Parkinson’s disease: management and guidance

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative condition resulting from the loss of the dopamine-containing cells of the substantia nigra, and its prevalence increases with age^[1]
. Using primary care data from 2015, a Parkinson’s UK report of the Clinical Practice Research Datalink found that the prevalence of PD is 4–5 per 100,000 people who are aged 30–39 years, compared with 1,696 per 100,000 people who are aged 80–84 years^[2]
. Prevalence rates almost double at each five-year interval between the ages of 50 and 69 years for both men and women. The lifetime risk of being diagnosed with PD is 2.7% — equating to 1 in every 37 people being diagnosed at some point in their lifetime. Owing to population growth and an increasing ageing population, the estimated prevalence of PD is expected to increase by 23.2% by 2025^[2]
.

Aetiology

The cause of PD still remains unknown but it has long been hypothesised that exposure to environmental risk factors may be one cause, along with an inherited susceptibility. The majority of cases are thought to arise sporadically, although up to 20% of people with PD also have a first-degree relative with PD. It is theorised that 24 genetic loci have a clinically significant association with PD risk^[3],[4],[5]
. Consequently, it is currently believed that parkinsonian syndromes are a blanket term for several neurodegenerative diseases. Studies show that age of onset is important and that onset after 50 years of age is less likely to be genetically influenced^[6]
. The development of PD is negatively associated with cigarette smoking, coffee and alcohol consumption, while physical activity has been shown to be beneficial in relieving symptoms in those undertaking the PD Warrior programme^[7]
.

Pathophysiology and presenting features

Classic presenting features of PD include motor symptoms, such as bradykinesia, rigidity, rest tremor and postural instability. However, non-motor symptoms, such as depression, cognitive impairment, pain and autonomic disturbances, are also often present and they can severely affect a patient’s quality of life^[8]
. There are several information sheets available for patients that cover the management of multiple common types of pain in PD^[9]
.

The motor symptoms are largely caused by the progressive loss of dopaminergic neurons in the substantia nigra compacta, which ultimately reduces dopaminergic input to the striatum and other brain regions^[10]
. Compensatory mechanisms in the brain are so effective that the clinical symptoms of PD may only develop when around 80% of dopaminergic neurons have degenerated^[1]
. By contrast, the Braak theory of PD suggests that the disease process starts in the olfactory bulb and lower part of the medulla, and it is not until stage 3 that the substantia nigra becomes involved in the process^[11]
. There is also direct evidence of Parkinson pathology being spread from the gastrointestinal (GI) tract to the brain in rodents^[12]
. There are therapeutic implications of gut involvement; it is known that swallowing and the stomach are the two main problems of PD therapy and lead to the use of non-oral therapies.

Historically, the three pathological hallmarks of PD were the presence of Lewy bodies, neuronal death in the pars compacta of the substantia nigra and the loss of pigmented neurons in pigmented brainstem nuclei. Lewy bodies are protein aggregates of abnormal alpha-synuclein and were believed to be pathogenic in PD, leading to cell death. The number of Lewy bodies increases with age, which correlates with the increasing incidence of PD in older people. However, it is important to note that the presence of Lewy bodies can be asymptomatic and not associated with PD^[3]
, as their presence can also be found in other neurodegenerative diseases (e.g. Alzheimer’s disease, multisystem atrophy and Lewy body dementia)^[3]
.

Diagnosis

PD is notoriously difficult to diagnose because patients present in different ways and there are no specific diagnostic tests available. Studies have found that diagnosis of PD in the community was incorrect in around 50% of patients, in up to 25% of patients in generalist care clinics and 6–8% in specialist clinics when diagnosed by an expert in movement disorders^[1]
.

If PD is suspected, patients should be referred quickly and untreated to a specialist with expertise in the differential diagnosis of the condition^[5]
.

After a formal diagnosis of PD has been made, patients should be reviewed regularly at 6–12-monthly intervals and if atypical clinical features develop, the diagnosis should be reconsidered^[5]
. These reviews should be undertaken by a member of the specialist team (e.g. the pharmacist, nurse or consultant).

PD and many of its symptoms can be potentially mimicked by any drug that is able to block dopamine receptors. Neuroleptics are the most common cause of drug-induced parkinsonism, with the atypical neuroleptics (e.g. quetiapine and clozapine) being the best options in PD for the treatment of hallucinations and confusion when used cautiously (see Table 1). Metoclopramide and prochlorperazine should be avoided, and domperidone, cyclizine and ondansetron are the better treatments to manage nausea and vomiting in PD. In addition, care needs to be taken when prescribing antihistamines, antidepressants, antipsychotics and antihypertensives in PD — particularly the calcium channel-blocking drugs flunarizine and cinnarizine — as all these drug groups need careful monitoring^[1],[13]
.

Management

Before starting on any treatment, it is important to discuss with patients their individual clinical circumstances (e.g. symptoms and comorbidities). Their lifestyle preferences are also important, for example people in full-time employment often prefer to have a once-daily dosage regimen if possible. As all medicines for PD are symptomatic, with no neuroprotective agents currently available, treatment should only be initiated when quality of life is affected^[5]
, and the potential benefits and side effects of these drug classes should be discussed with the patient (see Table 2)^[5]
.

Initiating pharmacological treatment

A dopamine agonist, levodopa or a monoamine oxidase-B inhibitor can be offered to people in the early stages of PD whose motor symptoms do not impact on their quality of life^[5]
.

Levodopa is the gold standard treatment when motor symptoms impact on quality of life, but after 7–10 years of disease progression, levodopa response can fluctuate and, therefore, be less effective at controlling motor symptoms^[1]
. Pharmacists and healthcare professionals should be aware that patients with PD may experience bowel and salivary difficulties (as described by James Parkinson in his original 1817 essay^[14]
). GI disturbances are a frequent non-motor feature in PD and exist in all stages of the disease^[15]
, as well as dysphagia, delayed gastric emptying and constipation. Recognition of delayed gastric emptying is important because it has implications for the absorption and action of levodopa. There is also evidence of additional small intestinal bacterial overgrowth in PD, the cause of which is unknown, and this impairs the absorption of levodopa and contributes significantly to response fluctuations^[16]
. For these reasons, non-oral therapies (e.g. patch formulation) are useful in PD management.

All dopaminergic medicines have the potential to cause impulse-control disorders and hallucinations. Dopamine agonists have the highest risk of impulse-control disorders^[17]
, excessive sleepiness, sudden sleep onset and psychotic symptoms (e.g. hallucinations or delusions). Impulse-control disorders can include compulsive gambling, hypersexuality, binge eating and obsessive shopping. It is important that a patient has a point of contact (e.g. the specialist pharmacist or specialist nurse involved in their care) should any impulse-control disorders develop. Management of impulse-control disorders involves modifying dopaminergic therapy by first gradually reducing any dopamine agonist. If this is ineffective, specialist cognitive behavioural therapy can be offered. It is important that patients and carers or family members are given oral and written information about impulse-control disorders when dopamine agonist therapy is initiated and this should be discussed at review appointments^[5]
.

Ergot-derived dopamine agonists (e.g. pergolide, bromocriptine and cabergoline) should only be offered as an adjunct to levodopa for people with PD who have developed dyskinesia or motor fluctuations despite optimal levodopa therapy and who have an inadequate response to a non-ergot agonist (e.g. ropinirole, pramipexole and rotigotine [patch]). However, the ergot-derived dopamine agonists are associated with severe fibrotic side effects that now limit their use. The oral non-ergot agonists (e.g. ropinirole and pramipexole) have the advantage that they can be prescribed as once-daily formulations. However, care needs to be taken when prescribing pramipexole in view of its availability as a base and a salt, with doses and strengths normally stated in terms of pramipexole base^[18]
. All dopamine agonist doses should be increased gradually, and withdrawn gradually to prevent symptoms of dopamine withdrawal (see Table 3).

As well as a dopamine agonist prescription, there is an increased risk of developing impulse-control disorders if a patient with PD has a past history of impulsive behaviours or a history of alcohol consumption and/or smoking^[19]
.

Switching to alternative drug treatments

A dopamine agonist, monoamine oxidase-B inhibitor or catechol-O-methyltransferase inhibitor can be offered as an adjunct to levodopa for people with PD who have developed dyskinesia or motor fluctuations, despite optimal levodopa therapy (see Table 4). If dyskinesia is not adequately managed by modifying existing therapy, amantadine is often used in practice, although the current evidence for its use is limited (see Table 4).

Importance of the multidisciplinary team

The updated National Institute for Health and Care Excellence (NICE) guidance acknowledges the importance of a multidisciplinary team when managing PD, with referral suggested to therapists trained in the management of the condition, for example physiotherapy^{[20],[21],[22]}
, occupational therapy^[23]
, speech and language therapy^[24],[25]
, and nutrition therapy^{[26],[27],[28]}
. In addition, NICE has recommended further research aimed at investigating whether physiotherapy started early in the course of PD, as opposed to after motor onset, confers benefits in terms of delaying symptom onset and/or reducing severity.

The role of the pharmacist

In view of the age of onset of symptoms of PD, patients often have several comorbidities (e.g. diabetes, cardiovascular disease, hypertension, asthma or chronic obstructive pulmonary disease), and pharmacists are well-placed to manage the patient holistically and advise on any potential medicine interactions that could occur. This was demonstrated in a recent study involving a PD-specific medicines-use review pilot across eight pharmacies in London^[29]
. In the pilot, patients welcomed the opportunity to talk to a pharmacist about their medicine concerns, in particular problems with non-motor symptoms, and a lack of understanding around their medicines and how they work^[29]
.

A local audit of PD patients in Dudley in 2015 identified medication as the area that concerned patients most (unpublished data). Furthermore, the author has received excellent patient feedback from her own pharmacist-led PD clinics, which illustrates the level of patient satisfaction when a pharmacist is involved in PD management.

Community pharmacists, who often have excellent professional relationships with their patients and are easily accessible, as well as ward-based pharmacists across all specialties, are essential PD patient advocates. Furthermore, they are well placed to ensure that PD patients understand the importance of their PD medicine and that they are getting it on time as per the Parkinson’s UK ‘Get it on Time’ campaign^[30]
.

An area where pharmacist input could also be important is in the management of drooling, which is often a problem for PD patients, and medicine is suggested by NICE if therapy has been unsuccessful. Glycopyrronium bromide^[5]
(not licensed) should be considered to manage drooling of saliva because this has the lowest adverse cognitive effect of all the anticholinergics. If this is contraindicated or not tolerated, a referral for botulinum A toxin can be considered, although this is not a licensed indication. It is also worth noting that speech and language therapy is suggested for improving safety and efficacy of swallowing and minimising risk of aspiration.

Patients with PD have complex medication regimens, making pharmacists an essential source of information. However, more pharmacy-based research regarding the role of pharmacists in the management of PD is needed.

Palliative care

It is important to consider a referral to the palliative care team at any stage of PD to allow discussion about end-of-life care^{[31],[32],[33]}
. Patients with PD and their carers should be offered oral and written information about disease progression, possible adverse effects, advance care planning, including advanced decisions to refuse treatment, ‘do not attempt resuscitation’ orders and lasting powers of attorney for finance and/or social care. It is also important to remember that family members or carers may have different information needs to the patient with PD.

Management of advanced PD

Deep brain stimulation may be considered for people with advanced PD^[5]
but only when symptoms are not controlled with medical therapy, which may include intermittent apomorphine injection or continuous apomorphine subcutaneous infusion.

PD research areas recommended by NICE

Since completion of the current NICE PD guidelines, there are several research questions that are being investigated (including the aforementioned physiotherapy study^[5]
).

Combination treatment for PD dementia

A cholinesterase inhibitor is suggested for people with mild-to-moderate or severe PD dementia. Rivastigmine is only licensed for mild-to-moderate dementia in PD^[34]
. Memantine can be considered if a cholinesterase inhibitor is not tolerated or is contraindicated^[35]
. A research question was designed to review the effectiveness of combination treatment with a cholinesterase inhibitor and memantine for people with PD dementia if treatment with a cholinesterase inhibitor alone is not effective or is no longer effective.

Psychotic symptoms (hallucinations and delusions)

If psychotic symptoms occur, the PD medicine that may have triggered the hallucinations or delusions should be reduced. Quetiapine^[36]
(not licensed) or clozapine^[37]
can then be considered when registration with a patient-monitoring service is needed. A research recommendation was made to identify the effectiveness of rivastigmine compared with atypical antipsychotic drugs for treating psychotic symptoms associated with PD.

Orthostatic hypotension treatment

If the existing medicine is not causing or adding to postural hypotension, midodrine is suggested first line as the only licensed medicine for this indication. If midodrine is contraindicated, not tolerated or ineffective, fludrocortisone should be considered. As fludrocortisone^[38]
tended to be prescribed first line for this indication prior to the licensing of midodrine, a research question has been set to find the most effective pharmacological treatment for PD patients with postural hypotension.

Rapid eye movement sleep behaviour disorder treatment

Clonazepam^[39]
or melatonin^[39]
are suggested to manage rapid eye movement (REM) sleep behaviour disorder if a medication review has failed to identify any other pharmacological cause. However, neither medicine is licensed for this condition. Therefore, a research recommendation has been made to identify the best first-line treatment for REM sleep behaviour disorder in PD.

Conclusion

The cause of PD is not fully understood and treatment is symptomatic and involves multidisciplinary team care. When the NICE guidelines are next updated, a scoping question to review the role of the pharmacist in the management of PD should be added. It is important to build up a body of evidence to identify how important the role of the pharmacist is to this patient cohort because medication is often the most problematic area for them. Many of these patients are prescribed very complex medicine regimens and, therefore, a consultation with a healthcare professional who is an expert in medicines could be invaluable to them.