In the UK, Parkinson's disease (PD) is estimated to have an annual incidence of 15–20 per 100 000 of the population over the age of 60 (Meira et al, 2021). Parkinson's is an incapacitating disease and categorised by long-lasting neurodegeneration of the striatal region of the brain that causes the absence of neurotransmitter dopamine (Borkar et al, 2018). The condition may progress to cause life–debilitating impairments, which can have a negative impact on quality of life and indirectly to those surrounding the individual, such as family and carers (Boyle and Ondo, 2015). PD is untreatable; however, a range of symptomatic treatments are available to develop the quality of life as well as longevity for the advanced PD service user, and research has shown apomorphine to be an effective treatment to manage those symptoms (Alonso-Canovas and Martinez-Castrillo, 2021).
Service users living with advanced-stage PD require the use of apomorphine. In subcutaneous formulations, it is an effective dopamine agonist, which is generally used to control symptoms. Where nerve cells that synthesise the chemical dopamine have died, apomorphine acts as a dopamine stimulation for nerve cells (Todd and James, 2008). The nerves are then able to control body movement and other functions, which helps reduce symptoms of bradykinesia, rigidity, mild memory and problems with thinking, balance and speaking, also known as ‘off’ periods in advanced PD (National Institute for Health and Care Excellence (NICE), 2017). The significance of apomorphine is that it is the oldest dopaminergic drug for treatment in advanced PD, yet the author challenges the widely held view that its subcutaneous administration route has not been altered, only refined, throughout recent decades.
Weil (1884) first theorised that the dopamine agonist apomorphine could be useful in people with advanced PD without providing any validation behind their hypothesis. Almost 70 years later, US neurologists Schwab and Prichard (1951) began clinical trials using apomorphine to treat PD symptoms. However, it was not until the mid-1980s when researchers Stibe et al (1988) successfully launched the apomorphine therapy on PD service users in London (Aronson, 2016). This pioneering research was able to show the efficiency of apomorphine therapy when used in a continuous infusion that reduced ‘off’ periods in 5–10 minutes, which meant service users were enabled to maintain their autonomy and live a better quality of life (Colosimo et al, 1994; Trenkwalder et al, 2015).
Apomorphine is only available in injection or infusion. It is normally prescribed when the symptoms of PD cannot be controlled or become unresponsive to oral therapies such as levodopa (Medline, 2019). The Food and Drug Administration (FDA) approved the use of levodopa in 1970, and it is still used in early stages of PD. A major drawback of this approach is that prolonged use of levodopa can cause symptoms of disabling biphasic or peak dose dyskinesia and dystonia (Colosimo et al, 1994; NICE, 2017). Carbone et al (2019) found in the APO202 study (Dewey et al, 1998) that dyskinesia as an adverse event was reported in 35% of the apomorphine subjects, compared with the 11% in the placebo group (see Table 1 for other adverse effects). In addition, dopamine agonists used in conjunction with Levodopa are considered the gold standard approach to relieve symptoms of PD, harmonised by apomorphine in its effect on motor fluctuations (caused by levodopa) (Frankel, 1990; Svenningsson et al, 2017; Royal Pharmaceutical Society, 2019). However, these results were based on data from several years ago, and it is unclear if apomorphine can be perceived as most effective if there are no other viable methods to compare to.
Table 1. Adverse events of subcutaneous and sublingual apomorphine delivery
| Subcutaneous apomorphine | Sublingual apomorphine |
|---|---|
|
|
There is a non-drug alternative to control symptoms of PD that includes deep brain stimulation (DBS). DBS involves the imbedding of electrodes onto precise areas of the brain. These electrodes create electrical impulses that are able to normalise irregular impulses (Little and Brown, 2020). Another problem to this approach is that it fails to consider service users with advanced PD who have complex comorbidities, as they are at a greater risk of undergoing complications associated with surgeries (Gülke and Pötter-Nerger, 2021). In the best interest of the service user with advanced PD, as an individual, this method may not be suitable, nor appropriate.
The district nursing service plays a key role in monitoring and in the administration of apomorphine therapy, as district nurses (DNs) visit advanced PD service users daily to prepare and apply the continuous subcutaneous apomorphine infusion (CSAI). The intervention involves the use of a thin tubing with a small needle at the end, which is then inserted into the skin (Rosa-Grilo et al, 2016). The complexity of this administration route can mean that, if complications arise for these housebound service users, the DNs are the first point of contact to return and assist with this. Perhaps the most serious disadvantage to this method results from home visits being prioritised as time crucial to avoid experiences of ‘off’ periods. This impacts the DN service, as longer durations of time are required to support these service users, leading to a task-focused approach rather than a holistic approach (Maybin et al, 2016; Queens Nursing Institute (QNI), 2017).
This article focuses on new clinical developments of alternative routes to apomorphine therapy. It aims to enhance the potential of non-invasive treatment, such as sublingual therapy, in provision of care for service users with advanced PD. It explores best practice considerations of apomorphine therapies, as well as present arguments for collaborative working in this intervention so that treatment and provision of care for advanced PD service users can be enhanced. The purpose of this article is to derive pertinent literature that presents evidence and contributes to the body of knowledge around current interventions of treatment, ensuring shared insight with all readers who collaborate and specialise in the care of individuals with advanced PD. As this has been a DN-led intervention for a number of decades, it is considered the gold standard in the management of symptoms in advanced PD service users. Thus far, the complications and adverse reactions of CSAI therapy persist, while demands on the DN service increase; there is an excessive need for more focus on a less complex intervention in delivery route of treatment.
Alternate apomorphine therapy developments
The usual route for apomorphine delivery has been subcutaneous, and it is licensed for treatment via administration of injection or infusion in the UK (Table 2). The indication for subcutaneous apomorphine treatment in advanced PD is of acute, intermittent ‘off’ periods and hypomobility in service users (NICE, 2022). It has proven effective, yet Titova and Chaudri (2016) concluded that skin problems such as nodules, skin irritation, and skin ulceration are the most commonly reported adverse events that can complicate efficiency of treatment and lead to withdrawal of treatment or non-compliance. There are both mechanical and inflammatory disadvantages to this route; Todd and James (2008) found the incidence of nodules is due to needles entering the skin, which alters blood flow. Furthermore, Katzenschlager et al (2021) discovered this can be minimised by ensuring exhaustive skin hygiene, making use of new needle technology, alternating injection site, and using localised massage and ultrasound therapy. Despite this, Aronson (2016) identified that service users with advanced PD require prolonged use of CSAI, which therefore means an increase of nodules, signifying reduced absorption and reduced efficiency of CSAI use.
Table 2. Differences between subcutaneous apomorphine and sublingual apomorphine
| Subcutaneous apomorphine | Sublingual apomorphine | |
|---|---|---|
| Administration | 12–14 hours, device used for continuous subcutaneous apomorphine infusion pump | Administered by placing under the tongue |
| Efficacy | 20–40 minutes for on period | 15–30 minutes for on period |
| Application | Injection | Rapid diffusion |
| Invasiveness | Invasive | Non-invasive |
| Availability of dose | 2/3/4/5 mg in 1 ml | Doses available |
| Complexity of administration | Complex assembly, requiring mandatory training | Simple administration |
| Cost | APO-go PFS 50 mg/10 ml £73.11 | Cost: Kynmobi – 10/15/20/25/30 mg = $33.70 |
Sublingual apomorphine intervention
There is an evident unmet need for an alternative administration route for apomorphine therapy, as the existing delivery system is complex and invasive. While this route still remains valuable, research is moving forward to match those in use in the US (Carbone et al, 2019). Active clinical development of a pioneering alternative to apomorphine delivery have been tested and shown to have effective results. In a pivotal phase 3, randomised, double-blind, placebo-controlled trial of advanced PD patients, the efficacy and safety of apomorphine sublingual film were evaluated. The findings from this trial showed a significant improvement of motor functions. It also revealed that the use of an apomorphine sublingual film was an effective, safe and well-tolerated treatment (Agbo et al, 2021).
The indication for use is treatment of acute, intermittent ‘off’ periods in service users with advanced PD, similar to the CSAI delivery, excluding the hypomobility. Instructions to administer a sublingual film specify not to remove until directly before use; drink water to moisten mouth; apply film to be placed under the tongue and leave to dissolve for up to 3 minutes; do not talk or swallow saliva during dissolving of film as this can disrupt absorption; and administer whole; do not cut, chew or swallow (Kynmobi, 2021) (Table 2). The sublingual apomorphine preparation consists of an innovative two-strip film, which contains apomorphine on the bilayer, which has shown reliability to regress ‘off’ periods in several experimental trials (Borkar et al, 2018). Olanow et al (2020) suggested that sublingual apomorphine has been known as a feasible alternative to the CSAI route for years. A Parkinson's-specific pharmacological approach to the use of sublingual apomorphine therapy purports to endorse and support quality of life for the person living with advanced PD (Hui et al, 2021). The significant advantages of this method are a lesser need for manual dexterity; no needles, skin irritation and pain, and easy administration, even during severe ‘off’ periods, which therefore reduces harm to the service user (Aronson, 2016).
Pharmacology
In the US, this pharmaceutical intervention has been approved and licensed under the brand name Kynmobi, whereas, in the UK, clinical trials remain in their third clinical phase. Moreover, Sunovion Pharmaceuticals, who introduced sublingual delivery to the US, has entered into a licensing agreement with BIAL Pharma (Sunovian, 2021) in the UK to introduce sublingual apomorphine into the UK, which is a promising development for individuals with PD (FDA, 2020). It delivers an effectual relief in service users with erratic ‘off’ phases, and provisional coadministration with an antiemetic drug such as domperidone has suggestively augmented tolerability towards new approaches and new formulations of the drug to reduce complications and increase its accessibility, safety and efficiency profiles (Carbone et al, 2019; FDA, 2020; Meira, 2021) (Table 3). A non-timed sublingual administration route is relevant to the challenges faced by DNs. As the workforce has decreased, it poses a direct threat to the safety of service users (Moffatt, 2019). The apomorphine delivery of CSAI requires altering for the benefit of both service user and DN service.
Table 3. Medication interactions and side-effects
| Medications | Indication | Interaction | Side-effect |
|---|---|---|---|
| Ondansetron | Antiemetics – to treat nausea and vomiting | Kynmobi (Sublingual film) APO-go PFS (Subcutaneous) | Loss of consciousness |
| Nitro-glycerine | Used to relieve chest pain in certain heart conditions | Kynmobi (Sublingual film) APO-go PFS (Subcutaneous) | Increase risk of lowered blood pressure |
| lisinopril Valsartan Hydrochlorothiazide Amlodipine | Anti-hypertensives to lower blood pressure | Kynmobi (Sublingual film) APO-go PFS (Subcutaneous) | Increased risk of lowered blood pressure |
| Metoclopramide Prochlorperazine Haloperidol | Dopamine antagonists work in the opposite way to Apomorphine which is a dopamine agonist | Kynmobi (Sublingual film) APO-go PFS (Subcutaneous) | Risk of Kynmobi not working well or having no effect. |
| Amiodarone Amitriptyline Flecainide Haloperidol Quetiapine | Affects the QT interval | Kynmobi (Sublingual film) APO-go PFS (Subcutaneous) | Increased risk of affecting the QT interval |
| Domperidone | Nausea and Vomiting | APO-go PFS 5 mg/ml | Palpitations, syncope, or near syncope, and orthostatic hypotension. |
| Clozapine Thioridazine Chlorpromazine Thiothixene | Reduces the symptoms of neuropsychiatric complications | APO-go PFS 5 mg/ml | Neuroleptic medicinal products may have an antagonist effect |
Importantly, abrupt withdrawal of dopaminergic medications can lead to Parkinsonism-hyperpyrexia syndrome; while it is rare, it is a life-threatening complication of the management of service users with advanced PD (Grover et al, 2018). The central hypodopaminergic state often goes undetected by health professionals, as it is a rare medical emergency and can be mistaken for sepsis or deterioration of PD. Additionally, clinical indications of this syndrome are comparable to neuroleptic malignant syndrome; characteristics consist of hyperpyrexia, stiffness, distorted consciousness, dysautonomia, leucocytosis and raised creatine kinase. The reintroduction of Parkinson's treatment is vital to prevent morbidity and mortality (Factor, 2008; Auffret et al, 2018).
Collaboration
The DN service, who perform the intervention of apomorphine therapy will already be working in collaboration with the wider multi-disciplinary team (MDT) to manage symptoms and adverse events of apomorphine therapy. Collaboration between DNs, GPs, PD specialist nurses and community pharmacists is essential to meet the complex needs of those living with advanced PD, as this can play a fundamental role in therapy compliance and in preventing adverse events (Boyle and Ondo, 2015). The drug's side effects can severely impact an individual with advanced PD lifestyle, such as sleep disturbances and the sudden onset of sleep, sedation, nausea, hypotension and fainting, anaemia and other blood disorders, as well as cardiac problems (palpitations) and hallucinations and delusions (Gibb and Lees, 1989; Aronson, 2016; Hui et al, 2021) (Table 4).
Table 4. Warnings and precautions associated with apomorphine drug use
| APO-go PFS (subcutaneous infusion) Kynmobi (sublingual film) | APO-go PFS (subcutaneous infusion) |
|---|---|
|
|
Individuals living with advanced PD require habitual clinical specialist care and a person to contact for assistance with medicines management, home visits, and educational provision from a PD specialist nurse (NICE, 2017; QNI, 2017; NMC, 2019). These are already being implemented with the use of CSAI intervention from DNs and the wider MDT. Furthermore, apomorphine therapy when delivered at a high standard ensures clinical excellence to safeguard advanced PD-specific service users from harm (Katzenschlager et al, 2021). This same approach should be transferred into the use of a sublingual apomorphinedelivery system.
In addition, achieving good communication between advanced PD service users, family, and informal carers is essential to empower the service user to contribute to shared decision-making and make appropriate choices about their own health (NICE, 2017). It is also important to recognise that apomorphine use can lead to impulsive and compulsive behaviours. Impulsive control disorders include pathological gambling (Molina et al, 2000), binge eating, spending disorders, increased libido and hypersexuality which can affect those around them, and they may be embarrassed or uncomfortable to talk about (Meira et al, 2021). DNs are holistic practitioners who have the expertise to recognise, support and refer when necessary, to the right services, as well as referring to the PD specialist nurse and GP who can also continue to offer support with these matters (Maybin et al, 2016). The importance of collaborative working means the service user will be able to have personalised care reflected from all health professionals involved and feel valued and respected that their health is suitably entrusted.
The role of the district nurse
The DNs are accountable for the administration of apomorphine intervention and responsible for care delivered during each home visit to assist with CSAI for advanced PD users. The DN's role is to ensure that a comprehensive assessment of the service user is carried out as this is a specialist DN requirement for maintaining high standards in the quality of care for these individuals (NICE, 2017; Duncan, 2021). The DNs take necessary risk assessments to safeguard advanced PD service users, but as the current technique is a prolonged invasive procedure, this increases the risk of adverse events, even if best practice considerations are followed.
DNs are able to build therapeutic relationships with these service users and may also be engaged in assisting families with personalised care plans (McCrory, 2019; Duncan, 2021). This is why DNs should lead the intervention of sublingual apomorphine therapy; it will empower advanced PD service users to maintain their autonomy and dignity (Alonso-Canovas and Martinez-Castrillo, 2021). The experience of ‘off’ periods can be debilitating when motor fluctuations are not controlled, and these individuals then have to wait for the DN's arrival before being able to regain control again. Due to the increase in demands of the DN service, this time-crucial intervention can be unpredictable to meet, even with best efforts made (Royal College of Nursing (RCN), 2019).
Key benefits
The use of a sublingual strip reduces the complexity of this administration route, which therefore means even if a DN visit is required there will be a reduced duration of ‘off’ periods, reduced time required for preparation and administration, reduced complexity during a home visit and reduced adverse events (Meira et al, 2021). This can enable the DNs to become less task-orientated and reduce stress, as well as allowing a more comprehensive approach to care for the service user with advanced PD. Hence, this is why an alternative delivery route system is long-awaited.
Dissemination
The DNs will monitor the treatment of sublingual apomorphine therapy. Difficulties can arise when attempting to influence policy; however, DNs already adhere to their medicines management policies in regard to apomorphine administration. They keep up to date with training, as well as document precise details of apomorphine delivery and report any adverse events, which are monitored through auditing (NMC, 2019). If tolerated well by the service user, the DNs can perform a risk assessment based on the shared care agreement between all care providers in the care of these specific service users. This includes the individual; the DN service; the family or informal carer; community pharmacists, GPs; and the PD specialist nurse, and, in return, the needs of the PD service user can be met and sustained(Boyle and Ondo, 2015).
The DNs can oversee the care of these service users and allocate a named nurse who regularly communicates with the wider MDT, as they should currently do with the CSAI, and use an integrative approach to then cascade within the DN team. The collaborative approach with the DN service will improve quality of care and enhance the standards delivered to these service users living with PD (Titova and Chaudri, 2016). In order for this intervention to be embedded into practice as proficiently as the CSAI has been, DNs should be prepared to advocate for the most appropriate treatment available for these service users (Duncan, 2021).
Unsolved considerations
In the history of apomorphine therapy, researchers were previously hindered in progress until domperidone was used in combination to reduce nausea. This meant tolerability was improved, but it also meant blood pressure was reduced (Hui et al, 2020). Despite the sublingual delivery system having a generally lower adverse reaction in comparison to the CSAI delivery, it does not come without reported complications such as oral cavity-related adverse events, dry mouth, lip oedemaand throat irritation (Borkar et al, 2018; Carbone et al, 2019). The adverse events go beyond nausea and vomiting and include a significant amount of cardiovascular side effects. This could mean seeking expert support from professionals who specialise in these specific health-related issues. This intervention needs a collaborative approach to ensure all areas of care are considered and acted upon, also ensuring timely access to resources are provided (NICE, 2017).
Conclusion
In conclusion, apomorphine therapy is the most efficient intervention for advanced PD service users. DNs play a key role in this intervention of apomorphine therapy for these individuals. Although proven effective, subcutaneous administration can affect both the service user and the DN service. The alternative routes to apomorphine administration, such as sublingual delivery, means it is less invasive and complex in its use. Service users living with advanced PD can be offered an alternative method, which safeguards them from adverse events. Evidence demonstrates effective collaboration is already taking place and these same high standards of clinical governance should be transferred so clinical excellence is maintained in the use of an alternative sublingual route. To embed this into contemporary practice, DNs should be prepared to advocate for the most appropriate treatment available for service users living with advanced PD. Although a sublingual delivery route is a promising development, caution should be advised in the increased risk of oral cavity-related adverse events. Recommendations derived from the evidence is for the need of further research in the efficiency and safety in sublingual delivery route.
Key points
- Apomorphine is considered the most effective symptomatic treatment in advanced Parkinson's disease
- Apomorphine therapy can lead to complications that can affect both service users and district nurse services
- District nurses work in collaboration with the wider multi-disciplinary team to ensure needs are met holistically to manage symptoms of advanced Parkinson's disease
- An alternative method to apomorphine delivery is currently active in clinical trials, awaiting approval for licenced use in the United Kingdom
CPD reflective questions
- What symptoms can develop from prolonged Levodopa treatment in advanced Parkinson's disease?
- What are the main aims of management and treatment of apomorphine therapies?
- What are the main treatment options in advanced Parkinson's disease?