Parkinson's disease (PD) is a degenerative disease of the central nervous system (CNS) that affects approximately 1% of the U.S. population over 65 years of age.1 The cardinal motor symptoms of PD are tremor, bradykinesia, and rigidity, with secondary or nonmotor symptoms including urinary incontinence, abnormal sweating, constipation, sleep disorders, depression, anxiety, pain, and fatigue (see Symptoms of Parkinson's Disease).2,3 Both motor and nonmotor symptoms contribute to the impaired quality of life experienced by patients with PD.4,5 Furthermore, motor complications-dyskinesia, dystonia, and symptom reemergence due to wearing off-can occur with long-term PD therapy.2 Over time, patients who have been stabilized on a therapeutic regimen may begin to experience a reemergence of symptoms as the effect of their medication wears off between doses. This wearing off or symptom reemergence may not be initially recognized by the patient or treatment team, therefore implementation of an effective strategy for managing these symptoms may be unnecessarily delayed.
Coordinating Communication
NPs play a key role in developing relationships with PD patients and their families, and in facilitating communication among patients, caregivers, and specialists. Effective professional and patient communication leads to a positive impact on the health of the PD patient, improved patient satisfaction, and improved adherence to medical recommendations.6 NPs can enhance the patient's comfort with provider and patient communication by using a patient-centered consultation style that affords patients the opportunity to be heard and involved in decisions concerning their treatment. Involvement in therapeutic decision making may increase the willingness of PD patients to adhere to treatment, potentially leading to improved quality of life.6
As the coordinators of communication among healthcare professionals, caregivers, and patients with PD, NPs can be instrumental in monitoring for symptom reemergence. Many patients may not recognize the significance of changes in nonmotor symptoms and, therefore, may not think an increase in fatigue or irritability, for example, is worth mentioning to their provider. Therefore, it is important for NPs to educate patients and their caregivers about wearing off and the possible symptoms that can occur. It is also necessary to assure them that in many cases, symptom reemergence can be successfully managed with appropriate pharmacotherapy. If changes in the patient's therapy are required, the NP should ensure that the patient understands the need for a change in treatment, as well as manage the patient's expectations and explain potential adverse effects.7
Role of Levodopa
PD is characterized by a progressive loss of dopaminergic neurons. The aim of treatment is to replace, mimic the actions, or increase the availability of dopamine in the brain (see Dopamine Levels). Levodopa is transported across the blood-brain barrier into the CNS where it is metabolized to dopamine.8 It was the first drug found to be effective in managing the symptoms of PD and is still considered the most effective option for managing these symptoms, despite the development of newer agents such as dopamine agonists.9 Almost all patients with PD will eventually require levodopa therapy, regardless of the initial therapy used.
The majority (over 99%) of orally administered levodopa is metabolized peripherally before it can enter the brain,8 primarily to dopamine (which does not cross the blood-brain barrier) by dopa decarboxylase (DDC) and by catechol-O-methyltransferase (COMT). High peripheral concentrations of dopamine that can occur following oral administration of levodopa are associated with adverse effects including nausea, vomiting, cardiac dysrhythmias, and hypotension. Therefore, levodopa is always given in combination with a DDC inhibitor, which could be either carbidopa (Parcopa, Sinemet) in the United States or benserazide (Madopar) in other countries.10 Recently, research has been directed toward inhibition of COMT. Two COMT inhibitors are currently available-entacapone (Comtan) in combination with levodopa and carbidopa (Stalevo); and tolcapone (Tasmar). Inhibition of peripheral metabolism of levodopa with DDC inhibitor and COMT inhibitors increases levodopa bioavailability, resulting in higher concentrations of dopamine in the brain that are maintained for longer periods.11,12
Treatment-Related Complications
Within 5 years of starting treatment with levodopa/carbidopa, approximately one-half of patients with PD develop motor complications that can significantly decrease quality of life (see Spectrum of Motor Complications).4,9,10 Dyskinesia and dystonia are two motor complications that occur most commonly when levodopa concentrations are at peak levels.10 Dyskinesias are involuntary movements of the limbs or twisting movements of the limbs, face, or trunk. Dystonias are dyskinesias that cause the patient's body to assume painful postures. These movements hamper the patient's ability to perform desired activities and hinder communication with others.9 Reemergence of these symptoms between doses of levodopa/carbidopa can also interrupt activities of daily living and increase the risk for falls and accidents.13 Furthermore, disability associated with wearing off may negatively impact caregiver quality of life as the patient's functional status deteriorates.14
Increasing attention is being paid to a number of nonmotor manifestations of PD. These symptoms may be categorized as autonomic (sweating, increased salivation), neuropsychiatric/cognitive (anxiety, fatigue, mood changes, difficulty in thinking, restlessness, irritability, hallucinations), and sensory (pain, paresthesias).15-17 Nonmotor symptoms have been less readily associated with the wearing off phenomenon. In one study, use of a novel, validated questionnaire specific for nonmotor symptoms in PD identified at least 10 symptoms with nonmotor features in the majority of patients. Further, the frequency of nonmotor symptoms correlated with the stage of disease.18
Nonmotor symptoms, which may occur as part of wearing off, are often neglected despite the fact that they can be more disabling than motor symptoms. Patients with PD and motor complications specifically report dysautonomic, cognitive, psychiatric, and sensory fluctuations (see Frequency of Common Nonmotor Wearing Off Symptoms).17
Recognizing Symptom Reemergence
Symptoms of wearing off often emerge within up to 3 years of initiation of PD treatment; this may affect almost 40% of patients within 2 years of initiation of conventional levodopa/DDCI therapy and nearly 50% of patients within 5 years.15 Typically, wearing off symptoms occur within hours after administration of a single dose of levodopa.15,19 Commencement of this phenomenon may be subtle and take the form of mild sensory symptoms in a limb or a vague feeling of malaise or a depressed mood. Patients may not associate these symptoms with falling levodopa levels and fail to report it. The more frequently described motor symptoms (a reemergence of tremor and stiffness) are easier to identify. Early recognition of wearing off symptoms and optimization of therapy can result in improved quality of life for patients with PD.
NPs play a crucial role in the therapeutic management of these patients. One strategy NPs can use to help recognize symptom reemergence is to encourage the use of daily diaries and timers. Patients should record when they take their medication as well as information about any untoward effects experienced after dosing and the effect of treatment on their symptoms, specifically whether symptoms improve after taking their medication and when symptoms return. In addition, patients should make a note of any new or worsening symptoms, even if they do not feel that the change is important at the time. This information allows the clinician to assess treatment efficacy, adverse events, and adherence to treatment, as well as identify any new symptoms or changes in frequency or timing of current symptoms. This also enables the clinician to tailor therapy based on individual needs.
Another effective strategy is the use of a patient questionnaire designed to identify patients with symptoms of wearing off. The 9-Symptom Wearing-Off Questionnaire (WOQ-9) was developed for routine clinical use to assess the presence of symptoms that are highly characteristic of wearing off (see The 9-Symptom Wearing-Off Questionnaire).20 At each visit, patients are asked to indicate if they have experienced any of the listed symptoms and whether they usually improve after the next scheduled dose of medication. The WOQ-9 is highly sensitive; during one validation study, it correctly identified symptom reemergence in 96% of PD patients.20 The WOQ-9 identified considerably more patients assessing their medication as wearing off than did the provider's examination. As the provider's assessment was regarded as the gold standard, the specificity of the WOQ-9 appeared to be low.20
Pharmacologic Strategies
As PD progresses, the loss of neurons in the substantia nigra decreases the capacity of the brain to maintain consistent dopamine levels. The level of stimulation of dopamine receptors in the brain also starts to reflect the peripheral concentrations of levodopa and fluctuates so that symptoms start to reappear between levodopa/carbidopa doses. Strategies for managing wearing off symptoms are based on the need to maintain stimulation of dopamine receptors for longer periods of time, thereby increasing the duration of symptom response to treatment (on time) and decreasing the amount of time symptoms are not controlled (off time). Viable options include the addition of monoamine oxidase type B (MAO-B) inhibitors, which delay the breakdown of dopamine in the brain; dopamine agonists, which usually have a longer half-life than levodopa; and agents that increase the availability of levodopa within the CNS, such as COMT inhibitors. Greater levodopa concentrations can be achieved in the brain by increasing levodopa absorption or increasing the amount of levodopa available to pass through the blood-brain barrier.8,10
MAO-B inhibitors
The MAO-B inhibitors selegiline (Eldepryl) and rasagiline (Azilect) reduced off time and improved functionality when added to stable levodopa regimens in PD patients with motor fluctuations in randomized, double-blind studies.2,21,22 Early use of either selegiline or rasagiline as monotherapy in levodopa-naive PD patients was associated with less functional decline compared with delayed treatment.2,19 Evidence from long-term studies suggests the advantage of earlier versus delayed treatment was maintained for up to 6 years with rasagiline and for up to 7 years with selegiline.23,24 In 2006, selegiline orally disintegrating tablet (ODT; Zelapar) was approved as adjunct therapy in PD patients taking levodopa. This formulation provides high bioavailability, and studies have reported a more pronounced reduction in off hours than that observed for conventional selegiline.25,26 The incidence of nausea appears to be lower with ODT than with the conventional formulation. In elderly PD patients, the more worrisome adverse effects of selegiline include anorexia, dry mouth, dyskinesia, and orthostatic hypotension.25 In patients receiving rasagiline in addition to levodopa therapy, adverse effects are dosedependent and include dyskinesia, accidental injury, nausea, headache, falls, weight loss, constipation, postural hypotension, arthralgia, vomiting, dry mouth, rash, somnolence, abdominal pain, anorexia, diarrhea, ecchymosis, dyspepsia, and paresthesia.25
Dopamine agonists
The addition of a dopamine agonist to levodopa therapy in PD patients may decrease off time, increase on time, improve motor function, and allow a reduction of the current dosage of levodopa;19 however, the dopamine agonist, pergolide, is no longer marketed in the United States, and in April of this year, the rotigotine transdermal system (Neupro) was recalled in the U.S. market (see Neupro Patch Recall). Adverse effects associated with dopamine agonists are common (see Adverse Events of Dopamine-Replacement Medication).
Increasing levodopa absorption
Another issue to have in mind with regard to wearing off symptoms is the influence on levodopa absorption by dietary modulation. Delayed gastric emptying is common in patients with PD and occurs more frequently in patients with response fluctuations.27 Because levodopa is absorbed in the proximal small intestine and not in the stomach, improving slowed gastric emptying may lead to more rapid absorption of levodopa.10 For this reason, when tolerated, levodopa should be taken before meals. Since the presence of dietary protein interferes with levodopa absorption, patients should also try to avoid a high protein diet; however, this is more likely in later disease stage.
Increasing levodopa availability in the brain
The two most common approaches to increase the amount of levodopa available for entry into the CNS are to increase the dose or to use controlled-release preparations.10 Unfortunately, increasing the dose of levodopa can induce dyskinesias or aggravate preexisting dyskinesia. Switching to a controlled-release levodopa/carbidopa preparation is another option, because it increases the duration of action of levodopa by 1 to 2 hours. However, the effects of the controlled-release formulation may be unpredictable.28
Use of COMT inhibition
Reduction in the peripheral metabolism of levodopa achieved with the use of a DDCI (carbidopa) can be augmented by the addition of a COMT inhibitor. Combined therapy with levodopa/carbidopa plus a COMT inhibitor provides more consistent and extended availability of levodopa.12 Both available COMT inhibitors, tolcapone and entacapone, have been shown statistically to significantly increase daily on time and reduce daily off time as well as reduce the daily levodopa requirements.2 However, tolcapone has been implicated with severe, life-threatening hepatotoxicity, and frequent monitoring of liver enzymes may be required.29,30 For this reason, entacapone is more commonly used in clinical practice. When added to an levodopa/carbidopa regimen in PD patients with motor fluctuations, entacapone increases the duration of response to levodopa, increases on time, decreases off time, may reduce the required daily dose of levodopa, and improves functional status and motor function.2,31 Entacapone may be added to levodopa/carbidopa as a separate tablet, or the patient may be switched to a one-tablet, fixed-dose, triple-drug formulation containing levodopa/carbidopa/ entacapone (LCE) provided that no relevant dyskinesias are present and the total daily dose of levodopa is 600 mg or less.32
Switching to one tablet at a time may improve adherence.6,32 Additionally, taking one tablet appears to be more acceptable to patients than a regimen consisting of levodopa/carbidopa plus entacapone.33,34 The results of a cost-effectiveness analysis suggest that use of the one-tablet LCE formulation to treat PD patients with wearing off provides better outcomes at a lower cost than treatment with traditional levodopa/carbidopa with other anti-Parkinson's medications added as needed.35 Patients with symptom reemergence due to wearing off who switched from levodopa/carbidopa to LCE had significant improvement in disease-specific quality of life and motor symptoms, as well as a reduced impact of PD symptoms on activities of daily living.33,36 The most common adverse events observed with LCE in clinical trials include dyskinesia, nausea, diarrhea, flu-like symptoms, dizziness, somnolence, and urine discoloration.33,36 Because most of these adverse events are a manifestation of the increased bioavailability of levodopa rather than an inherent characteristic of entacapone (with the exception of urine discoloration), they are usually managed successfully with a reduction in the levodopa dose rather than withdrawal of entacapone. The available doses of LCE offer the flexibility of more subtle levodopa titration without the need to split tablets.32 Dyskinesias, if they occur, may be managed by levodopa dose reduction, replacement of levodopa with a dopamine agonist, or by administration of amantadine (see Algorithm for the Management of Levodopa-induced Motor Complications).19
Consider Your Options
Productive and effective professional and patient communication is essential in managing long-term levodopa treatment, identifying wearing off and associated complications, and promoting adherence to therapy. Prompt identification of symptom reemergence due to wearing off and the recognition of adverse events can lead to the selection of an appropriate treatment regimen based on the individual PD patient. NPs, working together with patients and using tools such as patient diaries and the WOQ-9, can make therapeutic decisions that will ultimately impact the patient with PD. Although management of wearing off symptoms is challenging, it is an important goal to improve the quality of life in these patients. While choosing a therapeutic option, the healthcare professional should consider the risks and benefits associated with specific agents and individual patient risk factors to tailor therapy.19
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