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COMT inhibition in Parkinson’s Disease

Motor fluctuations

Read time: 10 mins

Motor fluctuations (MF) are caused by changes in the therapeutic response to levodopa in parallel with neuronal loss1,2. Overall, 1 in 10 patients each year develop MF after starting levodopa therapy2. Do you know the best way to diagnose MF in order to optimise patient treatment? 

MF occur in Parkinson’s disease when the clinical benefit of each levodopa dose declines2,3. Let’s look in more detail at the response to levodopa in order to understand how it changes with disease progression. 

Improvement in symptoms after levodopa administration is known as the ON state and the return of parkinsonian symptoms is known as the OFF state2,3

Response to levodopa 

The levodopa response can be divided into three phases (Figure 1)2

Example response to treatment with levodopa in a hypothetical patient with Parkinson’s disease

Figure 1. Example response to treatment with levodopa in a hypothetical patient with Parkinson’s disease (adapted from Aquino & Fox2 and Chou et al3).


Motor fluctuations can be associated with specific phases or with all of them as there are multiple forms of motor fluctuation that occur in Parkinson’s disease (PD) (Figure 2)2,3

Levodopa-related motor fluctuations

Figure 2. Levodopa-related motor fluctuations (adapted from Aquino & Fox2 and Chou et al3).


The therapeutic response to levodopa consists of the short-duration response (SDR) and the long-duration response (LDR). The SDR is an improvement in motor function that lasts a few hours after each dose of levodopa, whereas the LDR is a sustained antiparkinsonian effect that can last for up to 2 weeks after stopping treatment. During the early stages of levodopa therapy, the SDR may be unnoticed because it is masked by the LDR. However, as the LDR is progressively lost (due to disease progression with neuronal loss), patients lose the smoothing drug effect and the magnitude of the SDR increases, which clinically translates as motor fluctuations (Figure 3)4.  

Decline in the long-duration response (LDR) and increase in magnitude of the short-duration response (SDR) to levodopa

Figure 3. Decline in the long-duration response (LDR) and increase in magnitude of the short-duration response (SDR) to levodopa (adapted from Stocchi et al4).


Ask the expert 

What mechanisms drive the mismatch between plasma and cerebral levels of levodopa and the response? (1 minute)


Professor Olivier Rascol describes the short and long duration responses to levodopa which help to explain the difference in plasma and cerebral levels of levodopa which can vary between patients. 

Diagnosis of motor fluctuations 

Are motor fluctuations easy to diagnose? 

Wearing-off fluctuations can be difficult to detect as their presentation is highly variable and may affect both motor and non-motor symptoms. Wearing-off is the gradual re-emergence of symptoms that predictably occurs at the end of the levodopa dose2. Wearing-off usually becomes apparent when the duration of levodopa benefit is ≤4 hours and the intervals between doses are longer2.  

 

The incidence of wearing-off may be underestimated and under-diagnosed in routine neurological evaluation5.  

There are a number of factors that can aid diagnosis of motor fluctuations6

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Treatment strategies 

Are you up-to-date? Find out what the latest international guidelines advise for treating motor fluctuations.  

International guideline recommendations 

 

The International Parkinson and Movement Disorder Society updated their treatment guidelines for the motor symptoms of Parkinson’s Disease in 2018. Their recommendations for efficacious treatments of motor fluctuations fall into the following categories11

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Welcome:

References 

  1. Poewe W, Antonini A, Zijlmans JC, Burkhard PR, Vingerhoets F. Levodopa in the treatment of Parkinson’s disease: an old drug still going strong. Clinical interventions in aging. 2010;5:229–238. 
  2. Aquino CC, Fox SH. Clinical spectrum of levodopa-induced complications. Movement Disorders. 2015;30(1):80–89. 
  3. Chou KL, Stacy M, Simuni T, Miyasaki J, Oertel WH, Sethi K, et al. The spectrum of “off” in Parkinson’s disease: What have we learned over 40 years? Parkinsonism and Related Disorders. 2018;51:9–16. 
  4. Stocchi F, Jenner P, Obeso JA. When do levodopa motor fluctuations first appear in Parkinson’s disease? European Neurology. 2010;63(5):257–266. 
  5. Stocchi F, Antonini A, Barone P, Tinazzi M, Zappia M, Onofrj M, et al. Early DEtection of wEaring off in Parkinson disease: The DEEP study. Park Relat Disord. 2014;20(2):204–211. 
  6. Motor fluctuations and dyskinesias (diagnosis and management). Ann Indian Acad Neurol. 2011;14(Suppl 1):S13-5. 
  7. Stacy M, Bowron A, Guttman M, Hauser R, Hughes K, Larsen JP, et al. Identification of motor and nonmotor wearing-off in Parkinson’s disease: Comparison of a patient questionnaire versus a clinician assessment. Mov Disord. 2005;20(6):726–733. 
  8. Stacy M, Hauser R, Oertel W, Schapira A, Sethi K, Stocchi F, et al. End-of-dose wearing off in parkinson disease: A 9-question survey assessment. Clin Neuropharmacol. 2006;29(6):312–321. 
  9. Stacy M, Hauser R. Development of a patient questionnaire to facilitate recognition of motor and non-motor wearing-off in Parkinson’s disease. J Neural Transm. 2007;114(2):211–217. 
  10. Martinez-Martin P, Hernandez B. The Q10 questionnaire for detection of wearing-off phenomena in Parkinson’s disease. Park Relat Disord. 2012;18(4):382–385. 
  11. Fox SH, Katzenschlager R, Lim SY, Barton B, de Bie RMA, Seppi K, et al. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson’s disease. Movement Disorders. 2018;33(8):1248–1266. 
  12. Tasmar® (tolcapone) Summary of Product Characteristics. Meda AB. Available at: https://www.ema.europa.eu/en/documents/product-information/tasmar-epar-product-information_en.pdf. Last updated 08 Aug 2018. Accessed 3 February 2020. 
  13. Comtan® (entacapone). Summary of Product Characteristics. Novartis Europharm Ltd. Available at: https://www.ema.europa.eu/en/documents/product-information/comtan-epar-product-information_en.pdf. Last updated 03 Sep 2018. Accessed 3 February 2020. 
  14. Ongentys® (opicapone) Summary of Product Characteristics. Bial - Portela Ca, S.A. Available at: https://www.ema.europa.eu/en/documents/product-information/ongentys-epar-product-information_en.pdf. Last updated 13 Mar 2019. Accessed 3 February 2020. 

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