Key cogs in the management of Parkinson's disease

40 DrugTopics | DECEMBER 2016 | DrugTopics.com

IntroductionThe apothecary and surgeon James Parkin-son wrote of “paralysis agitans” in his pub-lication “An Essay on the Shaking Palsy” in 1817.1 Parkinson’s disease (PD) is an incur-able progressive movement disorder with a cardinal symptom of slowness of move-

ment (bradykinesia) that also includes rest-ing tremor, rigidity, and loss of postural refl exes.2 Dopamine replacement ther-apy substantially lessens motor handicap.2 Patients can also suffer from gait imbal-ance, pain, fatigue, depression, and sexual and cognitive changes.3 Its motor manifes-

GOAL: To assist pharmacists in manag-ing diffi cult-to-treat symptoms of Parkin-son’s disease

After participating in this activity, pharmacists will be able to:> Discuss Parkinson’s disease (PD),

its common and diffi cult-to-treat symptoms, and current guidelines

> Explain treatment approaches for depression, psychoses, and sleep disturbances in patients who have PD

> Outline the pharmacist’s role in assisting with adherence to PD therapy and symptom management overall and during the perioperative deep brain stimulation placement period

After participating in this activity, pharmacy technicians will be able to: > Recall common symptoms of

Parkinson’s disease (PD) and the typical medications used to treat them

> Identify typical and atypical problems associated with PD

> Recognize when to refer patients to the pharmacist for recommendations

The university of connecticut school of pharmacy is accredited by the Accreditation council for pharmacy Education as a provider of continuing

pharmacy education.

Pharmacists and pharmacy technicians are eligible to participate in the knowledge-based activity, and will receive up to 0.2 CEUs (2 contact hours) for completing the activity, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

ACPE# 0009-9999-16-066-H01-P ACPE# 0009-9999-16-066-H01-T

Grant funding: None

Activity Fee: There is no fee for this activity.

INITIAL RELEASE DATE: DECEMBER 10, 2016

EXPIRATION DATE: DECEMBER 10, 2018

To obtain CPE credit, visit www.drugtopics.com/cpe and click on the “Take a Quiz” link. This will direct you to the UConn/Drug Topics website, where you will click on the Online CE Center. Use your NABP E-Profi le ID and the session code: 16DT66-PJK28 for pharmacists or the session code: 16DT66-FZK23 for pharmacy technicians to access the online quiz and evaluation. First-time users must pre-register in the Online CE Center. Test results will be displayed immediately and your participation will be recorded with CPE Monitor within 72 hours of completing the requirements.

For questions concerning the online CPE activities, e-mail: [email protected].

EDUCATIONAL OBJECTIVES

FACULTY: KEVIN W. CHAMBERLIN, PHARMD, AND OUMAIMA SAHBANI, BS Dr. Chamberlin is associate clinical professor and assistant department head, Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Conn, and Pharmacy PGY1 Residency Program Director, UCONN John Dempsey Hospital, Farmington, Conn. Ms. Sahbani is a doctor of pharmacy candidate 2017, University of Connecticut School of Pharmacy, Storrs, Conn.

FACULTY DISCLOSURE: Dr. Chamberlin and Ms. Sahbani have no actual or potential confl ict of interest associated with this article.

DISCLOSURE OF DISCUSSIONS OF OFF-LABEL AND INVESTIGATIONAL USES OF DRUGS: This activity may contain discussion of unlabeled/unapproved use of drugs. The content and views presented in this educational program are those of the faculty and do not necessarily represent those of Drug Topics or Uni-versity of Connecticut School of Pharmacy. Please refer to the offi cial prescribing information for each product for discussion of approved indica-tions, contraindications, and warnings.

Abstract Pharmacists play an important role in identifying the signs and symp-toms of depression, psychosis, and insomnia in Parkinson’s disease (PD) and are an infor-mation source for patients, caregivers, and prescribers. Pharmacists also play an inte-gral role in managing PD medication regimens in the time leading up to and after deep brain stimulation. Pharmacists are in a unique position to address nonadherence in PD patients, which can lead to poorly controlled disease and comorbid symptoms. Comor-bid cognitive impairment or depression can heavily in� uence nonadherence, and phar-macists are on the front line of being able to identify symptoms and referring patients when appropriate. Recognizing symptoms and understanding when to refer a patient with these comorbid conditions is critical for patient safety and appropriate treatment.

AN ONGOING CE PROGRAM oF THE uNiVErsiTY oF coNNEcTicuT

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Key cogsin the management of Parkinson’s disease

EARN CE CREDIT FOR THIS ACTIVITY ATWWW.DrugTopics.com/cpE

2CPECREDITS

Kevin W. Chamberlin, PharmDAssociATE cLiNicAL proFEssor AND AssisTANT DEpArTmENT HEAD, pHArmAcY prAcTicE, uNiVErsiTY oF coNNEcTicuT scHooL oF pHArmAcY, sTorrs, coNN, & pHArmAcY pgY1 rEsi-DENcY progrAm DirEcTor, ucoNN JoHN DEmpsEY HospiTAL, FArmiNgToN, coNN.

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DrugTopics.com | DECEMBER 2016 | DrugTopics 41

PEER REVIEWED | CONTINUING EDUCATION

tations, autonomic and neurologic dis-orders, and sensorial symptoms prog-ress with disease worsening and create a high medication load for patients.4 Med-ication therapy management (MTM) has been shown to improve treatment effec-tiveness, safety, and convenience, and improve patients’ quality of life (QoL).4

PD is generally a late-life disease that develops after age 60 years and increases in prevalence to 4% at age 80 years. Age is the main known risk fac-tor for PD, although there appears to be some genetic predisposition.2,5 It is the 14th leading cause of death.6,7 In addi-tion to the well-known primary, disease-modifying symptoms, PD patients almost always develop nonmotor symptoms (NMS) that are as distressing as the pri-mary symptoms. NMS include sleep dis-orders, mood changes, cognitive impair-ment, blood-pressure fl uctuation, and gastrointestinal disturbances.8,9 A 2016 needs assessment by the American Academy of Family Physicians identifi ed that family physicians have a medical knowledge gap around diagnosing and managing the NMS of PD.10 Pharmacists play a critical role in bridging this gap with community-dwelling PD patients and their caregivers.

Depression in PDDepression is among the most com-mon comorbid problems associated with PD, occurring in about 30% to 40% of patients.11 Due to the prevalence of PD-related depression, clinicians should screen all PD patients for this disease state. Diagnosis of depression in PD patients can be extremely diffi cult due to the overlap in symptoms; however, the symptom profi le in PD patients is differ-ent than that in depressed patients with-

out PD. Common indicators of depres-sion in PD patients include anxiety, pes-simism, irritability, irrationality, and sui-cidal ideation without a suicidal plan.12 Therefore, it is imperative for physicians to utilize the proper screening tools when assessing their PD patients for depres-sion. Although there is no specifi c scale to assess comorbid depression in PD patients, using appropriate cut-off scores of scales such as the Hamilton Depres-sion Rating Scale and Beck Depression Inventory can be useful in evaluating PD patients for depression.12

Despite the fact that a large number of PD patients suffer from depression, few controlled clinical trials have evalu-ated the safety and effi cacy of pharma-cologic treatment in this patient popula-tion. Most available data comes from the use of tricyclic antidepressants (TCAs) in PD patients with depression. Multiple studies have reviewed the use of nortrip-tyline and amitriptyline for PD depression and found that both are effective in reliev-ing symptoms.13–15 A comparative study of low-dose amitriptyline and low-dose fl uoxetine found that amitriptyline was the more effective of these drugs in control-ling depression in PD patients, but higher dropout rates occurred among those on

amitriptyline than among those on fl uox-etine due to adverse events.15

TCAs have shown effi cacy in this patient population, but their adverse effects (eg, orthostatic hypotension, memory impairment, anticholinergic side effects) limit their use. Investigators have found that over 58% of PD patients expe-rienced orthostatic hypotension, with a fall in systolic blood pressure of at least 20 mm Hg. A fall of more than 20 mm Hg in systolic blood pressure increases the

risk of falls and syncope.16 Given that PD patients are prone to a fall in blood pres-sure, the added decrease from TCAs would be unwelcome. PD patients are also at increased risk for developing psy-chosis, which can be accelerated by the memory impairment that can arise from using TCAs. Although their anticholiner-gic effects can be limiting, anticholinergic agents are typically used in PD patients with tremor-dominant symptoms. There-fore, the anticholinergic effects of TCAs can be benefi cial in these patients to con-trol their motor symptoms as well as their depression.

Currently, insuffi cient evidence sup-ports or refutes the effectiveness of anti-depressants other than TCAs. Although TCAs are the most-studied antidepres-sant class in PD patients with depres-sion, clinicians tend to choose selec-tive serotonin reuptake inhibitors (SSRIs) as fi rst-line agents largely because of a proven record of overall safety, toler-

ability, and effi cacy in non-PD patients. According to one survey, 51% of the time that physicians prescribed antidepres-sants to their PD patients, they used an SSRI.17

In the same study that proved the effi -cacy of nortriptyline, the researchers found that paroxetine controlled-release was not effi cacious in the treatment of depression in PD patients.13 Two other separate studies looked into the use of

C O N T I N U E D O N P A G E 42 >

A 60-year-old man with Parkinson’s disease is struggling with depressive symptomsand his primary care physician wants a recommendation on the best pharmacologic

therapy to use to treat him. What information might you obtain from him before making a recommendation?

PAUSE AND PONDER

ssris have the po-tential to worsen motor function, a signifi cant concern in pD patients.


KEY COGS IN THE MANAGEMENT OF PARKINSON’S DISEASE


sertraline and found that it is useful in treating depressive symptoms without worsening parkinsonian features.18,19 Although these studies have shown effi -cacy of sertraline in PD patients, an important limitation to consider is that both studies were open label. It is clear that more double-blind, placebo-con-trolled trials are required to reach an evi-dence-based recommendation on SSRIs in PD patients with depression. The ben-efi t of using SSRIs over TCAs is that they do not have signifi cant anticholin-ergic side effects, which avoids worsen-ing memory in PD patients who are at

increased risk for psychoses and demen-tia. SSRIs have the potential to worsen motor function, a signifi cant concern in PD patients. The previously cited survey also found that 37% of physicians treat-ing PD patients with SSRIs observed at least a single case of worsening motor function.17 Further, an open-label, pro-spective study looked at the use of SSRIs in PD patients with depression and found that SSRIs do not worsen motor function when used at their recommended ther-apeutic doses.20 Sertraline’s adverse effects included light-headedness, sex-ual dysfunction, insomnia, and hyperac-tivity. For many physicians, these adverse effects are considered benign in compari-son to those of TCAs.17

Evidence from a randomized, placebo-controlled trial suggests that the dopa-mine agonist pramipexole improved depressive symptoms associated with PD and should be considered in the man-agement of PD depression.21 Another study comparing pramipexole to sertra-line concluded that pramipexole can be a potential alternative to antidepressants for PD patients.22 The adverse events noted within the trial are consistent with the known safety profi le of the drug, including nausea, headache, dizziness, and somnolence.

In the absence of a gold standard treat-ment for PD depression, drug selection should be individualized for each patient

based on the potential advantages and disadvantages each agent provides.

Psychosis in PDA population-based study of psychosis in PD patients found that psychosis occurs in over 50% of patients at some point over the course of the disease.23 Multi-ple studies have shown that psychosis is among the highest risk factors for admis-sion to a nursing home, increased hos-pitalization costs, and increased mor-tality in PD patients.24–26 Symptoms of psychosis in PD patients include hal-lucinations, illusions, and delusional behavior.27 As symptoms of psychosis begin to arise, patients experience hal-lucinations with retained insight, which

tends to degrade as the disease pro-gresses.27 Patients who experience hallu-cinations with retained insight are aware that they are exhibiting psychological dis-turbances and are able to attribute it to their disease state. Prevalence of psycho-sis in PD patients increases with chronic use of dopaminergic agents, which are known to cause psychosis and commonly employed in the treatment of PD.28 Dopa-minergic over-activity in the cerebral cor-tex and limbic system has been hypoth-esized to be involved in PD psychosis.28 Risk factors for PD psychosis include cog-nitive impairment, sleep disorders, longer duration of PD, and depression.29,30

Although it is not FDA approved for

this indication, clozapine is currently the gold standard treatment for PD psycho-sis. A landmark study used low-dose clo-zapine for the treatment of PD psychosis and found an improvement in symptoms. The study used clozapine doses between 6.25 mg/day and 50 mg/day, which is signifi cantly lower than the doses used for schizophrenia (300–900 mg/day). In this range, clozapine reduced the severity of psychosis in PD patients.31 Of the anti-psychotics, clozapine has been evaluated in PD patients for its low potential to exac-erbate parkinsonism. Multiple random-ized, clinical trials have demonstrated clozapine’s effi cacy without worsening motor symptoms.32 A retrospective anal-ysis assessing the long-term use of clo-zapine for PD patients with psychosis has shown that clozapine maintains its safety and effi cacy. The study found that of 39 patients evaluated, none discontinued clozapine due to motor worsening.33

Although clozapine’s effi cacy has been

You are working the evening shift at a local retail pharmacy and the wife of a 59-year-old man walks in and asks to speak with the pharmacist. When you come

to the counter, she says, “My husband has Parkinson’s disease and some cognitive impairment. He’s been acting more and more strange lately and not sleeping well. Can you recommend something?” What questions would you ask to obtain the information

you would need to make a recommendation?

PAUSE AND PONDER

< C ON T INUE D F ROM PAGE 41

most clinicians have opted for quetiapine due to its ease of use, as it does not require routine cBc monitoring.




demonstrated, physicians are hesitant to use it due to its potential for agranu-locytosis and required, ongoing monitor-ing.34 Product labeling requires strict mon-itoring of clozapine in which the complete blood count (CBC) is monitored weekly for the fi rst 6 months, biweekly for the next 6 months, and then monthly. If patients can tolerate the routine CBC monitoring, clo-zapine would be the treatment of choice.

Despite the insuffi cient evidence on the effi cacy of quetiapine in the treatment of PD psychosis, it is often used as a fi rst-line treatment. When compared to pla-cebo in a double-blind trial, quetiapine failed to exert a signifi cant antipsychotic effect at doses up to 200 mg/day. This study did show, however, that quetiap-ine did not worsen parkinsonism.35 Other investigators conducted a small random-ized, controlled trial comparing quetiapine

up to doses of 150 mg/day versus pla-cebo.36 Quetiapine failed to improve psy-chosis in PD patients, although the small sample size limits the ability for interpre-tation. An open-label trial compared que-tiapine to clozapine and found that que-tiapine was as effective as clozapine in reducing dopaminergic psychosis. This trial showed that clinical symptoms of hallucinations and delusions responded similarly to either agent.37 The results of this study demonstrated that quetiapine can be effective and well tolerated in this patient population; however, because this study contained a small sample size and was un-blinded, its validity is limited.

Due to confl icting data among ran-domized clinical trials, quetiapine has been regarded as having “insuffi cient evidence, acceptable safety risk with-out need for specialized monitoring, but

investigational practice implications.”38

Most clinicians have opted for quetiap-ine due to its ease of use, as it does not require routine CBC monitoring. Like clo-zapine, quetiapine has greater affi nity to 5HT2 receptors than to dopaminergic receptors, which decreases the potential for worsening of motor function. Multiple studies have demonstrated that quetiap-ine improves symptoms and is generally well tolerated within goal dosing of 50 to 150 mg nightly.32

Other multiple studies have looked into the use of risperidone to alleviate psy-chotic symptoms in PD patients and have found that it worsens motor function.39,40 One study compared clozapine to risperi-done and did not fi nd a statistically signif-icant difference in effi cacy between the agents.41 However, both this study and

C ON T INUE D ON PAGE 44 >

Sleep disorder management in Parkinson’s diseaseSLEEP DISTURBANCE

POSSIBLE CAUSE(S) PHARMACOLOGIC INTERVENTIONS NONPHARMACOLOGIC

INTERVENTIONS

Sleep onset unknown Drug-related (activation)

¾ Hypnotics (short-acting, Z-class such as zolpidem, zopiclone, eszopiclone; amitriptyline)¾ remove or reduce associated drug

Sleep hygiene:• regular sleep schedule (time of bed, time of awakening)• Avoid alcohol and stimulants after 3 pm• comfortable, dark, quiet sleep environment• Avoid consuming large amounts of food or liquids before bedtime

Stimulus control:• go to bed only when sleepy• minimize/avoid daytime napping• Keep bedroom for sleep and intimacy only (not reading, TV, etc.)• if diffi culty sleeping, get out of bed and only return when sleepy• practice relaxation techniques (eg, meditation, muscle relaxation)

REM sleep behavior disorder considerations:• remove hazards (objects in bedroom)• consider placing mattress on fl oor near bed

Sleep apneas:• Weight loss, as appropriate

Sleep maintenance (including wake after sleep onset or early awakening)

Wearing off, resting tremor, rigidityDrug-induced dyskinesiaDepression, anxietyNocturia

¾ Hypnotics (intermediate-type, such as temazepam; re-dose of short-acting, such as zolpidem IR)¾ increase frequency of levodopa and reduce dose per administration; add dopamine agonist¾ Antidepressant (SSRI, SNRI, TCA); anxiolytics; dopamine-agonist¾ urinary anticholinergics as appropriate (caution in patients with hallucinations and/or cognitive decline) (eg, oxybutynin); desmopressin nasal spray (monitor for nocturnal hypertension); dopamine agonist

Excessive daytime sleepiness

Drug-relatedrefractory

¾ remove/reduce dose of causative agent (eg, dopamine agonist)¾ consider stimulant therapy (eg, caffeine, methylphenidate, modafi nil)

Delirium, delusion, hallucination

Nr ¾ reduce dopaminergic drugs; consider atypical antipsychotics (quetiapine typically fi rst choice; avoid risperidone)

REM sleep behavior disorder

Nr ¾ Benzodiazepine (clonazepam fi rst choice); melatonin; pramipexole in combination with clonazepam; some evidence with melatonin

Restless leg syndrome (including periodic limb movement disorder)

pD treatment time of administrationAnemia (serum ferritin <50 µg/L)

¾ Dopamine agonist scheduled before bedtime¾ iron supplementation¾ Benzodiazepine (eg, clonazepam)

Sleep apneas Nr ¾ cpAp; surgical intervention

Abbreviations: CPAP, continuous positive airway pressure; IR, immediate release; NR, not reported; PD, Parkinson’s disease; REM, rapid eye movement; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. Source: Refs 61–63

TABLE 1




an open-label study of risperidone have reported worsening of parkinsonism.40

Pimavanserin is the fi rst drug that has been developed and FDA approved spe-cifi cally for the treatment of PD psychosis. Pimavanserin is a 5-HT2A inverse agonist that has no clinically relevant affi nity for other receptors, thus making it uniquely different in its effects from those of com-parator agents. This agent does not exert an effect on dopaminergic recep-tors, which accounts for the parkinso-

nian side effects seen with other antipsy-chotic agents. Pimavanserin was granted breakthrough therapy status based on the results of a phase 3 study that has shown signifi cant improvements in psy-chosis symptoms without worsening par-kinsonism.42 Although this drug is well tol-erated, associated adverse events seen within this trial included urinary tract infec-tions and falls. An increase in QT inter-val not associated with cardiac adverse events with the use of pimavanserin has also been noted in some patients.42

The drug is categorized under the anti-psychotic class and therefore bears the boxed warning of increased risk of death in elderly patients with dementia-related psychosis.43 Pimavanserin is typically dosed at 34 mg once daily (taken as 2 17-mg tablets), unless the patient is con-currently taking a strong CYP3A4 inhibi-

tor such as itraconazole, ketoconazole, clarithromycin, or indinavir, for which the dose should instead be initiated lower at 17 mg daily and maintained on this dose until the patient fi nishes the course of the CYP3A4 inhibitor.43

Sleep disturbances in PDSleeplessness is one of the biggest impacts on QoL, with sleep disorders occurring in upward of a third of PD patients.44,45 A Norwegian survey of 233 PD patients found that they may be more distressed by insomnia and depression

than by motor disability. Many report inability to sleep at night accompanied by excessive sleepiness during the day, the latter of which is experienced by PD patients 3.3 times more frequently than the general population.46,47 PD patients also suffer from insomnia and restless legs syndrome. Rapid eye movement (REM) sleep disorder occurs in 25% to 40% of PD patients by 5 years from the time of diagnosis and increases to 40% to 65% of PD patients by the 10-year mark.48 REM sleep disorder results in symptoms that include disturbed sleep and fl ailing arm and leg movements dur-ing dreaming.49

Dopamine agonists have been associ-ated with excessive daytime sleepiness (EDS), and monoamine oxidase B (MAO-B) inhibitors have many adverse effects and may cause sleep disturbances.45

Levodopa, in combination with a periph-eral decarboxylase inhibitor such as car-bidopa, is the most-effective pharmaco-logic therapy for PD and can often atten-uate motor symptoms as much as 20% to 70% in the fi rst 3 months of therapy.2 Ergoline dopamine agonists (DA) indi-cated for PD include bromocriptine and cabergoline; however, their use has fallen out of favor due to their established risk of valvular and lung fi brosis.50,51 Nonergo-line DA indicated for PD include amanta-dine, apomorphine, entacapone, prami-pexole, ropinirole, rotigotine, and tol-capone, which when used alone in PD, do not provoke dyskinesias compared to levodopa.2,46,52 Although often used alone in younger-onset PD (age <55 years), the addition of levodopa to DA monotherapy is often required within 3 years of diag-nosis.53 First identifi ed with pramipexole, DA as a class are now known to cause somnolence and impulse control disor-ders, among other treatment-associated adverse effects.54,55

MAO-B inhibitors used for PD, such as rasagiline and selegiline, provide mild symptomatic benefi t with a simpler treat-ment regimen than levodopa by decreas-ing the rate of turnover of striatal dopa-mine and prolonging the action of dopa-mine in the brain.56,57 Simplicity in regi-men is not without its disadvantageous adverse effects, however, as the class of MAO-B inhibitors are associated with orthostatic hypotension, hallucinations, anxiety, nausea, and sleep disturbances. Selegiline is a 5-mg tablet or capsule typ-ically dosed once at breakfast and again at lunch, although an orally disintegrat-ing tablet is also available that is adminis-tered only once daily and can be titrated from 1.25 mg daily up to 2.5 mg daily after 6 weeks based on clinical response and tolerability.58 A transdermal formula-tion of selegiline is available for the FDA-approved indication of depression, but not PD. Selegiline is a major CYP2B6 sub-strate and minor 1A2, 2A6, 2C8, 2D6, and 3A4. Clopidogrel, ticlopidine, and prasugrel are weak CYP2B6 inhibitors, whereas efavirenz and rifampin are mod-erate inducers. Selegiline weakly inhibits

Mnemonic for Parkinson’s patients considering deep brain stimulationD Does not cure

B Bilateral DBS is often required to improve gait; although unilateral DBS can have effects on walking

S Smooths on/off fl uctuations

I Improves tremor, bradykinesia, stiffness, and dyskinesia in many cases, but may not eliminate them

N Never improves symptoms unresponsive to the patient’s best “on”

P Programming visits occur many times in the fi rst 6 months, and follow-ups as frequently as every 6 months after

D Decreases medications in many, but not all

Note: “DBs iN pD” mnemonic developed by researchers at the university of Florida mcKnight Brain institute, gainesville, FL

Abbreviations: DBS, deep brain stimulation; PD, Parkinson’s disease. Source: Adapted from Ref 69

TABLE 2





1A2, 2A6, 2C19, and 2E1.59

Rasagiline is a newer MAO-B inhibi-tor than selegiline, dosed at 0.5 to 1 mg once daily as adjunctive therapy with levodopa or as 1 mg once-daily mono-therapy. Rasagiline is less likely to cause insomnia than selegiline.60 Rasagiline is a major substrate of CYP1A2. Ciprofl oxa-cin is a strong inhibitor of 1A2, and coad-ministration with rasagiline should be avoided. Allopurinol, caffeine, famotidine, and verapamil are examples of weak 1A2 inhibitors that a PD patient may be tak-ing.59

Of note, EDS was found to be pres-ent in more than half of PD patients sur-veyed in 2000.46 The investigators used the Epworth Sleepiness Scale (ESS), a measure of the general level of sleepi-ness in adults, to evaluate PD patients for sudden-onset sleep while driving. Almost 4% of patients enrolled had sud-den onset of sleep while driving. Interest-ingly, the authors were unable to iden-tify specifi c anti-PD drugs or drug classes associated with daytime sleepiness and sleep attacks while driving. The authors concluded that sudden-onset sleep with-out warning is infrequent overall among PD patients taking DA. The ESS demon-strated sensitivity for predicting prior epi-sodes of falling asleep while driving, and its specifi city was shown to be increased when used in conjunction with the Inap-propriate Sleep Composite Score. Inves-tigators could not state for certain if rou-tine assessment with these scales could effectively prevent future sleep attacks while driving.46

A recent study examining MTM ser-vices for PD patients in a community pharmacy also looked at sleeping prob-lems. Two pharmacists conducted MTM services and included 70 patients in the results, 51 of whom completed the expected 6 months of MTM. Demograph-

ics, pharmacotherapy, lifestyle, comor-bidities, memory and cognition, PD symp-toms, and QoL were reviewed in-person with patients in almost 74% of cases. Sleep disorder was identifi ed as among the most-frequent neurologic comorbid-ities, second only to depression (42.3% and 30.8%, respectively). The main inter-ventions were performed directly with the patients, and involved nonpharmaco-logic and medication rescheduling meth-ods to resolve sleeping problems. More than 71% of the recommendations were accepted, and all of them resolved the sleeping problems.4 Table 1 summarizes pharmacologic and nonpharmacologic sleep problem interventions.61–63

Deep brain stimulation for PDDeep brain stimulation (DBS) is the most commonly performed reversible, minimally destructive surgery for PD in North America.64 More than 25% of cur-rent PD patients have a DBS device, at a cost between $35,000 and $50,000

for unilateral placement, and upward of $70,000 to $100,000 for bilateral proce-dures.65,66 Other surgical options are abla-tive, and targets include pallidotomy (glo-bus pallidus), thalamotomy (thalamus), and subthalamotomy (subthalamus), all of which irreversibly destroy brain tis-sue in a precise region with a tiny heated probe.67 DBS involves the placement of a battery-operated electrode connected to an implantable pulse generator (IPG) (sim-ilar to a pacemaker) that delivers elec-trical current to a targeted area in the brain.66,68 Three primary targets for DBS infl uence nerve signals that cause tremor and other PD symptoms, including the ventral intermediate (VIM) nucleus of the thalamus, globus pallidus interna (GPi), and the subthalamic nucleus (STN).67 The device is then externally programmed, and adjustments to amplitude, frequency, and pulse width can be made. Patients have the ability to turn the device off as desired, but it is generally left on.


NICE and AAN recommendations for probe placement in deep brain stimulation

LOCATION FOR PD PATIENTS WHO ARE/HAVE SYMPTOMS REDUCED(%, DURATION OF EFFECT)

VIM ê insuffi cient evidence for reducing motor complications, medication use, or improvement of motor function

ê Tremor (92%, 8 years)ê Nonsignifi cant effect on rigidity, bradykinesia, gait problems

GPi ê responsive to levodopaê No dementia, depression ê Healthy, without signifi cant comorbiditiesê motor complications refractory to optimal medical treatment

ê Tremor (NR)ê rigidity (NR)ê Bradykinesia (NR)ê gait problems (NR)

STN ê responsive to levodopaê No dementia, depression ê Healthy, without signifi cant comorbiditiesê motor fl uctuations, dyskinesias, medication use ê motor complications refractory to optimal medical treatmentê Younger patients with shorter disease duration may have better outcomes than older patients with longer disease duration

ê Tremor (80%)ê rigidity (65%)ê Bradykinesia (51%)ê gait problems (NR)

Abbreviations: AAN, American Academy of Neurology; GPi, globus pallidus interna; NICE, National Institute for Health and Care Excellence; NR, not reported; PD, Parkinson’s disease; STN, subthalamic nucleus; VIM, ventral intermediate nucleus of the thalamus. Source: Refs 64,67,72,73

TABLE 3

DBs will not work in patients who are non-responders to standard pD medications.




Candidates for DBS include those who are responsive to levodopa therapy, neu-ropsychiatrically intact (eg, no dementia), and have intractable dyskinesias, motor fl uctuations, or tremor. Researchers at the University of Florida McKnight Brain

Institute developed a mnemonic for PD patients considering DBS, “DBS IN PD” (Table 2).69 This mnemonic helps tem-per PD patient expectations to meaning-ful improvements when considering DBS, as opposed to the unrealistic expecta-tion of dramatic improvement in PD symp-toms not always attained.69 Generally, the best candidates tend to be younger (<69 years, but older age is not a contraindi-cation), have had symptoms for at least 5 years, have experienced at least 30% improvement in symptoms from differ-ent combinations of PD medications with insuffi cient duration of effect, and have symptoms that are intolerable and inter-fering with daily functioning.70,71 If patients are still responding to medication, then DBS has the potential to affect PD symp-toms. DBS will not work in patients who are nonresponders to standard PD med-ications.70

The 2006 National Institute for Health and Care Excellence (NICE) clinical guide-lines for PD diagnosis and management give recommendations for best prac-tice based on experience of the Guide-line Development Group.72 This group suggests probe placement in 1 of the 3 target regions of the brain based on patient’s presentation. Table 3 describes which PD patient may have the best response to DBS placement in a given brain target.64,67,72,73 The Movement Disor-der Society-Unifi ed Parkinson’s disease rating scale (MDS-UPDRS) is the most commonly used scale to evaluate clini-

cal progression of PD.74 The MDS-UPDRS includes nonmotor and motor experi-ences of daily living, motor examina-tion, and motor complications that assist the practitioner in assessing the sever-ity staging of PD. The assessments are typically conducted through interviews and observation and used to assess the

patient longitudinally. Physicians use the MDS-UPDRS at baseline, when the patient is both on and off medication, to assess which symptoms will respond best to DBS.

Patients generally continue taking their PD medication regimen as prescribed until 12 hours prior to surgery. Patients will remain off medication for at least 12 hours after surgery. Remaining awake during the procedure leads to the best outcomes, as surgeons can accurately map and pinpoint locations that relieve specifi c PD symptomatology.67 Post sur-gery, the IPG is not immediately activated and patients typically must maintain their presurgery medication regimen. This lim-its acute dopaminergic withdrawal and malignant hyperthermia.75

Once the patient has recovered from surgery, external programming of the device can occur by a neurologist in the outpatient setting. Because STN-DBS can be synergistic with levodopa (STN stimulation can make levodopa more effective), medication reductions can occur while methodically ramping up DBS currents.76 Medication dose reduction in these patients can signifi cantly lower side effects such as dyskinesias typically caused by levodopa exposure.67 Patients who have GPi- and VIM-DBS do not typi-cally incur medication regimen changes post implantation due to lack of identifi ed synergy with the probe placement and standard PD therapies. These non-STN-DBS patients can typically have implant

intensity ramped more quickly due to the lack of drug synergy. Non-levodopa adjunctive therapies are typically dose-reduced fi rst, with levodopa and dopami-nergic-agonist therapies addressed sub-sequently. Most medication adjustments are achieved during the fi rst month after surgery.77 A simple goal of reducing or completely relieving motor fl uctuations and dyskinesias can be considered opti-mal treatment in many DBS patients.78

DBS is not without risks, with the high-est likelihood of complications occurring in the fi rst weeks post implantation. Infec-tion, cranial bleeding, and seizure are the most common postsurgical complica-tions.78 Infection is the most common sur-gical complication with DBS, with rates varying between 0% and 15% per patient and 0% and 9.7% per electrode.71 Most studies identify the highest risk of infec-tion to be within the fi rst month after sur-gery. Intracranial hemorrhage (both symp-tomatic and asymptomatic) is relatively low, rates ranging between 0% and 4.5% overall, but patients have poorer out-comes and longer hospital stays.71 Sei-zure rates are relatively low in postsur-gical DBS patients, with reported inci-dences between 0% and 4% and the overall risk of developing epilepsy close to 0%.71 Long-term complications often include hardware discomfort (1.1%) and loss of desired effect (1.4%). Hardware discomfort that required surgical revision has included wound infections (1.7%), lead misplacement or movement (1.7%), device malfunction or wire fracture (1.9%), and loss of effect (2.6%).79 The American Academy of Neurology reported a death rate in DBS surgery patients of 0.6%.64

Pharmacist’s rolePharmacists may improve care for patients with PD if they integrate cur-rent evidence-based guidelines and rec-ommendations into their daily practice. Guidelines that are used widely and well-respected include: • National Institute for Health and Care

Excellence (NICE) Parkinson’s disease in over 20s Clinical Guideline (CG35)72

• The American Academy of Neurology

A patient inquires with you about what medication changes they can expect if undergoing DBS implantation. What would

you want to know before responding?

PAUSE AND PONDER





(ANN) Practice Parameter: Treatment of Nonmotor Symptoms of Parkinson Dis-ease80

Pharmacists need to watch for another common problem. Nonadherence is fre-quent among PD patients, ranging from 33% to 73% in most studies. Much like adherence in HIV/AIDS, adherence in PD is profoundly infl uenced by the patient’s emotional readiness to initiate pharma-cologic therapy and expectations before initiating antiparkinsonian medications. This calls for much support and motiva-tional interviewing. The symptoms of PD patients are highly individualized, and their nonadherence refl ects the magni-tude and types of symptoms they expe-rience. The most common type of non-adherence in PD patients is timing non-adherence. The cause is multiple daily medication doses and self-adjustment to handle fl uctuating symptoms.81

Comorbid cognitive impairment or depression heavily infl uences nonadher-

ence, and failure to address them creates a progressive cycle of poorly controlled disease, increasing depression, and spi-raling uncontrolled symptoms. Psycho-sis clearly affects adherence, creating the need to involve a caregiver. Because most PD patients are older, their status with Medicare and their Medicare Part D plans are also fi nancial factors that can be barriers.81 Clinicians and pharmacists can educate patients that DBS can make medication cessation possible, but likely not probable.78

Pharmacists who have patients in their caseload who consider or undergo the DBS procedure need to know that DBS helps improve PD’s motor symptoms, but will not tackle symptoms unresponsive to medication. Medication changes are needed before surgery, immediately after surgery, and in the weeks and months thereafter. Although most patients still need to take medication after undergo-ing DBS, many patients experience con-

siderable reduction of their PD symptoms and are able to greatly reduce their med-ications. The amount of reduction varies from patient to patient but can be consid-erably reduced in most patients.67

ConclusionPharmacists are often the most-accessi-ble healthcare provider for many patients and caregivers, including those with Par-kinson’s disease. Pharmacists can offer insight, referrals, and recommendations to interprofessional team members for optimal management of parkinsonian dis-ease- and treatment-related symptoms and adverse effects. The ability to recog-nize when symptoms persist or worsen and to refer these patients for further medical intervention is paramount to patient safety.

References are available online at www.drugtopics.com/cpe. •

For immediate CPE credit, take the test now online at > www.drugtopics/cpe Once there, click on the link below Free CPE Activities

1. Which of the following is not a “best” characteristic of a Parkinson’s disease (PD) patient when considering deep brain stimulation (DBS)?

a. symptoms for 2 yearsb. Age <69 yearsc. short duration of effect from pD therapiesd. intolerable symptoms interfering

with daily functioning

2. The highest risk of complications following DBS implantation occurs after surgery in the � rst:

a. Hours b. Weeksc. months d. Years

3. Most medication adjustments are achieved during which time period following DBS implantation?

a. First few days b. First few weeksc. First month d. First year

4. Which of the following complications of DBS implantation typically occur in the � rst month or so following surgery?

a. Hardware discomfortb. Loss of desired effectc. Device malfunctiond. intracranial hemorrhage

5. Patients receiving GPi-DBS and VIM-DBS typically may have which of the following medication changes to their original levodopa regimen?

a. No changeb. Levodopa dose loweringc. Levodopa dose increased. These patients are not typically

on levodopa therapy.

6. Which of the following sleep disorder symptoms is not a symptom that necessarily occurs more frequently in PD patients?

a. sleep apneas

b. Flailing leg movementsc. Flailing arm movementsd. Daytime sleepiness

7. Which of the following MAO-B inhibitors approved for PD causes the least insomnia?

a. selegiline b. rasagilinec. phenelzine d. Tranylcypromine

8. In patients experiencing excessive daytime sleepiness, medication interventions can include:

a. Dose reduction of the dopamine agonistb. Dose reduction of the levodopac. consideration of add-on stimulant therapyd. A and c

9. STN-DBS placement patients may:a. Experience synergy with levodopab. Have slower intensity ramping

FOR PHARMACISTS

TEST QUESTIONS





1. Selegiline is available for the treatment of Parkinson’s disease (PD) in which of the following formulations?

a. Vial b. patchc. syrup and patchd. capsule and orally disintegrating tablet

2. Which of the following medications can have a major drug–drug interaction with rasagiline?

a. Aspirin b. ciprofl oxacinc. omeprazole d. Levofl oxacin

3. Which of the following MAO-B inhibitors approved for PD causes the least insomnia?

a. selegiline b. rasagilinec. phenelzine d. Tranylcypromine

4. Parkinson’s patients undergoing deep brain stimulation (DBS) implant surgery will typically need to stop their PD therapies:

a. 6 hours prior to surgery

b. 8 hours prior to surgeryc. 12 hours prior to surgeryd. They do not need to stop their medications

prior to surgery.

5. Patients receiving a STN-DBS implant might typically have the following changes to their original levodopa therapy:

a. Dose increaseb. Dose reduction c. Dose maintainedd. Levodopa is usually able to be discontinued

6. A patient brings in a prescription for pimavanserin, and you see in his pro� le that he has been taking indinavir. Which dose of pimavanserin is appropriate for this patient?

a. 34 mg once dailyb. 17 mg once dailyc. 17 mg twice dailyd. Do not fi ll pimavanserin

7. A patient has recently started clozapine and has been stable for 7 months. How often should her CBC be monitored?

a. Every 6 months b. monthlyc. Biweekly d. Weekly

8. Psychosis increases all of the following except?

a. risk for admission into nursing homesb. Hospitalization costsc. mortalityd. Worsening motor function

9. Depression occurs in what % of Parkinson’s patients?

a. 40% b. 51%c. 58% d. 20%

10. The gold standard for treatment of depression in PD is:

a. sertraline b. Nortriptylinec. Amitriptyline d. None of the above

FOR PHARMACY TECHNICIANS

c. Have levodopa doses reducedd. All of the above

10. Good sleep hygiene techniques to educate PD patients about include:

a. regular sleep timesb. Avoiding alcohol and stimulants

early in the dayc. consuming large amounts of fl uids

or food before bedtimed. reading in bed

11. Pimavanserin has the highest af� nity for which receptor?

a. 5HT2c b. 5HT2Ac. D1 d. D2

12. Which of the following is frequently monitored if a patient is placed on clozapine?

a. chemistry panelb. clozapine levelsc. complete blood countd. All of the above

13. All of the following have shown safety in Parkinson’s patients with psychosis except:

a. risperidone b. clozapinec. Aripiprazole d. A and c

14. Pimavanserin is labeled with a boxed warning for:

a. QT prolongationb. Agranulocytosisc. Dementia in elderly patientsd. Does not have boxed warning

15. Which of the following are risk factors for PD psychosis?

a. insomniab. Depressionc. chronic use of dopaminergic agentsd. All of the above

16. Which of the following is an antiparkinsonian that is also bene� cial for depression?

a. Benztropine b. Levodopac. sertraline d. pramipexole

17. Which of the following has been associated with orthostatic hypotension in PD patients?

a. sertraline b. Amitriptylinec. Fluoxetine d. paroxetine

18. A limiting side effect of sertraline for this patient population can be:

a. orthostatic hypotensionb. memory impairmentc. sexual dysfunctiond. Hallucinations

19. A patient is taking selegiline as part of her PD regimen and the primary care physician would like to add something for depression. Which of the following is the best choice?

a. Nortriptyline b. Amitriptylinec. sertraline d. pramipexole

20. Which of the following has shown the most ef� cacy in PD depression?

a. sertraline b. Fluoxetinec. paroxetine controlled released. citalopram

For immediate CPE credit, take the test now online at > www.drugtopics/cpe Once there, click on the link below Free CPE Activities

TEST QUESTIONS< C ON T INUE D F ROM PAGE 47


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