In this article, we will discuss the therapeutic management of restless leg syndrome, essential tremors, and Parkinson’s Disease.
Remember that there is currently no cure for these, and our goal is to manage symptoms and slow down the progression in the case of Parkinson’s Disease.
Restless Leg Syndrome (RLS)
There are three factors that we have to consider when considering therapeutic options for RLS:
- Frequency of symptoms
- Intermittent – Two or fewer episodes per week
- Chronic Persistent – Three or more episodes per week
- Severity of symptoms
- Presence of neuropathic pain
A refractory RLS is when the individual has failed the first-line agents at appropriate dosing.
RLS: Non-Pharmacologic Treatments
There is not a lot of data backing the effectiveness of non-pharmacologic treatments, except for iron supplementation in those who may be deficient (<75mcg/L).
Other approaches are stretching exercises, discontinuation of certain medications, and mentally-alerting activities.
Some of the agents that can worsen RLS are caffeine, nicotine, alcohol, neuroleptics, metoclopramide, and sedating antihistamines.
RLS: Pharmacologic Treatments
Levodopa: Intermittent RLS
Levodopa is a precursor to dopamine. This medication is the gold standard for Parkinson’s Disease, which we will discuss later on as well.
The most common adverse reactions are nausea, vomiting, and orthostatic hypotension. Dyskinesia is another potential adverse side effect, but since the dose recommended for RLS treatment is low compared to Parkinson’s Disease, we generally do not see this.
Any dopaminergic drug can have symptom augmentation, which means that symptoms worsen after the individual has been on the therapy for a long time. Symptom augmentation is extra bad with levodopa. It is seen in over 70% of the patients taking once-daily dosing of levodopa. Patients taking over 200mg/day are at a higher risk, and patients taking less than 3 times weekly have a lower risk.
If augmentation occurs, levodopa should be discontinued, and replaced with another agent, such as gabapentin or pregabalin.
Gabapentin and Pregabalin – Chronic persistent
These agents are alpha-2-delta calcium channel antagonists. These are especially beneficial for patients who also have co-morbid neuropathic pain, insomnia, or anxiety.
Common side effects include drowsiness, dizziness, unsteadiness, and cognitive disturbances.
They are typically dosed 1-2 hours before the onset of symptoms.
Dopamine Agonists – 2nd line for chronic persistent
These agents include pramipexole, ropinirole, and rotigotine (transdermal patch). These agents used to be first-line, but now are second-line.
Common adverse effects are nausea, vomiting, orthostatic hypotension (similar to levodopa), and somnolence.
Rare side effect: compulsive behaviors. Not usually a problem with lower doses that are typically used for RLS.
The onset is about 1-2 hours post-ingestion. Leg edema, constipation, insomnia, and nasal stuffiness may be present after discontinuation.
As with other dopaminergic agents, augmentation is also possible with dopamine agonists.
Benzodiazepines and Z-Hypnotics
Benzodiazepines have been shown to improve subjective ratings (patients feel better), but there are currently insufficient data and are not supported for the treatment of RLS.
Augmentation is not seen with these agents, but there is abuse potential that may limit their use.
Opioids
Opioids use should be avoided, and only be used in selected intermittent patients or refractory cases.
Side effects include drowsiness, dizziness, impaired coordination, and constipation.
Augmentation is not seen with these agents but abuses potentially limit their use.
Treatment Course
Intermittent RLS:
- Non-pharmacologic and replace iron if needed (ferrous sulfate 325mg PO up to TID). Please note that SSRIs can worsen RLS. A switch from SSRI to bupropion may be warranted.
- Intermittent use of carbidopa/levodopa as needed
Chronic Persistent RLS:
- Non-pharmacologic and replace iron if needed
- Gabapentin or pregabalin
- Dopamine agonists
RLS in Pregnancy
Pregnancy can start or worsen RLS. The symptoms usually peak in the 3rd trimester. There is insufficient data for recommendations, so avoid pharmacologic therapies if possible. These symptoms typically go away after pregnancy.
Stretching is recommended, and if really needed, a very low dose of clonazepam or carbidopa/levodopa during the 2nd and 3rd trimesters.
Essential Tremor
The goal of the treatment is to minimize disability and improve the quality of life. There is no cure.
The first-line agents are beta-blockers and avoidance of tremorgenic factor exposure.
Many medications can worsen or cause tremors, such as antiarrhythmics, corticosteroids, lithium, metoclopramide, nicotine, sympathomimetics, SSRIs, and thyroid.
ET: Pharmacologic Treatment
Adrenergic: beta-blockers. GABAminergic: primidone, and gabapentin
Beta-Blockers
Of all of the beta-blockers, propranolol is the most effective and the most studied. It can also cross the blood-brain barrier easier than most beta-blockers. As such, propranolol and propranolol LA should be used as first-line.
A lack of response for propranolol is predictive of other beta-blockers’ lack of response and no further may not be required. But if the patient has a response, but has intolerable side effects, other beta-blockers that are more selective may be tried.
Common side effects are fatigue, diminished exercise tolerance, depression, and bronchospasm.
Primidone
Remember that primidone is a potent inducer with two active metabolites: phenobarbital and PEMA. There is a titration range with primidone.
While primidone works well for essential tremors, it has a lot of side effects, and drug-drug interactions, and must be dose adjusted in both renal and hepatic impairments. This is why beta-blockers are recommended as first-line.
Common side effects include nausea, malaise, and fatigue.
Rare side effects include agranulocytosis and anemia.
It is important to note that propranolol and primidone can be used together. This allows for lower doses to be used.
Anticonvulsants – Gabapentin, Pregabalin, and Topiramate
These agents have favorable adverse and fewer drug-drug interactions compared to primidone. They’re considered the second-line agents.
The anti-tremor mechanism is unknown.
Common side effects are ataxia, sedation, and lethargy.
MISC Treatments
There are other agents being explored as potential treatment options. These are alcohol (benefit long recognized), benzodiazepines (adjunctive PRN), and botulinum toxin (still in the experimental realm).
Surgical options can be considered for certain patients who cannot be adequately controlled with pharmacotherapy.
Parkinson’s Disease (PD) Treatment
The goal of PD therapy is to maintain function for as long as possible. Remember that of all the disease states in the discussion today, only PD is one with neurodegenerative progression.
PD: Non-pharmacologic Treatment
Three crucial components are Diet, Exercise, and Support. Patients need to be educated regarding expectations and should be referred to support groups. These have been shown to be effective. Patients can be referred to the National Parkinson Foundation and American Parkinson Disease Association for more information and support groups.
Exercise, physical therapy, and occupational therapy are important in helping patients maintain their functioning. This also includes speech and swallowing therapy.
Because PD patients have problems with constipation, a diet high in fiber with adequate hydration is very important. The patients should be careful of high-fat or high-protein meals.
Surgeries are not the mainstay of the therapy but can be done if the patients cannot tolerate pharmacologic treatments or fail pharmacologic treatments.
- Pallidotomy – improve tremor
- Thalamotomy – severe tremor
- Deep Brain Stimulation
- Transplantation of dopaminergic cells
PD: Pharmacologic Treatment
There are two types of pharmacologic therapy: protective and symptomatic. Most therapies that we have available currently are symptomatic therapies.
The key with PD treatment is to start low and titrate slowly. Sometimes anticholinergic agents can be used in the younger population because they work great, but due to ADRs should not be used in the older population.
While levodopa will lose efficacy eventually, in patients who are older (70-80+ years), we can use levodopa right away because there is no reason to wait. Most levodopa ADRs are dose-dependent, as such if the patients are older already, it is fine to just start with this medication. There is currently no guideline that comes out and says when levodopa therapy should be started, but it is also generally regarded that the therapy can be started as soon as the quality of life is impacted.
MAO-B Inhibitors: neuroprotection and mild symptomatic benefit in early disease
The DATATOP study showed the delay in the need for levodopa therapy. This is why MOA-I is still considered the first-line.
Agents in this class are selegiline (Eldepryl), rasagiline (Azilect), and safinamide (Xadago).
- Selegiline – Dosed QD-BID before noon
- Rasagiline – The drug of choice
- Safinamide – Use in advanced PD with a lot of “off time.” This medication increases the “on time.”
Amantadine – “Livedo reticularis”
This medication is an antiviral that indirectly affects the release of dopamine. It also has a mild action on the cholinergic and NMDA receptor as an antagonist.
Caution should be used when dosing in renal impairment.
ER formulations have become available in the last few years that are approved for use during late stage of PD (Parkinson’s related dyskinesia.)
ADRs: sedation, vivid dreams, dry mouth, and livedo reticularis
The patient experiences livedo reticularis, amantadine should be discontinued and the reaction should go away.
Anticholinergics – Balance out DA and ACh
These agents are trihexylphenidyl (Artane) and Benztropine (Cogentin). These are most useful as monotherapy in younger patients with marked tremor
While it is not effective for bradykinesia, it is used adjunctively for dystonia, especially end-of-dose dystonia with levodopa.
Any anticholinergic medication usage in elderly patients should be made with caution.
ADR: dry mouth, blurred vision, constipation, urinary retention, and cognitive impairment.
Dopamine Agonists – the “mid-way” agents
These agents are used when MAO-I or amantadine can no longer give adequate control, but symptoms are not bad enough for levodopa.
As with RLS, start with a low dose and titrate up slowly. These agents are pramipexole, ropinirole, rotigotine, and apomorphine.
ADR: nausea, orthostatic hypotension, vivid dreams, compulsive behaviors, sudden sleep attacks (SOS). Rare ADRs include pleuropulmonary fibrosis and cardiac valvulopathy. These rare ones are generally only seen with older ( not pramipexole and ropinirole)
Levodopa – The gold standard (Sinemet)
This is the most effective agent even in akinesia. The medication needs to be combined with carbidopa, which helps levodopa get into the CNS without breaking down ahead of time. This reduces nausea and orthostatic hypertension.
Levodopa can cross the blood-brain barrier while dopamine cannot, which is why DA injection is ineffective.
Usually, the minimum effective dose is 75mg of carbidopa. Switching between IR and CR formulation is not a 1:1 ratio. The dose needs to be increased by 30%.
Duopa is levodopa intestinal gel used for motor fluctuations in the late stage of PD.
The most common ADR is nausea and vomiting, which can be especially bad during initiation and dose increases. They may be minimized by intake of food and anti-emetics.
Dyskinesias is the most serious ADR. It usually starts after 5-10 years of therapy (50% of patients after 5 years and 90% after 10 years). Individuals with the highest risk are those taking higher than 600mg daily or those diagnosed with PD when younger than 50 years old. The results are wearing off, end of dose, on-off.
Wearing Off Effect Treatment
Step one: adjust levodopa. When this happens, the levodopa dosage must be adjusted, and pay attention to high-fat and high-protein meals. Sometimes sustained-release carbidopa/levodopa is better than the IR formulation. Response duration greater than 2 hours is when benefits start to be observed. An IR dose may be given in the morning as an adjunct.
Step two: MAOI-B. Safinamide, as discussed, can be used to help with the wearing-off effect. Remember that MAOIs have a lot of interactions with other medications and high-tyramine foods.
Step three: Apomorphine, dopamine agonist/COMT inhibitors, Duopa
Apomorphine is a type of dopamine agonist meant for immediate action to snap the individual out of the off-period. It is available in the SL and SQ formulations. It is associated with a high level of nausea and must be pre-treat with trimethobenzamide. No more than 5 doses per day, and avoid usage with ondansetron due to profound hypotension.
COMT inhibitors act similarly to carbidopa and help preserve levodopa, leading to a reduction in the dose of levodopa needed to control the disease. Some reported up to 30% dose reduction. Like carbidopa, they are ineffective if used alone. COMT inhibitors are entacapone (Comtan), opicapone (Ongentys), and Tolcapone (Tasmar). Entacapone used to be the mainstay, but now opicapone is due to having fewer ADRs. Entacapone has high liver toxicity, and opicapone does not.
Dyskinesia Treatment
Step one: Levodopa dose reduction
Step two: DA agonist, amantadine, COMT inhibitor
Step three: anticholinergic therapy