Clinical Pharmacology

"Adverse Drug Event of the month"

Levodopa induced peak dose dyskinesia


Case report:

A 70-year-old female patient was brought to this institute on 10th May 2005 with complaints of continuous involuntary movements of the head and limbs since 5 days. The patient was diagnosed with Parkinson's disease and diabetes mellitus (type 2) five years prior and was on following treatment -

T.Levodopa 100mg + Carbidopa 25mg 1 tablet 5 times a day (+ 1 SOS)
T.Levodopa 200mg + Carbidopa 50mg CR 1 - ½ - ½ - 1
T.Amantidine (100mg) 1 - 0 - 1
T.Ropinirole (2mg) 1 - 1 - 2
T.Glipizide 5mg + Metformin 500mg 1 - ½ - 1 (since she was also a known case of type 2 diabetes mellitus)

The patient's condition was well controlled for the first two years after which she started getting on & off periods and also complained of intermittent peak dose dyskinesias.

On 5th May 2005 she was admitted to a private nursing home with altered sensorium. Her blood sugars were very high and urine showed trace proteins. She was treated there with Insulin; her blood sugars were brought under control and her sensorium improved. At the same time she was treated with the following drugs for her Parkinson's disease -

T. Levodopa 200mg + Carbidopa 50mg 5 times a day
T. Entacapone (200 mg) 5 times a day before every dose of levodopa
T.Levodopa 200mg + Carbidopa 50mg CR 1 - ½ - ½ - 1
T. Quetiapine (25mg) twice a day.

Amantidine was discontinued. On 7th May (i.e. after 2 days) she developed continuous dyskinesia (continuous involuntary movements of head and limbs) while still on the same medications which continued until 10th May 2005 when finally her relatives admitted her to this institute. On admission T. Entacapone was stopped immediately and she was put on following medications -

T. Levodopa 100mg + Carbidopa 25mg ½ tablets 6 times daily (at 7am, 10am, 1pm, 4pm, 7pm and 10pm)
T. Amantidine (100mg) 1-0-1 and
T. Ropinirole (2mg) 1-1-2 Now from 12th May she is on -
T. Levodopa 100mg + Carbidopa 25mg ½ tablets 3 times daily
T.Levodopa 200mg + Carbidopa 50mg CR 1 tablet at bedtime
T. Amantidine (100mg) 1-0-1 and
T. Ropinirole (2mg) 1-1-2

At present moment the patient still has dyskinesia but has improved partially.


Discussion:
The adverse event of dyskinesia was analyzed using the Naranjo's algorithm, which attempts to define a cause-effect relationship. The score on Naranjo's algorithm was 8, which means that the adverse event was probably caused by L-dopa (+ entacapone combination).

The patient was initially admitted with complaints of rigidity and bradykinesia, which is suggestive of wearing-off effect of levodopa. The physician then treated the patient with higher doses of levodopa/carbidopa along with entacapone (inhibitor of catechol-O-methyl transferase i.e. COMT). This could have lead to marked rise in serum levodopa levels and thus caused dyskinesia. In a few cases, simply reducing the dose of levodopa can relieve dyskinesias but in most cases this leads to an unacceptable increase of Parkinsonism. The threshold for dyskinesias in terms of plasma levodopa level often seems to be to the same as that for a therapeutic response and so it is unlikely that any therapeutic window between response and dyskinesias exists.

Use of levodopa is invariably associated with frequent appearance of dyskinesias and mental disturbances. Levodopa-induced involuntary movements appear at critical, high (most commonly) or low plasma levodopa levels, particularly in patients with severe akinesia, responding dramatically to levodopa. It is hypothesized that these involuntary movements result from stimulation of hypersensitive (compensating) dopamine receptors.

Entacapone belongs to a class of drugs, which are inhibitors of catechol-O-methyl transferase (COMT). COMT and monoamine oxidase (MAO) are responsible for the catabolism of levodopa. The principal therapeutic action of the COMT inhibitors is to block the peripheral conversion of levodopa to 3-O-methyl DOPA, increasing both the plasma half-life of levodopa as well as the fraction of each dose that reaches central nervous system. At present two drugs from this class are available- entacapone & tolcapone. Both of these agents have been shown in double-blind trials to reduce the clinical symptoms of "wearing off" in patients treated with levodopa/carbidopa. However use of tolcapone is restricted due to several reports of hepatotoxicity and fulminant hepatic failure. Entacapone has not been associated with hepatotoxicity and requires no special monitoring. In this particular patient use of high dose levodopa/carbidopa along with entacapone could have lead to marked rise of levodopa levels, which probably lead to uncontrollable continuous involuntary movements of head and limbs.

There is now increasing evidence that in Parkinson's disease levodopa [now a day always given with L-amino acid decarboxylase (LAAD) inhibitor] should be delayed and the dose restricted if symptoms permit. Early use and high doses are associated with an increased risk and earlier appearance pf motor oscillations and dyskinesias. As the disorder progresses, early combination of a restricted dose of levodopa [less than 600mg with a Lamino acid decarboxylase (LAAD) inhibitor] and a dopamine agonist will delay motor oscillations and reduce the risk of dyskinesias. Unrestricted levodopa monotherapy is associated with high risk of these complications.

Modified-release levodopa preparations are now increasingly used for the management of motor oscillations. They are most effective for the wearing-off effects and end of dose deterioration so commonly seen after a few years of standard levodopa/carbidopa combination therapy. However they are less helpful for dyskinesias.

Dose division, with more frequent smaller doses, is rarely helpful. Often the best option is to reduce the levodopa dose and add or increase the dose of a simultaneously administered dopamine agonist (e.g. Ropinirole). Unfortunately, dyskinesias cannot always be controlled by any medical therapy and may then require stereotactic neurosurgical treatment (thalamotomy or pallidotomy).


References:
1. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.
2. Standaert DG, Young AB. Treatment of central nervous system degenerative disorders. In: Hardman JG, Limbird LE, Gilman AG, editors. Goodman & Gilman's The pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill, Medical Publishing Division; 2001. p. 1381-8.
3. Levodopa. In: Dollery C, BoobisA, Rawlins M, Thomas S, Wilkins M editors. Therapeutic drugs. 2nd ed. UK: Churchill Livingston Company, 1999. p. L39-43.