Aspirin as a Pre-Treatment for Exercise in Multiple Sclerosis

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).

Inclusion Criteria:

- RRMS

- self report of overheating during exercise

- low physical disability (EDSS total score 4.5 or less); fully ambulatory without aid

- exacerbation-free (and no use of corticosteroids) for 6 weeks prior

- BMI 35 or lower

Exclusion Criteria:

- uncontrolled hypertension or vascular disease of the legs

- current medications for heart or blood pressure problem

- prior history of head injury, stroke, or other neurological disease/disorder

- currently taking antipyretics or pain medication daily

- presence of major depressive disorder or other psychiatric diagnosis

- formally diagnosed sleep disorder

- pulmonary disease, heart disease or other heart problem

- diabetes mellitus or problem with blood sugar levels

- lower body weakness or reliance on supportive devices for walking (as indicated
through EDSS)

- counter indications to aspirin use: history of confirmed peptic ulcer,
gastrointestinal or sever gynecological bleeding; tarry stool or fecal occult blood;
syndrome of asthma, rhinitis or nasal polyps