Non-Motor Side Effects in Early Parkinson's Therapy Linked to Comorbidities

ROCHESTER, New York, July 9 -- Somnolence, edema, and hallucinations in patients with early-stage Parkinson's disease may be related as much to co-morbid disease and other factors as they are to medication, investigators here reported.

In a secondary analysis of data from a completed clinical trial, patients assigned at baseline to treatment with pramipexole (Mirapex) were significantly more likely to experience somnolence (P< 0.001) and edema (P< 0.0001) when starting on therapy, compared with those started on levodopa, according to a report in the July 10 issue of Neurology.

But gender and comorbid illnesses were also significant risk factors for both somnolence and edema, and patients 65 and older and those with small cognitive deficits were also more likely to experience hallucinations, regardless of treatment assignment, said Kevin M. Biglan, M.D., M.P.H., of the University of Rochester, and colleagues in the Parkinson Study Group.

"When considering initial therapy with pramipexole, patients should be counseled regarding the increased risk of somnolence and be followed closely for this complication," they wrote. "Edema tends to occur later in the course of treatment and its relationship with initial pramipexole treatment may be easily overlooked unless a high clinical suspicion is maintained."

The investigators conducted a secondary analysis of data from the CALM-PD (Comparison of the Agonist Pramipexole versus Levodopa on Motor Complications of Parkinson's Disease) trial. Results of the trial were reported in 2000 in the Journal of the American Medical Association.

In the current study, the authors looked at the association of baseline patient characteristics with the onset or worsening of somnolence and edema, and with the development of hallucinations.

They created Cox proportional hazards regression models and calculated Kaplan-Meier estimates of the four-year incidence of the various endpoints.

They found that 35% of the patients developed or had worsening of somnolence during the study, 45% developed or had worsening of edema, and 17% developed hallucinations.

Risk factors for somnolence included initial therapy with pramipexole, with a hazard ratio of 2.22 (95% confidence interval, 1.41 to 3.50, P< 0.001), male gender (hazard ratio 1.79, 95% CI, 1.09 to 2.93, P=0.02), and having more than five systems with a comorbid illness (hazard ratio 1.62, 95% CI 1.04 to 2.51, P=0.03).

Risk factors for edema were pramipexole treatment (hazard ratio 3.18, 95% CI, 1.95 to 5.18, P< 0.0001), female gender (hazard ratio 1.46, 95% CI 0.94 to 2.27, P=0.09), and comorbid cardiac disease (hazard ratio 1.59, 95% CI 1.02 to 2.47, P=0.04).

Initial therapy with either pramipexole or levodopa was not associated with increased risk for hallucination, but age 65 and older was (hazard ratio 2.06, 95% CI, 0.98 to 4.32, P=0.06). So was the presence of comorbidites in more than five system (hazard ratio 3.42, 95% CI 1.59 to 7.38, P=0.002).

Mini-Mental State Examination scores were inversely associated with risk of hallucinations, with scores greater than 28 being associated with lower risk (hazard ratio 0.42, 95% CI, 0.19 to 0.91, P=0.03).

The authors noted that the non-motor complications of dopaminergic therapies appear to be common, with somnolence appearing in the CALM-PD trial in more than a third of patients, edema developing in almost half, and nearly a fifth of patients having hallucinations within four years of starting therapy.

"While it is generally believed that dopamine agonist treatment, especially treatment with D3 receptor specific agonists, is associated with a greater risk of hallucinations than levodopa, we did not find that initial pramipexole treatment independently increased the risk of hallucinations," the authors wrote. "This discrepancy may be explained by the fact that the CALM-PD cohort was relatively young, non-demented, and with mild disease of short duration."

Study limitations included patient self-report of somnolence, edema, and hallucinations, which could result in over- or under-reporting biases, the authors noted.

In addition, the analysis focused on baseline factors at the time of initial dopaminergic therapy and not on disease or on treatment-emergent factors.

The authors also acknowledged that they may have missed potential confounding factors, and that the patient sample was relatively young, healthy, and without active psychiatric or cognitive difficulties at baseline, making it difficult to generalize the results.