Slowing down a "slow" movement disorder: Selegiline’s benefit in treating Parkinson disease
Steven E. Lo, MD and
Samay Jain, MD
Parkinson disease (PD) is a chronic disorder of the nervoussystem that is characterized by tremors, slowness of movement,rigidity, and balance problems. There is no single "right way"to treat patients who have early stage PD and mild symptoms.One strategy is to use a medication called selegiline, whichhas been proven to relieve many symptoms in PD and may helpdelay the need to add stronger medications. In this issue ofNeurology, Dr. Pålhagen and his colleagues1 report ona study that evaluated if selegiline slows down the progressof symptoms in patients with PD who need to start the most effectiveof PD medications, levodopa. More information on PD and levodopacan be found on the next page.
Selegiline is a medication in the monoamine oxidase type B (MAO-B)inhibitor family of drugs. MAO is a protein in cells that canbreak down dopamine, the main chemical that is deficient inPD. Therefore, by inhibiting MAO, selegiline helps keep dopamineavailable for brain cells to use. Selegiline also helps keepany replacement dopamine (created from levodopa) from beingbroken down.
Dr. Pålhagen reported on the results of a long study lasting7 years in which selegiline plus levodopa was compared to placebo(a pill that looks like selegiline but does not contain medication)plus levodopa in a group of patients with PD. The goal of thestudy was to see what effect early and continued use of selegilinewould have in the progression of PD symptoms.
Levodopa was started on all patients in either group (selegilineor placebo) who needed a stronger medication because their PDsymptoms had worsened over the years. These patients were thenfollowed regularly for the next several years. At each evaluation,the investigators recorded how severe the patients’ PDsymptoms were (using a scale called the Unified Parkinson DiseaseRating Scale [UPDRS]; see the next page), how much levodopawas needed to treat PD symptoms, any complaints of side effectsfrom the medications, and any complaints of dyskinesias (seenext page) or "wearing-off" fluctuations (see next page). Afterthe patients were studied for a total of 7 years, the informationbetween the two groups was compared.
Twenty-nine of the 72 patients who got selegiline plus levodopacompleted the entire study. Similarly, 26 of the 69 patientswho got placebo plus levodopa finished. Many patients did notcomplete the study because of side effects. For those patientswho did finish the study, there was a significant differencein favor of the group that got selegiline.
Overall, the selegiline plus levodopa group had lower UPDRSscores (lower scores mean fewer PD symptoms) compared to theplacebo plus levodopa group. The difference in scores betweenthe two groups actually increased as time went on. By the 4thyear after adding levodopa the average difference in scoresbetween the groups was over 6 points. By the end of the 7 years,the average UPDRS scores of the selegiline plus levodopa groupwere still lower than their scores from when levodopa was added.The patients who got selegiline also did not need as much levodopato control their PD. At the 4-year point, those patients neededabout 100 mg less of levodopa compared to the patients who weregetting placebo. Finally, there were fewer patients on selegilinewho developed the "wearing-off" fluctuation, while both groupshad nearly equal percentages of dyskinesias.
Patients in the selegiline plus levodopa group had a greatertendency to have side effects from their treatment. Nausea wasthe most common side effect experienced.
This study showed that the use of selegiline with levodopa resultedin significantly better control of PD symptoms compared to ifpatients were to have used levodopa alone. An especially importantfeature of this study is its very long duration. Because thestudy followed patients over many years, the investigators wereable to see that patients with PD on selegiline did not worsenas much or as fast over time.
The data suggest that using selegiline in the early stages ofPD, and continuing it when levodopa is needed as well, leadsto less severe PD complaints. It appears that over time selegilineslows down the progression of PD symptoms. It is important tonote, however, that we do not know if selegiline actually slowsdown the process that causes PD.
PD is a chronic, progressive movement disorder that occurs whencells in a part of the brain called the substantia nigra die.It is not known why and how the special brain cells die. Thesecells make a chemical called dopamine, which is used to helpthe brain control and coordinate the many movements our bodymakes. When there is reduction in the level of dopamine madein the substantia nigra, the results include symptoms of resttremor (rhythmic shaking of a body part that only occurs whenthe part is not moving), rigidity or "stiffness" of body parts,bradykinesia (a term that refers to slowness of movement andtrouble starting movements), and postural instability (difficultymaintaining balance and body posture, which can often lead tofalls). But not every patient with PD has those four major symptoms,which sometimes makes the diagnosis of PD hard. As years goon, more cells die and the symptoms usually worsen, causingmore and more problems for those patients to do their normaldaily activities.
Levodopa is a medication that is converted into the brain chemicaldopamine once it is ingested and transported inside specificbrain cells. Therefore, it acts as a replacement for the dopaminea person with PD lacks. Although it is one of the oldest medicationsavailable for PD, it is still considered the "gold standard"medication because none of the newer medications can surpassits overall benefit on symptoms. Levodopa can cause a lot ofnausea as a side effect if it is given alone; therefore, itis always given in combination with a partner medication calledcarbidopa, which helps to prevent nausea from happening.
Dyskinesias are automatic movements of a body part that looklike dancing or restless motions. They have no purpose and patientshave very little control over them. Dyskinesias can have differentlevels of severity, from being only annoying or embarrassingto being so severe that patients are not able to write, eat,or do other activities. They also can be very hard to treat.Dyskinesias tend to occur in patients who have had PD for yearsand have been taking levodopa for many years. Nobody knows forcertain why or how dyskinesias develop, but they may be a complicationof long-term levodopa use.
"Wearing-off" describes the problem when PD medications no longerlast as long as they used to. As the disease progresses, theeffect of the same amount of levodopa may last a shorter amountof time. This means that patients will feel more PD symptomsbefore the next time they are supposed to take a dose of medication.This can lead to anxiety, discomfort, and decreased abilityto function during that period of time. "Wearing-off" is likelydue to the changes that occur in the brain as PD progresses.Fortunately, there are several strategies and medications thatcan be used to try to treat "wearing-off."
Levodopa remains our best oral medication for treating PD; whencompared head-to-head with other medications, it is still themost effective in treating symptoms. However, there is somethought that using levodopa for many years is associated withdeveloping dyskinesias. Although nobody has any definitive proofthat levodopa directly causes dyskinesias, many neurologistschoose to use other medications if possible before jumping straightto levodopa. This is especially true if a newly diagnosed patientwith PD is relatively young (for example, 40 to 60 years old)or has mild symptoms. However, most neurologists also agreethat if a patient’s symptoms are so severe that the patientcannot do normal activities or is at risk for falls, then levodopashould be given in any case. It is important to always keepa patient with PD’s quality of life in mind when choosingmedications.
The UPDRS stands for Unified PD Rating Scale. It is a gradingsystem used to measure the many symptoms of PD. It has fourmajor sections, which measure mental function/behavior/mood,ability to do daily activities, physical performance on examinationby doctors, and problems with treatment. Most of the categoriesare scored from 0 to 4 points, 0 being no symptom and 4 beingthe most severe level of the symptom. Therefore, the highera UPDRS score, the worse a patient’s PD symptoms. TheUPDRS is used in most PD clinical research studies, becauseit allows neurologists from different groups to score and comparetheir patients easily.
Pålhagen S, Heinonen E, Hågglund J, et al. Selegiline slows the progression of the symptoms of Parkinson disease. Neurology 2006;66:1200–1206.[Abstract/Free Full Text]
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