23 Jun 2014

Despite causing involuntary movements with long-term use, the classic Parkinson’s disease drug levodopa works as well, if not better than, other first-line medications for PD, according to a study in the June 11 Lancet online. This conclusion comes from a 14-year study of 1,620 people by the U.K.-based PD MED Collaborative Group. “You can start treatment with levodopa, and you will get the best results—and it is the cheapest,” said Richard Gray of the University of Oxford, chief investigator on the project. The study is the largest trial to date in Parkinson’s disease, addressing what Gray called a bread-and-butter question on the risks and benefits of different initial treatments over the long term.

People diagnosed with Parkinson’s have three choices for their first medication: levodopa or two newer medications, dopamine agonists and monoamine oxidase type-B inhibitors (MAOBIs). Levodopa manages motor symptoms the best, though over time, users usually develop random movements called dyskinesias. Because dopamine agonists and MAOBIs are less likely to cause these movements, physicians often prescribe them first, particularly in patients younger than 60. However, dopamine agonists have their own catalog of side effects, including daytime sleepiness and hallucinations. As for MAOBIs, the benefits and risks remain foggy—one study suggested a higher death rate with this treatment (Lees, 1995), but another posited MAOBIs could slow disease progression (The Parkinson Study Group, 1989).

Gray started the PD MED trial in 2000 while at the University of Birmingham. The study recruited patients at 89 sites across the United Kingdom, as well as one in the Czech Republic and one in Russia. Recruitment continued until 2009, and the researchers followed each patient for up to nine years after their enrollment, with a median follow-up of three years. Trial coordinators randomized their patients to one of the three medications as a first-line drug, and then prescribed other treatments as needed over the length of the trial. The medicines were provided on an open-label basis.

The main outcome measure was self-assessed mobility, measured by the 39-question Parkinson’s disease questionnaire (PDQ-39). It asks about a person’s ability to perform daily tasks such as carrying shopping bags or tying shoes. Levodopa performed just slightly better than the other two options. The PD MED group had set six points on the PDQ-39 mobility section as the minimum clinically meaningful difference. However, the actual benefit was a mere 1.8 points between levodopa and the other two drug classes, after seven years of follow up. “Although the differences in favour of initial levodopa treatment were significant and persistent, they were very small,” Anthony Lang and Connie Marras of the University of Toronto noted in a commentary accompanying the Lancet paper. The results echo those of a smaller trial in North America that compared starting out with levodopa versus a dopamine agonist (Parkinson Study Group CALM Cohort Investigators, 2009).

Compared with the dopamine agonists, the PDQ-39 mobility score was 1.4 points better for MAOBIs as a first therapeutic. “That was really unexpected,” Gray said. Doctors generally believe that while MAOBIs slow disease progress, they poorly control motor symptoms, he said. “MAOBIs may be better than people thought.” Based on these results, neurologists have no reason to start treatment with a dopamine agonist, claimed Gray.

During the early years of the PD MED trial, several studies and pharmaceutical ads encouraged neurologists to switch their patients to dopamine agonists to delay movement problems, noted Lang and Marras. More recently, physicians in North America have turned away from dopamine agonists, they wrote, due to concerns about side effects. “In the U.S., many of us use levodopa as the main treatment for older individuals, especially those after age 70,” Robert Hauser of the University of South Florida in Tampa told Alzforum. He was not involved in the PD MED trial. Doctors consider MAOBIs or dopamine agonists for the younger PD population, he said. No matter the starting medication, patients typically wind up with a multidrug treatment, added Wolfgang Oertel of Philipps University in Marburg, Germany. “Eventually they all need levodopa,” said Oertel, who also was not an author on the PD MED study.

Will the PD MED data change how doctors treat patients? Gray thinks the study will change prescribing behavior. He first presented the PD MED results at a meeting of the British Movement Disorders Group in Birmingham, U.K., in 2012, and surveyed the group before and after sharing the data. He claims that after hearing the PD MED conclusions, the number of physicians who said they would prescribe levodopa to a Parkinson’s patient under 70 more than doubled.

Others doubted the Lancet paper would make much difference to treatment. “It is perfectly consistent with what the expert community has been thinking for many years now,” said Hauser. Oertel said that in Germany, guidelines tell neurologists to offer patients a choice, noting the side effects to each medication. Nevertheless, Gray said prescriptions of dopamine agonists have been rising in the United Kingdom, a trend he attributes to advertising. Oertel agreed that ads contribute to prescription habits. Pharmaceutical marketing influences drug selection “dramatically,” he told Alzforum. For example, in 2000 a trial indicated that the dopamine agonist ropinirole reduced dyskinesias compared to levodopa (Rascol et al., 2000). A “fantastic marketing campaign” led to a peak in ropinirole prescriptions, said Oertel. In the United Kingdom, dopamine agonists can cost 10 times as much as levodopa or MAOBIs, Gray said, though as patents expire on some dopamine agonists, the difference may wane.

One thing missing from the PD MED data is guidance for patients aged 60 and younger, noted Hauser. “It is younger patients who are most prone to develop dyskinesia and therefore it is for those patients we seek an answer," he wrote. Only 12 percent of the study subjects were under 60. However, Lang and Marras noted, “This amounts to roughly 200 participants and therefore could have been quite informative.” Gray told Alzforum in an email, “We did look at the age <60 group separately but concluded that this was not meaningful … because of the small numbers.”—Amber Dance

Tried and True: Levodopa Still Best First-Line Parkinson’s Medication

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