Aspirin as a Pre-Treatment for Exercise in Multiple Sclerosis
Condition: Fatigue; Overheating
MeSH terms: Multiple Sclerosis
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Exercise has many benefits for people with multiple sclerosis (MS), such as improved physical
      symptoms, mood, fatigue, and cognition. However, many people with MS refrain from exercising
      because of the discomfort of exhaustion and overheating that they experience. This study
      investigates the use of aspirin before exercise as a treatment to reduce overheating and
      exhaustion, thereby availing many more people with MS the opportunity to benefit from
      exercise.

      The investigators recently published the first-ever report of elevated body temperature in
      relapsing-remitting MS (RRMS) patients relative to healthy controls, and elevated temperature
      was linked to worse fatigue. This finding that body temperature is elevated and linked to
      fatigue in RRMS lays the groundwork for a paradigm shift in our understanding and treatment
      of fatigue. That is, the focus shifts from exogenous to endogenous temperature, and from
      stimulant medication to cooling treatments.

      A recent study comparing healthy adults to adults with MS showed that whereas exercise
      increased body temperature in both groups, only in the MS group was it correlated with
      exhaustion. The reason for this may relate to the elevation in resting body temperature in
      relapsing-remitting MS (RRMS) patients relative to healthy controls. The finding is
      clinically meaningful, as elevated body temperature was correlated with worse fatigue in
      patients. Exercise Aim: To determine whether pretreatment with ASA (compared to placebo:
      within subject crossover design) before exercise results in improved exercise performance
      (i.e., increased time-to-exhaustion). The investigators hypothesize that participants will
      tolerate exercise for longer after taking ASA than placebo. This hypothesis is based on a)
      demonstrated efficacy of antipyretic for reducing body temperature during exercise in healthy
      controls, b) demonstrated efficacy of antipyretic for reducing fatigue in non-exercising MS
      patients, and c) demonstrated efficacy of elaborate (unblinded) cooling treatments (e.g.,
      cooling garments, cooling hand chamber) for improving exercise performance in MS patients.
      Note that this project is especially important for MS patients, who have a disease-specific
      body temperature elevation and sensitivity to heat (i.e., Uhthoff's).
    

Detailed description: 
      Exercise is beneficial for people with MS. Exercise has many benefits for persons with
      multiple sclerosis (MS), including increased muscle strength, improved balance, decreased
      fatigue, decreased depression, improved memory, and improved quality of life. In addition to
      clinical improvements, there is direct and indirect neural evidence for beneficial effects of
      exercise in MS. For example, work in the experimental autoimmune encephalopathy (EAE) animal
      model of MS has shown that exercise protects against demyelination, increases brain-derived
      neurotrophic factor (BDNF), and reduces myelin damage and axonal damage. Consistent with
      pre-clinical research, MS work in humans has shown increased BDNF and reduction in
      pro-inflammatory circulating cytokines (i.e., IL-22) in those who exercised for 24 weeks
      versus those who maintained a sedentary lifestyle over the same period of time. In
      preliminary MS work from our group, 12 weeks of aerobic exercise resulted in increased
      hippocampal volume and hippocampal functional connectivity. Exercise is being considered as a
      candidate disease-modifying treatment. However, exercise is only beneficial if people do it.
      Despite the preponderance of evidence for exercise's salutary effects, many MS patients are
      deterred by overheating and exhaustion brought about by exercise. And while there is good
      evidence for the long-term safety profile of exercise in MS, many patients are put off by
      short-term discomforts, despite being physically capable of exercising.

      Exercise causes overheating in people with MS. In healthy people, exercise triggers the
      conversion of metabolic to mechanical energy, resulting in the liberation of approximately
      30-70% of the total energy as heat, which causes an increase in core body temperature. As
      core body temperature increases, exercise performance worsens. Exercise in persons with MS
      also raises body temperature, and heat-related MS symptoms increase following exercise. This
      is consistent with Uhthoff's phenomenon: the well-known deleterious impact of heat exposure
      and exercise for persons with MS. The investigators recently added an essential piece to this
      puzzle, reporting for the very first time that persons with relapsing-remitting MS (RRMS)
      have elevated body temperature even before being exposed to heat or exercising (i.e., at
      rest) relative to healthy controls. Importantly, this elevation in body temperature is
      clinically meaningful as warmer resting body temperature is linked to worse fatigue in
      patients with RRMS.Not only does this finding represent a paradigm shift in the
      conceptualization of heat sensitivity / heat exposure in persons with MS, but it highlights
      the additional burden of exercise-induced heat for people who are already warmer before
      exercise begins. Exercise increases body temperature in everyone; however, it was recently
      reported that only for persons with MS (compared to healthy controls) is exercise-induced
      increase in body temperature linked to exhaustion. Elevated body temperature at rest in
      persons with RRMS may be a key reason for this, and may also point to cooling as an effective
      treatment.

      Cooling treatments are effective for people with MS. Elevated body temperature and its link
      to worse fatigue in RRMS patients aligns with positive results of several non-exercise trials
      of cooling treatments for reducing fatigue in MS patients none of which considered or
      targeted endogenously elevated body temperature. Aligned with this is evidence showing that
      cooling treatments administered to MS patients prior to or during exercise improve
      performance and reduce exhaustion. For example, in one study, ten MS patients used a
      hand-cooling chamber while walking on a treadmill: subjects kept one hand in the airtight
      device, a rigid chamber suspended by a bungee cord from above the treadmill throughout
      exercise. Cooling resulted in 33% increased exercise duration in the MS patients who kept
      their hand in the chamber. These findings support a beneficial impact of cooling during
      exercise, although these methods may be difficult to replicate / standardize, and implement
      clinically. In other work, whole-body precooling with a cooling vest and cap was used to
      successfully decrease perceived exertion during exercise. Yet another method of cooling via
      immersion in a cold water bath prior to exercise was found to reduce perceived exertion
      during exercise. By way of mechanism, Marino explained the heat-fatigue link in MS by
      proposing heat reaction blockade of action potentials in demyelinated neurons (i.e.,
      frequency-dependent conduction block), noting that when demyelination is present, only a
      small increase in temperature (e.g., the amount induced by exercise) is necessary to
      completely block action potentials. This is consistent with seminal work in the giant squid
      axon demonstrating the disruption of action potentials in the presence of small, incremental
      increases in exogenous heat, ultimately resulting in reversible 'heat block' (cessation of
      neuronal conduction). An encouraging observation was that all effects of warming were
      completely reversible in this experimental model.

      Cooling during exercise is an effective treatment for persons with RRMS. Taken together, the
      evidence supports cooling treatments as an effective means of improving exercise performance
      in patients with MS, although notably, no prior exercise study in MS has considered elevated
      core resting body temperature. Note that the finding of elevated body temperature was
      specific to RRMS; prior exercise cooling studies did not restrict their selection criteria to
      the relapsing-remitting phenotype. By doing so in the current proposal, the investigators
      expect to reveal a larger effect of cooling since relapsing-remitting MS patients with
      elevated body temperature at rest are most likely to experience exercise-induced fatigue (and
      are therefore most in need of effective cooling treatment). Prior methods of experimental
      cooling are cumbersome (e.g., cooling garments, immersion in a cool bath prior to exercise,
      insertion of one hand into a vacuum cooling chamber during exercise), thereby limiting
      replication and standardization for research use, and restricting practicality for clinical
      use. Here, the investigators propose to test the effectiveness of an oral antipyretic taken
      before exercise (i.e., administered 1-hour prior to exercise in order to reach peak serum
      concentration). Work in healthy adults has shown that antipyretic administration before
      exercise reduces body temperature during strenuous exercise in a hot environment, and
      improves performance (i.e., increases time-to-exhaustion). Aspirin (acetylsalicylic acid,
      ASA) has been selected, as it is shown to effectively reduce fatigue in prior non-exercise
      trials in MS (none of which considered aspirin's antipyretic mechanism of action as the key
      factor underlying treatment efficacy).
    

Intervention name(s): Acetylsalicylic acid at 1st visit, then Placebo at 2nd visit; Placebo at 1st visit, then Acetylsalicylic acid at 2nd visit
Intervention type(s): Drug; Drug
Intervention description(s): 650 mg dose of acetylsalicylic acid is administered in a capsule one hour prior to exercise; Placebo oral capsule is administered one hour prior to exercise; Placebo oral capsule is administered one hour prior to exercise; 650 mg dose of acetylsalicylic acid is administered in a capsule one hour prior to exercise
Other intervention name(s): aspirin; placebo; placebo; aspirin
Intervention MeSH terms: Aspirin
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Design is a within-subject crossover placebo-controlled experiment. Each participant will be seen for two exercise sessions (stationary cycling) on two days separated by one week, and will receive either ASA or placebo (treatment) at each session prior to commencing exercise. Order of treatment will be randomized and counter-balanced. As such, each participant will serve as his/her own control.
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Exercise; Time to Exhaustion