On-Off Phenomenon: When Levodopa Stops Working as Well

Levodopa is the "gold standard" medication for Parkinson's disease, which means it's the most beneficial and primary drug. It works by being converted into dopamine, which helps a person move and control their muscles. 

Unfortunately, as Parkinson's progresses levodopa doesn't work as well in eliminating or controlling symptoms for a significant amount of people. This is because levodopa wears off more quickly over time, triggering a medication "on-off" phenomenon."

How the Parkinson's On-Off Phenomenon Feels

Ideally, when a medication like levodopa is taken on a regular schedule, few changes in symptoms should be noticeable between doses. In other words, symptoms should remain relatively constant over time, regardless of when the medication was last taken.

However, when the "on-off" phenomenon starts in Parkinson's disease, a person may feel better ("on") soon after a new dose of the medication starts to take effect, and worse ("off") before another dose is scheduled. Eventually, the duration of “on” states becomes shorter and the wearing “off” happens sooner (too soon for another dose of levodopa).

In an "on" state, a person taking levodopa may feel energetic and able to move around more easily. However, in an "off" state the person may become very stiff and slow, and may even be unable to move at all for brief periods (a few minutes). Some may also have difficulty speaking and noticeably slur their words. As can be imagined, the "off" state can cause a frustrating decrease in function, in addition to anxiety, and acute dysphoria.

Managing the On-Off Phenomenon in Parkinson's

In some people taking levodopa, the "on-off" fluctuations are somewhat predictable; they know that the effects will wear off after about three hours, so can plan accordingly. For others, the "on-off" fluctuations are unpredictable. It is unknown why fluctuations are unpredictable in some cases.

There are options to try once the "on-off" phenomenon has begun:

• Motor fluctuations seem to respond to controlled-release forms of levodopa (called Sinemet CR) in some people. However, controlled-release levodopa does not work well for everyone and may cause other symptoms to get worse.
• A healthcare provider may shorten the interval between levodopa doses by about 30 to 60 minutes (especially in advanced Parkinson's) or increase the dosage as scheduled.
• Adding a dopamine agonist to levodopa can reduce the length of time people spend "off." This strategy also comes with a risk of serious side effects, like visual hallucinations and compulsive behaviors.
• Adding a COMT inhibitor, like Ongentys (opicapone) or Comtan (entacapone) can prolong and enhance the effect of levodopa but may also increase Parkinson's side effects such as dyskinesia (abnormal, involuntary muscle movements).
• When added to levodopa, MAO-B inhibitors may be beneficial (albeit with side effects). MAO-B inhibitors work by blocking the enzyme that normally inactivates dopamine in the brain.
• Amantadine has recently been found to improve dyskinesia, which can start after extended levodopa treatment.
• Inbrija (inhaled levodopa) is a quick, on-demand option to treat “off” times that occur between regularly scheduled doses of medication.
• For people with advanced Parkinson's disease, an intestinal gel infusion of levodopa may be tried and, during severe "off" episodes, an injectable drug called Apokyn (apomorphine hydrochloride injection) may be useful.
• Deep brain stimulation (DBS) is an alternative surgical therapy in which electrodes are inserted into the brain. It can only be tried when Parkinson's symptoms are not adequately controlled with medications.

A Word From Verywell

The "on-off" phenomenon is an unfortunate problem in the treatment of Parkinson's disease. While some people may notice it early on after starting levodopa, most notice it within three to five years.

Because there are a variety of ways to combat this phenomenon, it's important to discuss options with a healthcare provider. Individual needs may be better suited to one strategy or medication versus another. What works well for one person may not be as effective for someone else.