In reply: Parkinson disease

In Reply: I thank Dr. Keller for his thoughtful comments. They are most appreciated.

It is true that with availability of generic ropinirole and pramipexole, there are now cheaper alternatives to levodopa. Nonetheless, levodopa remains the cheapest and most efficacious medication for Parkinson disease to date. Whenever levodopa is compared head-to-head with any dopamine agonist, the general results remain consistent: levodopa affords better motor improvement with lesser side effects, but is more likely to lead to motor fluctuations, specifically dyskinesias. Therefore, in general, levodopa is the first choice in elderly patients where tolerability may be an issue, whereas a dopamine agonist may be the initial treatment of choice in younger Parkinson patients, who are able to tolerate the drug better and have a higher likelihood of developing dyskinesias.

It is a tougher task to determine which among the dopamine agonists is superior. The newer dopamine agonists have not been compared head-to-head. Therefore, it is practically a “coin toss” when selecting which dopamine agonist to try. Their mechanism of action (D2 and D3 receptor agonist activity) and frequency of intake (three times per day for generics; once daily for long-acting formulations), cost, and side effect profile are nearly identical, despite minor differences in their half-lives.

Regarding putative neuroprotective agents in Parkinson disease, indeed, isradipine is one of the medications currently undergoing investigation for its potential neuroprotective effect. While I personally have no objection to using it for a Parkinson disease patient who also happens to need an antihypertensive agent, I am more cautious about endorsing it as a neuroprotective agent until results of clinical trials have been released. Similarly, while a large epidemiologic study has shown that people who take ibuprofen are less likely to develop Parkinson disease, there has been no robust human trial that has shown the drug to slow the progression of Parkinson disease among patients who are already suffering from the disorder. Therefore, the current use of ibuprofen in Parkinson disease should be based more on its anti-inflammatory indications rather than its possible neuroprotective effect. Finally, we have shown, in a large, multicenter, global randomized controlled trial with a delayed-start design, that pramipexole is unlikely to possess any meaningful neuroprotective effect. Therefore, I am personally not that optimistic that dexpramipexole would demonstrate such an effect.

While in theory combining the use of catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO) type B inhibitors can synergistically work to inhibit the breakdown of other catecholamines and lead to adrenergic crisis when taken concomitantly, this has not been our experience. Perhaps it is because at recommended doses, the MAO inhibition is selective to type B (where receptors are more confined to the brain) and not type A (where receptors are more distributed throughout blood vessels, thereby having a higher likelihood of causing a hypertensive crisis as is seen in the use of nonselective MAO inhibitors). Therefore, at our center, we routinely use the two classes of agents concomitantly with minimal safety concerns.

In Reply: I thank Dr. Keller for his thoughtful comments. They are most appreciated.

It is true that with availability of generic ropinirole and pramipexole, there are now cheaper alternatives to levodopa. Nonetheless, levodopa remains the cheapest and most efficacious medication for Parkinson disease to date. Whenever levodopa is compared head-to-head with any dopamine agonist, the general results remain consistent: levodopa affords better motor improvement with lesser side effects, but is more likely to lead to motor fluctuations, specifically dyskinesias. Therefore, in general, levodopa is the first choice in elderly patients where tolerability may be an issue, whereas a dopamine agonist may be the initial treatment of choice in younger Parkinson patients, who are able to tolerate the drug better and have a higher likelihood of developing dyskinesias.

It is a tougher task to determine which among the dopamine agonists is superior. The newer dopamine agonists have not been compared head-to-head. Therefore, it is practically a “coin toss” when selecting which dopamine agonist to try. Their mechanism of action (D2 and D3 receptor agonist activity) and frequency of intake (three times per day for generics; once daily for long-acting formulations), cost, and side effect profile are nearly identical, despite minor differences in their half-lives.

Regarding putative neuroprotective agents in Parkinson disease, indeed, isradipine is one of the medications currently undergoing investigation for its potential neuroprotective effect. While I personally have no objection to using it for a Parkinson disease patient who also happens to need an antihypertensive agent, I am more cautious about endorsing it as a neuroprotective agent until results of clinical trials have been released. Similarly, while a large epidemiologic study has shown that people who take ibuprofen are less likely to develop Parkinson disease, there has been no robust human trial that has shown the drug to slow the progression of Parkinson disease among patients who are already suffering from the disorder. Therefore, the current use of ibuprofen in Parkinson disease should be based more on its anti-inflammatory indications rather than its possible neuroprotective effect. Finally, we have shown, in a large, multicenter, global randomized controlled trial with a delayed-start design, that pramipexole is unlikely to possess any meaningful neuroprotective effect. Therefore, I am personally not that optimistic that dexpramipexole would demonstrate such an effect.

While in theory combining the use of catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO) type B inhibitors can synergistically work to inhibit the breakdown of other catecholamines and lead to adrenergic crisis when taken concomitantly, this has not been our experience. Perhaps it is because at recommended doses, the MAO inhibition is selective to type B (where receptors are more confined to the brain) and not type A (where receptors are more distributed throughout blood vessels, thereby having a higher likelihood of causing a hypertensive crisis as is seen in the use of nonselective MAO inhibitors). Therefore, at our center, we routinely use the two classes of agents concomitantly with minimal safety concerns.

In Reply: I thank Dr. Keller for his thoughtful comments. They are most appreciated.

It is true that with availability of generic ropinirole and pramipexole, there are now cheaper alternatives to levodopa. Nonetheless, levodopa remains the cheapest and most efficacious medication for Parkinson disease to date. Whenever levodopa is compared head-to-head with any dopamine agonist, the general results remain consistent: levodopa affords better motor improvement with lesser side effects, but is more likely to lead to motor fluctuations, specifically dyskinesias. Therefore, in general, levodopa is the first choice in elderly patients where tolerability may be an issue, whereas a dopamine agonist may be the initial treatment of choice in younger Parkinson patients, who are able to tolerate the drug better and have a higher likelihood of developing dyskinesias.

It is a tougher task to determine which among the dopamine agonists is superior. The newer dopamine agonists have not been compared head-to-head. Therefore, it is practically a “coin toss” when selecting which dopamine agonist to try. Their mechanism of action (D2 and D3 receptor agonist activity) and frequency of intake (three times per day for generics; once daily for long-acting formulations), cost, and side effect profile are nearly identical, despite minor differences in their half-lives.

Regarding putative neuroprotective agents in Parkinson disease, indeed, isradipine is one of the medications currently undergoing investigation for its potential neuroprotective effect. While I personally have no objection to using it for a Parkinson disease patient who also happens to need an antihypertensive agent, I am more cautious about endorsing it as a neuroprotective agent until results of clinical trials have been released. Similarly, while a large epidemiologic study has shown that people who take ibuprofen are less likely to develop Parkinson disease, there has been no robust human trial that has shown the drug to slow the progression of Parkinson disease among patients who are already suffering from the disorder. Therefore, the current use of ibuprofen in Parkinson disease should be based more on its anti-inflammatory indications rather than its possible neuroprotective effect. Finally, we have shown, in a large, multicenter, global randomized controlled trial with a delayed-start design, that pramipexole is unlikely to possess any meaningful neuroprotective effect. Therefore, I am personally not that optimistic that dexpramipexole would demonstrate such an effect.

While in theory combining the use of catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO) type B inhibitors can synergistically work to inhibit the breakdown of other catecholamines and lead to adrenergic crisis when taken concomitantly, this has not been our experience. Perhaps it is because at recommended doses, the MAO inhibition is selective to type B (where receptors are more confined to the brain) and not type A (where receptors are more distributed throughout blood vessels, thereby having a higher likelihood of causing a hypertensive crisis as is seen in the use of nonselective MAO inhibitors). Therefore, at our center, we routinely use the two classes of agents concomitantly with minimal safety concerns.