The latest 2022 EAN/MDS guidelines [19] for the invasive treatment of PD recommend considering apomorphine pump infusion for people with advanced PD if fluctuations are not satisfactorily controlled with medication. However, these guidelines do not address apomorphine’s role in managing PD sleep disorders. Our study specifically focuses on treating sleep disorders, conducting a systematic evaluation of clinical trials on apomorphine from the past decade to assess its safety and efficacy in addressing sleep disorders in PD patients.
Our findings suggest that apomorphine can enhance and maintain sleep quality by addressing abnormal movements, daytime sleepiness, and insomnia, ultimately improving sleep disorders in PD patients. These factors significantly impact the quality of sleep in PD patients. Based on the difference in PDSS scores between patients with advanced PD and moderate to severe insomnia, subcutaneous nocturnal infusion of apomorphine alone can improve sleep disturbances, and it is safe and well tolerated. However, it is important to note that different routes of administration and doses can result in varying clinical effects, such as effects on daytime sleepiness.
Apomorphine for PD Sleep Disorder
PD often leads to a wide range of non-motor symptoms, with sleep disturbances being highly prevalent among PD patients [20]. In a prospective study by Gustavo Fernández-Pajarín[21], four PD patients received continuous apomorphine infusion over 24 h, resulting in noticeable improvements in sleep quality. Interestingly, this improvement does not appear to be solely linked to enhancements in the nocturnal OFF-time state, which is frequently observed in patients using overnight apomorphine infusion. Some prior research [8, 22, 23] has proposed that apomorphine’s primary mechanism of action, particularly in addressing PD OFF episodes, lies in its impact on D2 receptors in the caudate and shell nucleus. We contend that the alleviation of nocturnal motor symptoms stands as the primary driver behind the enhanced sleep quality experienced by advanced PD patients. Apomorphine, acting as a dopamine agonist, interacts with all dopamine receptor subtypes. Notably, D1 and D2 receptors predominantly influence motor functions. Continuous dopaminergic stimulation during the night may not necessitate as high a dosage as during the daytime. However, findings from Robbert W.K. Borgemeester’s research [24]also suggest that daytime-only injections may have a positive impact on nighttime sleep issues.
Regarding sleep enhancement, the study by Chaudhuri KR[12] suggests that apomorphine may be beneficial for addressing rapid eye movement behavior disorder (RBD) and restless legs syndrome (RLS). Valérie Cochen De Cock[11] proposes that sleep quality might be improved by enhancing the proportion of sleep stage N2, possibly at the expense of N3 and rapid eye movement sleep. Reuter I[16] indicates that sleep quality could be enhanced by mitigating freezing and turning difficulties during the night, reducing instances of nocturnal waking or nocturia, thereby reflecting an improvement in sleep quality. Gustavo Fernández-Pajarín’s study [13] highlights the importance of improving daytime sleepiness, although it is worth considering that apomorphine’s pharmacokinetics might differ from other dopamine agonists. After a thorough review of the literature, it becomes evident that most investigators favor apomorphine due to its ability to enhance motor symptoms, consequently leading to improved sleep quality. Expert reviews recommend conducting comprehensive sleep studies to assess the beneficial relationship between apomorphine treatment and sleep disturbances in PD patients. Thus, we suggest the need for further clarification regarding the scales available for evaluating sleep disorders in PD patients. The utilization of more definitive scales, along with more comprehensive and accurate statistical analyses, could enhance the robustness of study outcomes.
The improvement in sleep disturbances among PD patients attributed to apomorphine may involve additional mechanisms. However, the precise effects of apomorphine or other antiparkinsonian drugs in this regard remain uncertain, warranting further investigations and clinical trials.
Contraindications for Apomorphine[9]
1) Hemolytic anemia; 2)ECG changes (prolonged QT, atrial fibrillation, tachycardia, bradyarrhythmias, premature ventricular contractions); 3)Use of anticoagulants; 4) Diabetes and other conditions that hinder surgical wound healing; 5) Cellulite and other local infections; 6) Hypersensitivity to apomorphine or its components, such as sodium metabisulfite; 7) Severe psychiatric symptoms. LCIG is considered as an alternative when contraindications to apomorphine exist, or when patients exhibit poor compliance, resistance to the drug, severe cognitive impairment, or concerns about addiction and safety[19].
Route of Administration and Dosage
The absorption of the drug in the human body varies depending on the injection site; thus, necessitating individualized optimal apomorphine dosages.
Oral administration, the oldest method, is currently discouraged due to its high first-pass effect, very low bioavailability, and potential nephrotoxicity[7]. Intermittent subcutaneous injections, administered using a device similar to an insulin injection pen, involve a total daily dose of ≤ 100 mg and single injections of ≤ 10 mg. They are currently indicated for treating motor fluctuations (e.g., wear and tear and switch fluctuations) in ongoing studies [6, 9]. However, there is no consensus on the intermittent dosing strategy[25]. Continuous subcutaneous apomorphine infusion, facilitated by a portable syringe-driven pump[6], lacks robust supporting evidence. Intravenous infusion offers extremely high bioavailability, potentially reaching up to 100%[23]. Our study proposes continuous subcutaneous infusion at night (4 mg/h) to alleviate sleep disturbances with fewer adverse reactions at this dosage. However, long-term usage is discouraged, with the most severe adverse effect being the potential for catheter crystallization leading to thrombosis[23]. During continuous subcutaneous apomorphine infusion, dopamine agonists can be gradually phased out, as abrupt discontinuation may trigger dopamine agonist withdrawal syndrome[26].
In the study by L. Priano et al.[27] utilizing transdermal administration of apomorphine microemulsion (50 mg), results exhibited a notable decrease in arousal index and CAP rate/non-rem (p = 0.03; p = 0.01), along with an increase in total sleep time, sleep efficiency, and an improvement in sleep disturbances throughout the treatment period. Nevertheless, this approach warrants further consideration and validation. Sublingual administration is presently undergoing clinical trials[28–30], while the nasal formulation remains unvalidated [31]. It is anticipated that safer and more effective methods will emerge in the future.
Prevention of Adverse Effects
Subcutaneous nodules and erythema may naturally recede or can be treated with a combination of massage, emollient creams, and hyaluronidase[16]. Recent studies have demonstrated that subcutaneous hydrocortisone reduces nodule size[32]. For alleviating nausea and vomiting, oral domperidone 10 mg is recommended [33, 34]. However, patients with PD and a history of cardiac disease may opt for trimethoprim instead. In additional studies, rare hematological adverse reactions have been identified, necessitating appropriate testing for autoimmune hemolytic anemia[23]. It is noteworthy that all adverse events can be reversed after therapy discontinuation.