Wearing-Off
Early diagnosis and optimized treatment are key to managing wearing-off symptoms effectively

Quick links How common is wearing-off? What are the symptoms of wearing off? What is the effect of wearing-off? What can help with wearing-off? Wearing-off question Card Effective treatment of wearing-off Coping strategies Further information

 

What causes wearing-off?

‘Wearing-off‘ occurs as the duration of effect of one of the most commonly used drugs to treat PD – levodopa – diminishes over time as the disease progresses.

People with Parkinson's disease have reduced levels of dopamine – a chemical messenger in the brain that is involved in coordinating nerve and muscle cells to control movement and activities such as walking and talking. When dopamine drops beyond a certain level, symptoms of Parkinson's emerge, including tremor, muscle rigidity and problems with movement (especially slowness) known as motor symptoms and also some non-motor symptoms like anxiety.

The treatment of Parkinson's is based on topping up dopamine levels with levodopa – which is converted into dopamine in the brain. Levodopa is a short-acting drug, which means that each dose only provides additional dopamine for a few hours. During the first few years of treatment, because the brain still provides relatively high levels of dopamine, little additional dopamine is needed to keep symptoms at bay and most people have sustained improvement in symptoms with three doses of levodopa each day.

Unfortunately, as Parkinson's progresses the number of nerve cells producing and storing dopamine in the brain falls. With less brain dopamine available, a dose of levodopa that initially removed symptoms for four hours may not provide enough dopamine to maintain full control of symptoms until the next dose¹. The benefit of levodopa literally ‘wears off’ before it is time for the next dose. The effect of each dose of levodopa lasts for progressively shorter periods of time, and symptoms of Parkinson's reappear. These symptoms then typically improve 15-45 minutes after taking your next dose of Parkinson's medication.

Many people call the time when their drugs are controlling their Parkinson's symptoms their ‘on time’ and the time when they are suffering from wearing-off their ‘off time.’

For people who prefer to think in pictures, here is a diagram explaining what happens to levodopa levels in the body over a day:

Click on image to enlarge

How common is wearing-off?

It is thought that around one-third to one-half of people develop ‘wearing-off‘ after approximately five years of levodopa therapy. But recent research studies have revealed that it can happen earlier – with one out of three patients developing ‘wearing-off‘ within one to two years of starting to take levodopa.²

What are the symptoms of wearing-off?

The way in which wearing-off affects people is very variable.

“In a research study, we found the most common wearing-off symptom was tremor, followed by slowness,” explained Professor Robert Hauser, who is Professor of Neurology, Pharmacology and Experimental Therapeutics at the University of South Florida, Tampa, USA. “The commonest non-motor symptom of wearing-off was anxiety.”

The initial manifestation of wearing-off may be quite subtle. “Many people find they just don’t feel as well as they did when they first start to suffer from wearing-off,” added Professor Fabrizio Stocchi, Professor of Neurology, Institute of Neurology IRCCS, Meuromed, Rome, Italy.

Many people find their motor (movement) symptoms return during wearing-off. The key to identifying wearing-off is to note whether the symptoms tend to occur or worsen 2 or more hours after the last dose of levodopa medication, and improve after the next levodopa dose takes effect.

Some of the possible symptoms that you may experience with wearing-off are listed below.

Motor symptoms

• tremor - shakiness or trembling in the hands, arms, legs, jaw and face. Some people also report an internal tremor, where they feel a trembling inside even though this may not be visible
• rigidity - stiffness in the muscles causing movements to become more uncomfortable and potentially painful
• slowness of movement or 'bradykinesia' - where movements become slow and hesitant and it takes more time to perform daily activities or you find you are temporarily unable to perform these activities at all

But wearing-off symptoms can be much more subtle problems not associated with movement (non-motor symptoms).

Non-motor symptoms

• Symptoms that affect thoughts, feelings and sense of well-being:
  • anxiety, depression or irritability
  • slowness of thinking or memory problems
  • restlessness
• Symptoms that affect sensations may include:
  • tingling
  • pain
  • restlessness
  • fatigue
• Symptoms that result in changes to your 'autonomic nervous system'*
  • sweating
  • hypersalivation (when your mouth produces too much saliva)
  • changing body temperature
  • constipation

* The autonomic nervous system is an involuntary system in the body that regulates the control of certain muscle groups and organ function, such as blood pressure control, bowel and bladder function and salivation. Often you will be unaware of autonomic responses, as these occur as reflex actions.

What is the effect of wearing-off?

Research has shown that many people find the loss of energy during their ‘off time’ particularly disabling. It can be difficult to go about their normal activities – including walking or working – when they are experiencing wearing-off.

What can help with wearing-off?

Identifying Wearing-Off Early

If you think you are starting to have wearing-off, you should see your Parkinson's doctor to discuss the problem. Letting your doctor know about your wearing-off early can have several benefits. Your treatment can be optimized to reduce your symptoms. Wearing-off can be an early warning sign of another problem with long-term levodopa therapy – unwanted, uncontrolled movements (called dyskinesias). "It is possible that wearing off leads to the development of dyskinesia. If that is the case, treating wearing off early could reduce the risk of dyskinesias, although this remains to be proven,” explained Professor Hauser.

Don’t wait for your doctor to ask about wearing-off – tell him or her how long your treatment is lasting for, and what happens when it wears off. Doctors treating Parkinson's tend to focus on motor symptoms so they may not ask you about non-motor symptoms, such as anxiety or fatigue, which can occur in wearing-off.

It will help your doctor to understand what is going on if you give as much information as possible. One way to do this is to keep a diary for a few days, noting what time you take your levodopa or other Parkinson's medication, what time you start to suffer from wearing-off symptoms, and what these symptoms are.

An easy way to identify wearing-off yourself is by using the wearing-off question card. If you can answer one or more of the 19 questions with “I experience symptom” and “symptom improves after my next medication dose”, you may want to talk to your doctor about your wearing-off at next visit.

Wearing-off question card

 

The wearing-off question card has been developed together with Parkinson’s disease specialists, patients and the European Parkinson’s Disease Association. The wearing-off question card can be downloaded here from the Parkinson's Decision Aid website (www.parkinsonsDecisionAid.eu.com), or ask your doctor or local patient association about the card.

Effective treatment of wearing-off

“Wearing-off can be treated very successfully,” according to Professor Stocchi. There are several ways to increase the ‘on time’ with levodopa. The principle approach is to improve and smoothen out the delivery of dopamine to the brain and provide more continuous dopaminergic stimulation. There are different treatment strategies your doctor may propose to you:

• He may recommend adding another drug on to levodopa which could be either a COMT inhibitor such as entacapone (either on its own or in a combination tablet), a dopamine agonist or a MAOB inhibitor. COMT inhibitor and MAO inhibitor can be added even if the patient experiencing wearing off is already taking levodopa plus a dopamine agonist.
• Alternatively, you may be given a controlled release levodopa, that releases the drug slowly over time but the response can be less predictable than with other levodopa formulations.
• A further approach could be to change the timing of when you take your medication, increase the dose of levodopa or to take it more often. This strategy is very common but is not very successful in the long run.

Coping strategies

There are also things you can do to help yourself with wearing-off, in addition to seeing your doctor and optimizing your drug treatment.

Keeping healthy can help you feel better generally. Regular exercise (such as walking or swimming), eating a healthy diet and getting enough rest is beneficial.

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1. Poewe, W., Wenning, G. Levodopa in Parkinson’s disease: mechanisms of action and pathophysiology of late failure. In: Jankovic, Tolosa eds, Parkinson’s disease and movement disorders. Vol. 8. 4th ed. 2002; 104-115.
2. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson’s disease. JAMA 2000; 284: 1931-1938; Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol 1997; 42: 747-755.

 

Further information

• Wearing-off Questionnaire Card - This questionnaire card has been developed to help you identify the symptoms that improve after taking your medication, but often reappears before your next dose.
• Wearing-off Presentation - Presentation by Annette Bowron into improving the recognition of wearing-off in Parkinson's.
• Wearing-off Video - Led by Mary Baker (past-president of the EPDA), the session is a discussion and interview between Professor Fabrizio Stocchi, neurologist, Irma King with husband Paul King who has Parkinson's Disease and Annette Bowron, Parkinson's disease nurse specialist, on the phenomenon of wearing-off.