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COMT inhibition in Parkinson’s Disease

Use of levodopa

Read time: 10 mins

There is no single drug of choice for the initial treatment of Parkinson’s disease (PD) but levodopa is the mainstay of current treatment1. Did you know that motor fluctuations are related mainly to disease duration and levodopa dose, rather than length of levodopa exposure, suggesting that levodopa should be started as soon as a diagnosis of PD is made2–4

Dopamine agonists and monoamine oxidase B (MAOB) inhibitors are alternatives which can be used as first-line therapy or in combination with levodopa5. Other drug classes used with levodopa are catechol-O-methyltransferase (COMT) inhibitors and dopamine decarboxylase (DDC) inhibitors which inhibit peripheral levodopa metabolism5. The increase in peripheral levodopa and the reduction in peripheral 3-OMD (which competes with levodopa for crossing the BBB) increases levodopa bioavailability in the brain6–9

BIAL_Parkinsons_Levodopa_Fig1__F23BA16D-F42E-4F2B-9341DB26D8ACCBA2.png

Figure 1. Strategies to reduce the peripheral metabolism of levodopa and boost dopamine levels in the brain (Adapted from Fox et al5).
COMT, catechol-O-methyltransferase; DDC, dopamine decarboxylase; 3-OMD, 3-O-methyldopa.

Anticholinergics are also used in PD but mainly for the relief of mild movement symptoms (such as tremors and muscle stiffness), in younger patients in the early stages of PD1. N-methyl-D-aspartate (NMDA) receptor antagonists are also sometimes used to reduce dyskinesia and control motor symptoms10

Want to find out more about the use of levodopa? 

How levodopa works

The dopamine precursor levodopa is the most effective symptomatic treatment for PD1,11.  

As levodopa undergoes rapid and extensive metabolism by DDC and COMT12, only 1% of an oral dose actually reaches the brain11. Consequently, levodopa is co-administered with a DDC inhibitor and a COMT inhibitor to increase bioavailability and delivery to the brain6–9

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When to start levodopa

Initially it was thought that delaying treatment with levodopa until PD symptoms became limiting would reduce adverse events such as1,12,16

 

  • dyskinesia (abnormal movements) 
  • motor fluctuations, such as the wearing-off effect 
  • neurotoxicity and acceleration of neurodegeneration 
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Use of levodopa references

  1. Zahoor I, Shafi A, Haq E (2018). Pharmacological Treatment of Parkinson’s Disease.In: Stoker TB, Greenland JC (Eds),  Parkinson’s Disease: Pathogenesis and Clinical Aspects [Internet]. Available at: http://www.ncbi.nlm.nih.gov/pubmed/30702845 (accessed 16 January 2020). 
  2. Cilia R, Akpalu A, Sarfo FS, Cham M, Amboni M, Cereda E, et al. The modern pre-levodopa era of Parkinson’s disease: Insights into motor complications from sub-Saharan Africa. Brain. 2014;137(10):2731–2742. 
  3. Aquino CC, Fox SH. Clinical spectrum of levodopa-induced complications. Movement Disorders. 2015;30(1):80–89. 
  4. Scott NW, Macleod AD, Counsell CE. Motor complications in an incident Parkinson’s disease cohort. Eur J Neurol. 2016;23(2):304–312. 
  5. 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. 
  6. Gervas JJ, Muradás V, Bazán E, Aguado EG, de Yébenes JG. Effects of 3-OM-dopa on monoamine metabolism in rat brain. Neurology. 1983;33(3):278–82. 
  7. Nutt JG, Woodward WR, Gancher ST, Merrick D. 3‐O‐Methyldopa and the response to levodopa in Parkinson’s disease. Ann Neurol. 1987;21(6):584–588. 
  8. Gomes P, Soares-da-Silva P. Interaction between L-DOPA and 3-O-methyl-L-DOPA for transport in immortalised rat capillary cerebral endothelial cells. Neuropharmacology. 1999;38(9):1371–80. 
  9. Dingemanse J, Waters, Schapira, Nutt, Obeso, Reichmann, et al. Issues important for rational COMT inhibition. Neurology. 2000;55(11 SUPPL. 4). 
  10. Parkinson’s drugs | Parkinson’s UK. https://www.parkinsons.org.uk/information-and-support/parkinsons-drugs. Accessed 20 January 2020. 
  11. Parkinson’s disease in adults. 2017 http://www.nice.org.uk/guidance/ng71/. Accessed 20 January 2020. 
  12. Bressman S, Saunders-Pullman R. When to start levodopa therapy for Parkinson’s disease. N Engl J Med. 2019;380(4):389–390. 
  13. Gershanik OS. Improving l-dopa therapy: The development of enzyme inhibitors. Movement Disorders. 2015;30(1):103–113. 
  14. Lewitt PA. Levodopa for the treatment of Parkinson’s disease. N Engl J Med. 2008;359(23):2468–76. 
  15. Verschuur CVM, Suwijn SR, Boel JA, Post B, Bloem BR, Van Hilten JJ, et al. Randomized delayed-start trial of levodopa in Parkinson’s disease. N Engl J Med. 2019;380(4):315–324. 
  16. Kalia L V., Lang AE. Parkinson’s disease. The Lancet. 2015;386(9996):896–912. 
  17. PD Med Collaborative Group, Gray R, Ives N, Rick C, Patel S, Gray A, et al. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet (London, England). 2014;384(9949):1196–205.