Pharmacotherapy for Parkinson Disease

Parkinson disease (PD) diagnoses are on the rise, with an estimated 90,000 new cases of PD diagnosed per year in the United States, compared with previous estimates of 40,000 to 60,000 new cases annually.¹ PD management has become increasingly complex, with the availability of new delivery mechanisms of older medications, drugs with novel mechanisms of action, and a multitude of surgical therapies. Despite its evolution, the goal of medical management of PD remains the same: maximizing function while minimizing side effects. The first step is to ascertain the effects of parkinsonian symptoms—both motor and nonmotor—on the individual, and then to work with the individual and caregiver to determine reasonable goals for treatment. Not all symptoms need to be treated (ie, not all symptoms are bothersome or dangerous), and nonmedical therapies always should be considered in parallel with medications.

During the development of an individualized medication treatment plan, the balance of potential benefits and risks must be considered. Stage and severity of disease may affect which medications may provide more benefit. Age, frailty, impaired cognition, or psychiatric comorbidities may influence the potential for side effects. Polypharmacy can be difficult to avoid in PD, so it is often best to have single medications serve multiple purposes or try to adjust an existing medication before adding a new one. The feasibility of the treatment plan also should be discussed. Individuals may do shift work or rely on caregivers to administer medications, and therefore the timing and frequency of medication and monitoring may be a challenge for some people. Some individuals may have diurnal variations in symptoms, and keeping a symptom and medication administration log can allow for adjustments in medications to maximize function for different times of day or different activities.

Initial Medication Therapy

The practitioner first must consider whether the individual needs medication. For a person who is not affected by symptoms, a reasonable initial approach could be to suggest that the individual engage in vigorous exercise or physical therapy and return for follow-up monitoring, deferring the initiation of dopaminergic therapy. In individuals who have modest symptoms, or who are interested in possible neuroprotective medications, rasagiline, a monoamine oxidase B (MAO-B) inhibitor, dosed at 1 mg daily could be considered, based on data from the ADAGIO trial (NCT00256204).² Selegiline could be offered, but this medication can increase hypertension and cause insomnia, and therefore is recommended to be dosed in the morning and early afternoon.³

For individuals with functional impairments caused by motor symptoms, dopaminergic therapy is recommended. Levodopa is the mainstay of PD therapy, delivered as carbidopa-levodopa. It is now well-known that motor complications of PD are associated with duration of disease, rather than time on levodopa, and levodopa has greater benefit for motor symptoms compared with dopamine agonists and MAO-B inhibitors.⁴

The standard dosing used at initiation of therapy is carbidopa-levodopa 25 mg/100 mg tablets, 3 times a day. Carbidopa-levodopa 10 mg/100 mg tablets are available but provide insufficient carbidopa for most individuals and are less well-tolerated. The dose should be titrated slowly to allow for adjustment to side effects, most notably nausea, sedation, and lightheadedness. The author starts therapy for patients with ½ tablet of 25 mg/100 mg tablets twice daily and increases the dose weekly by ½ tablet until reaching the initial goal dose of 1 tablet, 3 times a day. Many individuals need a higher dose to see an effect. Some individuals have symptomatic benefit at more modest doses. For initial therapy, there is no need to avoid taking levodopa with food or protein specifically, as patients with early PD are typically minimally impacted by the difference in absorption of levodopa that occurs when taken with protein. Patients may choose to purposefully take levodopa with food to offset the side effect of nausea.

Close interval follow-up for 6 to 8 weeks is advised after initiation of therapy to assess for effect and for dose adjustment. Some individuals may not notice an effect of medication, but improvements may be noted objectively upon examination or by family and friends.

For individuals younger than 65 years who have mild to moderate symptoms, a dopamine agonist may be used, as these individuals are at higher risk for dyskinesia. This author prefers long-acting formulations for ease of dosing. The rotigotine patch may be better tolerated, but the adhesive may not be as effective in those with large amounts of body hair or hyperhidrosis. Other options include pramipexole and ropinirole. People should be counseled about potential side effects, including excessive sedation, sudden sleep attacks, hallucinations, impulse control disorders (including excessive gambling or shopping), binge eating, and hypersexual behaviors. People older than 70 years or with cognitive impairment have greater risk of developing these adverse effects.⁵

Tremor-Dominant PD

For people with tremor-dominant PD without cognitive symptoms, amantadine can be considered as monotherapy, although this can cause cognitive impairment, hallucinations, lower extremity edema, and livedo reticularis. Anticholinergics such as trihexyphenidyl can be considered in younger individuals but may carry an increased risk for dementia over the long term. Tremors may respond to propranolol, but this medication will not improve other motor symptoms.⁶

Continuing Therapy: Medication Changes for Advancing Disease

PD symptoms advance over time and almost all individuals will develop motor complications within 15 to 20 years of diagnosis, with 40% experiencing a diminished response to medication within 4 to 6 years. Some individuals develop motor fluctuations as early as several months from diagnosis.⁴

Therefore, medication adjustments will be needed, and individuals should be followed on a regular basis to ensure that they do not lose function because of an inadequate medication regimen. Surgical therapies also should be considered once motor fluctuations or refractory tremor occur and should be presented as an option alongside medication management. The reader is referred to a separate article in this issue which provides an overview of “Treatment of Movement Disorders with Neuromodulation”.

Wearing-Off

The most common approach to managing wearing-off of medication (eg, a good motor response followed by a return of symptoms before the next dose) is increasing individual levodopa (or dopamine agonist) doses or reducing the interval between doses. When this approach causes other complications (eg, intolerable dyskinesias, orthostatic hypotension, logistic challenges to dosing multiple times per day), adjunctive medications can be helpful.^4,5

Other Formulations of Carbidopa-Levodopa. The older carbidopa-levodopa controlled-release formulation (Sinemet CR [carbidopa-levodopa; Bristol Myers Squibb Company, New York, NY]) often provides inadequate symptom relief because of variable bioavailability and slow onset of action. The newer extended-release option (Rytary [carbidopa and levodopa; Amneal Pharmaceuticals, Bridgewater, NJ]) is formulated with beads that provide both an initial and prolonged increase in levodopa plasma concentrations. When switching an individual from immediate-release carbidopa-levodopa, higher doses of the extended release carbidopa and levodopa (Rytary) may be needed.⁷

COMT (Catechol-O-methyl transferase) Inhibitors. Entacapone can be added to each dose of carbidopa-levodopa to prolong its effects. Opicapone (Ongentys; Neurocrine Biosciences, San Diego, CA) is dosed once a day, but it has a greater cost than entacapone.

MAO-B Inhibitors. Rasagiline and selegiline are additive options for wearing-off. Safinamide (Xadago; Newron Pharmaceuticals, Morristown, NJ), the newest option, has data supporting an increase in daily “on” time without troublesome dyskinesia.⁸ Zonisamide, an antiseizure medication which has some MAO-B inhibitory activity in addition to other mechanisms, has also been shown to be helpful for wearing-off.⁵

Istradefylline. Istradefylline (Nourianz; Kyowa Kirin, Tokyo, Japan) has a novel mechanism of action as an adenosine receptor antagonist, and can have efficacy in wearing-off as well. ^4,5

Other Options for Wearing-Off

In specific wearing-off cases of increased motor symptoms at night or on waking, a nighttime dose of controlled-release carbidopa-levodopa or opicapone may be helpful in extending the effect of levodopa through the night.For people who have sudden or unpredictable wearing-off, options include taking additional tablets of carbidopa-levodopa or taking faster-acting formulations such as sublingual dissolvable carbidopa-levodopa or inhaled levodopa powder (Inbrija [levlodopa inhalation powder]; Acorda Therapeutics, Ardsley, NY). Dopamine agonists such as apomorphine are available as a subcutaneous injection (Apokyn [apomorphine HCI]; Supernus Pharmaceuticals, Rockville, MD]) or sublingual film (Kynmobi [apomorphine HCI sublingual film]; Synovion Medical, Marlborough, MA), but can cause hypotension, nausea, and QT prolongation, and are contraindicated for use with certain antiemetics, such as ondansetron.⁹ For individuals who have delayed effectiveness of levodopa, ensuring that the medication is taken on an empty stomach, crushing levodopa and administering it with a carbonated beverage or orange juice and treating any associated constipation are helpful.¹⁰

Dyskinesias

Lowering the levodopa dose may be an initial option but this strategy may need to be supplemented with other medication changes to control motor symptoms adequately. Dyskinesias can be a side effect of any increase in dopaminergic tone in individuals with PD, including with addition of medications for wearing-off. Amantadine is an NMDA receptor antagonist that has efficacy in dyskinesias. Many individuals can tolerate the short-acting formulation, typically dosed as 100 mg 2 times a day. Long-acting formulations may be better tolerated by some with ease of dosing once a day. However, all formulations can cause hallucinations, dizziness, peripheral edema, constipation, and orthostatic hypotension.^4,5

Freezing of Gait

Early in the course of disease, freezing of gait may be more responsive to dopaminergic therapies. There are data showing that MAO-B inhibitors and istradefylline may be effective in freezing of gait.¹¹ However, this symptom can be refractory to medication treatment as the disease advances.

Dystonia

Focal dystonias, such as foot dystonia, occur in many people with PD. In some instances, dystonia may be levodopa-responsive and occur mainly as an “off” phenomenon. Botulinum toxin therapy typically is used first for this symptom.

Management of Nonmotor Symptoms

PD is a systemic disease, with effects on multiple body systems. Nonmotor symptoms have an important effect on quality of life. Consultants outside of neurology are helpful, but it is not uncommon for neurologists to trial medications before the individual sees another specialty consultant.

Apathy

There is no clearly effective treatment for apathy, but for some, treatment of comorbid depression with selective serotonin reuptake inhibitors or treating cognitive impairment with cholinesterase inhibitors such as rivastigmine may be helpful.^12,13

Cognitive Decline

Rivastigmine is approved by the Food and Drug Administration (FDA) for treatment of PD dementia. Other cholinesterase inhibitors such as donepezil may be efficacious, but insufficient evidence is available.¹²

Constipation

Constipation is important to treat, because constipation can interfere with levodopa absorption.⁹ Dietary changes and hydration are a starting point, but medication may be needed. Probiotics and oral fiber supplements are efficacious and useful; the first adjunctive medication recommended by most practitioners is polyethylene glycol. Lubiprostone (Amitiza; Takeda Pharmaceuticals, Lexington, MA) also is likely effective.^12,14

Depression and Anxiety

Selective serotonin reuptake inhibitors as well as venlafaxine likely are efficacious for treatment of depression and anxiety.^12,13 Bupropion is another frequently used option, given that it may also weakly inhibit reuptake of dopamine.¹⁵ MAO-B inhibitors such as rasagiline can be taken with a single antidepressant without significant risk of serotonin syndrome.¹⁶

Fatigue

For individuals with fatigue or daytime sleepiness, in addition to sleep apnea evaluation and optimization of nighttime sleep, several options are available. Selegiline or venlafaxine may be used because of their adrenergic effects. Modafinil has been used for excessive daytime sleepiness as well. However, medications to treat fatigue may worsen insomnia, and therefore paradoxically worsen daytime sleepiness that is caused by inadequate sleep.¹²

Hallucinations and Psychosis

Hallucinations and psychosis almost always are paired with cognitive dysfunction. If the symptoms are not bothersome (eg, benign visual hallucinations), they do not warrant treatment, but if they lead to safety concerns, cause emotional distress, or pose challenges to caregivers, medication is indicated. The first approach is to consider whether contributory medications can be stopped or lowered: this includes anticholinergics, dopamine agonists, amantadine, or any other medication that can worsen cognition.

For treatment, dopamine-blocking antipsychotics should be avoided when possible. Quetiapine is a reasonable first choice as a more serotonergic acting antipsychotic, typically taken at low doses, starting with 25 mg at bedtime and escalating slowly. Quetiapine carries a black box warning of an increased risk of death from all causes, which should be discussed with the individual and caregiver. Another option is pimavanserin (Nuplazid; Acadia Pharmaceuticals, San Diego, CA), which has a lower mortality risk compared with other atypical antipsychotic medications. However, pimavanserin can take several weeks to have efficacy and is more costly. Clozapine can be used but may be logistically challenging because of the requirement of close monitoring for agranulocytosis.^12,13

Impulse Control Disorders

Impulse control disorders frequently are associated with dopamine agonist use (particularly in younger individuals and those with a history of addictions or substance use disorder) and warrant a slow taper of the dopamine agonist. A slow taper is needed to avoid dopamine agonist withdrawal syndrome, which consists of mood changes, including depression, anxiety, agitation, fatigue, and orthostatic hypotension, as well as worsened motor symptoms.¹³

Insomnia

Insomnia is particularly prevalent among people with PD. Initial treatment can include low-dose melatonin 2 hours before the intended bedtime. Eszopiclone, a medication that interacts with GABA receptor complexes, is another evidence-based suggestion.^12,13

Nausea

Nausea often occurs as a side effect of carbidopa-levodopa and is often worst with initiation of medication. Supplemental carbidopa may be helpful with each dose, but this may come at high cost. Domperidone may be efficacious but is not commercially available in the United States.¹⁰ Other options include non–dopamine-blocking antiemetics such trimethobenzamide or ondansetron.¹² Nausea can occur as a side effect of apomorphine; in these instances, ondansetron is contraindicated because of the risk of hypotension.⁹

Orthostatic Hypotension

To address orthostatic hypotension, lowering or discontinuation of antihypertensives should be the first step. Medication options include midodrine, fludrocortisone, droxidopa, and pyridostigmine.¹⁷

Pain

Pain may be multifactorial, and treatments should be targeted to the underlying mechanism. In general, there is some evidence of efficacy for safinamide (though the mechanism is not clear) and cannabis for pain relief in PD.¹³

REM Sleep Behavior Disorder

REM sleep behavior disorder is most often an intermittent problem, but some individuals have more frequent episodes that can be bothersome, or severe REM sleep behavior disorder that can lead to injury because of falls out of bed, injury to the bed partner, or disturbances to the sleep of others in the household. In these cases, medication can be recommended, starting with low-dose melatonin, with a dose of 6 mg being the average efficacious dose.¹⁸ If this is ineffective, therapy can be escalated to low doses of clonazepam, most commonly 0.5 to 1 mg at bedtime. It is often preferred to start with melatonin given its more favorable side effect profile.^13,14

Sialorrhea

Sialorrhea often occurs with more severe hypomimia. Atropine drops can be used but the anticholinergic effects may be a contraindication for some individuals. Botulinum toxin—notably rimabotulinum toxin B—is efficacious for reducing saliva production, although monitoring for dysphagia, dry mouth, and tooth decay is needed.¹³

Urinary Incontinence

Determining the underlying cause of urinary incontinence is an important first step. For individuals with overactive bladder, solifenacin, a bladder-selective antimuscarinic can be useful. Mirabegron acts on beta-3 adrenergic receptors and can be useful for overactive bladder in people with PD.^12,13

Conclusion

The Table provides an overview of medication options for symptoms associated with PD. The medication treatment plan for people with PD can be complex because of the number of symptoms and systems involved. It is best to prioritize the individual’s goals, simplify medication regimens when possible, and proceed with caution, ideally starting with the most effective medication, and changing 1 medication at a time. The practitioner also should look beyond medication management of PD. Nonmedication therapies, in addition to workup for surgical treatments—known to be effective in management of PD—also are necessary.^5,12,13 Multidisciplinary care should be the standard for people with PD, emphasizing communication among team members to optimize care. Attention to the needs of care partners, who have a vital role in the well-being of the person with PD, is critical. Using these strategies, individuals with PD are poised to maintain good function and quality of life for many years.