On-Off Phenomenon: L-Dopa Stops Working as Well

Sinemet CR (levodopa+carbidopa). Credit: Photo Researchers / Getty Images

Levodopa (often abbreviated as L-dopa) is the "gold standard" medication for Parkinson's disease. However, as Parkinson's progresses, levodopa doesn't work as well in eliminating or controlling your symptoms — the drug starts to wear off more quickly. This leads to the "on-off phenomenon" in Parkinson's disease.

Ideally, when you take doses of a medication like levodopa on a regular schedule, you shouldn't notice much difference in your symptoms between doses — your symptoms should remain relatively constant over time, regardless of when you last took your medication.

However, when the on-off phenomenon starts in Parkinson's disease, you'll feel better ("on") as a new dose of your medication starts to take effect, and worse ("off") before you're due for another dose. Eventually, the duration of “on” states becomes shorter and “wearing off” happens sooner — too soon for another dose of levodopa.

Researchers estimate that about 40% of people with Parkinson's disease will start to experience fluctuations in the ability of levodopa to control their symptoms within about four to six years of starting the medication.

How Does the Parkinson's 'On-Off Phenomenon' Feel?

One medical study described the "on" period as akin to switching on a light, and the "off" period as the return of darkness, or the light going off.

In an "on" state, the person with Parkinson's disease may feel energetic and may be able to move around more easily. In an "off" state, the person may become very stiff, slow and may even be unable to move at all for a few minutes.

As one patient put it in a 1989 edition of the Journal of Neurology, Neurosurgery and Psychiatry:

"'On' is quite simply normal; I can survive a dinner party, drive a car, write a fair, round hand, my voice is normal. I can fall asleep rather easily unless I am trying not to. 'Off' on the other hand is very unpleasant. I lose almost all motor power in my legs; and this paralysis increasingly now spreads to my arms. Sometimes odd pains and cramps move round the body. There is no position in which I am comfortable. I can't write, I can't type, my speech is slurred and low-powered."

Coping with the On-Off Phenomenon

In some persons with Parkinson's disease, the "on-off" fluctuations are somewhat predictable. They know that the effects of levodopa will wear off after about three hours, so they can plan accordingly.

For other people, unfortunately, the "on-off" fluctuations are unpredictable, and this of course is the more dangerous state. No one knows why fluctuations are unpredictable in some cases.

There are a few options available once you start experiencing the on-off phenomenon.

Motor fluctuations seem to respond to controlled-release forms of levodopa in some cases, but that version of the drug doesn't work well for everyone, and may cause other symptoms to get worse.

Your doctor can consider replacing levodopa or adding medications to your prescription drug regimen. Dopamine agonists can reduce the length of time you spend "off," but they come with a risk of some serious side effects. A drug called a MAO-B inhibitor also may help (albeit with side effects). COMT inhibitors can enhance the effect of levodopa, but may increase side effects from it.

There are two other options for advanced Parkinson's disease where the on-off phenomenon has taken hold: a continuous infusion of levodopa, and an injectable drug called Apokyn (generic name: apomorphine hydrochloride injection). Both can be effective, but both come with numerous cautions and side effects. Your best bet is to discuss all your options with your doctor.


Factor SA. Treating the "off" periods in Parkinson's. Parkinson's Disease Foundation newsletter, fall 2003.

Fasano A et al. Intrajejunal levodopa infusion in advanced Parkinson's disease: long-term effects on motor and non-motor symptoms and impact on patient's and caregiver's quality of life. European Review for Medical and Pharmacological Sciences. 2012 Jan;16(1):79-89.

Lees AJ. The on-off phenomenon. Journal of Neurology, Neurosurgery and Psychiatry. Special supplement 1989:29-37.

Martinez-Martin P et al. EuroInf: a multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson's disease. Movement Disorders. 2015 Apr;30(4):510-6.

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