What is "Wearing Off" ?

Due to their proven efficacy, levodopa therapies are prescribed eventually to most people with Parkinson’s disease (PD). However, long-term use of levodopa may give rise to certain complications where symptom control fades out causing the effect of the drug to wear off.

Figure 3. Typical pattern of wearing off during the day in someone having PD

Wearing off’, ‘fading effect’ and ’end-of-dose effect’ all describe the same inconvenient situation where levodopa no longer seems to work as effectively as it used to. In the early days of treatment with levodopa, people with PD experience a period where the Parkinson’s symptoms are well controlled for the entire day5. This is a time when people often feel contented with their treatment and is commonly referred to as the ‘honeymoon period’. However, over the years, the effect of levodopa seems to fade and symptom control may become more irregular (Figure 3). During this period of wearing off, the medicine seems to suddenly stop working, allowing Parkinson’s symptoms to re-emerge and worsen before the next dose of levodopa is due (Figure 3). Because this fading effect is usually seen towards the end of the dose period, wearing off is also referred to as the ‘end-of-dose effect’.

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The Parkinon’s symptoms that tend to return during wearing off may include both motor and non-motor symptoms such as tremor, stiffness, slowness, shuffling, muscle cramping, reduced dexterity and agility, mood changes, slowness of thinking, anxiety or even pain at the end-of-dose period.

As Parkinson's disease (PD) progresses, levodopa appears to become less effective in eliminating motor symptoms. Eventually the duration of “on” states becomes shorter and “wearing off” happens sooner than when the person takes a dose of levodopa. In an "off" state, the person becomes very stiff, slow and may even be unable to move for a few minutes. In some persons with PD, 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, 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. Motor fluctuations seem to respond to controlled-release forms of levodopa.

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One of the mainstays of treating Parkinson’s disease is levodopa. However, over time, sufferers and their caregivers may find that the drug does not work as well as it did to begin with. Slowness, tremor and other symptoms begin to reappear between doses. This effect, known as levodopa “wearing-off”, is because the brain cells that produce dopamine from levodopa do not function as they did originally. People with Parkinson’s disease can clearly recognize when the drug is working effectively – i.e. they are “on” – and when it is not – they are “off”.

Over the years, several strategies have been developed to deal with the wearing-off problem. Increasing the levodopa dose helps, but it may produce more side effects, especially involuntary movements (dyskinesias). The daily dose of levodopa can be divided into smaller amounts given more frequently, but there are practical limitations to this. Control-release levodopa preparations are available, and are helpful in some people, but their absorption into the body is not always constant, so that responses sometimes fluctuate. Addition of a dopamine agonist (bromocriptine, pergolide, ropinerole) can also help, by directly stimulating the dopamine receptors in the brain; however, these drugs are not as powerful as levodopa.

A new approach is the use of what are known as COMT inhibitors. COMT is an enzyme that breaks down levodopa in parts of the body other than the brain, so that blocking it means that more levodopa from a given dose is available to be converted to dopamine within brain. In other words, these drugs make more efficient use of levodopa by prolonging the effect of each dose.

A clinical study done in Scandinavia has been published which involves one of these drugs, entacapone. It demonstrates quite clearly the benefits achieved by a COMT inhibitor in patients with levodopa wearing-off symptoms.

Over a six-month period, more than 150 people with Parkinson disease with wearing-off symptoms – average age 62 years – were given either entacapone or a dummy matching Tablet (placebo), along with each dose of levodopa that they were taking. They had to be taking 4 to 10 daily doses of levodopa, and have an average “on” time after each dose of less than four hours. Their dose of levodopa could be adjusted during the study, as necessary.

The participants in the study visited the neurologist 6 times during the study, as well as 2 weeks after the end of the drug treatment. For 5 days before each visit they completed a daily diary in which they recorded the effect of the first morning levodopa dose, and the “on”, “off”, or “in bed” status for each half hour during the 24 hours. They also completed questionnaires and physical exams at the first and the last visit, and underwent a battery of lab tests.

The main analyses consisted of averaging the total daily “on” time and the “off” time after the first morning levodopa dose, using the diary information. Other effects were also analyzed, including participants’ assessments of the benefit from a single levodopa dose, and their overall assessment of treatment over the six months.

The average total daily “on” time increased by 70 minutes more in the patients given entacapone than in those given the dummy tablets. Similarly, the total “off” time decreased by 80 minutes more with entacapone than with placebo. Both these effects were highly significant. The participants described significantly greater overall benefits with entacapone than with placebo. Two weeks after the end of the study, the increases in the duration of levodopa effects had disappeared.

Entacapone was associated with some nausea and diarrhea in as many as 20% of those taking it, but these effects were also seen in over 7% percent of the people taking the placebo. Some worsening of the side effects of levodopa occurred, but lowering the actual levodopa dosage was able to reduce this. Otherwise, entacapone produced no side effects.

The results of this study support the underlying theory that the use of entacapone can improve life for Parkinson patients with wearing-off symptoms. There have been some reports of liver toxicity with another COMT inhibitor, tolcapone, and patients taking it should have tests of liver function every few weeks during the first year of treatment. To date, there have been no reports of liver toxicity with entacapone, which may therefore represent a more satisfactory approach to the wearing-off problem.

Orignally posted on Telemanagement - http://www.tele-management.ca/2013/08/parkinsons-disease-dealing-with-wearing-off/