PD = Parkinson’s disease, FDA = Food and Drug Administration, UK = United Kingdom, HCl = hydrochloric acid|
Click here to view
Apomorphine (C17H17NO2), a derivative of morphine, is a non-ergot dopamine agonist (DA) with high selectivity for D2, D3, D4, and D5 and to a lesser extent for D1 dopamine receptors. It activates serotonergic 5HT1A receptors but has antagonist properties on other serotonergic (5HT2A, 5HT2B, and 5HT2C) receptors and adrenergic (α2A, α2B, and α2C) receptors.
Its chemical structure [Figure 2] accounts for its dopaminergic and non-dopaminergic properties. The ortho-catechol group confers structural similarity to dopamine, whereas the piperidine moiety confers possible antipsychotic action. Apomorphine is lipophilic and moderately soluble in saline and water. Its lipophilicity and affinity to dopaminergic receptors are attributed to the tetracycline aporphine ring. It rapidly oxidizes when exposed to air or light but strong acids and antioxidants prevent its oxidation.
| Pharmacology of Apomorphine|| |
Although apomorphine has poor oral bioavailability (<4%), following subcutaneous administration into the abdominal wall, it is rapidly 100% absorbed. Time to peak plasma concentration is 10–60 min. Almost 10–30 min later, peak concentration in the cerebrospinal fluid (CSF) occurs. Its extremely lipophilic structure allows apomorphine to cross the blood–brain barrier. Bioavailability after subcutaneous administration is similar to that after intravenous administration. It shows linear pharmacokinetics over a dose of 2–8 mg when single subcutaneous injection is administered in the abdominal wall.
Apomorphine improves motor function in patients with PD 3 min after intravenous administration or 5 min after subcutaneous administration. The duration of action is dependent on both the dose and the mode of administration. The elimination half-life is 30–90 min. Onset of action is rapid but duration of effect is brief.
Apomorphine’s absorption, volume of distribution, plasma clearance, and half-life are similar for subcutaneous injection, subcutaneous infusion, and intravenous infusion; however, absorption varies from patient to patient. Subcutaneous absorption is influenced by factors such as injection site, state of the skin, volume and depth of injection, and presence of subcutaneous nodules. Subcutaneous route is preferred. Sublingual, buccal, nasal, and rectal administrations have either been tried or are in trials. Intravenous administration trial was halted as it crystallizes the drug leading to thrombosis and pulmonary embolism. An oral lipid-based formulation tested in rat models remains to be validated in humans.
Volume of distribution is about 1–2 times the bodyweight due to its lipophilicity. Maximum apomorphine concentration in blood versus CSF is achieved after 10 and 30 min of subcutaneous injection, respectively. Its clinical effect is directly related to its concentration in brain, which is eight times higher than that in plasma. Even if its plasma concentration drops below threshold, its pharmacodynamic effect lasts up to 30 min.
Apomorphine has high clearance of 3–5L/kg/h, and is mainly metabolized by liver; only 3%–4% is excreted unchanged in urine due to its systemic oxidation. Factors such as regional fat, blood flow, and differences in metabolic enzyme profiles cause high intersubject variability in the maximum concentration (Cmax), time to reach maximum concentration (Tmax), and area under the plasma concentration–time curve. Future studies should be aimed to study apomorphine’s pharmacokinetics and pharmacodynamics in Indian population to elucidate its clinical effects in different subgroups of Indian patients with PD. The clinical use of apomorphine as well as monitoring pharmacovigilance and underpinning research pose several challenges in the Indian context.
In a nutshell, apomorphine shares similarities in action and structure to levodopa, which is the current gold standard for PD treatment. This similarity stems not only from the clinical profile but also from the neuropharmacology, as apomorphine is a dopamine receptor agonist that also has relevant activity on serotonergic and alpha-adrenergic receptors.
| Clinical Spectrum and Indications|| |
Historically, apomorphine has a broad clinical spectrum and has been used in aversive conditioning, gastric emptying, respiratory disorders, mental disorders, PD, chorea, muscle spasms, restless leg syndrome, tardive dyskinesia, Tourette syndrome, and erectile dysfunction. It is approved in some countries for emesis, erectile dysfunction, and PD. Human tissue studies and in vivo study using amyloid positron emission tomography (PET) scans show apomorphine reduces amyloid deposition in the human brain. It may be a potential procognitive therapy in PD. Intermittent subcutaneous apomorphine injection or continuous subcutaneous apomorphine infusion (CSAI) is indicated to manage levodopa-induced “off” states in fluctuating PD. Intermittent subcutaneous apomorphine injection is used as and when needed during the “off” times, whereas CSAI is used throughout the day using prefilled syringe. Subcutaneous apomorphine bypasses the gastrointestinal tract, and is useful for patients with severe “off” periods and gastrointestinal complications. CSAI replicates the concept of continuous drug delivery,, and stabilizes plasma levels of apomorphine, thereby avoiding peaks and troughs.
In clinical practice, apomorphine injection is also indicated as apomorphine response test (ART) where it is repeatedly given as bolos-dose injections to determine the dopaminergic responsiveness and the appropriate dose for apomorphine therapy. ART [Table 1] has 80% ability to predict the dopaminergic responsiveness to clinically diagnose the parkinsonian syndromes and different stages of PD. However, National Institute for Health and Care Excellence (NICE) guidelines do not recommend routine use of ART.
| Role of Apomorphine in PD|| |
Symptomatic treatment for PD controls symptoms and minimizes side effects, especially late complications such as motor and nonmotor fluctuations and dyskinesia. Though levodopa is considered the gold standard for all stages of PD, its long-term use induces motor fluctuations and dyskinesias as the disease progresses. Manipulation of oral therapies in advanced PD is usually not effective and causes more dyskinesias and wearing-off symptoms. Poor levodopa absorption is responsible for different variants of levodopa-induced motor fluctuations such as early-morning “off,” delayed “on,” dose failure, and no “on.” Oral/transdermal DAs, among others, can be used to manage these complications but become ineffective. Device-aided adjunct strategies used for controlling persistent motor complications include DBS, CSAI, and levodopa/carbidopa intestinal gel (LCIG)., Though DBS and LCIG are highly effective in managing motor fluctuations, both are invasive treatments requiring surgery and carrying their own risks [Table 2]. Therefore, subcutaneous intermittent apomorphine injection or CSAI is more patient friendly and the least invasive treatment options for levodopa-induced motor fluctuations. Moreover, compared with other DAs, apomorphine closely resembles levodopa with pharmacological effects, qualitatively and quantitatively comparable to levodopa.
|Table 2: Comparison of deep brain stimulation, continuous subcutaneous apomorphine infusion, and levodopa–carbidopa intestinal gel,,|
Click here to view
| Apomorphine Injection/Infusion for Motor Symptoms|| |
Apomorphine injection provides rapid and effective relief from both unpredictable and predictable “off” periods [Table 3], [Figure 3].,,,,,,,, The efficacy of apomorphine infusion in reversing severe, sudden “off” states and improving dyskinesias in advanced PD, despite optimized oral therapy, is widely accepted.,,,,,
|Table 3: Summary of studies showing the efficacy of intermittent subcutaneous apomorphine injections in Parkinson’s disease patients,,,,,,,,|
Click here to view
|Figure 3: Reasons for using subcutaneous intermittent apomorphine injections in patients with Parkinson’s disease|
Click here to view
Stibe et al. have shown similar clinical efficacy of apomorphine infusion and oral levodopa with significant reduction in daily “off” periods by 6.3h with apomorphine infusion. Chaudhuri et al. reported 85% reduction in “off” periods in levodopa-treated PD with refractory motor fluctuations. Subsequently, meta-analysis of 24 open-label or comparative studies reported 59.3% mean reduction in “off” time and 32.5% mean reduction in dyskinesias with approximately 22%–81% reduction in concomitant levodopa dose.
The first randomized, double-blind, placebo-controlled study showed efficacy of apomorphine injection as acute therapy for “off” episodes in advanced PD. After 20 min of its administration, there was a significant improvement in mean Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores, and the effects lasted up to 40 min. Adverse events were similar between apomorphine and placebo. Apomorphine injection also significantly reduced the time-to-on in patients with PD with morning akinesia. The mean time-to-on decreased from 60.86 ± 18.11 min with levodopa to 23.72 ± 14.55 min with apomorphine.
In a multicenter study, in patients with advanced PD, with mean follow-up of 19.93 ± 16.3 months, apomorphine infusion significantly reduced the “off” periods with improved UPDRS scores and reduced dyskinesia. The mean daily levodopa dose decreased by 605 mg.
In a randomized controlled trial (RCT) of apomorphine subcutaneous infusion (TOLEDO), it was efficient and well tolerated in patients with PD with persistent motor fluctuations despite optimized oral/transdermal therapy. At week 12, mean apomorphine dose of 4.68 mg/h showed significant reduction in “off” time compared with placebo (−2.47 vs. −0.58h/day) without increasing dyskinesias. Apomorphine infusion was efficient even in the elderly showing consistent results irrespective of age. In patients with PD with on–off fluctuations and disabling dyskinesias, apomorphine infusion reduced the “off” times and improved the dyskinesias. These results significantly correlated with the 55% reduction in oral levodopa and with the final apomorphine dose confirming that replacement of oral medication with CSAI may reverse the sensitization process that causes drug‐induced dyskinesias in PD. CSAI is usually performed during waking time of 12–16h, but for patients experiencing nocturnal hypokinesia, 24-h infusion can be programmed by using wearable sensors to yield objective and quantifiable outcomes.
Good clinical response was seen with ART and apomorphine infusion in Indian patients also. Apomorphine 3–5 mg showed good clinical benefit in ART with no unexpected side effects or significant difference among patients pretreated with domperidone either for 3 days or on the day of testing. Apomorphine infusion significantly reduced the “off” periods as well as the levodopa dose with no clinically limiting adverse effects. The main limitation was suboptimal utilization of apomorphine infusion. Few patients discontinued the therapy even after good clinical benefits due to the cost burden. Currently, subjects need to spend approximately 800–1500 INR/day depending on the dose needed. Few patients decided to reduce the dose (to reduce cost burden) leading to suboptimal benefits. Proper health insurance or government health schemes for poor patients may help to overcome financial burden that is affecting clinical outcomes. Long-term studies with bigger cohorts are needed to understand the clinical benefits/limitations in Indian patients.
| Apomorphine Injection/Infusion for Nonmotor Symptoms|| |
Total burden of nonmotor symptoms (NMS) is a major determinant of Quality of Life (QoL) and >90% of patients with PD experience NMS. Subcutaneous apomorphine has potential nonmotor effects such as improvement in “off”-related pain, swallowing, constipation, insomnia, somnolence, restless leg syndrome, urinary dysfunction, and apathy. CSAI, compared to conventional treatment, showed significant improvements in NMS such as hyperhidrosis, nocturia, urgency of micturition, and fatigue after 1 year of follow-up. DAs are associated with impulse control disorders (ICDs), and should be avoided in the elderly with cognitive impairment. However, the incidence of ICD with apomorphine appears to be lower than with other DAs as it does not strongly activate dopamine D3 receptors responsible for ICD.
Apomorphine is well tolerated and may be tolerated in patients with mild visual hallucinations (VHs) in PD probably due to its anti-serotonergic activity and piperidine moiety.,, CSAI has also significantly improved the on/off times even in the elderly patients with advanced PD with VH and orthostatic hypotension, provided they are concomitantly treated for cholinergic deficits, VH, and orthostatic hypotension. In another study, CSAI did not affect the neuropsychological symptoms in patients with PD. A clinicopathological study showed the potential of apomorphine to reduce cognitive impairment in PD as there was reduced amyloid-beta deposition in subjects who used apomorphine antemortem. Considering the apomorphine’s NMS benefits and no related data in Indian patients with PD, future studies are warranted with NMS as primary outcomes, especially neuropsychiatric symptoms and ICDs, for better understanding in the Indian population.
| CSAI versus LCIG versus DBS|| |
Though DBS is effective in controlling PD symptoms and motor complications, it is invasive and has adverse effects [Table 4]. It reduces the phonetic verbal fluency and word-naming speed in the medium and long term, worsens the cognitive function and neuropsychiatric status, but CSAI does not affect the cognitive function and neuropsychological symptoms.,, LCIG and CSAI, like DBS, can also increase the “on” times without causing any dyskinesias.,, However, CSAI is easy to use for patients/caregivers, less invasive, and cheaper than LCIG. NICE recommends considering CSAI before using more invasive therapies such as DBS or LCIG., The Navigate Project, involving 103 expert opinions across major European countries, recommended that CSAI be considered in patients not suitable for DBS, who cannot afford DBS, in older non-demented patients, and who are suitable for levodopa infusion therapies.
In EuroInf study Cohen's effect sizes (≥0.8 considered as large) were "large" with both therapies with respect to total motor, nonmotor, and quality-of-life scores, this open-label, nonrandomized, comparative study, in advanced Parkinson's patients, both IJLI and Apo infusion therapy appear to provide a robust improvement in motor symptoms, motor complications, quality-of-life. All treatments significantly improved QoL, nonmotor, and motor symptoms with each treatment showing distinct effect profiles [Table 2]. DBS improved the urinary/sexual functions, mood/cognition, sleep/fatigue, and miscellaneous domain. LCIG improved the mood/cognition, sleep/fatigue, miscellaneous domain, and gastrointestinal symptoms. CSAI improved the mood/cognition, perceptual problems/hallucinations, attention/memory, and miscellaneous domain. Therefore, nonmotor and motor symptoms should be assessed holistically, and treatment choices should be based on individual patient profiles. Either DBS or CSAI or LCIG is recommended for patients aged <70 years with motor fluctuations or dyskinesias, otherwise healthy. For patients aged >70 years, CSAI or LCIG should be considered first before opting for DBS. For patients aged >70 years with mild/moderate cognitive dysfunction or other DBS contraindications, CSAI or LCIG should be considered with reduction/cessation in oral treatment.,
| DBS and Apomorphine|| |
The two techniques of continuous dopaminergic stimulation are not mutually exclusive and can be combined to improve patient response. In a recent paper by Sesar et al., addition of apomorphine improved “off” time by 2h in a subset of patients who had undergone DBS, and the effects has started to wane after 5–10 years.
| Apomorphine Side Effects and Their Management|| |
Skin reactions (bruising, subcutaneous nodules, and abscess formation) at injection/infusion site, nausea, and somnolence are the most common side effects of subcutaneous apomorphine.,, Somnolence and skin reactions account for premature discontinuation of injection/infusion. Incidence of adverse effects is higher with infusion than that with injection,, especially infusion-site skin reactions and psychiatric adverse events if high doses are administered., Risk of skin reactions can be reduced by skin hygiene, using new needles, using Teflon needles, changing and massaging the injection site, injecting at 45°–90° angle, using lower concentration, applying ultrasound therapy, and using silicone gel dressings., Domperidone or trimethobenzamide should be used along with apomorphine to control nausea/vomiting. Dose modifications may also help to reduce the adverse effects. Apomorphine may cause ICDs such as binge eating, compulsive sexual disorder, and punding, though low in occurrence. CSAI may cause hemolytic anemia, and patients should be monitored with hemolytic parameters, blood cell counts, and Coombs test to detect antibodies against red blood cells.
An open-label study assessing the long-term safety of apomorphine injection reported mild/moderate events of nausea and vomiting, falls, dyskinesias, dizziness, somnolence, hallucinations, yawning, and injection-site bruising. Serious events reported were syncope, drug-induced psychosis, and postural hypotension. Postural hypotension can be managed by increasing fluid/salt intake, raising bed ends, changing the position slowly, and using compression stockings. TOLEDO reported that apomorphine infusion was well tolerant with no unexpected safety signals. Most common side effects of apomorphine versus placebo were skin reactions (44% vs. 0%), nausea (22% vs. 9%), and somnolence (22% vs. 4%). Also, neuropsychiatric events in apomorphine versus placebo groups were 13% versus 7.5%. However, dose reductions resolved almost all neuropsychiatric events. Serious events reported were severe orthostatic hypotension and abnormal persistent nonhemolytic hematology test results.
Prashanth et al. reported nausea, vomiting, sleepiness, yawning, postural hypotension, dizziness, and profuse sweating with ART in Indian patients with PD. In this study, vomiting and postural hypotension were identified as critical limiting factors for ART interfering with clinical assessment. Side effects such as subcutaneous nodules, nausea, and hypersexuality, which were clinically not limiting were reported with CSAI in the same study. Common adverse effects associated with apomorphine are shown in [Table 4].
| Future Delivery Strategies|| |
Improvements in subcutaneous route are underway, specially to reduce skin reactions, which cause treatment complications and intolerance. Sublingual and nasal routes are currently under development [Table 5].
|Table 5: Current and future apomorphine based treatment strategies,,,,,,,,|
Click here to view
Safety and tolerability of ND0701 (concentrated formulation of apomorphine base for continuous subcutaneous delivery), in a preclinical study in mini pigs and an open-label phase 1 study in healthy human volunteers, was superior to commercially available apomorphine hydrochloride formulation, although bioavailability was comparable. ND0701 showed no systemic toxicity, and infused sites showed less frequent, less severe nodules that recovered faster compared with sites treated with the commercially available formulation.
Sublingual apomorphine (APL-130277) is reported to be a convenient, rapid, and reliable method for treating “off” episodes. Full “on” response was achieved by 78.9% of patients within 30 min, and 60.0% remained fully “on” for ≥90 min. In a randomized controlled study, APL-130277 was an efficient on-demand treatment for “off” episodes. At week 12, UPDRS-III scores were significantly improved in APL-130277 compared with placebo. Patients experienced mild/moderate oropharyngeal side effects, nausea, somnolence, and dizziness. Long-term safety and efficacy are currently under investigation. The US Food and Drug Administration (FDA) has accepted resubmitted new drug application (NDA) for APL-130277. In mid-2018, it had asked for additional information following the first NDA. A response to the resubmission is expected from FDA by May 2021.
VR040, inhalable powder formulation, was safe and tolerant in patients with PD though the dose ranges tested (0.2, 0.5, and 0.8 mg) showed limited efficiency. However, dose range of 1.5–4.5 mg significantly improved UPDRS-III scores and reduced the number of “off” periods, compared with placebo., VR040 has rapid absorption (2–7 min) that is translated to rapid reversal (10 min) from “off” states. No further updates regarding VR040 are available.
| Clinical Practice Recommendations for Apomorphine Injection/Infusion|| |
On every visit, clinicians should ask patients with PD about their motor/nonmotor fluctuations. Insufficiently controlled motor fluctuations and cognitive decline related to nonmotor fluctuations are indications for device-aided therapies. Clinicians should analyze the risk/benefits of adjusting the existing dose regimen versus incorporating an adjuvant therapy and should monitor the outcomes of prescribed changes. Patients needing levodopa more than five times/day with severe, troublesome “off” periods (>1–2h/day), despite optimized oral/transdermal levodopa or non-levodopa-based therapies, should be assessed by a specialist for advanced therapies even if disease duration is <4 years. ART, antiemetic prophylaxis, and close medical supervision are recommended before using apomorphine injection/infusion, to maximize treatment adherence. ART protocol is shown in [Table 1].
Domperidone should be avoided in patients of PD with preexisting cardiac disease as it causes ECG parameters QT interval & Corrected QT interval prolongation with increased risk of ventricular tachyarrhythmia and sudden cardiac death. No more than 20 mg domperidone is recommended up to three times/day and for <2 weeks.
Patients with troublesome “off” periods, despite optimized oral medication, can use apomorphine injection as rescue therapy because of fast clinical response (7–10 min) that lasts up to 45–60 min. The physician or nurse should provide proper injection/infusion training for patients/caregivers for therapy compliance and preventing adverse events. Patients requiring >4–6 injections/day are recommended to switch to CSAI. Initial CSAI dose is 0.5 or 1 mg/h, which can be up titrated with daily increments of 0.5 or 1 mg/h. The optimal infusion rate is around 4–7 mg/h. Concomitantly, oral DAs and other antiparkinsonian drugs should be gradually discontinued. In patients using injection/infusion, reduction/cessation of DA is the preferred treatment for resolving ICD; but it may cause DA withdrawal syndrome (DAWS), which is unresponsive to other medications. While reducing DAs, patient should be monitored for the resolution of ICDs, loss of motor control, and DAWS. If there is loss of motor control, substitution with LCIG, catechol-O-methyltransferase inhibitor, or monoamine oxidase inhibitor should be considered. Subthreshold DA dose should be maintained, which is effective at preventing DAWS and resolving ICDs with no loss of motor control. Concomitant administration of apomorphine with ondansetron and other 5HT3 antagonists may induce severe hypotension and syncope and is therefore contraindicated., Treatment choice should be personalized based on the risks, adverse effects, patient’s symptoms, personal preferences, treatment availability, and local expertise. [Table 6] lists out the criteria for using apomorphine injection/infusion.
| Apomorphine and Its Scenarios in India|| |
CSAI utilization in India has its own challenges and advantages due to its regional and sociocultural variations. The primary benefit is that of people who are not willing for surgical interventions due to their beliefs or contraindications; this is a welcome option. The challenges are plenty as attributable to any newer therapies. The challenges include awareness, associated comorbidities, and socioeconomic/cultural beliefs. The acceptance, understanding, and care of CSAI have their own learning curve, both at the health care and patient levels. India is also one of the leading hotspots for other noncommunicable disorders including diabetes, which require regular monitoring and intensive skin care regimen to improve the compliance and reduce adverse events. The lack of general knowledge of CSAI therapy in primary care levels and associated myths may also add to the hurdles. The limitations of health insurance coverage in India add to the hurdle of acceptance and compliance. A proposed research collaboration between the Parkinson’s Research Association of India (PRAI) and UK centers may oversee these challenges to some extent, whereas local monitoring system by the providers will help real-life support.
| Conclusions|| |
Apomorphine injection provides rapid and effective relief from predictable and unpredictable “off” periods. Apomorphine infusion significantly decreases the time spent in “off” without concurrent increase in dyskinesias. Nonmotor and motor symptoms should be assessed holistically, and treatment choices should be based on individual patient profiles due to intersubject variability of apomorphine’s pharmacology. Subcutaneous apomorphine showed promising results in the Indian population, with no unexpected side effects, paving way for future studies to understand more about the clinical benefits/limitations and to reduce paucity of apomorphine data in Indian population. Good health insurance and government schemes for poor people may reduce the financial burden on patients. Improved subcutaneous delivery strategies are underway to decrease skin complications and improve patient compliance. Sublingual and nasal routes are also under clinical development showing promising results.
The authors thank B. Mounika and Dr. Natasha Das for their meticulous work formatting the manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Correspondent B Apomorphine, new medication for treatment of Parkinson’s, launched in India [Internet]. BioVoiceNews2018 [cited 2020 Feb 13]. Available from: https://www.biovoicenews.com/apomorphine-new-medication-for-treatment-of-parkinsons-launched-in-india/. [Last accessed on 2020 May 07].
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.
Auffret M, Drapier S, Vérin M The many faces of apomorphine: Lessons from the past and challenges for the future. Drugs R D 2018;18:91-107.
Arppe AE Ueber eine merkwürdige Veränderung des Morphins durch Schwefelsäure. Justus Liebigs Annalen der Chemie 1845;55:96-101.
Matthiessen A, Wright CRA III. Researches into the chemical constitution of the opium bases. Part I—On the action of hydrochloric acid on morphia. Proc Royal Soc London 1869;17:455-60.
Pessoa RR, Moro A, Munhoz RP, Teive HAG, Lees AJ Apomorphine in the treatment of Parkinson’s disease: A review. Arq Neuropsiquiatr 2018;76:840-8.
touchNEUROLOGY2017. A landmark year for apomorphine—Advancing Parkinson’s disease management with new clinical evidence [Internet]. [cited 2020 Feb 17]. Available from: https://touchneurology.com/a-landmark-year-for-apomorphine-advancing-parkinsons-disease-management-with-new-clinical-evidence/. [Last accessed on 2020 May 07].
Ribarič S The pharmacological properties and therapeutic use of apomorphine. Molecules 2012;17:5289-309.
Carbone F, Djamshidian A, Seppi K, Poewe W Apomorphine for Parkinson’s disease: Efficacy and safety of current and new formulations. CNS Drugs 2019;33:905-18.
Auffret M, Drapier S, Vérin M Pharmacological insights into the use of apomorphine in Parkinson’s disease: Clinical relevance. Clin Drug Investig 2018;38:287-312.
National Center for Biotechnology Information. Apomorphine, CID=6005 [Internet]. PubChem Database [cited 2020 Feb 13]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/107882. [Last accessed on 2020 May 11].
Borkar N, Mu H, Holm R Challenges and trends in apomorphine drug delivery systems for the treatment of Parkinson’s disease. Asian J Pharm Sci 2018;13:507-17.
Borkar N, Andersson DR, Yang M, Müllertz A, Holm R, Mu H Efficacy of oral lipid-based formulations of apomorphine and its diester in a Parkinson’s disease rat model. J Pharm Pharmacol 2017;69:1110-5.
Neef C, van Laar T Pharmacokinetic-pharmacodynamic relationships of apomorphine in patients with Parkinson’s disease. Clin Pharmacokinet 1999;37:257-71.
Jenner P, Katzenschlager R Apomorphine—Pharmacological properties and clinical trials in Parkinson’s disease. Parkinsonism Relat Disord 2016;33(Suppl 1):13-21.
Yarnall AJ, Lashley T, Ling H, Lees AJ, Coleman SY, O’Sullivan SS, et al
. Apomorphine: A potential modifier of amyloid deposition in Parkinson’s disease? Mov Disord 2016;31:668-75.
Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJ New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer’s disease. J Biol Chem 2002;277:42881-90.
Ray Chaudhuri K, Qamar MA, Rajah T, Loehrer P, Sauerbier A, Odin P, et al
. Non-oral dopaminergic therapies for Parkinson’s disease: Current treatments and the future. NPJ Parkinsons Dis 2016;2:16023.
Chaudhuri KR, Rizos A, Sethi KD Motor and nonmotor complications in Parkinson’s disease: An argument for continuous drug delivery? J Neural Transm (Vienna) 2013;120:1305-20.
Jenner P Wearing off, dyskinesia, and the use of continuous drug delivery in Parkinson’s disease. Neurol Clin 2013;31:S17-35.
Antonini A Apomorphine and levodopa infusion therapies for advanced Parkinson’s disease. J Mov Disord 2009;2:4-9.
Deleu D, Hanssens Y, Northway MG Subcutaneous apomorphine: An evidence-based review of its use in Parkinson’s disease. Drugs Aging 2004;21:687-709.
National Institute for Health and Care Excellence (Great Britain). Parkinson’s disease in adults: Diagnosis and management : Full guideline [Internet]. 2017 [cited 2020 Feb 21]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK447153/. [Last accessed on 2020 May 14].
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.
Fabbri M, Rosa MM, Ferreira JJ Adjunctive therapies in Parkinson’s disease: How to choose the best treatment strategy approach. Drugs Aging 2018;35:1041-54.
Fackrell R, Carroll CB, Grosset DG, Mohamed B, Reddy P, Parry M, et al
. Noninvasive options for ‘wearing-off’ in Parkinson’s disease: A clinical consensus from a panel of UK Parkinson’s disease specialists. Neurodegener Dis Manag 2018;8:349-60.
Stibe CM, Lees AJ, Kempster PA, Stern GM Subcutaneous apomorphine in parkinsonian on-off oscillations. Lancet 1988;1:403-6.
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.
Hughes AJ, Bishop S, Kleedorfer B, Turjanski N, Fernandez W, Lees AJ, et al
. Subcutaneous apomorphine in Parkinson’s disease: Response to chronic administration for up to five years. Mov Disord 1993;8:165-70.
van Laar T, Jansen EN, Essink AW, Neef C, Oosterloo S, Roos RA A double-blind study of the efficacy of apomorphine and its assessment in ‘off’-periods in Parkinson’s disease. Clin Neurol Neurosurg 1993;95:231-5.
Ostergaard L, Werdelin L, Odin P, Lindvall O, Dupont E, Christensen PB, et al
. Pen injected apomorphine against off phenomena in late Parkinson’s disease: A double blind, placebo controlled study. J Neurol Neurosurg Psychiatry 1995;58:681-7.
Merello M, Pikielny R, Cammarota A, Leiguarda R Comparison of subcutaneous apomorphine versus dispersible madopar latency and effect duration in Parkinson’s disease patients: A double-blind single-dose study. Clin Neuropharmacol 1997;20:165-7.
Pfeiffer RF, Gutmann L, Hull KL Jr, Bottini PB, Sherry JH; APO302 Study Investigators. Continued efficacy and safety of subcutaneous apomorphine in patients with advanced Parkinson’s disease. Parkinsonism Relat Disord 2007;13:93-100.
Pahwa R, Koller WC, Trosch RM, Sherry JH; APO303 Study Investigators. Subcutaneous apomorphine in patients with advanced Parkinson’s disease: A dose-escalation study with randomized, double-blind, placebo-controlled crossover evaluation of a single dose. J Neurol Sci 2007;258:137-43.
Hattori N, Nomoto M; 6500-004 Study Group. Sustained efficacy of apomorphine in Japanese patients with advanced Parkinson’s disease. Parkinsonism Relat Disord 2014;20:819-23.
Isaacson S, Lew M, Ondo W, Hubble J, Clinch T, Pagan F Apomorphine subcutaneous injection for the management of morning akinesia in Parkinson’s disease. Mov Disord Clin Pract 2017;4:78-83.
Odin P, Ray Chaudhuri K, Slevin JT, Volkmann J, Dietrichs E, Martinez-Martin P, et al
; National Steering Committees. Collective physician perspectives on non-oral medication approaches for the management of clinically relevant unresolved issues in Parkinson’s disease: Consensus from an international survey and discussion program. Parkinsonism Relat Disord 2015;21:1133-44.
Trenkwalder C, Chaudhuri KR, García Ruiz PJ, LeWitt P, Katzenschlager R, Sixel-Döring F, et al
; Expert Consensus Group for Use of Apomorphine in Parkinson’s Disease. 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.
Katzenschlager R, Hughes A, Evans A, Manson AJ, Hoffman M, Swinn L, et al
. Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson’s disease: A prospective study using single-dose challenges. Mov Disord 2005;20:151-7.
Chaudhuri KR, Critchley P, Abbott RJ, Pye IF, Millac PA Subcutaneous apomorphine for on-off oscillations in Parkinson’s disease. Lancet 1988;2:1260.
Todorova A, Ray Chaudhuri K Subcutaneous, intranasal and transdermal dopamine agonists in the management of Parkinson’s disease. Park Dis Curr Futur Ther Clin Trials 2016;48-62.
García Ruiz PJ, Sesar Ignacio A, Ares Pensado B, Castro García A, Alonso Frech F, Alvarez López M, et al
. Efficacy of long-term continuous subcutaneous apomorphine infusion in advanced Parkinson’s disease with motor fluctuations: A multicenter study. Mov Disord 2008;23:1130-6.
Bhidayasiri R, Sringean J, Anan C, Boonpang K, Thanawattano C, Ray Chaudhuri K Quantitative demonstration of the efficacy of night-time apomorphine infusion to treat nocturnal hypokinesia in Parkinson’s disease using wearable sensors. Parkinsonism Relat Disord 2016;33(Suppl 1):36-41.
Chaudhuri KR, Odin P, Antonini A, Martinez-Martin P Parkinson’s disease: The non-motor issues. Parkinsonism Relat Disord 2011;17:717-23.
Rosa-Grilo M, Qamar MA, Evans A, Chaudhuri KR The efficacy of apomorphine—A non-motor perspective. Parkinsonism Relat Disord 2016;33(Suppl 1):28-35.
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.
Radhakrishnan DM, Goyal V Parkinson’s disease: A review. Neurol India 2018;66:26-35.
Borgemeester RW, Lees AJ, van Laar T Parkinson’s disease, visual hallucinations and apomorphine: A review of the available evidence. Parkinsonism Relat Disord 2016;27:35-40.
Borgemeester RWK, van Laar T Continuous subcutaneous apomorphine infusion in Parkinson’s disease patients with cognitive dysfunction: A retrospective long-term follow-up study. Parkinsonism Relat Disord 2017;45:33-8.
Alegret M, Valldeoriola F, Martí M, Pilleri M, Junqué C, Rumià J, et al
. Comparative cognitive effects of bilateral subthalamic stimulation and subcutaneous continuous infusion of apomorphine in Parkinson’s disease. Mov Disord 2004;19:1463-9.
De Gaspari D, Siri C, Landi A, Cilia R, Bonetti A, Natuzzi F, et al
. Clinical and neuropsychological follow up at 12 months in patients with complicated Parkinson’s disease treated with subcutaneous apomorphine infusion or deep brain stimulation of the subthalamic nucleus. J Neurol Neurosurg Psychiatry 2006;77:450-3.
Dafsari HS, Martinez-Martin P, Rizos A, Trost M, Dos Santos Ghilardi MG, Reddy P, et al
; EUROPAR and the International Parkinson and Movement Disorders Society Non-Motor Parkinson’s Disease Study Group. Euroinf 2: Subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson’s disease. Mov Disord 2019;34:353-65.
Martinez-Martin P, Reddy P, Katzenschlager R, Antonini A, Todorova A, Odin P, et al
. Euroinf: A multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson’s disease. Mov Disord 2015;30:510-6.
Sesar Á, Fernández-Pajarín G, Ares B, Rivas MT, Castro A Continuous subcutaneous apomorphine infusion in advanced Parkinson’s disease: 10-year experience with 230 patients. J Neurol 2017;264:946-54.
Pietz K, Hagell P, Odin P Subcutaneous apomorphine in late stage Parkinson’s disease: A long term follow up. J Neurol Neurosurg Psychiatry 1998;65:709-16.
LeWitt PA, Ondo WG, Van Lunen B, Bottini PB Open-label study assessment of safety and adverse effects of subcutaneous apomorphine injections in treating “off” episodes in advanced Parkinson disease. Clin Neuropharmacol 2009;32:89-93.
Ramot Y, Nyska A, Adar L, Durlach C, Fishelovitch D, Sacco G, et al
. ND0701, A novel formulation of apomorphine for subcutaneous infusion, in comparison to a commercial apomorphine formulation: 28-day pharmacokinetic study in minipigs and a phase I study in healthy volunteers to assess the safety, tolerability, pharmacokinetics and relative bioavailability. CNS Drugs 2018;32:443-54.
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.
Olanow CW, Factor SA, Espay AJ, Hauser RA, Shill HA, Isaacson S, et al
; CTH-300 Study Investigators. 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.
Grosset KA, Malek N, Morgan F, Grosset DG Phase IIa randomized double-blind, placebo-controlled study of inhaled apomorphine as acute challenge for rescuing “off” periods in patients with established Parkinson’s disease. Eur J Neurol 2013;20:1445-50.
Grosset KA, Malek N, Morgan F, Grosset DG Inhaled dry powder apomorphine (VR040) for “off” periods in Parkinson’s disease: An in-clinic double-blind dose ranging study. Acta Neurol Scand 2013;128:166-71.
Grosset KA, Malek N, Morgan F, Grosset DG Inhaled apomorphine in patients with ‘on-off’ fluctuations: A randomized, double-blind, placebo-controlled, clinic and home based, parallel-group study. J Parkinsons Dis 2013;3:31-7.
Prakash N, McFarthing K, Simuni T Clinical trial highlights—Infusion therapies. J Parkinsons Dis 2020;10:5-17.
Ray F FDA accepts resubmitted new drug application for APL-130277... [Internet]. Parkinson’s News Today. 2020 [cited 2020 Mar 12]. Available from: https://parkinsonsnewstoday.com/2020/01/06/fda-accepts-resubmitted-new-drug-application-apl-130277-apomorphine-film-parkinsons/. [Last accessed on].
Samuel M, Rodriguez-Oroz M, Antonini A, Brotchie JM, Chaudhari KR, Brown RG, et al
. Management of impulse control disorders in Parkinson’s disease: Controversies and future approaches. Mov Disord 2015;30:150-9.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]