Long Duration Response in Parkinson's Disease: Levodopa Revisited

Werner Poewe; Alberto J. Espay


Brain. 2020;143(8):2332-2335. 

In This Article

The Long-duration Response and Levodopa's Impact on the Natural History of Parkinson's Disease

Soon after the early use of levodopa to treat Parkinson's disease in the 1960s, investigators noted two temporal profiles of response, one of 'short duration' (SDR) and another of 'long-duration' (LDR) (Muenter and Tyce, 1971). The SDR corresponds to the rapid onset and offset of effect between doses of levodopa, lasting a few hours, largely matching plasma levodopa concentrations; the LDR is active beyond the elimination of levodopa, declining to baseline days to weeks after. While the SDR is generally believed to reflect the peripheral pharmacokinetics of the drug, the mechanisms underlying the LDR are poorly understood. Experimental and clinical evidence have resulted in a number of assumptions: that LDR only establishes itself after prolonged exposure to levodopa, it is responsible for ~30–50% of the total levodopa response in early Parkinson's disease, its magnitude progressively diminishes with advancing disease, and its eventual loss is at least partially responsible for the development of motor fluctuations (Nutt etal., 2002; Anderson and Nutt, 2011). The findings by Cilia and colleagues challenge most of these assumptions. They calculated the LDR as the difference between the 'natural-OFF' state (predicted using disease duration regressed from baseline) and the overnight-OFF state; and the SDR as the difference between the overnight-OFF and the ON state. When using their regression formula to estimate the annual pretreatment UPDRS decline and the measured UPDRS OFF scores at Months 12 and 24 in different strata of disease duration (≤5, 6–10 and >10 years) they calculated a relative contribution of the LDR to the total levodopa response of 60–65% independent of disease duration, indicating a more robust LDR than the SDR even after more than 10 years of disease. This is evidence against a progressive decay of the LDR with advancing Parkinson's disease. Intriguingly, these results are in line with recent observations suggesting that the LDR is larger in magnitude among those with more severe disease prior to treatment (Nagao etal., 2019), as was the case with the long untreated cohort from Ghana. Furthermore, since about two-thirds of their patients had already developed motor fluctuations at 12 months of treatment, this study also questions the hypothesis that levodopa motor complications are related to a loss of the LDR. In fact, the motor scores in the practically defined OFF condition at Month 12 and beyond—including a subgroup followed for 4 years—were consistently and significantly lower (better) than the pretreatment baseline.

Interestingly, in a subgroup observed for 24 h after the initiation of levodopa, the overnight OFF score was already significantly improved compared to the untreated baseline OFF, challenging the notion that an LDR needsup to 9 months to become established. Although OFF state motor performance declined after a 1-year follow-up, both UPDRS part II and III OFF scores remained significantly better than baseline, including for the subgroup followed-up to Year 4. ON state motor function remained unchanged, however in the context of increasing levodopa dose requirements.

Taken together, the findings by Cilia and colleagues provide new insights into the most important dopaminergic replacement strategy for Parkinson's disease. While confirming early estimates of disability prevalence in untreated 'modern pre-levodopa era' patients, the new observations on OFF state motor function challenge the notion of ostensibly 'nondopaminergic' motor symptoms and clarify key features of the long-duration response of levodopa: it is robust from the outset, does not decay over time, and appears to be independent of disease duration. As the overnight OFF UPDRS motor scores remain below the expected annual 'natural' decline, the authors also offer a cautionary note when using such scores as measures of true disease progression.