Focusing on Reward a Solution to MS-Related Fatigue?

NASHVILLE, Tennessee — Interventions that stimulate the reward system may be the most effective treatment for fatigue directly related to multiple sclerosis (MS), experts said.

Here at a symposium dedicated to the topic of MS-related fatigue, held on May 29, 2024, at the Consortium of Multiple Sclerosis Centers 2024 Annual Meeting, three clinicians offered their perspectives on how to manage this common complaint.

All of the experts emphasized they were addressing MS-related fatigue that is not directly linked to depression, insufficient sleep, exertion-induced energy loss, or any other condition presented as fatigue but has a treatable etiology that is independent of MS. 

“I do not ask patients if they have fatigue,” said John DeLuca, PhD, codirector of the Center for Multiple Sclerosis Research, Kessler Foundation, East Hanover, New Jersey. As a complaint, fatigue is generally difficult to define in objective terms, and it means different things for different patients, added DeLuca, who noted the cause of the disorder must be determined before it can be effectively treated. 

A Treatable Symptom

When patients present with fatigue, said DeLuca, they should be asked a series of questions about sleep, mood, and the types of limitations that they attribute to fatigue. The first goal, he said, is to identify treatable causes, such as sleep apnea, physical complaints, or neurasthenia.

While there appears to be a type of fatigue caused by MS or, at least, fatigue not related to any other source, it is best addressed as a process-of-elimination diagnosis, he said. 

Despite multiple instruments to measure fatigue, DeLuca said it remains difficult to reliably characterize it as a stand-alone clinical issue.

In MS, as in life in general, many individuals face “high-effort, low-reward” tasks with the sensation of fatigue, Deluca said. Tasks that they should do, such as exercise, are met with a sense of fatigue that conceals, even from themselves, the underlying problem that the task does not seem worth the effort.

In trying to help patients focus on what they mean by fatigue, DeLuca tries to elicit what fatigue means to them.

Driver of Behavior Change

“The question I ask is what are you not doing now that you would like to do,” he said. The goal is to prompt patients to think about what causes them to complain of fatigue and what “reward” might help them resist it.

The concept of reward is critical, said DeLuca. Two other expert panelists, Frederick W. Foley, PhD, Director of Neuropsychology and Psychosocial Research, Holy Name Medical Center, Teaneck, New Jersey, and Anthony Feinstein, MD, PhD, professor of psychiatry at the University of Toronto, Toronto, Ontario, Canada, agreed.

The current standard of care for MS-related fatigue is cognitive behavior therapy (CBT). CBT has several potential and perhaps related mechanisms of benefit, but behavior change is dependent on the patient’s ability to relate to its benefits.

“The concept of reward is critical throughout CBT,” said Foley, a psychologist who routinely offers this therapeutic approach to manage fatigue in MS. Foley noted that CBT is associated with “one of the strongest sets of evidence” for benefit of any type of intervention, including drugs.

One of the goals of CBT is simply to get patients engaged in self-care by helping them recognize and overcome the obstacles in the way of the rewards of yielded by accomplishment. 

Citing exercise as an example, Foley said that when physical activity occurs it spurs dopamine release which has antifatigue effects. Even if exercise offers a long list of additional benefits in MS, it is the sense of reward that can contribute to controlling the sense of fatigue. Reward gives patients more coping confidence, said Foley, indicating this is self-reinforcing. 

However, he noted, not all patients experience a sense of reward from exercise. For those who don’t respond to exercise, Foley said he looks for other ways individual patients can attain a sense of reward to help them overcome fatigue. 

Feinstein also endorsed the concept of stimulating the reward system as a way of battling MS-related fatigue using CBT. He said there is no strong evidence to support off-label use of medications including amantadine, modafinil, and methylphenidate, to treat MS-related fatigue.

In particular, he cited the randomized controlled TRIUMPHANT-MS, which showed no difference between amantadine, modafinil, and placebo in treating fatigue in this patient population.

However, he said, he still offers pharmacologic treatment to select patients, noting that there is evidence of a clinically meaningful placebo effect related to the stimulation of the dopamine-based reward system.

DeLuca reported financial relationships with Biogen, Bristol Myers Squibb, EMD Serono, Genentech, and MedRhythms. Foley reported no potential conflicts of interest. Feinstein reported financial relationships with Merck and Novartis.