This site is intended for healthcare professionals
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

Strategies to reduce the peripheral metabolism of levodopa and boost dopamine levels in the brain

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

DDC and COMT inhibitors increase bioavailability and delivery of levodopa to the brain

Figure 2. DDC and COMT inhibitors increase bioavailability and delivery of levodopa to the brain (Adapted from Gershanik13 and Lewitt14).
COMT, catechol-O-methyltransferase; DDC, DOPA decarboxylase; HVA, homovanillic acid; MAO, monoamine oxidase; 3-MT, 3-methoxytyramine; 3-OMD, 3-O-methyldopa.


MAO-B inhibitors are a levodopa-sparing treatment approach which directly inhibit dopamine degradation in the brain. Their use evolved because of initial concerns about complications associated with long term levodopa use (including motor fluctuations and dyskinesia) and potential levodopa neurotoxicity12. However, more recent evidence suggests that starting levodopa treatment as soon as a patient is diagnosed with PD has beneficial effects11,12,15 and MAO-B inhibitors can be used in combination with levodopa to enable a levodopa dose reduction1

Ask the expert 

Why does wearing-off develop with levodopa therapy? (3 minutes) 

Professor Olivier Rascol describes the strategy behind replacing lost dopamine in PD using levodopa and adjunctive treatments to enhance dopamine levels within the brain. 

Welcome:

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 
     

However, there is now considerable evidence that motor fluctuations are related mainly to the duration of disease and dose of levodopa rather than the duration of levodopa exposure2–4

Let’s take a look at the key studies supporting levodopa treatment at the time of diagnosis2,15,17

Key studies supporting levodopa treatment at the time of diagnosis


Levodopa in EArly Parkinson's disease (LEAP) study

The effect of early vs. late levodopa/carbidopa treatment on UPDRS score

Figure 3. The effect of early vs. late levodopa/carbidopa treatment on UPDRS score (Adapted from Verschuur et al15).
Higher score indicates more severe disease. Error bars denote 95% confidence intervals.


The rates of dyskinesia and levodopa-related fluctuations in motor response also did not differ significantly between groups at week 8015.  

Study comparing Ghanaian and Italian patients with PD 

The effect of early vs. late levodopa treatment on time until motor complications, wearing-OFF and dyskinesia (matched for therapy regimen)

Figure 4. The effect of early vs. late levodopa treatment on time until motor complications, wearing-off and dyskinesia in Ghanaian patients with PD and Italian PD control subjects with motor fluctuations (Adapted from Cilia et al2).


Disease duration (Figure 4) and levodopa daily dose (mg/kg of body weight) were associated with motor fluctuations and dyskinesia, rather than disease duration at the initiation of levodopa2

Open-label PD MED trial of newly-diagnosed PD patients 

Although patients in the levodopa group were more likely to develop dyskinesias, there was no significant difference in motor fluctuations between patients receiving levodopa alone and those given levodopa-sparing therapy with dopamine agonists (DAs) or monoamine oxidase B (MAOB) inhibitors17. In addition, a small but persistent benefit in patient mobility was seen in the levodopa group (Figure 5)17

Persistent benefits for patient-rated mobility scores when treatment is initiated with levodopa (39-item patient-rated Parkinson’s disease questionnaire)

Figure 5. Persistent benefits for patient-rated mobility scores when treatment is initiated with levodopa (39-item patient-rated Parkinson’s disease questionnaire. Lower score means higher mobility.) (Adapted from PD MED Collaborative Group17).


These collective data suggest that levodopa treatment should start early2,15,17

Welcome:

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. 

Developed by EPG Health for Medthority in collaboration with BIAL, with content provided by BIAL. Job code: ON/FEV20/G/183.