Nurse Navigator Newsletter

Parkinson's Navigator for Nurses
A Newsletter for Nurses in Neurology

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Medication Therapy

Progressions Over Time

Major Side Effects

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Issue: #2

April/2010

Greetings!

The Nurses Navigator is a quarterly e-newsletter focusing on best practices in nursing care for patients with Parkinson's and other related movement disorders. Articles will be written by nurses, mid-levels and specialists with a wide range of experience and expertise.

Since many patients rely on nursing care as their primary contact and information source we thought it would be helpful to provide information, tools and insights from fellow practitioners.

If you know of other colleagues that would benefit from this newsletter, please do forward it along.

Thanks for reading.

Sincerely,
005

Bill Bell
Editor/Executive Director
877-980-7500 | bbell@nwpf.org

Medication Therapy

Should levodopa be started as the initial therapy for newly diagnosed Parkinson's?

"Levodopa is toxic to nerve cells and loses effect over time. I was told I should wait to start medicines so I do not want treatment until things are worse?"

This comment is commonly heard in clinical practice and is based on a series of misconceptions propagated on the internet and other informational sources. Treatment should be initiated when motor symptoms cause functional disability. Many believe that medicines should be initiated at time of diagnosis regardless of the degree of disability. L-dopa offers clear symptom improvement and remains the gold standard of therapy.

Levodopa the mainstay of therapy,is converted to dopamine in dopaminergic nerve cells. It remains an effective medicine and for some individuals the best first choice. Controversy over the use of levodopa early in the disease spring from the observation that levodopa causes motor complications after years of use. It is estimated that 40% of patients experience these complications after 4-5 years levodopa therapy. Studies identified that motor complications associated with long-term use of levodopa therapy can occur as early as 2 years into therapy45. (The reader is referred to the Winter Edition of Nurses navigator click herefor a description of motor fluctuations and dyskinesia).

Levodopa's short half life (90 minutes) coupled with a loss in viable dopaminergic cells over time, leads to a pulsatile release of dopamine in the nigrostriatal system (region of the brain associated with dopamine nerve cell loss in Parkinson's). This pulsatile stimulation of post-synaptic dopaminergic receptors may, in part, contribute to motor fluctuations and dyskinesias.  The risk of developing motor complications increases with total levodopa dose and degree of disease progression. In addition people with younger onset Parkinson's disease (defined as disease onset < 40 y.o.) are at greater risk of developing earlier and more severe motor fluctuation and dyskinesia than individuals with later onset.

Therefore, initial use of dopaminergic agents with a longer half life is an alternative strategy to early levodopa therapy (often referred to as a levodopa sparing strategy) and may delay the onset of motor complications. This strategy may be especially pertinent to younger patients that are at greater risk of these complications.

Clinical pearl: Talk to your patient about their reasons to delay treatment as this highlights an opportunity for education.

What other treatment options could be considered in place of levodopa?

Other initial treatment options include dopaminergic agonists, monoamine oxidase B (MAO B) inhibitors and amantadine.  Collectively these medicines can delay the use of levodopa and are associated with minimal risk of dyskinesia when used as monotherapy.

The monoamine oxidase B inhibitors (MAO B) inhibitorsselegeline and rasagiline are effective as initial monotherapy.. MAO B inhibitors block the enzymatic process that degrades dopamine in the brain. Selegeline is metabolized to an amphetamine so should be used with caution in the elderly or in individuals prone to anxiety, cognitive difficulties or insomnia.  Zydis selegeline is a rapidly disintegrating tablet that minimizes first pass metabolism resulting in a reduction in amphetamine compounds.

Rasagiline (Azilect) is a selective MAO B inhibitorshown to be effective throughout the course of disease including as initial therapy. More recent studies suggest that early use of Azilect may modify symptom progression over time. Using a delayed-start design patients with early disease were randomized to receive 1mg of rasagiline vs. placebo and followed over 18 months. The placebo group (delayed start) received active drug at 9 months. The early start group performed better on motor testing than the delayed start group suggesting early use of this drug modifies symptom progression of disease.  It is not known whether this drug is neuroprotective (Neuroprotection refers to the ability to protect nerve cells that are vulnerable to future cell death from damage.) or the whether the observation is caused by other factors not yet identified. Slowing disease progression is currently one of the major unmet needs in Parkinson's, and rasagiline is the first drug to show such an effect in a well designed prospective clinical study. Rasagiline may not be effective enough for more advanced symptoms. This and its cost do limit its use in many patients.

The dopaminergic agonists ropinirole and pramipexole, effectively treat motor symptoms when used as initial monotherapy and may delay time to onset of motor complications. The effect of early treatment with levodopa vs. the dopaminergic agonists ropinirole or pramipexole were studied in two controlled trial with the primary outcome of time to onset of motor complication. Patients with early PD were randomized to receive either a dopaminergic agonist or levodopa. Agonists were titrated to an effective dose and open label addition of levodopa was allowed in either treatment arm to optimize motor function if needed. The incidence of end-of -dose wearing off at 4 years was 47% in the pramipexole group and 63% in the levodopa group and dyskinesia was noted in 25% vs. 54% in the respective treatment arms. Similarly the probability of developing dyskinesia at 5 years was lower in the ropinirole group at 20% vs. 45% in the levodopa group. Taken together, these studies support the concept that early use of dopaminergic agonists may reduce or delay motor complications seen with levodopa use and should be considered as initial treatment especially in those patients at higher risk of developing these long-term complications. However side effects such as sedation, lightheadedness and dizziness are greater with this group of medicines.

The side effect profile, cost of therapy and long-term risk of developing motor complications should be considered when choosing initial therapy. In general, dopaminergic agonists are more expensive, have a higher risk of cognitive side effects than levodopa, and should be used with caution in the elderly, or individuals with cognitive difficulties. Dopamine agonists are better tolerated in younger patients and should be considered as initial therapy in this group that is also at greater risk of significant motor complications. Conversely, levodopa should be considered in individuals with cognitive problems or older patients who are at a lower risk of developing significant motor complications.

Clinical pearl: Medical therapy is tailored to the individual. A levodopa sparing strategy may be considered for younger patients, individuals without cognitive issues or comorbid medical problems. In others, levodopa may be the best choice for initial therapy given its better side effect profile.

005

Dr. Monique Giroux is the medical director of the Northwest Parkinson's Foundation. She specializes in movement disorders with a focus on rehabilitation and wellness for Parkinson's patients

Progressions Over Time

Q. What are the treatment options once motor fluctuations and dyskinesia occur?

A. Motor symptom control becomes more difficult as the disease progresses.
Over time the control of motor fluctuations and dyskinesia becomes a primary treatment goal. Levodopa associated treatment strategies include fractionation of levodopa dosage with more frequent dosing throughout the day, use of controlled release levodopa formulations, or the use of a COMT inhibitor such as entacapone or tolcapone.

Table 1 outlines commonly used medications in relation to disease state.

Entacapone inhibits levodopa metabolism essentially increasing its duration of effectiveness seen as an increase in total daily on-time with levodopa by slightly greater than one hour. Patients with a limited response to entacapone may benefit from switching to tolcapone with an increase in on-time. However, tolcapone is associated with potential hepatotoxicity requiring liver enzyme monitoring. Efficacy of tolcapone is evident within a few weeks and should be discontinued in 3 weeks if no increase in on-time is noted.
The addition of a dopaminergic agonist and MAOB inhibitor can also reduce off-time in patients already on Ldopa.For patients that continue to experience significant off-time despite optimization of their oral regimen, subcutaneous apomorphine may be helpful. Onset of action within 10 minutes allows this medication to be used on an as needed basis or "rescue" treatment, that is, to be given during a motor off state to enhance movement until the next oral medication dose takes effect.However, the difficulties with self administration in the off-state, cost, orthostatic hypotension, risk of dyskinesia and hallucinations associated with this treatment limits its use in some patients.

Dyskinesia often renders control of motor off-time more difficult. The prior strategies can improve on-time but may increase dyskinesia requiring a reduction of levodopa dose.To date, amantadine, an antiviral and NMDA glutamate receptor antagonist, is the only available medication that both improves motor symptoms and in some patients reduces dyskinesia severity. Amantadine is renally excreted and should be used cautiously in older patients with reduced renal clearance.
As additional medications are added to optimize motor control, risk of adverse side effects can increase. The most common side effects that can be seen with all dopaminergic agents include nausea, vomiting, sedation, hypotension, leg edema, hallucinations, and confusion.It is common practice for the patient or physician to discontinue the last medication added when more than one medication is used to treat motor symptoms and intolerable side effects occur.
However, it is important to consider the relative contribution of the entire class of dopaminergic medications an individual is taking and eliminate the medication most likely to contribute to a particular side effect rather than the last added agent.In older patients with cognitive decline simplification of a patient's medication strategy to levodopa monotherapy may be necessary to reduce confusion and/or hallucinations.It is also helpful to implement one change at a time not only to identify the cause of any new problems but also to best identify the change that led to improvement.
Figure 1; Dopaminergic medicines and their sit or mechanism of action.
005

Medications used to treat Parkinson's disease
Initial Therapy
Carbidopa/Levadopa
Dopaminergic agonist - ropinirole, pramipexole
MAOB inhibitor - selegeline
Amantadine
Advance Disease
Motor Fluctuations:
COMT inhibitor - entacapone, tolcapone
MAOB inhibitors - selegeline, rasagiline
Dopaminergic agonist - ropinirole, pramipexole
"Rescue Therapy" - s.c. apomorphine
Dyskinesia - amantadine

005 Sierra Farris, PA-C, is a physician assistant at the Booth Gardner Parkinson's Care Center with over 10 years experience specializing in treating people with Parkinson's and movement disorders.

What are the Major Side Effects Associated With Dopaminergic Therapy?

In general, dopaminergic medicines share similar side effects.

It is first important to understand the general side effects caused as a dopamine class effect. Dopaminergic medication includes any type or class of medication that enhances the dopamine availability in the brain. Levodopa containing medications such as carbidopa/levadopa (Sinemet, Stalevo, and Parcopa) improve the symptoms of PD by directly supplementing our brain reserves of dopamine.

The dopamine agonists are a group of medications that have a molecular structure similar to dopamine, yet have longer lasting action in the brain than levodopa and include ropinirole (Requip), pramipexole (Mirapex) and rotigotine (Neupro).

Medications that block or delay the breakdown of dopamine in the brain are called enzyme inhibitors and include rasagiline (Azilect), selegeline (Eldepryl and Zelapar), entacapone (Comtan and Stalevo) and tolcapone (Tasmar). Amantadine (Symmetrel) is a commonly used medication to reduce dyskinesia or provide mild symptomatic benefit, however the mechanism of how this drug works isn't fully understood. Each of these medicines has a different mechanism of action (See Figure 1) but each effectively enhances function of the dopaminergic system.

Therefore, they share many side effects attributed to dopamine. All of these medications can cause similar side effects related to the enhancement of our dopamine system and include sleepiness, nausea, dizziness, low blood pressure, mental fogginess, fatigue, vivid dreams, confusion and hallucinations and impulsivity control problems.

Side effects can be avoided or reduced. Side effects can be anticipated if any dopaminergic medication is increased too quickly or when given at high doses. Dopaminergic medications are better tolerated if given in smaller doses and increasing gradually over several weeks. This applies to starting your first dopaminergic medication or adding on additional medications. Giving the brain and body time to adjust can help avoid side effects that may limit medication options.

Other tips to avoiding or limiting side effects are to take dopaminergic medication initially with food to limit nausea and plenty of water to fully swallow the medication. Once the body has adjusted, nausea and dizziness are not typically persistent side effects but can linger with the higher doses of any dopaminergic medication. Caffeine or exercise may be helpful if daytime sleepiness or fatigue persists as a lot of daytime napping will disrupt nighttime sleep. The first step to improving lightheadedness due to orthostatic hypotension is to be sure an individual is drinking the appropriate volume of fluids daily.

The cognitive or emotional side effects of confusion, hallucinations or impulse control problems are best mitigated by early and open conversations with your health care provider before these problems spin out of control. Psychosis is a condition where the person can lose insight while experiencing a quick decline in mentation or rational thought and can be precipitated by medication interactions or combined side effects and can be reversed with proper medical care.

Many times, medication adjustments can eliminate or improve any of the side effects mentioned above. In general amantadine, selegeline and dopamine agonists have a higher risk of causing confusion, hallucinations than levodopa. If these problems exist, it may be necessary to reduce these agents and use levodopa in there place if possible. More information on medical treatment of these problems will be addressed the next edition of the Nurses Navigator.

There are side effects that are unique to individual medicines. Leg swelling or even body swelling can occur with dopamine agonists and amantadine and may require smaller more frequent dosing or adding on additional dopaminergic medications to keep all the individual doses lower. The pressure from increased fluids in the legs can increase the risk of blood clot formation in the legs.

Low blood pressure can occur after taking any dopaminergic medication, however, dopamine agonists are longer lasting and may need to be reduced if dizziness with standing is occurring due to blood pressure drops.

Diarrhea can occur with agents that contain COMT inhibitors such as carbidopa/Ldopa/entacapone (Stalevo), entacapone (Comtan) or entacapone (Tasmar) and should be avoided if diarrhea is moderate to severe due to the risk of dehydration and malnutrition. Liver enzyme monitoring by a blood test is required when taking tolcapone due to past reports of life threatening liver failure.

Dry mouth, dry eyes, blurred vision, urinary retention, constipation, memory problems, leg rash and swelling can occur specifically with use of amantadine and may limit the dose. Selegeline is converted to an amphetamine like compound in the body and can be associated with insomnia, anxiety and hallucinations.

In addition, the MAO B inhibitors, selegeline and rasagiline, can cause fatal interactions if given with, pain or psychiatric medications and should be reviewed with the pharmacist before taking with any over the counter medications. Selegeline and rasagiline can also cause a type of drug interaction called serotonin toxicity that can affect blood pressure, body temperature, muscles stiffness and mentation if taken with some types of antidepressants, namely selective serotonin re-uptake inhibitors so caution is used with this combination of therapy.

Side effects associated with specific Parkinson's medicines:

General Dopaminergic side effects:

Sedation

Confusion

Lightheadedness

Nausea

Hallucinations

Specific drug side effects:

Dopamine agonist (ropinirole, pramipexole)- sedation, sleep attacks, confusion, hallucinations, impulsivity control

COMT inhibitors(entacapone)- diarrhea

COMT inhibitor (Tolcapone)-diarrhea, liver toxicity

MAOB inhibitor (Rasagiline and Selegeline)- drug interactions, possible serotonin syndrome when used in combination with SSRIs.

MAOB inhibitor (Selegeline)- amphetamine effects- insomnia, hallucinations, anxiety

Amantadine - levido reticulation, leg swelling. anticholinergic side effects of constipation, urinary retention, dry eyes, blurry vision, and memory loss.

Clinical pearl: Last medicine added may not be the first to stop if your patient experiences a side effect. Many patients are on multiple medicines to treat their disease. It is important to review all of the medicines, especially those with CNS activity to determine which one is the most appropriate to change.

References

Arevalo G, Jorge R, Garcia S, Scipioni O, Gershanik O. Clinical and pharmacological differences in early- versus late-onset Parkinson's disease. Movement Disorders 1997;12(3):277-84.

Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001): Treatment guidelines. Neurology 2001;56(Suppl 5):S1-S88.

Miyasaki J, Martin W, Suchowersky O, Weiner J, Lang A. Practice Parameter: Initiation of treatment for Parkinson's disease: An evidence based review. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;58:11- 7.

The Parkinson's Study Group A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Archives of Neurology 2002;61:561-6.

The Parkinson's Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The New England Journal of medicine 1993;328:176-83.

The Parkinson's Study Group. Levodopa and progression of Parkinson's disease. The New England Journal of medicine 2004;351:2498-508.

The Parkinson's Study Group. Pramipexole vs. levodopa as initial treatment for Parkinsons disease: 4 year randomized controlled trial. Archives of Neurology 2004;61(7):1044-53.

Rascol O, DJ B, Korczyn A, DeDeyn P, Clarke C, Lang A. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. The New England Journal of Medicine 2000;342:1484-91.

The Northwest Parkinson's Foundation (NWPF) plays a vital role in helping people with Parkinson's live meaningfully with the disease. A large part of our mission is education, both for the medical professional and for patients, caregivers and families. At both levels we have the opportunity to improve the day-to-day for those touched by this debilitating disease set. With the addition of Dr. Monique Giroux as Medical Director, we are positioned to become a leader in professional education as well as patient education.

The NWPF currently serves 25,000 people throughout the Northwest and beyond. Our primary constituency resides in the Northwest (Washington, Oregon, Idaho, Montana and Alaska), home of 70,000+ Parkinson's patients.

This program is generously supported by educational grants from Teva Neuroscience.