Optimizing Drug-Induced Side Effects in Parkinson’s Disease
Friday, January 15th, 2010Significant strides have been made in the management of Parkinson’s disease (PD) motor symptoms such as tremor, slowness of movement, and rigidity; however, treatment side effects pose a key therapeutic challenge. Upon initial onset of the disease, patients are typically prescribed levodopa, a drug taken orally several times a day to increase dopamine levels in the brain to alleviate motor symptoms.
As the disease progresses, changes in the body’s response to levodopa give rise to therapy complications such as delayed onset and decreased duration of motor symptom relief per dose. Chronic treatment can also lead to side effects such as dyskinesias, which can take on various debilitating forms: irregular brief rapid movements (chorea) during the “On” state at peak dose and sustained twisting movements (dystonia) during the “Off” state when the medication has worn off. Approximately 30% of patients diagnosed with PD exhibit levodopa-induced dyskinesia within 5 years of treatment[1] and 59-100% by 10 years[1-3]. Quality of life has been shown to be negatively impacted by dyskinesias[4], specifically mobility[5], activities of daily living[5, 6], communication[5, 6], and bodily discomfort[6].
Figure 1: Blood Levodopa Concentration
Adjustments in medication to reduce drug side effects often sacrifice control of motor symptoms, and balancing this tradeoff poses a significant challenge for management of advanced PD. Alternate strategies to better control motor fluctuations have aimed efforts at developing drug administration methods to minimize swings in blood levodopa concentration. Figure 1 highlights the typical drug cycles that patients may experience throughout the day when taking levodopa in discrete intervals[7]. Over time this approach shrinks the size of the “On” state window requiring higher doses to achieve the same effect and increasing the frequency and severity of dyskinesia. The ideal scenario would be to maintain levodopa concentration in the “On” state where levodopa is effective at alleviating motor symptoms without inducing dyskinesia. Studies have suggested that continuous drug administration may better mimic the normal physiological release of dopamine in the brain in order to attain more stable therapy benefits[8, 9].
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7. Keijsers, N.L., et al., Online monitoring of dyskinesia in patients with Parkinson’s disease. IEEE Eng Med Biol Mag, 2003. 22(3): p. 96-103.
8. Olanow, C.W., et al., Continuous dopamine-receptor treatment of Parkinson’s disease: scientific rationale and clinical implications. Lancet Neurol, 2006. 5(8): p. 677-87.
9. Olanow, C.W., Levodopa/dopamine replacement strategies in Parkinson’s disease–future directions. Mov Disord, 2008. 23 Suppl 3: p. S613-22.
