What Is OFF in Parkinson Disease?


Daniel E. Kremens, MD, JD: Parkinson disease, classified as a movement disorder, is a progressive disease that worsens over time. Levodopa is the gold standard medication for the treatment of Parkinson disease. However, with time its effect can become unpredictable, resulting in what we call OFF. The phenomenon of OFF greatly impacts the patient’s quality of life.

In this NeurologyLive® Peer Exchange discussion, I am joined by a panel of my colleagues, all experts in the field of Parkinson disease. Together we are going to discuss the impact of OFF on the patient, and debate the best treatment options available, as well as provide practical perspectives on how to best treat this condition.

I am Dan Kremens, the co-director of the Parkinson’s Disease and Movement Disorders Program, and associate professor of neurology in the Department of Neurology at Sidney Kimmel Medical College at Jefferson University, in Philadelphia, Pennsylvania.

Today I am joined by Dr Jill Giordano Farmer, an assistant professor and director of the Parkinson’s Disease and Movement Disorder Program at Drexel Neurosciences Institute in Philadelphia, Pennsylvania; Dr Stuart Isaacson, the director of the Parkinson’s Disease and Movement Disorder Center of Boca Raton in Boca Raton, Florida; Dr Peter LeWitt, the director of the Parkinson’s Disease and Movement Disorders Program at Henry Ford Hospital in West Bloomfield, Michigan, and professor of neurology at Wayne State University School of Medicine in Detroit, Michigan; and Dr Rajesh Pahwa, the Laverne and Joyce Rider Professor of Neurology, chief of the Parkinson’s Disease and Movement Disorder Division, and director of the Parkinson’s Foundation Center of Excellence at the University of Kansas Medical Center in Kansas City, Kansas.

Welcome. Thanks for joining us, and let’s begin.

I think the first thing we’d like to talk about is, a lot of us talk about this concept of OFF. We say it in front of our patients. We discuss it among each other. But I think there’s a lot of lack of understanding about what OFF actually means. So Peter, what do we mean when we talk about OFF in Parkinson disease?

Peter LeWitt, MD, M.Med.Sc: Well, the first thing to emphasize is it has a number of meanings. In clinical studies, it has a more precise meaning that gets drugs approved and allows us to talk about the drugs. But for the patient experience, OFF means a couple of things. It’s reemergence of Parkinson disease symptoms, primary slowness of movement, non-motor features as well. It also refers to the patient’s perception of whether medications are doing the maximum that they can. Most Parkinson disease symptoms—be it tremors, slowness of movement, difficulty with handwriting, voice not working right—all of these respond, to some extent, to medication. And when they’re not doing their peak improvement, that’s what OFF might be; or reemergence of symptoms.

Now medication is so effective, especially levodopa, that patients judge the OFF by what the medication is doing. As physicians, I think we do the same thing. We know we have a fickle drug in levodopa, one that is not well absorbed. And the consequences of that inadequate absorption, or clearance, or delays of other sorts have consequences for patients. So OFF time, in a sense, is failure of a very effective therapy that becomes more and more of a burden to a patient as the years go by, which is a difference from the way levodopa works in the first few years. This is sometimes called the honeymoon period.

Rajesh Pahwa, MD: Yes, and after decades of patients having OFF, we don’t have a standard definition of OFF. We all use our words on what OFF is. OFF is not a patient is on and a patient is off. OFF is really a time period. The bottom line is, if my patients are not adequately controlled during the day, that’s when the patient’s having OFF. And the OFF symptom could be, like Peter said, motor or non-motor symptoms. But to me, some of the people out there consider OFF only if there is a functional impairment. And to me, you don’t have to have functional impairment for a patient to have OFF.

Peter LeWitt, MD, M.Med.Sc: Stu, I think this notion of OFF as a continuum between optimal control, normalcy, no Parkinsonian features is an important concept because that abrupt change from on to off is probably a different phenomenon—the freezing of gait, maybe a non-dopaminergic symptomatology. But it’s something that the clinician has to differentiate to be effective at taking that information and translating it to a therapy, such as an on-demand therapy, a continuous therapy, maybe polypharmacy as well.

Rajesh Pahwa, MD: And the thing is, some patients feel like they’re missing something if they go to a support group or something and patients are talking about OFF. Really, they are fortunate they have not reached the point when they are having OFF periods. To me, that’s part of the education we have not quite provided to our patient. That, “Yes, you are on levodopa. You’re going to have this time period when you’ll have a good global control of symptoms, and then you will come to a time during the day when your symptoms are not under optimal control.” That’s what we need to cut back, because that’s when life can be difficult for them.

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