Volume 211 - Issue 6
Updates and advances in the treatment of Parkinson disease
Authors: Michael W Hayes, Victor SC Fung, Thomas E Kimber and John D O'Sullivan
Med J Aust 2019; 211 (6): 277-283. || doi: 10.5694/mja2.50224
Published online: 17 June 2019
Published online: 17 June 2019
New therapies show promise, but effective treatment of non-motor, non-dopaminergic symptoms remains a major challenge
Summary
- Parkinson disease (PD) is a complex neurodegenerative disorder that can present heterogeneously with a combination of motor and non‐motor symptoms.
- α‐synuclein, a neuronal protein, can undergo aberrant conformational change resulting in the intra‐neuronal accumulation of toxic oligomers that form Lewy bodies, the pathological hallmark of PD.
- There is evidence that pathological α‐synuclein exhibits prion‐like behaviour in its mode of transmission through the nervous system.
- The choice of initial dopaminergic treatments should be individually tailored but long term outcomes appear to be equivalent.
- There is level A evidence supporting the benefit of three different device‐assisted therapies in treating troublesome motor fluctuations and dyskinesias.
- Stem cell transplantation as currently being trialled is predominantly a symptomatic therapy targeting only limited regions of the brain affected by PD, and will need to be proven to be not only as effective but as safe as currently available device‐assisted therapies.
- New modes of treatment including active immunisation against oligomeric α‐synuclein and drugs that alter cellular metabolism show some promise.
- The inability to effectively treat a range of non‐motor, non‐dopaminergic symptoms remains a major therapeutic challenge.
Parkinson disease (PD) is now conceptualised as a complex neurodegenerative disorder that can present in diverse ways with a combination of motor and non‐motor symptoms. This has resulted in recently published new clinical diagnostic criteria1 which incorporate key non‐motor manifestations including rapid eye movement (REM) sleep behaviour disorder, hyposmia and constipation. Biomarkers such as cardiac sympathetic denervation as measured by ¹²³I‐metaiodobenzylguanidine scintigraphy and substantia nigra hyperechogenicity on transcranial ultrasound are now recognised as supportive criteria. The clinical diagnostic accuracy of PD based on older criteria is estimated to be about 80%.2
α‐synuclein, a neuronal protein widespread in pre‐synaptic terminals probably related to vesicle trafficking, can undergo aberrant conformational change resulting in the intra‐neuronal accumulation of toxic oligomers that form Lewy bodies, the pathological hallmark of PD. Research interest has recently focused on the prion‐like behaviour of α‐synuclein as a potential mechanism of spread through the nervous system, probably starting in the peripheral enteric (gut) nervous system or olfactory bulb. A key observation triggering the prion hypothesis was made in post‐mortem studies of PD patients who had been surgically grafted with fetal mesencephalic brain tissue more than a decade earlier. A small proportion of these grafted neurons had developed, in a time‐dependent process, α‐synuclein containing Lewy body pathology, suggesting that there had been direct transmission from the native PD‐affected neurons to the grafted neuron in a prion‐like manner.3 Subsequently, Lee and colleagues4 showed that the injection of synthetic α‐synuclein into mice resulted in progressive transneuronal spread of Lewy pathology in a typical PD distribution. However, there is no evidence of inter‐individual transmissibility.
Non‐motor symptoms typically pre‐date the onset of the classical motor signs of PD by years. About 80% of people who present with later onset REM sleep behaviour disorder will eventually, sometimes after more than a decade, develop motor manifestations of a synucleinopathy (PD, Lewy body dementia or multiple system atrophy).5 This observation, coupled with other risk markers such as olfactory loss, has formed the basis of successful attempts to identify prodromal PD, an important step which will allow potential neuroprotective agents to be trialled at an earlier stage of the disease.6 These premonitory symptoms of PD presumably also offer clues as to the pathogenesis of PD.7
Current dopamine‐related therapeutic strategies remain effective in compensating for dopamine deficiency, but more advanced PD is complicated by dysfunction of additional non‐dopaminergic neuronal networks. This narrative review represents an evidence‐based review of Parkinson disease treatment derived from systematic reviews, original articles and studies. It also includes evidence from expert recommendations, specialist society guidelines (International Parkinson and Movement Disorder Society), as well as personal experience.
Early treatment
General considerations
The goals of therapy in PD should be patient‐centred, in order to maximise quality of life and minimise disability. The first step in management is the delivery of the diagnosis. Even years later, “satisfaction with the explanation of the condition at diagnosis” still has an impact on quality of life,8 but unfortunately many patients report a poor experience with this process.9 There is no single way of delivering the diagnosis that has been proven to be optimal, and the approach should be individualised.10
The Global Parkinson's Disease Survey8 of over 1000 patients found that mood was the greatest determinant of quality of life in PD, but despite 50% of patients being classified as depressed using the Beck Depression Inventory, only 1% self‐reported depression. Therefore, a high index of suspicion, use of corollary symptoms or screening tools may be required to accurately assess mood. It is also important to address other non‐motor symptoms such as apathy, fatigue, and autonomic symptoms which also impact on quality of life.11
When to start treatment
Treatment should be started when motor or non‐motor symptoms begin to cause physical or social disability and impair quality of life.12 Patients will sometimes hesitate to commence treatment because of a misguided fear that medications are harmful, or that they are only effective for a finite period.13 It is important to reassure them that there is no evidence to support these concerns and, instead, delaying treatment is associated with a progressive decline in quality of life.
Disease‐modifying therapy
No treatment has been unequivocally shown to modify the progression of the underlying disease process. A study in de novo PD showed that patients whose treatment with rasagiline 1 mg was delayed by 9 months did not experience the same symptomatic benefit as those who started treatment immediately, suggesting that earlier treatment may have had a neuroprotective effect.14 However, the 2 mg treatment arms of the same study did not show a difference. Similar study designs with pramipexole15 and, most recently, levodopa16 also did not show a difference between the immediate and delayed start arms, arguing against a neuroprotective effect of those drugs.
Symptomatic therapy for motor symptoms
There is level A evidence (Supporting Information) to support initial treatment with dopamine agonists, levodopa (levodopa–carbidopa or levodopa–benserazide) and monoamine oxidase (MAO)‐B inhibitors (Box 1). Each has potential advantages and disadvantages, and treatment should be individualised depending on the characteristics and needs of the patient, comorbid non‐motor symptoms, and intercurrent medical illnesses and medications. The UK‐based PD MED study was a pragmatic open‐label study comparing patients randomised to initial treatment with one of these three different drug classes, followed by routine clinical treatment after randomisation (a large proportion of patients subsequently crossed treatment arms).17 There was a minor reduction (5–10%), in the incidence of dyskinesias in those randomised to initial levodopa‐sparing agents at 2–5 years, which had narrowed to 3% at 7 years, but otherwise little difference between the three groups. This provides reassurance that in a real‐life setting, there is no absolute right or wrong choice.
Non‐pharmacological therapy
A number of different exercise and physical therapies have been trialled to improve walking, balance and falls in PD, including balance, resistance and aerobic exercise, external cueing and treadmill walking, movement strategy training, dance (particular partnered dance) and Tai Chi. Systematic reviews confirm that improvements can occur in balance, mobility and muscle strength.18 Most studies have focused on patients with more long‐standing as opposed to early PD, but a recent study of de novo patients showed that high intensity treadmill exercise resulted in less decline in motor function at 6 months compared with usual care.19 Given the established general health and mood benefits of exercise, it is our practice to recommend a combination of moderate aerobic, active balance and resistance exercises to all patients.
Management of patients with motor fluctuations and dyskinesias
Background
After several years of levodopa therapy, patients commonly experience fluctuations in their motor response (motor fluctuations).20 Motor fluctuations may manifest as a decline in motor symptoms before the next dose is due (“wearing‐off phenomenon”, or “end‐of‐dose deterioration”), a delayed response to a dose (“delayed on”), or even a failure of motor response (“no on”). In addition to the development of motor fluctuations, “on” periods may begin to be associated with involuntary movements (peak‐dose dyskinesias). Later, dyskinesias may occur at variable times in the dosing cycle, during wearing‐off periods as well as at peak dose (diphasic dyskinesias).
A number of pharmacokinetic factors likely contribute to motor fluctuations. Levodopa may not be reliably delivered to the small intestine, its site of absorption, as a result of delayed gastric emptying.21 Additionally, competition from dietary amino acids may impede absorption of levodopa from the small intestine (and across the blood–brain barrier).22 Data are conflicting on the issue of whether Helicobacter pylori infection can exacerbate motor fluctuations by interfering with levodopa absorption.23,24 The use of domperidone and camicinal, another gastroprokinetic drug, enhances gastric emptying with more rapid absorption of L‐dopa in the proximal small bowel and reduction of “off” time.25
Central factors affecting levodopa pharmacodynamics also contribute to motor fluctuations and dyskinesias. Progressively degenerating nigrostriatal neurons start to lose the capacity to store dopamine pre‐synaptically. Thus, dopamine is released in an increasingly pulsatile fashion, with over‐stimulation of post‐synaptic dopamine receptors (causing peak‐dose dyskinesias) followed by rapid clearance of dopamine (causing offs).26
Management
A number of strategies can be employed to manage motor fluctuations in levodopa‐treated patients with PD. Adjunctive dopaminergic therapy such as a dopamine agonist (oral or transdermal), a catechol‐O‐methyl transferase inhibitor or MAO‐B inhibitor can be added to the levodopa‐based regimen. In randomised controlled trials, each of these three medication classes reduced daily off time by a mean of 1–2 hours relative to placebo.27,28,29 Opicapone, a once‐daily oral catechol‐O‐methyl transferase inhibitor, was non‐inferior (at a dose of 50 mg daily) to entacapone in the reduction in daily off time.30 Of the dopamine agonists, transdermal rotigotine has been shown to improve early morning motor symptom control.31
Other strategies to manage motor fluctuations include dividing the daily levodopa dose into smaller aliquots administered more frequently.32 High quality evidence on the place of controlled release levodopa formulations is lacking. We recommend that controlled release levodopa preparations be reserved for administration at bedtime, as their efficacy can be unreliable, possibly due to erratic gastrointestinal absorption.
Safinamide is an α‐aminoamide with several different modes of action, including MAO‐B inhibition and modulation of glutamate release.33 Recent studies with safinamide added to levodopa have shown an improvement in on time without exacerbation of troublesome dyskinesia, a potential advantage over other adjunctive dopaminergic therapies.34 Zonisamide, a mixed MAO‐B inhibitor, channel blocker and glutamate release inhibitor, is efficacious in the treatment of wearing‐off symptoms at a dose of 50 mg daily.35
In addition to adjunctive oral or transdermal dopaminergic therapy, intermittent subcutaneous apomorphine injections can be helpful for patients experiencing troublesome off episodes.36
Immediate release amantadine can help suppress levodopa‐induced dyskinesias. Recent studies have provided level A evidence for the efficacy of extended release amantadine in reducing dyskinesias, an effect achieved at the same time as reducing off time.37
Device‐assisted therapies for motor fluctuations and dyskinesias
In most patients with PD, motor fluctuations and dyskinesias are relatively mild and can be adequately managed by adjustment of the oral/transdermal medication regimen. However, for patients experiencing disabling motor fluctuations and dyskinesias despite optimised medical therapy (including ≥ 4–5 doses of levodopa per day), device‐assisted therapies should be considered (Box 2).38 Level A evidence supports the use of deep brain stimulation surgery (targeting either the subthalamic nucleus39 or globus pallidus interna40), subcutaneous apomorphine infusion,41 and levodopa–carbidopa intestinal gel infusion via a percutaneous gastrojejunostomy tube42 in such patients. All three device‐assisted therapies reduce daily off time by several hours compared with baseline, increase on time without troublesome dyskinesias, and improve performance of activities of daily living and quality of life. No blinded, randomised trials comparing the efficacy of the three device‐assisted therapies exist. Long term adherence to apomorphine infusion may be difficult to achieve in some patients.43 However, apomorphine is the least invasive of the three device‐assisted therapies, as well as the most straightforward to initiate and discontinue.
Evidence suggests that subthalamic nucleus deep brain stimulation in selected younger patients with PD (< 60 years) with a relatively short (< 3 years) history of motor fluctuations and dyskinesias produces a greater improvement in motor function and quality of life compared with optimised medical therapy.44 The United States Food and Drug Administration has recently approved the use of magnetic resonance imaging‐guided focused ultrasound thalamic lesioning for treatment of (unilateral) tremor‐dominant PD but reliable clinical trial evidence is still pending.
Individual patient characteristics (eg, nature of motor symptoms, age, comorbidities) and therapy‐specific risks and adverse effects influence the optimal choice of device‐assisted therapy. These issues are summarised in Box 3 and addressed in greater detail in expert reviews.38,45 Patients requiring consideration of a device‐assisted therapy should be referred to a neurologist specialising in the management of PD, preferably in a clinic that offers all three options.
Non‐motor symptoms
Non‐motor symptoms are increasingly identified in patients at all stages of PD and contribute significantly to morbidity. The topic has recently been reviewed in this journal.46 A patient‐rated non‐motor symptom questionnaire47 may be helpful in busy clinical settings where the focus is often on motor symptoms.
Sleep disturbance
Around one‐third of patients with PD report insomnia, excessive daytime somnolence, REM sleep behaviour disturbance or restless legs syndrome.46 Recent evidence suggests that the topical dopamine agonist rotigotine improves sleep,48 and that the selective MAO‐B inhibitor rasagiline reduces fatigue.49 Melatonin or clonazepam may help manage insomnia and REM sleep behaviour disorder in some patients, although clinical trials have not been conclusive.
Autonomic dysfunction
Orthostatic hypotension is common in PD and is aggravated by increased dopamine replacement therapy and reduced oral fluid intake due to dysphagia or self‐restriction to minimise urinary symptoms. However, treatment of orthostatic hypotension can aggravate supine hypertension. There is some evidence that shorter‐acting drugs like droxidopa, a synthetic noradrenaline precursor,50 and midodrine might be preferable to longer‐acting pressor agents such as fludrocortisone, especially when there is coexisting supine hypertension.51 Standing blood pressures should be measured and it may be necessary to prioritise symptomatic orthostatic hypotension over sitting or supine hypertension. Urinary dysfunctions, including urgency and nocturia, are among the most prevalent non‐motor symptoms in PD52 but evidence concerning effective therapies is limited. In one randomised controlled trial, solifenacin reduced incontinence but not the frequency of micturition compared with placebo.52 Constipation is also very common, with limited evidence supporting the use of the osmotic laxative macrogol and, more recently, lubiprostone. 53 Box 4 provides some practical suggestions to manage autonomic symptoms given the limited clinical trial evidence.
Mood disturbance
Depression and anxiety remain common but under‐recognised and undertreated causes of significant morbidity in PD. There is evidence for the dopamine agonist pramipexole and the selective noradrenaline reuptake inhibitor venlafaxine in addition to earlier trials supporting tricyclic antidepressants nortriptyline (level C) and desipramine.53 Adverse effects of antidepressants include orthostatic hypotension and sleep disturbance. Non‐motor wearing‐off can manifest as acute anxiety or dysphoria, often responsive to dopaminergic medication adjustment.
Neuropsychiatric symptoms
Psychotic symptoms may occur in up to 60% of patients with PD; risk factors include advanced age, PD severity and duration, comorbid dementia, depression, REM sleep behaviour disorder and visual disorders.54 Symptoms range from mild illusions to frank visual hallucinations and paranoid delusions. Reduction of dopaminergic drugs is often necessary in conjunction with identifying and treating coexisting delirium. The highly selective serotonin 5‐HT2A inverse agonist pimavanserin has been shown to be effective in reducing psychosis in PD (level A) without worsening motor symptoms,55 but it is not yet registered with the Therapeutic Goods Administration. Clozapine is also effective (level B), but its use is limited by haematological and cardiac toxicity.53 Quetiapine (level C) is unlikely to aggravate motor parkinsonism and had similar efficacy to clozapine in comparator trials, although it was not effective in three randomised controlled trials and can cause sedation and hypotension.56 More conventional antipsychotics including olanzapine and risperidone worsen motor symptoms and can potentially trigger parkinsonism–hyperpyrexia syndrome due to dopamine blockade.
Impulse control disorders typically involve compulsive gambling, buying, sexual behaviour and binge eating, often with serious personal, psychosocial and financial consequences. Dopamine agonists confer an impulse control disorder risk of around 20% and a cumulative risk of around 40% over 5 years. Male sex, younger age, earlier PD onset, a premorbid impulse control disorder, a personal or family history of substance abuse, bipolar disorder and gambling problems increase the risk of impulse control disorder.57 Dopaminergic drug dose reduction is often necessary but can be complicated by motor worsening and dopamine agonist withdrawal syndrome characterised by dysphoria and depression. Some evidence supports benefit from cognitive behaviour therapy.58 Dopamine dysregulation, hobbyism and punding (repetitive stereotypical behaviour) are related problems more common with shorter acting dopaminergic treatments including levodopa. All such patients, and preferably family and carers, should be educated about and assessed for impulse control disorders.
Cognitive impairment
Cognitive dysfunction is common, increasing with PD duration but also occurring earlier in the disease, and is often a major concern for patients and carers. Rivastigmine remains the only pharmacological treatment with level A evidence for management of dementia in PD.53 It is only reimbursed on the Pharmaceutical Benefits Scheme for Alzheimer disease, although over one‐third of patients with PD have coexistent Alzheimer pathology and clinical differentiation between the two during life can be difficult.59 There is emerging evidence of benefit from exercise and cognitive rehabilitation to prevent cognitive decline in PD but more rigorous trial designs and outcomes are required.
Newer treatment strategies
In order to circumvent the contribution of delayed gastric emptying to motor fluctuations, novel oral formulations or parenteral delivery of levodopa have been developed.60 IPX066 is an extended release formulation of levodopa–carbidopa that is marketed in the United States for treatment of motor fluctuations and reduced off time by 1.2 hours compared with immediate release treatment.61 Inhaled levodopa62 has been shown to be effective in improving motor function compared with placebo in fluctuators and was approved for use by the Food and Drug Administration in December 2018. Subcutaneous forms of levodopa are currently being trialled.
Beyond a purely symptomatic approach to managing PD lies the goal of neuroprotective or even restorative therapies. The emergence of inducible pluripotent stem cell technology has bypassed the ethical issues of transplanting fetal stem cell tissue. Stem cell transplantation as currently being trialled63 remains predominantly a symptomatic therapy targeting only limited regions of the brain affected by PD, and will need to be proven to be not only as effective but as safe as currently available device‐assisted therapies. A rash of commercial stem cell clinics have largely utilised mesenchymal stem cells injected systemically without strict clinical trial protocols. Another restorative option is delivering glial‐derived neurotrophic factor to specific brain regions via a novel delivery system. Recent publications report encouraging but inconclusive results in patients with PD.64
A further therapeutic approach involves using active and passive immunisation techniques. A vaccine (PD01A) that produces antibodies to oligomeric α‐synuclein has been reported to show proof of principle and there are phase I studies utilising monoclonal antibodies against aggregated α‐synuclein, a form of passive immunisation.65
The massive cost of developing new drugs has led to recent interest in repurposing medications previously used in other areas. An observation that diabetes mellitus may be a modest risk factor for PD, as well as increasing the rate of progression,66 has resulted in some clinical trial evidence that glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors may slightly slow PD symptomatic progression over a 12‐month period. A rationale for this is that glycation enhances α‐synuclein toxicity via cellular processes and glycation inhibitors reverse this effect. It has also been proposed that increased central (brain) insulin resistance may reduce neuronal survival.67 Exenatide, a glucagon‐like peptide‐1 receptor agonist that can cross the blood–brain barrier, resulted in a small motor benefit compared with placebo over 48 weeks when measured after a 3‐month washout.
A rare lysosomal storage disorder, Gaucher disease, has unexpectedly offered insights into the genetic and cellular mechanisms of PD. Deficiency of the enzyme glucocerebrosidase due to homozygous or compound heterozygous mutations in the glucocerebrosidase gene cause autosomal recessive Gaucher disease, while heterozygous mutations have emerged as the most common genetic risk factor for PD.68 Lysosomal glucocerebrosidase deficiency impairs α‐synuclein clearance, in turn further reducing glucocerebrosidase activity. Ambroxol, an established drug with mucolytic effects, increases glucocerebrosidase activity69 and is currently being trialled (https://clinicaltrials.gov/ct2/show/NCT02941822) in patients with a heterozygous glucocerebrosidase mutation. These insights into cellular dysfunction offer a new type of potential treatment, termed substrate reduction therapies.
Box 1 – Treatment options for early Parkinson disease
|
Drug class |
Drugs available in Australia |
Prescribing status |
Level of evidence* |
Comments |
|||||||||||
|
|
|||||||||||||||
|
Levodopa |
Levodopa–carbidopa IR |
PBS |
A |
Most potent anti‐Parkinsonian effect. Maximal therapeutic dose usually tolerated with slow titration. Peripheral dopa‐decarboxylase inhibition reduces gastrointestinal tract and peripheral cardiovascular dopaminergic side effects. Frequent dosing required with advancing disease and delayed gastric emptying results in unpredictable motor fluctuations as levodopa only absorbed from small intestine. CR preparations should help contract these problems, but in reality absorption becomes even more unpredictable, resulting in ongoing motor fluctuations. |
|||||||||||
|
Levodopa–benserazide IR |
PBS |
A |
|||||||||||||
|
Levodopa–carbidopa CR |
PBS |
A |
|||||||||||||
|
Levodopa–benserazide CR |
PBS |
A |
|||||||||||||
|
Dopamine agonists |
Pramipexole |
PBS |
A |
Initiating treatment with a dopamine agonist compared with levodopa will result in an approximate 35% v 50% risk of developing dyskinesias after 3–5 years of treatment. Pramipexole but not rotigotine also has some antidepressant benefits. Risk of side effects of impulse control disorder approaches 50% over 5 years; also danger of excessive daytime somnolence sufficient to cause sleep attacks and motor vehicle accidents. |
|||||||||||
|
Rotigotine |
PBS |
A |
|||||||||||||
|
Ropinirole |
TGA |
A |
|||||||||||||
|
Bromocriptine, cabergoline |
PBS |
A |
Ergot dopamine agonists. Similar efficacy to non‐ergot dopamine agonists. Possibly less somnolence but risk of impulse control disorders probably similar. Risks of cardiac valvular, pleuropulmonary and retroperitoneal fibrosis that may be difficult to diagnose and may require regular monitoring have led to caution; now rarely used in view of other therapeutic options available if patients intolerant of non‐ergot dopamine agonists. |
||||||||||||
|
Monoamine oxidase inhibitors |
Rasagiline |
PBS |
A |
Rasagiline may have small disease‐modifying effect; all have potentially mild to moderate symptomatic benefit with occasional mildly affected patients able to maintain as monotherapy for a while. |
|||||||||||
|
Safinamide |
PBS |
A |
|||||||||||||
|
Selegiline |
PBS |
A |
|||||||||||||
|
Anticholinergics |
Benzhexol |
PBS |
B |
Used occasionally for control or rest or re‐emergent tremor unresponsive to dopaminergic therapy at desired doses; does not treat akinesia; beware of anticholinergic side effects. Concerns about long term risks of cognitive impairment. |
|||||||||||
|
Benztropine |
PBS |
B |
|||||||||||||
|
Catechol‐O‐methyltransferase inhibitors |
Entacopine |
PBS |
A |
Primarily for extending on time when levodopa used ≥ 3 times daily. Multidose options available as carbidopa–levodopa–entacapone formulation but may need to reduce levodopa dose slightly when switching from levodopa alone. |
|||||||||||
|
Other |
Amantadine |
PBS |
A |
Most useful as add‐on therapy in later disease for treatment of dyskinesias. Can be used in early disease as alternative to other therapies for mild anti‐Parkinsonian effect. |
|||||||||||
|
|
|||||||||||||||
|
CR = controlled release; IR = immediate release; PBS = Pharmaceutical Benefits Scheme; TGA = Therapeutic Goods Administration. * See Supporting Information for explanation of levels of evidence. ◆ |
|||||||||||||||
Box 2 – When to refer for consideration of a device‐assisted therapy38
- ■Motor fluctuations cause disability or reduced quality of life
- ■Response to treatment is inconsistent
- ■Dyskinesias or motor fluctuations require frequent treatment adjustment without apparent benefit
- ■Levodopa required four or more times daily
Box 3 – Broad indications and considerations for device‐assisted therapies
|
|
Deep brain stimulation |
Levodopa–carbidopa intestinal gel infusion |
Subcutaneous apomorphine |
||||||||||||
|
|
|||||||||||||||
|
Dyskinesias |
Probable benefit |
Probable benefit |
Probable benefit |
||||||||||||
|
Medication‐refractory tremor |
Probable benefit |
|
|
||||||||||||
|
Mild dementia |
|
Probable benefit |
Possible benefit |
||||||||||||
|
Dysarthria/dysphagia |
|
Probable benefit |
Probable benefit |
||||||||||||
|
Impulse control disorders |
Probable benefit |
Possible benefit |
|
||||||||||||
|
Age > 70 years |
Possible benefit |
Probable benefit |
Probable benefit |
||||||||||||
|
Depression |
|
Possible benefit |
Probable benefit |
||||||||||||
|
Goal of monotherapy |
|
Probable benefit |
|
||||||||||||
|
|
|||||||||||||||
|
|
|||||||||||||||
Box 4 – Treatments for autonomic symptoms
|
Condition |
Treatment |
Prescribing status |
Comment |
||||||||||||
|
|
|||||||||||||||
|
Orthostatic hypotension |
Fludrocortisone 0.1–0.3 mg daily |
PBS |
|
||||||||||||
|
Midodrine 2.5–10 mg daily |
SAS |
|
|||||||||||||
|
Domperidone 10–30 mg daily |
PBS |
Caution in older patients with drugs increasing QT interval |
|||||||||||||
|
Pyridostigmine 30–90 mg daily |
PBS restricted |
|
|||||||||||||
|
Droxidopa 300–1800 mg daily |
SAS |
|
|||||||||||||
|
Thigh‐high compression stockings |
|
|
|||||||||||||
|
Head‐up tilt in bed 15–25 cm |
|
|
|||||||||||||
|
Urinary dysfunction |
Oxybutinin 5–15 mg daily |
PBS |
Usually limit medication to night‐time |
||||||||||||
|
Solifenacin 10–15 mg daily |
TGA |
Anticholinergics can worsen constipation |
|||||||||||||
|
Mirabegron 50–100 mg daily |
TGA |
|
|||||||||||||
|
Tolteridone 2–4 mg daily |
TGA |
|
|||||||||||||
|
Amitriptyline 10–30 mg daily |
PBS |
|
|||||||||||||
|
Nortriptyline 5–25 mg daily |
PBS restricted |
|
|||||||||||||
|
Constipation |
Macrogol |
PBS |
|
||||||||||||
|
|
Stool softeners |
OTC |
|
||||||||||||
|
|
Magnesium sulfate |
OTC |
|
||||||||||||
|
|
Probiotics |
OTC |
|
||||||||||||
|
|
Adequate fluid, fibre and fruit |
|
|
||||||||||||
|
Erectile dysfunction |
Sildenafil 25–100 mg |
PBS restricted |
|
||||||||||||
|
Tadalafil 20 mg |
PBS restricted |
|
|||||||||||||
|
Vardenafil 10–20 mg |
PBS restricted |
|
|||||||||||||
|
Apomorphine 1–6 mg subcutaneous |
PBS restricted |
|
|||||||||||||
|
Sialorrhoea |
Botulinum toxin (A or B) into parotid glands |
Off label |
Some include submandibular glands with ultrasound guidance |
||||||||||||
|
1% topical atropine 1–2 drops sublingual |
PBS (off label) |
Can cause confusion |
|||||||||||||
|
Glycopyrolate 0.4 mg sublingual |
TGA |
|
|||||||||||||
|
|
|||||||||||||||
|
PBS = Pharmaceutical Benefits Scheme; OTC = over the counter; SAS = Special Access Scheme; TGA = Therapeutic Goods Administration. ◆ |
|||||||||||||||
Competing interests
No relevant disclosures.
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Provenance: Commissioned; externally peer reviewed.
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