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

By Neil Osterweil, Senior Associate Editor, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
July 09, 2007

MedPage Today Action Points
Advise patients that sleepiness, swelling, and hallucinations are common side effects seen among patients who are started on dopaminergic therapies for treatment of early Parkinson's disease.

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.


The CALM-PD trial was sponsored by Boehringer Ingelheim, but the secondary analysis was not supported by industry. The authors reported that they had nothing to disclose.


Primary source: Neurology
Source reference:
Biglan KM et al. "Risk factors for somnolence, edema, and hallucinations in early Parkinson disease." Neurology 2007;69:187-195.

that i have never read anywhere, not once, a recommendation that PWP be counseled regarding the risk of developing dyskinesia if they take levodopa.

I have been taking pramipexole for about six years and experience both somnolence and edema, and a) i also get about 5 hours of sleep per night - i wonder if the researchers assessed the amount of sleep folks were getting every night, and b) let me see, would i prefer slightly swollen ankles or involuntary movements that make it impossible for me to work... hmmmm... that's a tough one.

just skimming the study, a couple of interesting points - they not only did not exclude participants on the basis of experiencing either somnolence or edema (which they did do for hallucinations) they did not even assess the prevalence at baseline.

and this i will never understand - the participants were carefully randomized to either the pramipexole or the levodopa arm. then they allowed open label levodopa treatment at any time. for pete's sake, why the heck bother with the randomizing?

Moreover, theoretically, a participant in the pramipexole arm could have started levodopa on the second day of the study - if that person had developed any of the three side effects in question, s/he would have been counted among those whose side effects were associated with initial pramipexole therapy. i can't find anywhere in this study where it takes the addition/timing of open label levodopa into account.

And your point was.........?

1) i find it interesting that counseling is recommended for potential somnolence but not for potential dyskinesia, wearing off and on-off fluctuations

2) the data regarding the associations between all three of these side effects is muddied by the fact that the folks in the pramipexole arm were free to add levodopa at any time.

3) (this is a new one) what is edema doing in the company of the other two side effects? presumably, somnolence is considered an important issue because it has the potential to kill should one fall asleep at the wheel, and presumably hallucinations are considered important because they could negatively impact one's ability to function in a big way.

but edema? I don't see it having the potential to be fatal, nor, in the vast majority of cases, negatively impacting one's ability to function; moreover, the incidence rate of edema characterized as severe by one of the studies referenced by this study was 1.6%.

in fact, on the pramipexole product labeling, the incidence of nausea is more than 3x higher than that of edema - why is it not included in this constellation of side effects to be concerned about?

in summary, i think that this study (and many others) are making truly minor issues into major issues, and they are doing it based on muddy data, and it is being done at the expense of both a particular type of drug and at the expense of attention, money and time that could be spent on issues that are genuinely major.

i hope that is clearer.

Well if they are going to come in with new treatments, I guess they have to get rid of the old competition. They wouldn't try to oust l-dopa....too many hopelessly relying upon it.

I AM a cynic.....lol
paula

hi paula,

If you mean too many pharmaceutical companies relying on the income streams it generates, I agree.

And I do mean streams, plural. Let's take Novartis as an example:

Novartis/Orion make/market the levodopa product stalevo.
Novartis owns Roche, which makes another levodopa product.
Novartis also owns Sandoz, which also makes a levodopa product.
Novartis (N)/Sandoz (S)/Orion (O) also make the following levodopa adjuncts:

bromocriptine (N,S)
amantadine (S)
clozapine (S)
amitriptyline (S)
selegiline (S)
entacapone (O)

As another example, let's look at Teva, which makes a generic sinemet:

Teva (T) and its generic arm, Ivax (I), also make the following levodopa adjuncts:

selegiline (I, T)
pergolide, until recently (I)
clozapine (I, T)
amantadine (T)
amitriptyline (T)
rasagiline (T)

As long as the status quo is maintained, i.e., as long as levodopa is considered unbeatable (which is merely a euphemism for the PD pharmaceuticals market being too small to justify the risk involved in trying to outdo levodopa) and as long as the adjuncts continue to fail to fix the problems levodopa causes, levodopa provides the industry with infinite room for growth.

And that is what the new focus on non-motor symptoms is about – it is creating a whole new market – as is the elevation of minor side effects to a level at which they can garner more study, i.e., again, creating a market.

And each new market contributes to the maintenance of the status quo, because dollars, time and brainpower that are needed to address the REAL shortcomings of PD therapy are diverted elsewhere.