pd treatment adverse events

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Adverse Events from the Treatment

of Parkinsons Disease

Kelvin L. Chou, MDDepartment of Neurology, University of Michigan Medical School, 1500 East Medical

Center Drive, 1914 Taubman Center, Ann Arbor, MI 48109-5316, USA

Parkinsons disease (PD) is a neurodegenerative disorder characterized

clinically by resting tremor, rigidity, bradykinesia, and postural instability.

Effective medications exist to treat these motor symptoms but can be asso-

ciated with adverse effects. When severe, these adverse effects can interfere

with a patients quality of life. In this article, the most common adverse

events from PD treatment are discussed, including nausea, dyskinesias,

somnolence, compulsive behaviors, psychosis, and peripheral edema. Addi-tionally, melanoma and weight loss, two conditions that have been variably

linked to PD treatment, are reviewed.

Nausea/vomiting

Nausea is one of the most common side effects of PD treatment with

a dopaminergic agent, although 16% of patients who have PD and are

not on dopaminergic agents may experience nausea [1]. Although nausea

may occur with all dopaminergic agents, vomiting is rare. When the firstlevodopa trials were conducted, patients experienced marked nausea and

vomiting. This was because levodopa was predominantly metabolized to

dopamine by peripheral decarboxylase. Dopamine does not cross the

blood-brain barrier, but circulating dopamine can induce nausea by stimu-

lating the chemoreceptive trigger zone in the area postrema of the brain-

stem, one of the few brain structures without a blood-brain barrier.

Adding a peripheral decarboxylase inhibitor, such as carbidopa or bensera-

zide, to levodopa significantly reduces nausea and allows more levodopa to

cross the blood-brain barrier. All levodopa preparations now are coupledwith a peripheral decarboxylase inhibitor. Carbidopa is approved for use

This work is supported by a grant from Teva Neuroscience.

E-mail address: http://[email protected]

0733-8619/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.

doi:10.1016/j.ncl.2008.05.003 neurologic.theclinics.com

Neurol Clin 26 (2008) S65S83
mailto:http://[email protected]://www.neurologic.theclinics.com/http://www.neurologic.theclinics.com/mailto:http://[email protected]


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within the United States, whereas benserazide is used in countries through-

out Europe.

Patients commonly experience nausea when starting a dopaminergicagent or when increasing their dosage of dopaminergic agent. The nausea

often is mild, and patients tend to develop a tolerance over time. Taking

the medication with food also may reduce nausea, although this is not often

recommended, as co-administration with food leads to poorer absorption

and variable plasma levels, which may contribute to motor fluctuations.

If nausea occurs with a carbidopa/levodopa preparation, administering

additional carbidopa may be beneficial because inhibition of peripheral

decarboxylase may be incomplete in some patients. As much as 200 to

300 mg per day of additional carbidopa may be needed to achieve completeinhibition [2]. If nausea occurs with a dopamine agonist, using a slower

titration or switching to another agonist may be helpful.

If a patient continues to experience nausea despite these measures, an

antiemetic, such as domperidone or trimethobenzamide, may be given.

Not all antiemetics may be used in patients who have PD. Medications,

such as metoclopramide and prochlorperazine, commonly are prescribed

for nausea, but both block dopamine receptors and worsen PD. Domperi-

done is a dopamine antagonist that does not cross the blood-brain barrier

and thus is safe to use in patients who have PD. Two small, double-blind,randomized trials have demonstrated that domperidone is better than

placebo at preventing nausea in patients who have PD treated with bromo-

criptine [3,4]. More importantly, domperidone did not cause worsening of

motor symptoms. In one single-blind trial, domperidone was equivalent to

carbidopa in preventing nausea/vomiting associated with levodopa treat-

ment [5]. Domperidone is not approved for use in the United States, so

trimethobenzamide may be substituted. Although there are no specific trials

of trimethobenzamide for nausea related to dopaminergic drugs, it is

commonly used in the United States to prevent nausea and vomitingassociated with apomorphine [6].

Dyskinesias

Dyskinesias, along with motor fluctuations, are the main motor compli-

cations of levodopa therapy. A retrospective analysis of studies investigating

incidence of dyskinesias with levodopa treatment estimated that slightly

more than one third of patients who had PD had dyskinesias after 4 to

6 years [7]. Early-onset PD and higher doses of levodopa are the biggestrisk factors for the development of dyskinesias [8,9]. Dyskinesias may affect

any part of the body and can be choreic or dystonic. They may manifest

when plasma levodopa levels are at their peak (peak-dose dyskinesias), as

plasma levodopa levels are rising and falling (diphasic dyskinesias), or

when plasma levodopa levels are low (off-state dystonia). Dyskinesias

typically are mild but may interfere with quality of life when painful or

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severe, as seen in advanced PD [10]. Current evidence regarding dyskinesia

prevention strategies are described elsewhere in this journal supplement and

are not discussed here.One way of treating dyskinesias is to modify the antiparkinsonian

regimen. Peak-dose dyskinesias are related directly to the amount of levo-

dopa given per dose, so decreasing individual doses generally reduces dyski-

nesias. The amount of clinical benefit to motor symptoms in PD may

decline, however, and patients may experience increasing off periods.

Thus, a decrease in individual doses of levodopa often has to be combined

with more frequent administration, a practice termed dose fractionation.

There are significant limitations to this approach, however, which are

detailed in the article by Dewey elsewhere in this issue. Discontinuingcatechol-O-methyltransferase (COMT) inhibitors or monoamine oxidase

(MAO)-B inhibitors also may be helpful in reducing peak-dose dyskinesias.

Sustained-release formulations in theory could reduce dyskinesias, as

they are released slowly throughout the day. In practice, however, they

tend to prolong the duration of dyskinesias and increase the severity of

dyskinesias in the late afternoon or early evening [11]. Patients who have

dyskinesias and are on sustained-release levodopa formulations may benefit

from switching to immediate-release levodopa.

Diphasic dyskinesias can be difficult to treat. The same strategies(discussed previously) can be tried, but there are no data to support one

strategy over the other. Other options include overlapping the doses of levo-

dopa to prevent trough plasma levodopa levels until late in the evening or

administering very small doses of levodopa frequently (such as 50 mg of

levodopa given hourly while awake) [12].

Strategies for treating off-state dystonias are similar to strategies to reduce

motor fluctuations in PD and may include changing the levodopa dosing

schedule or adding dopamine agonists, COMT inhibitors, or MAO-B inhibi-

tors (discussed in the article by Dewey elsewhere this supplement).Recent evidence-based reviews recommend amantadine for treating dyski-

nesias in PD [13,14]. Amantadine is believed to have an antidyskinetic effect

through its action at the N-methyl-D-aspartate receptor. Amantadine can re-

duce dyskinesias between 24% and 60% [1519]. In one study, the effect of

amantadine was maintained for up to a year. Some patients, however, are

reported to have had rebound dyskinesias when amantadine was discontin-

ued [18]. Side effects include confusion, peripheral edema, and livedo

reticularis.

A double-blind, placebo-controlled trial of clozapine demonstrates anincrease in on time without dyskinesias with a corresponding decrease

in on time with dyskinesias [20]. The potential for agranulocytosis and

the frequent blood monitoring required make it an unattractive agent,

however. Buspirone is reported effective in one small crossover trial of

10 patients [21], but only seven patients completed the trial, and there are

no other large randomized studies. Clinical trials of other drugs reported

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to be helpful for treating dyskinesias were uncontrolled or failed to show

efficacy in large double-blind trials [12,22].

Although pallidotomy commonly was used as a surgical intervention fordyskinesias with good results [14], most surgical centers have turned to deep

brain stimulation (DBS) to treat patients who have motor fluctuations and

dyskinesias. There are two main targets for DBS in patients who have PD:

the globus pallidus interna (GPi) and the subthalamic nucleus (STN).

Although DBS of the GPi reduces dyskinesias in open-label reports and

blinded evaluations of patients on and off stimulation [23,24], a recent prac-

tice parameter determined that there was insufficient evidence to determine

the efficacy of GPi DBS for dyskinesias [13]. Part of this lack of evidence is

because most centers prefer to place electrodes in the STN DBS. In a meta-analysis of outcomes, STN DBS reduced dyskinesias in patients who had

PD by an average of 69.1% [25]. This occurs along with a reduction in levo-

dopa dosage, which is mainly responsible for the improvement in dyskine-

sias. Based on existing studies, STN DBS is considered possibly effective

for reducing motor fluctuations, dyskinesias, and antiparkinsonian medica-

tions in PD [13]. Adverse effects from DBS surgery may include surgical

complications, such as hemorrhage, stroke, infection of the device, seizures,

delirium, and stimulation-related effects, such as dystonia, confusion, pares-

thesias, dysarthria, and diplopia, depending on the stimulation site.

Somnolence

Excessive daytime somnolence (EDS) is a common problem in PD

[2628], and its prevalence ranges from 33% to 76% [2931]. There is con-

troversy as to whether or not sleepiness in PD is related to the disease itself

or drug treatment [3234] but likely it is due to both. Other contributors to

EDS in PD include sleep fragmentation, depression, dementia, psychosis,

and dopaminergic treatment [33,3539].Difficulty sleeping at night may be the result of problems falling asleep

(sleep-onset insomnia) or staying asleep (sleep-maintenance insomnia).

Many factors may have an impact on a PD patients ability to fall asleep,

including less than optimal control of motor symptoms causing tremor,

rigidity, dystonia, or pain. Furthermore, patients who have EDS may take

frequent daytime naps and consequently are not tired at night. Akathisia

and restless legs syndrome (RLS) also may be present, causing patients to

pace all night or forcing them to fall asleep in reclining chairs. Oral selegiline

is a MAO-B inhibitor that has an amphetamine metabolite. Patients whotake this medication late in the day may have increased wakefulness and

sleep-onset insomnia [40].

There are several reasons why patients who have PD may have difficulty

maintaining sleep, including nocturia, difficulty turning over in bed, leg

cramps, vivid dreams or nightmares, and pain [41,42]. Such problems may

wax and wane over time, but poor sleep related to turning over in bed or vivid

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dreams tends to worsen over time [39]. Periodic limb movements of sleep

(PLMS), often associated with RLS, also may contribute to nocturnal awak-

enings. Estimates of the prevalence of PLMS in patients who have PD rangefrom 30% to 80% [43]. Rapid eye movement sleep behavior disorder (RBD)

also frequently is present in PD, resulting in vocalizations and acting out of

dreams. This may cause patients to wake up in the middle of the night and

have difficulty falling back asleep. EDS in PD also may be caused by sleep-

disordered breathing; although the prevalence of sleep apnea syndrome in

PD is unclear, a recent case-control study diagnosed sleep apnea in 43% of

patients who had PD and were referred for polysomnography [44].

Depression can occur in up to 50% of patients who have PD [45,46] and

commonly is associated with early morning awakening. Dementia is anothercommon feature of PD, with the prevalence estimated as high as 41% [47].

If dementia is present, sundowning may occur, with resulting confusion and

disorientation preventing a restful sleep. Dementia also is a risk factor for

psychosis [48], and the hallucinations and delusions that occur may contrib-

ute to sleep-onset insomnia.

The medications used to treat PD may affect sleep, and the biggest

offenders are the dopamine agonists [38], although levodopa also can cause

sedation. Large trials in patients who have de novo PD show that somno-

lence occurs in approximately 30% of patients treated with dopamine ago-nists [4951]. These patients often report feeling sleepy for a short period of

time after taking their dose, as opposed to a chronic sleepiness. There also

are reports of dopamine agonists causing sleep attacks, defined as sudden,

irresistible, overwhelming sleepiness without awareness of falling asleep

[52]. Since 1999, when this phenomenon was first reported by Frucht and

colleagues [52], many studies have been published debating whether or

not these episodes of sudden onset of sleep (SOS) truly occur. The wealth

of evidence suggests that SOS is uncommon, that patients who have SOS

also tend to have EDS, and that dopaminergic medications in general arethe main influencing factors [35,5356]. EDS and SOS episodes can be a haz-

ard for patients who have PD who drive and they should be warned about

this potential problem.

When treating EDS in PD, stressing good sleep hygiene is important.

Patients should try to avoid naps and increase daytime physical activity

so sleep can be consolidated into one long block at night. Avoiding stimu-

lants at bedtime and sedating medications during the day also is essential.

Treating other factors contributing to sleep-onset or sleep-maintenance

insomnia also may help. For example, if patients experience discomfort inbed due to rigidity or pain, adjustment of dopaminergic medications may

allow them to feel more comfortable. A sustained-release formulation of

levodopa and a peripheral decarboxylase inhibitor at bedtime may prevent

wearing-off symptoms overnight [57]. In patients who have continuing

motor fluctuations and dyskinesias despite optimal medical management,

DBS STN may improve sleep [58]. Decreasing fluid intake in the evening,



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emptying the bladder before bed, and using a bedside commode overnight

are useful strategies for combating nocturia. If nocturia is the result of blad-

der hyperactivity, an anticholinergic medication, such as oxybutinin ortolteridone, can be prescribed. Any other sleep disorders, such as obstructive

sleep apnea, RBD, or RLS, should be addressed and treated.

If patients continue to experience daytime somnolence despite these

measures, reducing the dose of dopaminergic medications may help. This

often is not possible, however, as patients may have intolerable declines in

motor function. Stimulants, such as methylphenidate, caffeine, and amphet-

amines, often are used to treat EDS in PD, but there are scant data support-

ing their use. Modafinil, a wake-promoting agent, may be effective for some

patients, although the available data are mixed. Two double-blind, placebo-controlled crossover studies of modafinil using small numbers of patients

determined that subjective sleepiness (using the Epworth Sleepiness Scale)

improved significantly in those patients on the medication [59,60]. One of

these crossover studies used an objective measure, the Maintenance of

Wakefulness Test, which was no different in the modafinil and placebo

groups [59]. A recent double-blind, placebo-controlled, parallel trial involv-

ing 40 patients who had PD, however, showed no difference in ESS scores or

in Multiple Sleep Latency Test (an objective measure of sleep) results with

modafinil compared with placebo [61]. Modafinil seems well toleratedwith minimal side effects.

Compulsive behaviors

Several complex behaviors are reported to occur in patients who have

PD, including pathologic gambling, hypersexuality, punding, and compul-

sive shopping, eating, or medication use [62]. These behaviors are referred

to as impulse control disorders, or compulsive or repetitive behav-

iors in the literature. In general, compulsive behaviors consist of reward-based, unrestrained, and often unplanned actions and behaviors that

ultimately result in negative consequences. These actions and behaviors

seem related to dopaminergic medication use [6365]. It can be argued

that punding, a form of behavior where patients perform repetitive, pur-

poseless movements [66], is not a reward-based action but often it is

included among these behaviors due to its repetitive nature.

A recent survey of 297 patients who had PD estimated the lifetime preva-

lence of pathologic gambling, hypersexuality, and compulsive shopping to be

6.1% [64]. In patients taking dopamine agonists, the lifetime prevalence ofthese behaviors increased to 13.7%. Prevalence for pathologic gambling

and hypersexuality falls generally in the 3% to 8% range [64,65,6769] and

seems more common than compulsive shopping [64,69]. Punding estimates

vary greatly, reportedly occurring between 1.4% and 14% of patients who

have PD [70,71]. Compulsive medication use occurs in approximately 4%

of patients [72,73], whereas the prevalence of uncontrolled eating is unknown.

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The mechanism for development of these behaviors is not well under-

stood, but several factors likely contribute to repetitive behaviors in PD,

including use of dopamine agonists and individual susceptibility [62]. Dopa-mine is a key neurotransmitter in the reward system of the brain [74], and

many of these compulsive behaviors, especially pathologic gambling, are

attributed mostly to the dopamine agonists [65,69], as opposed to levodopa,

a precursor to dopamine. The nonergot agonists have a higher affinity for

the dopamine D3 receptor, which is found primarily in the mesolimbic path-

ways responsible for reward behaviors, and this may be what differentiates

the agonists from levodopa in terms of causing compulsive behaviors

[75,76]. This theory is supported by the fact that several patients who

have RLS have developed pathologic gambling while being treated withdopamine agonists [7780]. Alternatively, excessive use of levodopa, as

seen in compulsive medication use, or tonic stimulation of the postsynaptic

dopamine receptor by agonists could interfere with signaling involved with

reward learning in the brain [62]. Certain clinical features also may increase

susceptibility to compulsive behaviors, including younger age at onset

[76,81], male gender [76], a history of repetitive behaviors [69], novelty seek-

ing behavior [70,81], and a history of substance or alcohol abuse [81].

Patients should be counseled about the possibility of developing these

types of behaviors before initiating dopamine agonists. Once patients startagonist treatment, the identification of compulsive behaviors may be diffi-

cult, as they rarely are volunteered. Clinicians, therefore, should question

all patients specifically about such behavior. Even when patients report

such behaviors, they tend to be minimized. Often, corroborating patient

accounts with other family members is necessary.

There are little data on the treatment of compulsive behaviors in patients

who have PD. In one study, 15 subjects were contacted for a telephone inter-

view a mean of 29.2 months after developing compulsive behaviors on

a dopamine agonist [82]. The investigators found that overall, patients haddecreased their agonist use and increased their levodopa dosage amount

but had similar levodopa equivalent dosages to baseline. Ten of these patients

no longer met criteria for an impulse control disorder, suggesting that discon-

tinuing or reducing the dopamine agonists may be helpful. Switching patients

to a different agonist may be helpful in some cases [83] but not consistently.

Antidepressants and antipsychotics may be tried, but compulsive behaviors

seen in PD do not seem to respond to these agents as effectively as typical ob-

sessive-compulsive disorders do [70,84,85]. Pathologic gambling and compul-

sive medication use may resolve with DBS, but whether this is due tostimulation itself or medication reduction is unknown [86,87].

Psychosis

Psychosis occurs in up to 40% of patients who have PD [8890] and likely

is related to a combination of drug treatment, advanced disease, and



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cognitive impairment. Although currently there is no uniform way to diag-

nose psychosis in PD, a group of experts recently proposed diagnostic crite-

ria [91], with the key components being the presence of hallucinations,delusions, illusions, or a sense of presence that occurs for at least 1 month

after the onset of PD motor symptoms. Hallucinations are abnormal per-

ceptions that can occur in any sensory modality without a physical stimulus

and are different from illusions, which are real sensory perceptions that are

distorted. A sense of presence occurs when a patient feels that someone else

is present even though no one is there. Delusions are false, irrational beliefs

that are maintained even though they have no basis in reality.

Visual hallucinations are the most common manifestation of psychosis in

PD, but auditory, olfactory, and gustatory hallucinations also may occur[88,90,92,93]. Hallucinations in nonvisual modalities, however, tend to

occur in conjunction with visual hallucinations [9295]. Delusions are less

common than visual hallucinations and occur in approximately 5% to

10% of patients [96,97]. Risk factors for psychosis include advanced stages

of PD, dementia, antiparkinsonian medications, and impaired vision [48,90].

PD psychosis is associated with higher levels of caregiver stress [98], nursing

home placement [99,100], and mortality [101,102].

After ruling out potential infectious or metabolic factors, reducing the

dosages of antiparkinsonian medications is the first step in treating PDpsychosis. When hallucinations or delusions are severe, however, it may

be necessary to add an atypical antipsychotic immediately in conjunction

with reducing PD drugs. The recommended order for discontinuing

these medications is (1) anticholinergic agents, (2) MAO inhibitors, (3)

amantadine, (4) dopamine agonists, (5) COMT inhibitors, and finally

(6) levodopa [103]. Although in some cases, discontinuing or reducing

medications can be helpful in ameliorating psychotic symptoms, patients

may not be able to tolerate them because of worsening motor function.

If psychosis persists despite decreasing antiparkinsonian agents to the low-est possible level, then an atypical (or second-generation) antipsychotic

should be initiated.

In a recent practice parameter, the American Academy of Neurology

(AAN) recommended clozapine (level B evidence) for the treatment of PD

psychosis [104]. This recommendation was based on two well-designed, dou-

ble-blind, placebo-controlled trials, one conducted by the Parkinson Study

Group (PSG) in the United States [105] and the other by the French Cloza-

pine Parkinson Study Group [106]. Both trials were similar in design and re-

ported that low-dose clozapine improved psychosis in PD without causingmotor decline. In the PSG trial, patients took a mean dosage of 25 mg

per day, whereas in the French study, patients were on a mean dosage of

37 mg per day. Despite the efficacy data, clozapine has not enjoyed wide-

spread use, mainly because of the potential for agranulocytosis, which ne-

cessitates frequent blood monitoring. Clozapine also may cause sedation,

sialorrhea, and weight gain.

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Quetiapine is considered the next best option for controlling psychosis in

PD. Large open-label reports suggest that most patients experienced

improved psychosis with minimal motor decline on this medication[107,108]. In addition, two separate blinded-rater trials comparing quetia-

pine to clozapine demonstrated that both drugs were equally effective for

psychosis without worsening parkinsonism [109,110]. Two recent double-

blind, placebo-controlled trials, however, reported no difference between

quetiapine and placebo on PD psychotic symptoms [111,112]. Because of

these results, future double-blind studies with larger numbers of subjects

clearly are needed. Nevertheless, the AAN practice parameter states, que-

tiapine may be considered (Level C) for patients who have PD and psycho-

sis [104]. The major side effect of quetiapine is sedation.The AAN practice parameter recommends against using olanzapine for

psychosis in PD [104]. This recommendation is based on several randomized

trials. Two parallel trials, one in the United States and the other in Europe,

comparing olanzapine to placebo, demonstrated no benefit of olanzapine on

psychosis in PD and unequivocal worsening of parkinsonism [113]. A sepa-

rate trial comparing olanzapine to clozapine was aborted early because the

patients who had PD and were on olanzapine suffered significant motor

problems not seen in the clozapine group [114].

There are open-label data only on the other three atypical antipsychotics,risperidone, ziprasidone, and aripiprazole, for the treatment of psychosis in

PD; thus, they cannot be recommended at this point. Small studies of risper-

idone [115119] and aripiprazole [120,121], however, suggest that these

agents worsen parkinsonian signs in patients who have PD. In a large trial

of 410 patients who had PD and mildmoderate dementia, rivastigmine

improved psychotic symptoms as measured by the Neuropsychiatric Inven-

tory [122]. Whether or not this agent would help psychosis in patients who

have PD and who do not have dementia remains to be seen.

Peripheral edema

Peripheral edema is a recognized complication of amantadine therapy

[123] but also is associated with use of the dopamine agonists. Although orig-

inally believed related to the ergot properties of bromocriptine [124] and per-

golide [125,126], evidence now suggests that peripheral edema is an agonist

class effect [127129]. Peripheral edema is reported to occur in 6.4% of pa-

tients treated with ropinirole [130] and approximately 15% of patients on

pramipexole [128,131]. Risk factors for the development of peripheral edemareported in pramipexole studies include female gender, older age, cardiac dis-

ease, and diabetes [127,128]. The development of edema does not seem re-

lated to dosage [127,128]. The underlying pathophysiology is unclear,

although dopamine clearly has effects on the sympathetic nervous system.

Peripheral edema resulting from PD therapy does not always need to be

treated, especially if mild. Patients can have trouble fitting into their shoes,



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however, and some may even have difficulty walking [129]. Fortunately, it dis-

appears on discontinuation of the offending medication [129]. Because the

phenomenon is not dose dependent, reducing the dosage usually does nothelp. Many clinicians use diuretics if patients cannot tolerate other PD med-

ications, but there are no data to support or refute their use in this population.

Melanoma

It is a well-established observation that there is a higher rate of melanoma

in patients who have PD [132136]. A large epidemiologic study of 14,088

patients who had PD identified from a national registry found 44 cases of

melanoma, with a standardized incidence ratio (compared with a normalpopulation) of 1.95 (95% CI, 1.42.6) [133]. Why patients who have higher

rates in PD compared to the general population is unclear, but treatment

with levodopa has been implicated since the 1970s, when Skibba and col-

leagues [137] reported a case of a patient who had PD and had melanoma.

Although in this case, the patient was diagnosed before levodopa treatment,

several case reports followed, with some reporting melanoma occurrence af-

ter levodopa was started and some reporting melanoma before levodopa

treatment [134]. Because levodopa is a substrate for tyrosine hydroxylase,

which converts levodopa to melanin, the association between levodopause and melanoma in patients who have PD seemed reasonable, if not con-

clusive. Levodopa then was found to be toxic to melanoma cells in vitro,

however [138]. Despite the lack of understanding of how levodopa may in-

crease the risk for melanoma, the Food and Drug Administration added the

warning of melanoma to the levodopa prescribing instructions and lists a his-

tory of melanoma as a contraindication to levodopa use.

Several lines of evidence demonstrate, however, that the link between

levodopa usage and melanoma in PD is not causal. Reviews of existing

case reports on levodopa, melanoma and PD have shown that melanomaoccurred before levodopa treatment in many instances [134,139,140].

An analysis of the Deprenyl and Tocopherol Antioxidative Therapy of Par-

kinsonism (DATATOP) study found no difference in melanoma incidence

rates before and after treatment with levodopa [141]. Olsen and colleagues

[132] conducted a large population-based study that found an increased

prevalence of melanoma in patients who had PD (0.57%) compared with

controls (0.40%) (odds ratio 1.44; 95% CI, 1.032.01) before the date of first

hospital contact and presumably levodopa treatment. Finally, a separate

nested case-control study conducted by the same investigators found norelationship between the occurrence of melanoma and the amount of levo-

dopa received by the patients before the diagnosis of melanoma [142].

These findings suggest that a common environmental or genetic factor

likely is responsible for the development of melanoma and PD in the

same patient. One possible consideration is social class. Patients who have

PD tend to be in a higher socioeconomic class [143], and higher

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socioeconomic status is predictive of melanoma [144], presumably because

of more opportunities for sun exposure. Driver and colleagues [145], how-

ever, found a strong relationship between PD and melanoma incidence,despite controlling for socioeconomic factors, supporting the theory that

PD and melanoma share a common genetic trait.

Because patients who have PD are at higher risk for melanoma, they

should be warned about this and instructed to watch for suspicious-looking

moles or skin lesions. Limiting activities in the sun also is a reasonable pre-

caution, but if outside activities are necessary, patients should be aware of

how to protect their skin. Finally, regular visits to a dermatologist for a com-

prehensive skin examination should be encouraged so that abnormal skin

lesions are identified and treated early.

Weight loss

Weight loss is a common comorbidity in PD that may be related to use

of dopaminergic medications. It is estimated that approximately half of

patients who have PD experience weight loss [146]. The weight loss occurs

throughout the course of the disease [147149], more so as parkinsonism

progresses [148,150152], but even may precede the diagnosis [147]. In addi-

tion to severity of motor symptoms, the presence of dyskinesia, female gen-der, older age, hallucinations, and dementia are implicated as risk factors

for weight loss in PD [148,149,151,152]. The decreasing weight seems due

more to loss of fat than muscle [146,149,152].

The exact reasons for weight loss in PD are unclear. Patients who have

PD often have problems that could contribute to decreased energy intake,

including decreased olfaction, dysphagia, nausea, anorexia, and poor gas-

trointestinal motility and absorption. A few reports have demonstrated

that patients who have PD continue to lose weight despite increased caloric

intake [147,153], suggesting that increased energy expenditure is the morelikely reason for weight loss in PD. This has been supported by several stud-

ies demonstrating increased resting energy expenditure in patients who have

PD [152,154,155], but one study found no change in daily resting energy

expenditure and a lower daily total energy expenditure in patients who

had PD as a result of decreased physical activity [156], arguing against

this hypothesis. Potential reasons for increased resting energy expenditure

in PD include the presence of muscle rigidity, tremor, dyskinesias, and

autonomic dysfunction. Markus and colleagues concluded that increased

muscle rigidity and dyskinesias likely resulted in weight loss in their patients[154]. This claim seems to be supported by patients commonly gaining

weight after pallidotomy and bilateral STN DBS.There is no clear correla-

tion, however, between amelioration of dyskinesias and weight gain in the

pallidotomy [157159] or DBS literature [160].

More research is needed into the underlying basis for weight loss in PD.

Only then can evidence-based recommendations to treat this condition be



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made. In the meantime, clinicians should monitor the weight of their pa-

tients closely and use strategies to optimize caloric intake. The reduced

body mass and increased risk for falls as PD becomes more advancedputs patients at risk for hip fractures, so supplementation with vitamin D

and calcium also is a sensible recommendation.

Summary

Several adverse effects result from the treatment of PD. Some have been

recognized for a long time (nausea and dyskinesias) whereas some are just

being increasingly recognized (peripheral edema and compulsive behaviors).

Although discontinuation of an offending medication is the proper way tomanage drug-induced symptoms, this may not always be possible in patients

who have PD because of intolerable motor decline. Furthermore, some med-

ications used to treat the side effects of dopaminergic medications also can

worsen PD. This is seen with some of the antinausea agents (metoclopra-

mide and prochlorperazine) and most of the antipsychotic medications,

with the exception of clozapine and possibly quetiapine. Further research

focusing on investigating other agents or strategies to manage adverse effects

of PD treatment is needed to affect patient outcomes in PD positively.

Note added in proof

Rotigotine transdermal system (Neupro) recently has been recalled in the

United States because of a manufacturing problem leading to the formation

of crystals in the patch matrix, which impede absorption of rotigotine into

the skin. It currently is unknown if this problem can or will be solved by the

maker of rotigotine transdermal system, but currently the drug is not

expected to be available in United States pharmacies after April 2008, unless

re-introduced by the manufacturer at a later date.

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