16 Movement C LINICAL N EUROLOGY N EWS • January 2007

see whether it activates 5-HT2B receptors, risk of a valvulopathy when using aman- Echo Monitoring May Be Indicated said Dr. Roth, whose research group at the tadine, Dr. Litvan said. Valve Damage from page 1 University of North Carolina, Chapel Hill, “These findings will have little impact in has been instrumental in unraveling the my practice. Due to the risks of retroperi- dose of either pergolide or cabergoline (adjusted incidence rate ratio 4.9; 95% con- molecular mechanisms underlying valvu- toneal and pleural fibrosis I have tended and the severity of valve regurgitation, ac- fidence interval 1.5 to 15.6), but not with lopathic drugs. not to use ergot derived DA and following cording to Dr. Renzo Zanettini and asso- current use of any other dopamine agonist. In the editorial, he and his colleagues the 2004 reported risk of a fibrotic valvu- ciates in the cardiac rehabilitation unit In what investigators termed an “unex- “urged pharmaceutical companies and reg- lopathy secondary to pergolide I discon- and Parkinson Institute of the Istituti Clin- pected” finding, concurrent use of aman- ulatory agencies to screen candidate drugs tinued the use of pergolide in patients who ici di Perfezionamento, Milan. tadine also had a significant association and their major metabolites at 5-HT2B re- were referred to me who were on this “Our findings confirm safety concerns with regurgitation (adjusted incidence rate ceptors” before initiating clinical trials of drug. There are no appropriately powered related to the use of pergolide and show ratio 3.5 (95% confidence interval 1.1 to new drugs “to prevent “fen-phen”-type head-to-head studies that evaluate if there that an increased risk of cardiac valvu- 11.3), although they said the role of this disasters.” are differences between ergot and non–er- lopathy also exists in patients taking caber- antiviral/antidyskinetic medication “re- In the meantime, “I recommend that got derived DA, but in practice non–ergot goline,” the authors concluded. quires further investigation.” physicians do not prescribe medications derived DA are as good as ergot-derived In the U.S., pergolide carries an FDA Daily doses of greater than 3 mg of ei- with 5-HT2B agonist activity,” he said in an DA. I had difficulty switching pergolide to warning of possible cardiac valvulopathy ther pergolide or cabergoline, or the use of interview. a non–ergot derived DA in and fibrotic complications that discour- either drug for 6 months or more, con- Dr. Griffin called the Increased mitral a small number of patients ages its use in patients with a history of ferred a “particularly elevated” adjusted in- journal studies “a little and only one preferred to valvular heart disease and recommends a cidence-rate ratio, reported Dr. René worrying,” since they af- tenting, an early remain on this drug despite baseline cardiovascular evaluation and pe- Schade of the department of clinical phar- firm what had been pos- indicator of valvular the warnings. Routine riodic echocardiograms. macology, Charité-Universitätsmedizin, tulated to be a class ef- dysfunction, was echocardiograms seem in- Cabergoline has been the subject of case Berlin (N. Engl. J. Med. 2007;356:29-38). fect of drugs that act as dicated for patients who reports and one case-control study from In both New England Journal of Medi- agonists at the 5-HT2B seen in patients opt to continue to be treat- Japan (Neurology 2006;67:1225-9), sug- cine studies, valvular abnormalities in pa- receptor. taking ergot-derived ed with DA that are 5HT2b gesting an association with valvulopathy. tients taking pergolide or cabergoline were Patients exposed to per- agonists,” she said. Dr. Zanettini and colleagues noted the seen in the mitral, aortic, and tricuspid golide and cabergoline and non–ergot- Pergolide, marketed in presence of increased mitral tenting, a valves. Pergolide and cabergoline are po- have echocardiograms, derived DA agents. the United States as Per- geometric measure of the position of the tent agonists of 5-hydroxytryptamine2B said Dr. Griffin, noting max, is manufactured by leaflets that can be an early indicator of (5-HT2B) serotonin receptors, unlike more information is need- Valeant Pharmaceuticals valvular dysfunction, in patients receiving dopamine agonists that were not associ- ed before he would call for a moratorium International. Cabergoline, marketed as ergot-derived dopamine agonists such as ated with elevated cardiac valve disease in on their use. Dostinex, is manufactured by Pfizer Inc. pergolide and cabergoline. Patients re- the study. They share this mechanistic Less troubling is evidence in one study Valeant no longer promotes the product, ceiving non–ergot-derived dopamine ago- pathway with fenfluramine and dexfen- of tenting in patients exposed to other but still makes it available for those who nists also had increased mitral tenting. fluramine, antiobesity drugs withdrawn dopamine agonists, he said. While they prescribe it. Although the latter patients did not have from the market in 1997 due to reports of may prove to be partial agonists of the 5- FDA has approved Pfizer’s revised label evidence of elevated rates of frank regur- valvular heart disease and pulmonary hy- HT2b receptor, other anti-Parkinsonian for Dostinex (cabergoline) (www.fda.gov). gitation, this finding “suggests that follow- pertension in patients taking the so-called drugs do not appear to have the same po- The new labeling includes: “As with oth- up echocardiographic monitoring is ad- “fen-phen” combination. tential impact on the valves as pergolide er ergot derivatives, pleural effusion/pul- visable in all patients with Parkinson’s “Clearly, practitioners should avoid pre- and cabergoline, he said. monary fibrosis and valvulopathy have disease who are treated with dopamine ag- scribing drugs that are potent 5-HT2B-re- Neurologist Dr. Irene Litvan, Raymond been reported following long-term ad- onists,” they wrote (N. Engl. J. Med. ceptor agonists—a growing list of med- Lee Lebby Professor of Parkinson Disease ministration of cabergoline.” 2007;356:39-46). ications that now includes ergot Research at the University of Louisville The Milan study was supported by the The second study, a nested case-control derivatives (ergotamine, methysergide, (Ky.) and director of the movement disor- Italian Parkinson Association, the Grigioni study drawn from the United Kingdom and dihydroergotamine), dopamine ago- der program there, said in an interview Foundation for Parkinson’s Disease, and Is- General Practice Research Database, cal- nists (pergolide and cabergoline), and am- that these articles confirm the importance tituti Clinici di Perfezionamento. Investi- culated incidence rates of newly diag- phetamine derivatives (fenfluramine and of not using 5HT2b agonists in general. gators disclosed support from Glaxo- nosed cardiac valve regurgitation in 11,417 methylenedioxymethamphetamine Neurologists have other options for treat- SmithKline, Pfizer, Boehringer Ingelheim, patients who had received prescriptions for [MDMA, or “ecstasy”]),” Dr. Bryan L. ing Parkinson’s. and Novartis. The Berlin-based study, antiparkinsonian medications. Roth wrote in an accompanying editorial “Ropinirole and pramipexole are excel- which included investigators from Berlin Cardiac valve regurgitation rates were el- (N. Engl. J. Med. 2007;356:6-9). lent DA [dopamine agonists] and recently and McGill University Health Centre in evated with current use of pergolide (ad- Amantadine, which was associated with approved inhibitors of MAO-B have ex- Montreal, was supported by Schering, Glax- justed incidence-rate ratio 7.1; 95% confi- an elevated risk of valvular heart disease in panded our armamentarium,” she said. oSmithKline, Boehringer Ingelheim, As- dence interval 2.3 to 22.3) and cabergoline the Berlin study, should be investigated to Further studies are needed to assess the tra-Zeneca, Novartis, and Organon. ■ Frequency, Pain of Restless Legs Should Guide Therapy

BY JOHN R. BELL said. If it’s partially responsive...then I will antidepressants (except for bupropion and somnia. “It’s almost like narcolepsy,” he Associate Editor consider the dopamine agonists. If I really trazodone) and antihistamines. said. Moreover, DA agonists risk the phe- get desperate...I might consider sedation.” A disadvantage of the DA agonists is nomenon of augmentation, whereby an B ALTIMORE — When deciding which For painless nightly RLS, he advises a that they take 2 hours to reach peak dose increase in dosage leads to an increase in drug to prescribe for a patient with restless DA agonist as first-line therapy, opiates as effect (3 hours if taken with a meal or af- symptoms, so that a patient is treated ef- legs syndrome, the frequency and painful- a second-line choice, and sedatives as third- ter symptom onset), compared with 30-60 fectively for a time period in which RLS oc- ness of symptoms are crucial to making the line treatment. Frequent painless RLS (2- minutes for opiates. Thus dopamine ago- curs (e.g., bedtime), but then the RLS be- correct choice, Dr. Christopher J. Earley 3 nights per week) warrants a sedative nists are most useful for situations such as gins to occur either before or after the said at a neurology meeting sponsored by first, followed by opiates and, if those fail, airplane flights, he said, but less practical treated period. “Augmentation is the sin- Johns Hopkins University. levodopa. For occasional RLS (less than for nighttime RLS. Dr. Earley favors lev- gle biggest reason why you have to stop “For [75%]-80%, depending on the pop- twice per week), he advises either a half or odopa for occasional nonpainful RLS. “If this drug.” He advised that when patients ulation that you deal with, pain is not what whole tablet of carbidopa 25 mg/levodopa you have any doubts about whether this is taking a DA agonist for sleep complain of they experience,” said Dr. Earley, a neurol- 100 mg (available as Sinemet and Parcopa RLS or not RLS, you can use the lev- RLS symptoms before or after bedtime, ogist at Johns Hopkins. A far greater portion brands) as needed for first-line therapy. odopa”-carbidopa combination (carbidopa the physician should not prescribe addi- instead describe their RLS as uncomfort- “This is going to be effective in 99.9% of 25 mg/levodopa 100 mg) of half to 1 ½ tional drugs. able, he said. But for those with painful RLS, patients, barring side effects like nausea,” tablets for 3 days. “If they get no real ben- Notably, opiates do not pose augmen- that pain must be treated. “So I tend to use he said. efits from that, this is not RLS—at least tation risk, he said. With opiates, “you’re the antiseizure medications [e.g., He recommends a DA agonist and a not the RLS that I know.” going to get about 85% of them up walk- gabapentin, lamotrigine, pregabalin] or the sedative as second- and third-line treat- The DA agonists do have other disad- ing away relatively happy.” opiates as my first line of treatment, as op- ment, respectively. Drugs that can aggra- vantages besides their delayed effect, Dr. Iron deficiency has been implicated as a posed to the dopamine [DA] agents, when vate RLS include neuroleptics and Earley noted. They can cause compulsive possible cause of RLS, he noted. “I check I’m dealing with painful symptoms,” he antiemetics, as well as SSRIs and tricyclic behaviors. They also can cause hyper- ferritins in everybody,” he said. ■