Meds that improve some symptoms can exacerbate others
SAN ANTONIO -- Roughly three out of four people living with Parkinson's disease (PD) also have sleep disorders, and there is growing recognition that sleep problems are greatly complicated by the disease, its symptoms, and the many medications used to treat it.
"Sleep disorders are among the most common non-motor symptoms in PD, and sleep is something clinicians have to continually monitor when considering medication dosing," Scott Kutscher, MD, of Stanford School of Medicine in California, told MedPage Today"Sleep issues can appear years before the classic motor symptoms of Parkinson's, but it has only been relatively recently that sleep has become part of the diagnostic workup of the disorder," he added.
Insomnia, excessive daytime sleepiness, sleep fragmentation, circadian rhythm disorders, restless leg syndrome, and rapid eye movement (REM) behavior disorder are all common in patients with Parkinson's disease.
Although there is some debate about whether having PD increases the risk for obstructive sleep apnea (OSA), a recent review of the literature found an increased frequency of OSA and other sleep-disordered breathing conditions associated with the neurodegenerative disorder.
One mechanism suggested for this association is that upper airway musculature may be affected by involuntary movements characteristic of the disease, resulting in abnormal spirometry and upper airway obstruction.
PD is also associated with autonomic dysfunction, which may impair breathing control, particularly during non-REM sleep. Sleep fragmentation may also be associated with respiratory disturbances.
"Sleep fragmentation is very common among Parkinson's patients," Kutscher said, adding that fragmented sleep can result from symptoms of the disease and medications used to treat it, as well as nocturia, hallucinations, and altered dream phenomena.
The incidence of restless leg syndrome (RLS) has been reported to affect as many as 12% of people with PD, but it is not clear if the two disorders share a common pathophysiology.
A 2012 review noted that evidence pointing towards a link includes the fact that dopaminergic drugs are efficacious treatments for both conditions, suggesting a common underlying dopamine dysfunction.
Those authors wrote that one of the strongest arguments against a common pathophysiology is the role of iron in RLS and PD. Elevated iron levels in the substantia nigra contribute to oxidative stress in PD, but RLS is a disorder of relative iron deficiency, with symptoms responding to replacement therapy.
Levodopa, dopamine agonists, and other drugs used in the treatment of PD can all impact sleep, albeit in different ways. For example, it has been shown that increasing doses of dopamine before bedtime increase sleep fragmentation and decreases REM sleep.
In a 2015 review examining the impact of PD drugs on sleep issues, Kutscher and colleagues noted that while levodopa was one of the first drugs utilized for the management of RLS, its use can cause increased severity of RLS symptoms, with "earlier symptoms during the day, faster onset of symptoms when at rest, spreading of symptoms to the upper limbs and trunk, and shorter duration of treatment effect."
Daytime sleepiness is a frequent side effect of both levodopa and the dopamine agonists ropinirole and pramipexole, he explained.
"Of great clinical concern is the phenomenon of sleep attacks. Characterized by sudden daytime onset of sleep, seemingly without warning or provocation, these episodes can be highly disruptive and potentially dangerous," Kutscher wrote.
He added that while higher total dopaminergic drug dosing has been implicated in the sleep attack phenomenon, it has not been correlated to any one specific drug or dosage.
Dopamine agonists are considered first-line therapy for RLS, but there is evidence that, like levodopa, the drugs can worsen symptoms in some patients.
Kutscher noted that excessive daytime sleepiness, sleep attacks, and the initiation of compulsive behaviors (including gambling, shopping, eating, and sexual manifestations) are all recognized potential side effects of dopamine agonist therapy.
Ropinirole and pramipexole for RLS are generally prescribed at low doses in PD patients, beginning with doses of 0.25-1 mg and 0.125-0.5, respectively.
"Even at lower RLS doses, [compulsive behavior] incidences of up to 14% have been suggested," Kutscher and colleagues wrote. "All patients initiating therapy should be counseled to monitor for these symptoms."
Sleep issues associated with other drugs widely used in PD include the following, the authors said:
- The cognition drug donepezil can improve auditory hallucinations that disrupt sleep, but nighttime use of the drug has been linked to insomnia and nightmares due to REM suppression; morning dosing may alleviate these side effects
- The atypical antipsychotic quetiapine, also used to treat nocturnal hallucinations, may contribute to insomnia and sleep fragmentation
- The atypical antipsychotic clozapine, used for visual hallucinations and related sleep disturbances, requires careful white blood cell monitoring; the drug's use is limited in the United States
- The anti-seizure drug Klonopin (clonazepam), widely used in the treatment of REM behavior disorder, can cause dizziness, drowsiness, and an increased risk of falls
Kutscher told MedPage Today that interactions between medications used in the treatment of PD and sleep issues are one of the biggest challenges in managing patients with the disorder.
He said the emergence of non-pharmacological therapies -- such as deep brain stimulation and targeted stimulation of the pedunculopontine nucleus for PD motor issues, and bright light therapy for circadian disturbances -- has the potential to improve sleep symptoms.
"Sleep in PD is held in delicate balance, influenced by the disease process, medications, comorbid symptoms, and a variety of other factors," Kutscher concluded in the review. "Physicians should have an intimate knowledge of the many sleep problems apparent in PD, as well as appreciate the challenge presented by diverse therapeutic options that can both ameliorate and aggravate symptoms."
https://www.medpagetoday.com/clinical-challenges/chest-sleep/75757
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