You are here
Parkinson’s Disease and Its Management. Part 4
Parkinson’s disease (PD) is a progressive disorder in which the patient’s response to pharmacotherapy decreases over time, resulting in various motor complications. In addition, the occurrence of dyskinesias and dystonias in patients with advanced disease further complicates clinical management.1–3 Several factors, such as the dose and the duration of therapy, are associated with the development of motor complications in patients with PD.4 The prevalence of motor fluctuations, or movement problems, is reported to be as high as 60% to 90% in PD patients after five to 10 years of treatment.2,4
In part 3 of this five-part series, published in the October 2015 issue of P&T, we reviewed the role of nondopaminergic pharmacotherapies and adjunctive options in the management of PD, as well as nonpharmacological treatment strategies. In this installment, we focus on managing the motor complications of PD.
In PD patients, motor fluctuations most commonly result from levodopa-related “wearing-off,” or the re-emergence of motor symptoms before the next scheduled levodopa dose. Although more subtle, wearing-off features may include non-motor features, such as depression and anxiety.5–7 Wearing-off can have either an acute or gradual presentation.1–3,8 The suggested cause of this phenomenon is postjunctional alterations of striatal dopaminoceptive systems, in addition to reduced dopamine levels in the striatum due to the degeneration of presynaptic dopaminergic terminals.6
The management of wearing-off usually involves increasing or manipulating dopaminergic stimulation.10 In addition, addressing potential dietary issues, such as the avoidance of protein consumption during dosing, may improve levodopa absorption and provide benefit in some patients.11
Levodopa dose adjustments for the management of wearing-off may involve fractionating the dose or increasing individual doses.3 Responses to the fractionation of levodopa can be variable because peaks and troughs are not eliminated, whereas increasing individual doses of the drug may put patients at increased risk of peak-dose dyskinesias.2,3,10,11
Although the controlled-release carbidopa/levodopa product Sinemet (Merck) was designed to treat PD patients who are experiencing wearing-off, it has not demonstrated significant benefits compared with regular-release carbidopa/levodopa products.16–21 In addition, delayed and often unpredictable responses resulting from erratic absorption have been reported with Sinemet, along with dyskinesias.16,18 Tolerability is similar between the controlled-release and regular-release carbidopa/levodopa products.16,21 Anecdotal reports have suggested a potential role for the bedtime administration of controlled-release carbidopa/levodopa for the treatment of nocturnal akinesia.16
A controlled study of Rytary (Impax Pharmaceuticals), a new extended-release carbidopa/levodopa product, reported a reduction in “off” time of 1.2 hours daily compared with an immediate-release product. This new formulation contains beads that release the two drugs at different rates compared with the polymeric-based erosion-tablet delivery system used in current controlled-release products.22
Rytary was approved for the treatment of PD in January 2015.23 In that same month, the Food and Drug Administration (FDA) also approved a carbidopa/levodopa enteral suspension (Duopa, AbbVie) for the treatment of motor fluctuations in patients with advanced PD. The product is administered using a small, portable infusion pump that delivers carbidopa and levodopa directly into the small intestine for 16 continuous hours via a procedurally placed tube. In a 12-week, phase 3, double-blind, double-placebo, active-control, parallel-group trial, Duopa significantly reduced daily mean “off” time (per 16 waking hours) at 12 weeks by four hours, which resulted in an average of 1.9 fewer hours of “off” time compared with immediate-release carbidopa/levodopa tablets.24
The addition of adjunctive pharmacotherapies is usually necessary to manage wearing-off in patients with advanced PD who are receiving carbidopa/levodopa products. Adjuvants include dopamine agonists and levodopa potentiators, such as catechol-O-methyltransferase (COMT) and monoamine oxidase type B (MAO-B) inhibitors.25–27 When added to carbidopa/levodopa, dopamine agonists have demonstrated the greatest improvements in “off” time and in PD assessment scores compared with the addition of COMT or MAO-B inhibitors. In the presence of adjunctive therapies, it is recommended that the levodopa dose be reduced to minimize the incidence of dyskinesias and other adverse effects.27,28
Acute episodes of “off” time may be managed with subcutaneous (SC) injections of the dopamine agonist apomorphine.29,30 Apomorphine is indicated only for acute “off” episodes in advanced PD in patients when other therapies have been optimized. The antiemetic trimethobenzamide should be given as premedication due to apomorphine’s side effect of severe nausea and vomiting.29,30 An evidence-based review of several long-term, open-label studies found that SC apomorphine infusions were successful in aborting “off” periods in a total of 233 PD patients.31 In an early study, 24 patients treated with SC apomorphine were followed for a median period of 22 months. “Off” time was reduced significantly (P < 0.001) in these subjects from 50.0% before treatment to 29.5% with apomorphine.32 Investigators in Spain evaluated long-term (at least three months) continuous SC apomorphine in 82 patients with advanced PD. The mean follow-up period was 19.9 months. The authors found a statistically significant reduction in “off” hours compared with baseline values, based on self-scoring diaries (6.64 hours per day at baseline versus 1.36 hours per day after treatment) and on Unified Parkinson’s Disease Rating Scale (UPDRS) total and motor scores (both P < 0.0001).33
DELAYED OR ABSENT RESPONSE TO CARBIDOPA/LEVODOPA
Patients with advanced PD may experience a delayed response or no response to carbidopa/levodopa therapy. The causes of these phenomena include absorption problems related to delayed gastric emptying and changes in receptor dynamics.10,16
The management of a delayed response or the lack of a response to carbidopa/levodopa generally consists of interventions to improve the duodenal absorption of levodopa, such as reducing tablet disintegration in the stomach or facilitating the gastric-emptying time.7,13 Practical suggestions have included avoiding protein meals with levodopa doses; drinking a full glass of water after chewing or crushing a tablet; or using the oral-disintegration tablet formulation.15,25,26 The use of SC apomorphine may be necessary in some patients who fail to respond to carbidopa/levodopa.29
FREEZING OF GAIT
Another complication that occurs in the later stages of PD is “freezing of gait” (FOG). FOG occurs in up to 60% of PD patients and is more common in males than in females. It is also more common in patients with akinetic–rigid PD than in those with tremor-dominant forms of the disease. Patients describe FOG as being unable to move or feeling “stuck to the floor.”34 The occurrence of FOG can confer a significant risk of falls and subsequent fractures.34,35 Several factors can trigger FOG in PD patients, including anxiety and obstacles to walking. FOG may occur in older individuals with PD when they are turning, initiating a step, crossing a busy road, or duel-tasking, or when they are confronted with spatial restrictions.34,37 The pathophysiology of FOG is unclear, but imaging studies have implicated the presence of dysfunctional parietal–lateral right-sided premotor circuits or the loss of norepinephrine associated with degeneration of the locus coeruleus.37,38
Limited data suggest that dopaminergic agents may improve “on” time in PD patients with FOG,34,37,39 although PD symptoms related to gait generally show a poor response to these drugs.40 The MAO-B inhibitor selegiline has been effective in reducing the development of FOG in patients with early PD41 as well as in those with advanced disease.42 Rasagiline, another MAO-B inhibitor, has also been shown to have a positive effect on FOG.41,43 In the large-scale LARGO and PRESTO trials, the drug demonstrated a significant effect on the UPDRS subscores of FOG and postural instability and gait disorder (PIGD) in patients with advanced PD.44,45 Moreover, in a LARGO ancillary study, rasagiline significantly reduced FOG in comparison with placebo.46 More recently, in a case report, treatment with rasagiline provided a rapid and sustained reduction in the frequency and duration of FOG in an 84-year-old man with a four-year history of the disorder.47
Alternative treatments, such as the selective norepinephrine reuptake inhibitor (SNRI) atomoxetine, botulinum toxin injections, and methylphenidate, have been studied in PD patients with FOG, but there is little evidence to support their use in this setting.33,36 Atomoxetine (Strattera, Lilly) is currently indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD),48 but since it enhances noradrenergic transmission, Jankovic studied its effects on FOG in five PD patients. He noted only a small, nonsignificant improvement in the total Gait and Balance Scale (GABS) score compared with placebo.49 Botulinum toxin injections were similarly ineffective. Wieler and colleagues administered botulinum toxin A to 12 subjects with PD and FOG and reported no significant improvements.50 In an open-label pilot study, Giladi and colleagues injected botulinum toxin into the calf muscles of the affected legs of patients who demonstrated FOG as a predominant symptom. Seven of the ten patients reportedly showed improvement for a mean period of six weeks (range: one to 12 weeks).51 Fernandez and colleagues, however, tried the same approach in a double-blind, placebo-controlled study and saw no improvement in FOG.52
The role of deep-brain stimulation (DBS) in FOG continues to be investigated.36,39 In a recent study, low-frequency (60 Hz) bilateral subthalamic-nucleus DBS significantly reduced FOG in seven patients with PD. The therapeutic benefits persisted over the study’s six-week assessment period.53
Pharmacotherapeutic dose adjustments have little effect in patients with FOG; therefore, supportive care, walking devices, and other aids are often used. The treatment of FOG may also focus on attention strategies, such as walking on a path with a pattern (zebra lines) and visual or auditory cueing. An interesting method for managing FOG consists of using a stimulus, such as stepping over an object, sounding an alarm bell, or walking to music, to paradoxically relieve the patient’s “freezing.” 36,38,39 A case report described a PD patient with freezing episodes who was able to ride a bicycle without difficulty.54
Researchers in Europe and Israel have developed a smart-phone app aimed at preventing FOG in PD patients. The app combines wearable sensors, audio biofeedback, and external cueing to provide motivational training tailored to each patient. The results are monitored remotely by medical professionals.55
Dyskinesias are commonly associated with dopaminergic (levodopa) therapy in PD patients. They usually occur within three to six years after the initiation of treatment56–60 and affect 30% to 80% of PD patients.57,60,61 The clinical presentation of dyskinesias can vary from unilateral or generalized symptoms to more-specific manifestations (e.g., athetotic or oculogyric). Some patients will tolerate mild treatment-associated dyskinesias in exchange for improved motor control, whereas others experience presentations that are incapacitating.58–60 There are two types of dyskinesia: peak-dose (or “on”-period) and diphasic dyskinesia. Peak-dose dyskinesias are associated with high plasma levels of levodopa, paralleling the drug’s maximal benefits, and present with choreic features involving the upper extremities, trunk, and neck. Diphasic dyskinesias appear at the onset and offset of levodopa’s clinical effects, coinciding with the increase and decrease in levodopa levels. Diphasic dyskinesias often occur when walking and may interfere with a patient’s gait.60,62–64 In general, dyskinesias initially affect the legs, but they can spread to the arms, torso, head, and neck, and may involve the muscles used in respiration and speech. Some patients experience dyskinesias soon after their first dose of carbidopa/levodopa, while others may develop these disorders over the course of several years.56,58,59,63
A retrospective evaluation of 109 patients with PD reported that their age at the time of diagnosis was a predictor for the development of levodopa-induced dyskinesias. According to this study, after five years of levodopa dosing, the risk of developing dyskinesias was higher in younger patients (ages 40 to 49 years; 70%) than in older patients (ages 70 to 79 years; 24%).65 Other risk factors for developing dyskinesias include genetic factors, the severity of PD, and being female.62,64
The pathophysiology of levodopa-induced dyskinesias is complex, and these movement complications can originate in multiple regions of the brain. Levodopa-induced dyskinesias have been linked to nigrostriatal dopaminergic loss, pulsatile stimulation of receptors, changes in striatal transmission, and circuit alterations associated with synaptic abnormalities.66,67 Research has also implicated nondopaminergic receptor systems, including glutamatergic, opioid, and serotonergic systems.67–71
Levodopa-related dyskinesias may be precipitated by adjustments in PD medications, such as increasing the carbidopa/levodopa dose or adding dopamine agonists or levodopa potentiators (e.g., COMT or MAO-B inhibitors). Severe dyskinesias may result in rhabdomyolysis and dehydration, and they can be life-threatening.66,67 The onset of dyskinesias may be delayed by starting patients on dopamine agonists rather than on carbidopa/levodopa.72–74
Several therapeutic strategies are used to manage dyskinesias, including adjusting existing PD medications, conducting trials of adjunctive pharmacotherapies, and performing DBS.75–80 Initial interventions may involve lowering the dose of existing carbidopa/levodopa therapy and discontinuing or adjusting the dose of a levodopa potentiator, such as entacapone. If carbidopa/levodopa doses are reduced, the addition of a dopamine agonist or other adjunctive therapies may be required.64,80 All dose-adjustment options and drug discontinuations require careful titration and monitoring to avoid the re-emergence of motor symptoms.64,75,80
The randomized, controlled Comparison of the Agonist Pramipexole Versus Levodopa on Motor Complications of Parkinson’s Disease (CALM-PD) trial evaluated the risk of developing dyskinesias in patients with early PD initially treated with either the dopamine agonist pramipexole or levodopa. After a median follow-up period of six years, the patients receiving levodopa experienced significantly more dyskinesias compared with the pramipexole-treated patients (36.8% versus 20.4%, respectively), but there was no difference between the two groups in the incidence of disabling or painful dyskinesias.81,82
Four randomized controlled studies (two 24-week phase 3 trials and two four-week phase 2 trials) compared pramipexole with placebo in a total of 669 patients with idiopathic PD and long-term complications of levodopa therapy. Although the reduction in “off” time was significantly greater with pramipexole in all four investigations, no significant changes were noted in dyskinesia scales. Moreover, dyskinesia as an adverse event was reported more often in the pramipexole group.83
In a randomized, open-label study conducted in Japan, 34 PD patients with levodopa-induced dyskinesias were randomly assigned either to an add-on group (n = 18), in which pramipexole was added to the existing drug regimen for the treatment of PD without changing the dose or the administration of the other drugs, or to a “switch” group (n = 16), in which the current dopamine agonist was switched to pramipexole. After 24 weeks of treatment, the overall study population showed no changes in UPDRS subscores for dyskinesia.74
Researchers have also treated PD patients with dyskinesias using dopaminergic stimulation via continuous intrajejunal infusions.14,76 For example, in a randomized, double-blind, double-dummy, double-titration trial, Olanow and colleagues compared levodopa/carbidopa intestinal gel infusions with immediate-release oral levodopa/carbidopa in 66 adults with advanced PD. After 12 weeks of treatment, mean “on” time without troublesome dyskinesia was significantly greater with the intestinal gel than with oral therapy (4.11 hours versus 2.24 hours, respectively; P = 0.0059).78,84
In a prospective study, Zibetti et al. observed the safety and efficacy of continuous levodopa/carbidopa intestinal gel in 59 adults with advanced PD and dyskinesias treated for seven years. The duration of dyskinesias was reduced from 1.7 hours at baseline to 1.2 hours at follow-up (P = 0.002), and dyskinesia disability was reduced from 1.0 to 0.5 hours (P < 0.001).85
Although continuous intrajejunal infusions of levodopa/carbidopa gel have been shown to reduce dyskinesias and improve motor fluctuations in PD patients, the surgical procedure involved and the discomfort of tubing protruding from the abdomen may be contraindications in some patients.78,86 Currently, this form of levodopa administration remains investigational in the U.S.
In an early study, Colzi et al. investigated continuous waking-day dopaminergic stimulation with SC apomorphine in 19 patients with PD and disabling levodopa-induced dyskinesias. The patients were treated for a minimum period of 2.7 years. SC apomorphine achieved a mean 65% reduction in dyskinetic severity and a mean 85% reduction in frequency and duration.87
Katzenschlager and colleagues retrospectively assessed the effects of a continuous SC infusion of apomorphine in 12 PD patients with disabling dyskinesias. The mean apomorphine dose was 75.2 mg per day. After six months, the treatment had provided a marked reduction in dyskinesias.79
The efficacy of intermittent SC apomorphine injections as an add-on to levodopa therapy in patients with advanced PD was investigated in one short-term, randomized, double-blind, placebo-controlled trial and in one short-term and six long-term, open-label, uncontrolled studies that involved a total of 195 patients. Although SC apomorphine, as an add-on to levodopa, helped prevent “off” periods and improve PD motor scores, the combination treatment also tended to increase dyskinesias.31
While it appears that SC apomorphine can reduce the potential for dyskinesias in some PD patients, administration problems, tolerance, and psychiatric side effects may limit the use of this approach.79
The role of glutamate N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of dyskinesias led to the use of NMDA receptor antagonists in PD patients.69,88 One such drug, amantadine (1-aminoadamantane), has been effective in managing dyskinesias in PD patients, with treatment benefits extending beyond one year.89–92 In a double-blind, randomized, placebo-controlled, cross-over trial, Sawada and colleagues assigned 36 PD patients with dyskinesias to treatment with amantadine (300 mg per day) or placebo for 27 days. At 15 days after washout, the treatments were crossed over. Secondary outcome measures included the UPDRS-IVa, which is related to dyskinesias. This measure showed significant improvement in the amantadine-treated patients compared with the placebo-treated patients (mean: 1.83 versus 0.03, respectively).89
Wolf and colleagues provided evidence supporting the long-term use of amantadine in PD patients with dyskinesias. They conducted a randomized, double-blind, placebo-controlled, parallel-group study to assess the antidyskinetic effect of amantadine in 32 PD patients who were switched to amantadine or placebo after having been on stable amantadine therapy for levodopa-induced dyskinesias for least one year. The study’s primary outcome was the score change in UPDRS-IV items 32 and 33 (severity and duration, respectively) between baseline and three weeks after the treatment switch. The authors reported a significant increase in the two UPDRS-IV items from 3.06 to 4.28 (P = 0.02) at the three-week follow-up in the patients switched to placebo compared with no significant change between baseline and follow-up values (3.2 to 3.6) in the patients who remained on amantadine.90
The three-month AMANDYSK trial evaluated the long-term efficacy of chronic treatment with amantadine in 57 PD patients with levodopa-induced dyskinesias. Like the study by Wolfe and colleagues, the primary outcome measure of this randomized, double-blind, placebo-controlled, parallel-group, wash-out trial was the change from baseline in UPDRS-IV items 32 and 33. These parameters deteriorated more in patients switched to placebo compared with those maintained on amantadine (+1.7 units versus +0.2 units, respectively; P = 0.003). Moreover, the authors found that withdrawing amantadine significantly aggravated patients’ dyskinesias within a median period of seven days.91
Monitoring amantadine and adjusting the dosage according to the patient’s renal function are important, especially in elderly patients. Adverse events related to the central nervous system, including hallucinations and confusion, may occur with this drug, and patients should be monitored for vision changes due to corneal edema.92,93
Another NMDA antagonist, memantine (1-amino 3,5-dimethyl-adamantane hydrochloride), has been used to manage levodopa-induced dyskinesias in PD patients with varying results. In an early study, Merello et al. evaluated the effect of memantine on dyskinesias in 12 PD patients who were randomly assigned to active treatment or placebo in a cross-over design. The authors reported that although memantine improved UPDRS motor scores, it had no effect on drug-induced dyskinesias in these patients.94 Similarly, in a recent randomized, double-blind, placebo-controlled, crossover study, the primary outcome measure—a change in observed dyskinesia ratings—did not reach statistical significance in 15 PD patients treated with memantine. Seven of these patients showed 32% reductions in their dyskinesias, whereas dyskinesias increased by 33% in three others. The remaining five patients showed no change.95 In a Swedish report, two out of three cognitively impaired PD patients “seemed to benefit” from treatment with memantine in terms of their dyskinesias.96 In view of the results from these and similar studies, further research is needed to validate the use of memantine as an antidyskinetic agent in PD patients.64,72
Riluzole (Rilutek, Sanofi), another NMDA receptor inhibitor, has been studied as a dyskinesia treatment in PD patients with little success. Rilutek is approved for the treatment of amyotrophic lateral sclerosis.97 Braz and colleagues reported that riluzole could extend the duration of the “on” state in 16 PD patients but was unable to reduce apomorphine-induced dykinesias.98 In another study, Bara-Jimenez et al. evaluated the antidyskinetic effect of riluzole in 15 patients with moderately advanced PD. Again, the treatment failed to lessen the severity of levodopa-induced motor complications.99
Other medications evaluated for the management of dyskinesias in PD include the atypical antipsychotic clozapine and the anticonvulsant levetiracetam. Durif and colleagues treated 50 PD patients with clozapine or placebo for 10 weeks in a double-blind, parallel-group study. The clozapine group showed a significant reduction in the duration of “on” periods with levodopa-induced dyskinesias compared with the placebo group at the end of the study (clozapine, 5.68 hours on day 0 and 3.98 hours at study end; placebo, 4.54 hours on day 0 and 5.28 hours at study end; P = 0.003).100 The mechanism behind this effect is not fully understood, although it may involve interactions with dopaminergic and serotonergic receptor systems.101 Safety concerns with clozapine include its association with rare but serious blood dyscrasias.100
Mixed results have been reported with levetiracetam in the management of dyskinesias. For example, Wolz and colleagues conducted a randomized, double-blind, placebo-controlled, parallel-group study of levetiracetam in 32 PD patients with moderate-to-severe levodopa-induced dyskinesias. After 11 weeks of treatment, mean changes in UPDRS item 32 and 33 scores from baseline showed significant improvement in dyskinesias in the levetiracetam group (−20%; P = 0.012), but not in the placebo group (−8%; P = 0.306). Levetiracetam and placebo were not significantly different, however, in terms of mean changes from baseline in the modified abnormal involuntary movement scale (AIMS).102
Stathis et al. investigated the efficacy of levetiracetam in 38 PD patients with dyskinesias using a double-blind, placebo-controlled, parallel-group design. The two dosages of levetiracetam (500 mg per day and 1,000 mg per day) significantly increased “on” time without dyskinesias by 46 minutes (P = 0.004) and 55 minutes (P = 0.018), respectively. Moreover, UPDRS item 32 showed a decreased duration of dyskinesia at the higher dosage (P = 0.009).103
Adenosine A2A receptor (A2aR) antagonists are being investigated as another treatment option for levodopa-associated dyskinesias.104,105 Studies have shown that expression of the A2aR receptor is increased in PD patients with dyskinesias.107
In two placebo-controlled studies, the A2aR antagonist istradefylline (Kyowa Pharmaceutical) improved “off” time without increasing dyskinesias in levodopa-treated PD patients.107,108 Another A2aR antagonist, preladenant (Merck), was ineffective at treating PD patients in three separate phase 3 trials, and its development was discontinued.109 A phase 3, placebo-controlled study of tozadenant (Biotie Therapies) began in July 2015; the drug was effective at reducing “off” time in a phase 2b study.100 Other A2aR antagonists are in development at the preclinical and early clinical levels.
Various surgical procedures, including DBS, have also been used to manage dyskinesias in PD patients.105,111–113 DBS is considered a surgical treatment alternative for PD patients with motor fluctuations and severe dyskinesias.113
Dystonias are another complication that may occur in PD patients, usually in those at more-advanced stages of the disease. Dystonias are primarily characterized by involuntary, sustained muscle contractions resulting in twisting or squeezing movements. These muscle contractions may be viewed as another form of “off” time, presenting as abnormal postures in fixed and painful positions. Dystonias can affect many parts of the body but are most common in the feet. Although they can occur at any time during treatment, they are usually experienced in the morning upon rising. Painful morning dystonias occur in approximately 40% of PD patients and appear to be secondary to the rigidity and akinesia associated with reduced dopaminergic stimulation.2,12,60
Dystonias are difficult to manage, although they may respond to adjustments in dopaminergic therapy if they occur during the “off” state.114 A small study reported that controlled-release levodopa products were beneficial in treating early-morning dystonia.115 Additional therapies for dystonias, although not well studied in this setting, include muscle relaxants, botulinum toxin, and DBS.116–118
Dystonias have been associated with serious complications, such as choking (resulting from involvement of the laryngeal area) and fixed postural changes that result in kyphosis and a restricted pulmonary capacity. The management of these complications may include breathing and trunk exercises, general conditioning, and postural re-education. Pulmonary function may be improved with coughing techniques, incentive spirometry, and respiratory therapy. Aggressive management, such as ventilator support, laryngeal adductor botulinum injections, or tracheostomy, may be required in some patients.25,26,114,118–120
The occurrence of motor complications is a key component of PD and presents a clinical challenge to practitioners. Such features include wearing-off,1–3,8 a delayed or absent response to carbidopa/levodopa therapy,10,16 FOG,34–38 dyskinesias,56–64 and dystonias.2,9,57
The management of wearing-off usually involves increasing dopaminergic stimulation as well as manipulating doses.10 Interventions to improve the duodenal absorption of levodopa, such as reducing tablet disintegration in the stomach, are the primary methods for managing a delayed or absent response to carbidopa/levodopa.10,16 Limited data support the use of dopaminergic agents in PD patients with FOG.34,36,39 Current approaches used to manage dykinesias include adjusting existing PD medications and the use of DBS. Other investigational therapies continue to be evaluated.75–80 Dystonias may respond to adjustments in dopaminergic therapy if they occur during the “off” state.114 Researchers continue to seek improved management options for PD patients with motor complications.25,26,114
In the next issue of P&T, the final installment of this five-part article will discuss the management of nonmotor complications of PD.
- Stocchi F, Jenner P, Obeso JA. When do levodopa motor fluctuations first appear in Parkinson’s disease?. Eur Neurol 2010;63:257–266.
- Gershanik OS. Clinical problems in late-stage Parkinson’s disease. J Neurol 2010;257;(suppl 2):S288–S291.
- Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:983–995.
- Olanow CW, Kieburtz K, Rascol O, et al. Factors predictive of the development of levodopa-induced dyskinesia and wearing-off in Parkinson’s disease. Mov Disord 2013;28:1064–1071.
- Kim HS, Cheon SM, Seo JW, et al. Nonmotor symptoms more closely related to Parkinson’s disease: comparison with normal elderly. J Neurol Sci 2013;324:70–73.
- Bouwmans AE, Weber W. Neurologists’ diagnostic accuracy of depression and cognitive problems in patients with parkinsonism. BMC Neurol 2012;12:37
- Stacy M. The wearing-off phenomenon and the use of questionnaires to facilitate its recognition in Parkinson’s disease. N Neural Transm 2010;117:837–846.
- Pahwa R, Lyons KE. Levodopa-related wearing-off in Parkinson’s disease: identification and management. Curr Med Res Opin 2009;25:841–849.
- Bravi D, Mouradian MM, Roberts JW, et al. Wearing-off fluctuations in Parkinson’s disease: contribution of postsynaptic mechanisms. Ann Neurol 1994;36:27–31.
- Melamed E, Ziv I, Djaldetti R. Management of motor complications in advanced Parkinson’s disease. Mov Disord 2007;22;((suppl) 17):S379–S384.
- Cereda E, Barichella M, Pedrolli C, et al. Low-protein and protein-redistribution diets for Parkinson’s disease patients with motor fluctuations: a systematic review. Mov Disord 2010;25:2021–2034.
- Müller T. Motor complications, levodopa metabolism, and progression of Parkinson’s disease. Expert Opin Drug Metab Toxicol 2011;7:847–855.
- Antonini A, Odin P, Opiano L, et al. Effect and safety of duodenal levodopa infusion in advanced Parkinson’s disease: a retrospective multicenter outcome assessment in patient routine care. J Neural Transm 2013;120:1553–1558.
- Chaudhuri KR, Rizos A, Sethi KD. Motor and nonmotor complications in Parkinson’s disease: an argument for continuous drug delivery?. J Neural Transm 2013;120:1305–1320.
- Espay AJ. Management of motor complications in Parkinson disease: current and emerging therapies. Neurol Clin 2010;28:913–925.
- Pahwa R, Busenbark K, Huber SJ, et al. Clinical experience with controlled-release carbidopa/levodopa in Parkinson’s disease. Neurology 1993;43:677–681.
- Koller WC, Hutton JT, Tolosa E, Capilldeo R. Immediate-release and controlled-release carbidopa/levodopa in PD: a 5-year randomized multicenter study. Neurology 1999;53:1012–1019.
- Jankovic J, Schwartz K, Vander Linden C. Comparison of Sinemet CR4 and standard Sinemet: double blind and long-term open trial in parkinsonian patients with fluctuations. Mov Disord 1989;4:303–309.
- Hutton JT, Morris JL, Roman GC, et al. Treatment of chronic Parkinson’s disease with controlled-release carbidopa/levodopa. Arch Neurol 1988;45:861–864.
- Ahlskog JE, Muenter MD, McManis PG, et al. Controlled-release Sinemet (CR-4): a double-blind crossover study in patients with fluctuating Parkinson’s disease. Mayo Clin Proc 1988;63:876–886.
- Lieberman A, Gopinathan G, Miller E, et al. Randomized double-blind cross-over study of Sinemet controlled release (CR4 50/200) versus Sinemet 25/100 in Parkinson’s disease. Eur Neurol 1990;30:75–78.
- Hauser RA, Hsu A, Kell S, et al. Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson’s disease and motor fluctuations: a phase 3 randomised, double-blind trial. Lancet Neurol 2013;12:346–356.
- Impax Pharmaceuticals. Impax Pharmaceuticals announce FDA approval of Rytary (carbidopa and levodopa) extended-release capsules for the treatment of Parkinson’s disease. January
82015;Available at: https://investors.impaxlabs.com/Media-Center/Press-Releases/Press-Release-Details/2015/Impax-Pharmaceuticals-Announce-FDA-Approval-of-RYTARY-Carbidopa-and-Levodopa-Extended-Release-Capsules-for-the-Treatment-of-Parkinsons-disease/default.aspx. Accessed July 15, 2015
- AbbVie. AbbVie announces U.S. FDA approval of Duopa (carbidopa and levodopa) enteral suspension for the treatment of motor fluctuations in patients with advanced Parkinson’s disease. January
122015;Available at: http://news.abbvie.com/2015-01-12-AbbVie-Announces-U-S-FDA-Approval-of-DUOPA-carbidopa-and-levodopa-Enteral-Suspension-for-the-Treatment-of-Motor-Fluctuations-in-Patients-with-Advanced-Parkinsons-Disease. Accessed July 15, 2015
- Richard BD. Management of motor complications in Parkinson’s disease. Neurology 2004;62;(suppl 4):S3–S7.
- Fabrizio S, Tagliati M, Olanow CW. Treatment of levodopa-induced motor complications. Move Disord 2008;23;(suppl 3):S599–S612.
- Talati R, Reinhart K, Baker W, et al. Pharmacologic treatment of advanced Parkinson’s disease: a meta-analysis of COMT inhibitors and MAO-B inhibitors. Parkinsonism Relat Disord 2009;15:500–505.
- Stowe R, Ives N, Clarke CE, et al. Meta-analysis of the comparative efficacy and safety of adjuvant treatment to levodopa in later Parkinson’s disease. Mov Disord 2011;26:587–598.
- Factor SA. Literature review: intermittent subcutaneous apomorphine therapy in Parkinson’s disease. Neurology 2004;62;(suppl 4):S12–S17.
- Broussolle E, Marion MH, Pollak P. Continuous subcutaneous apomorphine as replacement for levodopa in severe parkinsonian patients after surgery [letter]. Lancet 1992;340:859–860.
- Deleu D, Hanssens Y, Northway mg. Subcutaneous apomorphine: an evidence-based review of its use in Parkinson’s disease. Drugs Aging 2004;21:687–709.
- Pietz K, Hagell P, Odin P. Subcutaneous apomorphine in late stage Parkinson’s disease: a long term follow up. J Neurol Neurosurg Psychiatry 1998;65:709–716.
- Garcia Ruiz PJ, Sesar Ignacio A, Ares Pensado B, et al. Efficacy of long-term continuous subcutaneous apomorphine infusion in advanced Parkinson’s disease with motor fluctuations: a multi-center study. Move Disord 2008;23:1130–1136.
- Okuma Y, Yanagisawa N. The clinical spectrum of freezing of gait in Parkinson’s disease. Mov Disord 2008;23;(suppl 2):S426–S430.
- Okuma Y. Freezing of gait and falls in Parkinson’s disease. J Parkinsons Dis 2014;4:255–260.
- Thanvi B, Treadwell SD. Freezing of gait in older people: associated conditions, clinical aspects, assessment, and treatment. Postgrad Med J 2010;86:472–477.
- Peterson DS, Pickett KA, Duncan R, et al. Gait-related brain activity in people with Parkinson disease with freezing of gait. PLoS One 2014;9:e90634
- Espay AJ, Fasano A, van Nuenen BF, et al. “On” state freezing of gait in Parkinson disease: a paradoxical levodopa-induced complication. Neurology 2012;78:454–457.
- Walton CC, Shine JM, Mowszowski L, et al. Freezing of gait in Parkinson’s disease: current treatments and the potential role for cognitive training. Restor Neurol Neurosci 2014;32:411–422.
- Stocchi F. Rasagiline: defining the role of a novel therapy in the treatment of Parkinson’s disease. Int J Clin Pract 2006;60:215–221.
- Giladi N. Medical treatment of freezing of gait. Move Disord 2008;23;(suppl 2):S482–S488.
- Shoulson I, Oakes D, Fahn S, et al. Impact of sustained deprenyl (selegiline) in levodopa treated Parkinson’s disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann Neurol 2002;51:604–612.
- Leegwater-Kim J, Bortan E. The role of rasagiline in the treatment of Parkinson’s disease. Clin Interv Aging 2010;5:149–156.
- Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005;62:241–248.
- Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily study): a randomised, double-blind, parallel-group trial. Lancet 2005;365:947–954.
- Giladi N, Rascol O, Brooks DJ, et al. Rasagiline treatment can improve freezing of gait in advanced Parkinson’s disease: a prospective, randomized, double blind, placebo and entacapone controlled study. Neurology 2004;62;(suppl 5):A329–A330.
- Coria F, Cozar-Santiago Mdel P. Rasagiline improves freezing in a patient with primary progressive freezing gait. Move Disord 2008;23:449–451.
- Strattera (atomoxetine) prescribing information Indianapolis, Indiana: Lilly USA. April 2015;Available at: http://pi.lilly.com/us/strattera-pi.pdf. Accessed July 23, 2015
- Jankovic J. Atomoxetine for freezing of gait in Parkinson disease. J Neurol Sci 2009;284:177–178.
- Wieler M, Camicioli R, Jones CA, Martin WR. Botulinum toxin injections do not improve freezing of gait in Parkinson disease. Neurology 2005;65:626–628.
- Giladi N, Gurevich T, Shabtai H, et al. The effect of botulinum toxin injections to the calf muscles on freezing of gait in parkinsonism: a pilot study. J Neurol 2001;248:572–576.
- Fernandez HH, Lannon MC, Trieschmann ME, Friedman JH. Botulinum toxin type B for gait freezing in Parkinson’s disease. Med Sci Monit 2004;10:CR282–4.
- Xie T, Vigil J, MacCracken E, et al. Low-frequency stimulation of STN-DBS reduces aspiration and freezing of gait in patients with PD. Neurology 2015;27:84415–420.
- Snijders AH, Toni I, Ružička E, et al. Bicycling breaks the ice for freezing of gait. Mov Disord 2011;26:367–371.
- American Friends of Tel Aviv University. Great strides: smart-phone app may prevent dangerous freezing of gait in Parkinson’s patients. June
252015;Available at: https://www.aftau.org/weblog-medicine--health?=&storyid4704=2208&ncs4704=3. Accessed July 16, 2015
- Calabresi P, Di Filippo M, Ghiglieri V, et al. Levodopa-induced dyskinesias in patients with Parkinson’s disease: filling the bench-to-bedside gap. Lancet Neurol 2010;9:1106–1117.
- Batla A, Stamelou M, Mencacci N, et al. Ropinirole monotherapy induced severe reversible dyskinesias in Parkinson’s disease. Mov Disord 2013;28:1159–1160.
- Hong JY, Oh JS, Lee I, et al. Presynaptic dopamine depletion predicts levodopa-induced dyskinesia in de novo Parkinson disease. Neurology 2014;82:1597–1604.
- Lennert B, Bibeau W, Farrelly E, et al. Assessment of treatment patterns and patient outcomes in levodopa-induced dyskinesias (ASTEROID): a US chart review study. Am Health Drug Benefits 2012;5:347–358.
- Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol 2000;47;(suppl 1):S2–S9.
- Hung SW, Adeli GM, Arenovich T, et al. Patient perception of dyskinesia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2010;81:1112–1115.
- Guridi J, González-Redondo R, Obeso JA. Clinical features, pathophysiology, and treatment of levodopa-induced dyskinesias in Parkinson’s disease. Parkinsons Dis 2012;943159:
- Colosimo C, Martínez-Martín P, et al. Task force report on scales to assess dyskinesia in Parkinson’s disease: critique and recommendations. Mov Disord 2010;25:1131–1142.
- Tambasco N, Simoni S, Marsili E, et al. Clinical aspects and management of levodopa-induced dyskinesia. Parkinsons Dis 2012;745947:
- Ku S, Glass GA. Age of Parkinson’s disease onset as a predictor for the development of dyskinesia. Mov Disord 2010;25:1177–1182.
- Lewitt PA. Relief of parkinsonism and dyskinesia: one and the same dopaminergic mechanism?. Neurology 2010;74:1169–1170.
- Loonen AJ, Ivanova SA. New insights into the mechanism of drug-induced dyskinesia. CNS Spectr 2013;18:15–20.
- Huot P, Johnston TH, Koprich JB, et al. The pharmacology of L-DOPA-induced dyskinesia in Parkinson’s disease. Pharmacol Rev 2013;65:171–222.
- Ahmed L, Bose SK, Pavese N, et al. Glutamate NMDA receptor dysregulation in Parkinson’s disease with dyskinesias. Brain 2011;134:979–986.
- Sgambato-Faure V, Cenci MA. Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson’s disease. Prog Neurobiol 2012;96:69–86.
- Parkinson Study Group CALM Cohort Investigators. Long-term effect of initiating pramipexole vs levodopa in early Parkinson disease. Arch Neurol 2009;66:563–570.
- Stocchi F, Rascol O, Kieburtz K. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol 2010;68:18–27.
- Whone AL, Watts RL, Stoessl AJ. Slower progression of Parkinson’s disease with ropinirole versus levodopa: the REAL-PET study. Ann Neurol 2003;54:93–101.
- Utsumi H, Okuma Y, Kano O, et al. Evaluation of the efficacy of pramipexole for treating levodopa-induced dyskinesia in patients with Parkinson’s disease. Intern Med 2013;52:325–332.
- Khan TS. Off spells and dyskinesias: pharmacologic management of motor complications. Cleve Clin J Med 2012;79;(suppl 2):S8–S13.
- Calandrella D, Antonini A. Pulsatile or continuous dopaminomimetic strategies in Parkinson’s disease. Parkinsonism Relat Disord 2012;18;(suppl 1):S120–S122.
- Wright BA, Waters CH. Continuous dopaminergic delivery to minimize motor complications in Parkinson’s disease. Expert Rev Neurother 2013;13:719–729.
- Olanow CW, Kieburtz K, Odin P, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol 2014;13:141–149.
- Katzenschlager R, Huges A, Evans A, et al. Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson’s disease: a prospective study using single-dose challenges. Mov Disord 2005;20:151–157.
- Manson A, Stirpe P, Schrag A. Levodopa-induced dyskinesias: clinical features, incidence, risk factors, management and impact on quality of life. J Parkinsons Dis 2012;2:189–198.
- Constantinescu R, Romer M, McDermott MP, et al. Impact of pramipexole on the onset of levodopa-related dyskinesias. Mov Disord 2007;22:1317–1319.
- Parkinson Study Group CALM Cohort Investigators. Long-term effect of initiating pramipexole versus levodopa in early Parkinson disease. Arch Neurol 2009;66:563–570.
- Clarke CE, Speller J, Clarke JA. Pramipexole for levodopa-induced complications in Parkinson’s disease. Cochrane Database Syst Rev 2000;
Issue 2Art. No.: CD002261. 10.1002/14651858.CD002261
- Guthikonda LN, Lyons KE, Pahwa R. Continuous infusion of levodopa-carbidopa intestinal gel in Parkinson’s disease. J Comp Eff Res 2014;3:331–333.
- Zibetti M, Merola A, Artusi CA, et al. Levodopa/carbidopa intestinal gel infusion in advanced Parksinson’s disease: a 7-year experience. Eur J Neurol 2014;21:312–318.
- Fernandez HH, Vanagunas A, Odin P, et al. Levodopa–carbidopa intestinal gel in advanced Parkinson’s disease open-label study: interim results. Parkinsonism Relat Disord 2013;19:339–345.
- Colzi A, Turner K, Lees A. Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1998;64:573–576.
- Elahi B, Phielipp N, Chen R. N-methyl-D-aspartate antagonists in levodopa-induced dyskinesia: a meta-analysis. Can J Neurol Sci 2012;39:465–472.
- Sawada H, Oeda T, Kuno S, et al. Amantadine for dyskinesias in Parkinson’s disease: a randomized controlled trial. PLoS One 2010;5:e15298
- Wolf E, Seppi K, Katzenschlager R, et al. Long-term antidyskinetic efficacy of amantadine in Parkinson’s disease. Mov Disord 2010;25:1357–1363.
- Ory-Magne F, Corvol JC, Azulay JP, et al. Withdrawing amantadine in dyskinetic patients with Parkinson’s disease: the AMANDYSK trial. Neurology 2014;82:300–307.
- Rodnitzky RL, Narayanan NS. Amantadine’s role in the treatment of levodopa-induced dyskinesia [editorial]. Neurology 2014;28:82288–289.
- Kubo S, Iwatake A, Ebihara N, et al. Visual impairment in Parkinson’s disease treated with amantadine: case report and review of the literature. Parkinsonism Relat Disord 2008;14:166–169.
- Merello M, Nouzeilles MI, Cammarota A, Leiguarda R. Effect of memantine (NMDA antagonist) on Parkinson’s disease: a double-blind crossover randomized study. Clin Neuropharmacol 1999;22:273–276.
- Wictorin K, Widner H. Memantine and reduced time with dyskinesia in Parkinson’s disease. Acta Neurol Scand 2015;Aug
- Lökk J. Memantine can relieve certain symptoms in Parkinson’s disease. [Memantin kan lindra vissa symtom vid Parkinsons sjukdom: förbättring i två av tre beskrivna patientfall med dyskinesi och kognitiv svikt. Lakartidningen 2004;101:2003–2006.
- Rilutek (riluzole) prescribing information Bridgewater, New Jersey: Sanofi-Aventis. 2008;Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020599s011s012lbl.pdf. Accessed August 20, 2015
- Braz CA, Borges V, Ferraz HB. Effect of riluzole on dyskinesia and duration of the on state in Parkinson disease patients: a double-blind, placebo-controlled pilot study. Clin Neuropharmacol 2004;27:25–29.
- Bara-Jimenez W, Dimitrova TD, Sherzai A, et al. Glutamate release inhibition ineffective in levodopa-induced motor complications. Move Disord 2006;21:1380–1383.
- Durif F, Debilly B, Galitzky M, et al. Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study. Neurology 2004;62:381–388.
- Fox SH, Chuang R, Brotchie JM. Serotonin and Parkinson’s disease: on movement, mood, and madness. Mov Disord 2009;24:1255–1266.
- Wolz M, Löhle M, Strecker K, et al. Levetiracetam for levodopa-induced dyskinesia in Parkinson’s disease: a randomized, double-blind, placebo-controlled trial. J Neural Transm 2010;117:1279–1286.
- Stathis P, Konitsiotis S, Tagaris G, et al. Levetiracetam for the management of levodopa-induced dyskinesias in Parkinson’s disease. Mov Disord 2010;26:264–270.
- Gottwald MD, Aminoff MJ. Therapies for dopaminergic-induced dyskinesias in Parkinson disease. Ann Neurol 2011;69:919–927.
- Stacy M, Galbreath A. Optimizing long-term therapy for Parkinson disease: options for treatment-associated dyskinesia. Clin Neuropharmacol 2008;31:120–125.
- Tomiyama M. Adenosine receptors and dyskinesia in pathophysiology. Int Rev Neurobiol 2014;119:117–126.
- Lewitt PA, Guttman M, Tetrud JW, et al. Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces ‘off’ time in Parkinson’s disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann Neurol 2008;63:295–302.
- Hauser RA, Shulman LM, Trugman JM, et al. Study of istradefylline in patients with Parkinson’s disease on levodopa with motor fluctuations. Mov Disord 2008;23:2177–2185.
- Merck Provides Update on Phase III Clinical Program for Pre-ladenant, the Company’s Investigational Parkinson’s Disease MedicineMerck & Co., Inc. Merck provides update on phase III clinical program for preladenant, the company’s investigational Parkinson’s disease medicine. May
232013;Available at: http://www.mercknewsroom.com/press-release/research-and-development-news/merck-provides-update-phase-iii-clinical-program-prelade. Accessed August 24, 2015
- Biotie Therapies. Biotie announces start of tozadenant phase 3 study in Parkinson’s disease July
212015;Available at: https://www.emc-direct.de/investors/releases/pr-story.aspx?ResultPageURL=http://cws.huginonline.com/B/132030/PR/201507/1940083.xml. Accessed August 25, 2015
- Merola A, Zibetti M, Artusi CA, et al. 80 Hz versus 130 Hz sub-thalamic nucleus deep brain stimulation: effects on involuntary movements. Parkinsonism Relat Disord 2013;19:453–456.
- Moro E, Lozano AM, Pollak P, et al. Long-term results of a multi-center study on subthalamic and pallidal stimulation in Parkinson’s disease. Mov Disord 2010;25:578–586.
- Volkmann J. Deep brain stimulation for the treatment of Parkinson’s disease. J Clin Neurophysiol 2004;21:6–17.
- Jankovic J, Stacy M. Medical management of levodopa-associated motor complications in patients with Parkinson’s disease. CNS Drugs 2007;21:677–692.
- Khor SP, Hsu A. The pharmacokinetics and pharmacodynamics of levodopa in the treatment of Parkinson’s disease. Curr Clin Pharmacol 2007;2:234–243.
- Pacchetti C, Albani G, Martignoni E. “Off” painful dystonia in Parkinson’s disease treated with botulinum toxin. Mov Disord 1995;10:333–336.
- Schjerling L, Hjermind LE, Jespersen B. A randomized double-blind crossover trial comparing subthalamic and pallidal deep brain stimulation for dystonia. J Neurosurg 2013;119:1537–1545.
- Jankovic J. Medical treatment of dystonia. Mov Disord 2013;28:1001–1012.
- Archibald N, Newman P. Recurrent choking in Parkinson’s disease. Pract Neurol 2009;9:347–353.
- Stocchi F, Tagliati M, Olanow CW. Treatment of levodopa-induced motor complications. Mov Disord 2008;23;(suppl 3):S599–S612.