2016 acsm eamc - murray

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ETIOLOGY AND TREATMENT OF EXERCISE-ASSOCIATED MUSCLE CRAMPS: EMERGING RESEARCH

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▪ Bob Murray, PhD, FACSM - Challenges of EAMC Research▪ Kevin Miller, PhD, AT, ATC - EAMCs: Characteristics & Cures▪ Bruce Bean, PhD - Activating Sensory Neurons to Affect Muscle Cramps▪ Tom Wessel, MD, PhD - Neurology of Muscle Cramps

SYMPOSIUM AGENDA

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• Bob Murray - consultant• Kevin Miller - research funding, 2014• Bruce Bean - company co-founder • Tom Wessel - chief medical officer

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▪ 40-yr-old male cyclist,racing since age 15

▪ Leg cramps began in 2009▪ Progressively more frequent▪ Occur at high power outputs▪ No impact of bike position,

time of year, weather▪ Has tried variations

of hydration, sports drinks, electrolytes, pickle juice, beet juice, training adjustments, nifedipine, albuterol, nitroglycerin [during angiogram]

CASE STUDY: EAMCs IN AN EXPERIENCED CYCLIST

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DIFFERENTIATING MUSCLE CRAMPS

Katzberg HD. Neurogenic muscle cramps. J Neurol 262:1814-1821, 2015.

• Neurogenic muscle cramps - EAMCs, nocturnal • Myopathic muscle cramps - electrically silent• Myotonia - delayed relaxation• Myokymia - irregular twitching/rippling• Neuromyotonia - stiffness and twitching • Hypertonia - stiffness with upper motor neuron signs• Dystonia - co-contractions of agonists and antagonists• Stiff limb syndrome - painful muscle spasms

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DIFFERENTIATING MUSCLE CRAMPS

Katzberg HD. Neurogenic muscle cramps. J Neurol 262:1814-1821, 2015.

• Neurogenic muscle cramps - EAMCs, nocturnal • Myopathic muscle cramps - electrically silent• Myotonia - delayed relaxation• Myokymia - irregular twitching/rippling• Neuromyotonia - stiffness and twitching • Hypertonia - stiffness with upper motor neuron signs• Dystonia - co-contractions of agonists and antagonists• Stiff limb syndrome - painful muscle spasms

✓

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WHAT IS A MUSCLE CRAMP?

Def. “… a sudden, involuntary, painful contraction of a muscle or part of it, self-extinguishing within seconds to minutes and is often accompanied by a palpable knotting of the muscle.”

▪ Fasciculations / twitches▪ One muscle or part of it▪ A muscle group▪ Whole-body

EXTENT

Minetto MA et al. (2013) Origin and development of muscle cramps. Exerc Sports Sci Rev 41(1):3-10.

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CRAMP INCIDENCE

• 68% of triathletes (lifetime)• 30-50% of marathon runners (lifetime)• 95% of PE students (lifetime)• 50% of endurance athletes report nocturnal leg

cramps at least 1/wk; 50% of those athletes suffer them nightly

• 50% of those over age 65 report nocturnal cramps at least 1/wk

• 44-80% in neuro- and myopathic disorders• 55-75% in diabetics

Katzberg HD. Neurogenic muscle cramps. J Neurol 262:1814-1821, 2015.Minetto MA et al. Origin and development of muscle cramps. Exerc Sports Sci Rev 41(1):3-10, 2013.Norris FH et al. An electromyographic study of induced and spontaneous muscle cramps. Electroencephalogr Clin Neurophysiol 9(1):139-147, 1957. Schwellnus MP et al. Muscle cramping in athletes - risk factors, clinical assessment, and management. Clin Sports Med 27(1):183-194, 2008.

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▪ Occurs in active muscles▪ Premonitory twitching (fasciculations)▪ Triggers seem many and varied▪ Happen in some athletes,

not in others▪ Range widely in severity, duration,

and location▪ Some “cures” seem to work for some

people some of the time▪ Neurogenic origin

WHAT DO WE KNOW ABOUT EAMCs?

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3 THEORIES OF EAMC ETIOLOGY

produce volume/ECF changes that alter sensitivity of the motor nerve and/or NMJ.reduce inhibition from GTOs and increase activation of muscle spindles. increase persistent inward currents (PICs) that eventually exceed the excitation threshold of motor nerves, resulting in fasciculations or full-blown cramps.

Fatigue, hyperthermia, dehydration, and/or other factors ...

Katzberg HD. (2015) Neurogenic muscle cramps. J Neurol 262:1814-1821.Miller KC. (2015). Rethinking the cause of exercise-associated muscle cramping: moving beyond dehydration and electrolyte loss. Curr Sports Med Rep 14(5):353-354. Minetto MA et al. (2013) Origin and development of muscle cramps. Exerc Sports Sci Rev 41(1):3-10.

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A CRAMP IS A FAILURE OF NORMAL NEUROMUSCULAR FUNCTION

WHAT TRIGGERSEAMCs?

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PREDISPOSITION TO EAMCs

Hyper-excited alpha motor

neurons

Exercise- fatigue (central, peripheral)- intensity (competition)- duration- muscle length- environment (Ta, RH)- hydration status- sweat loss- mineral loss- muscle ischemia

Disease- exertional sickling- diabetes- parathyroid dysfunction

Nutrition- low muscle glycogen- chronic dehydration- mineral deficiencies

Individual- cramp Hx- recent muscle injury/damage- fitness- medications (e.g., statins)- agonist imbalances

8 CHALLENGES WITH EAMC RESEARCH

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1. No animal model for cramping2. Difficult to study spontaneous cramping3. Tough to isolate central mechanisms4. Challenging to study motor nerves5. Strong placebo effect6. Difficult to find suitable placebos7. Influence of ingrained misconceptions8. Research approaches crude, but useful

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8 CHALLENGES WITH EAMC RESEARCH

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• Electrically induced muscle cramps

• Isometrically induced muscle cramps

• Field/survey studies

• Observation and anecdotes

EAMC RESEARCHOPTIONS

… in some people, some of the time …

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• stretching • staying hydrated• staying salted• staying cool• i.v. saline• potassium• magnesium • calcium• pickle juice• mustard• kimchi• apple cider vinegar• quinine• massage• pinch upper lip• muscle cooling• electrical stimulation (skin, muscle, tendon)• orthotics• analgesic pads• bar of soap under bedsheets• medications (e.g., sedative, anti-seizure,

Na/Ca channel blockers)

WHAT STOPS EAMCs?

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EAMCs: CHARACTERISTICS & CURES

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ACTIVATING SENSORY NEURONSTO INHIBIT MUSCLE CRAMPING

Dr. Bruce Bean is Professor of Neurobiology at Harvard Medical School, where he oversees a research lab studying the physiological function and pharmacology of sodium, calcium and potassium ion channels. He has previously held faculty positions at the University of Iowa and Oregon Health Sciences University.

Dr. Bean’s particular research interest is in mechanisms underlying hyperexcitability of neurons, a phenomenon implicated in a number of diseases, including epilepsy, chronic pain, and amyotrophic lateral sclerosis.

Dr. Bean has served on the Advisory Council for the National Institute of Neurological Diseases and Stroke and on the Scientific Review Board for the Howard Hughes Medical Institute and is a member of the National Academy of Sciences and the American Academy of Arts and Sciences.

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Bruce P. Bean, PhD

Department of Neurobiology

Harvard Medical School

Activating Sensory Neurons to Inhibit Muscle Cramping

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Overview

• Most muscle cramping is NOT caused by dehydration, lactic acid build-up, or electrolyte imbalance.

• Cramping likely originates from hyperexcitability of the alpha motor-neurons innervating the muscle.

• Excitability of motor neurons is regulated by complex mechanisms, including feedback from muscles, local spinal cord circuits, and modulatory inputs from the brain (serotonin, norepinephrine, and dopamine and other transmitters).

• Cramping can be inhibited by chemical neurostimulation of sensory neurons in the mouth, using agents derived from natural products (TRP channel stimulation), through a pathway that reduces hyperexcitability of motor neurons.

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Muscle cramping is poorly understood

Rod MacKinnon, MD Rockefeller University 2003 Nobel Prize in Chemistry

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Cramping is not caused by dehydration or electrolyte imbalance

Increased running speed and previous cramps rather than dehydration or serum sodium changes predict exercise-associated muscle cramping: a prospective cohort study in 210 Ironman triathletes

MP Schwellnus, N Drew, M Collins, Br J Sports Med 2011;45:650–656.

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Cramping is not caused by dehydration or electrolyte imbalance

Significant and serious dehydration does not affect skeletal muscle cramp threshold frequency

Euhydrated Dehydrated (4.7±0.5% of body mass) by exercise

Cramp threshold frequency

15±5 Hz 13±6 Hz (=0.12)

Cramp Intensity 94.2±41% 115.9±73% (p=0.2)

Cramp Amplitude 0.18±0.06 mV 0.18±0.09 mV

[Na+] plasma 141.9±3.1 mM 149.5±1.8 mM

[K+] plasma 4.9±0.4 5.0±0.4

Braulick KW, Miller KC, Albrecht JM, et al. Br J Sports Med 2013;47:710–714.

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Experimental models of muscle spasms: persistent firing of motor neurons

Muscle spasms in a rat model of spinal cord injury reflect long-lasting firing of motoneurons.

K.C. Murray, M.J. Stephens, E.M. Ballou, C.J. Heckman, D.J. Bennett J. Neurophysiol. 105: 731-748, 2010.

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Experimental models of muscle spasms: persistent firing of motor neurons

Self-sustained long-lasting firing produced by Ia synaptic input in the motoneuron of a cat.

K.C. Murray, M.J. Stephens, E.M. Ballou, C.J. Heckman, D.J. Bennett J. Neurophysiol. 105: 731-748, 2010.

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Persistent firing originates from “bistable” behavior of motor neurons

In recordings from cat motor neurons, stimulating excitatory input to a motor neuron produces persistent firing, which can be interrupted by a brief inhibitory input.

J Hounsgaard et al., J. Physiol. 405: 345, 1988.

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Human cramps likely also reflect bistable behavior of motor neuron firing

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Muscle cramp can be reproducibly induced by brief repetitive stimulation of motor end-plates at 5-20 Hz

Flexor hallucis brevis

Stimulated with 180 microsecond biphasic square pulses at 8, 10 or 12 Hz for 5 seconds.

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Electrically-induced cramping requires feedback to the spinal cord

Mechanisms of cramp contractions: peripheral or central generation? M.A. Minetto, A. Holobar, A. Botter, R. Ravenni, D. Farina J Physiol 589:5759–5773, 2011

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Drinking pickle juice decreases cramp duration and acts within 90 seconds (Miller et al., 2010)

K.C. Miller, G.W. Mack, K.L. Knight, J. Ty Hopkins, D.O. Draper, P.J. Fields, and I. Hunter, Med Sci Sports Exerc. 42:953-961, 2010.

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• Hypothesis: Drinking pickle juice acts by stimulating sensory nerve endings in the mouth, esophagus or stomach via activation of TRPV1 and/or TRPA1 channels.

• Much more potent and efficacious TRPV1 and TRPA1 activators are available in many natural products, including capsicum (TRPV1), mustard (TRPA1), wasabi (TRPA1), garlic (TRPA1), cinnamaldehyde (TRPA1), and many others.

How?

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Drinking a beverage containing natural TRPV1 and TRPA activators produces long-lasting inhibition of electrically-induced muscle cramping

Subject drank 50 mL of a beverage containing a combination of natural TRPV1 and TRPA1 activators.

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Drinking a beverage containing natural TRPV1 and TRPA activators produces long-lasting inhibition of electrically-induced muscle cramping

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Hypothesized mechanism of action: chemical neurostimulation via TRP channels

Activation of a trigeminal sensory neuron by TRPA1 and TRPV1 agonists.

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TRPV1 TRPA1

Brian Davis, U Pittsburgh

Hypothesized mechanism of action: chemical neurostimulation via TRP channels

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Summary

• Most muscle cramping is NOT caused by dehydration, lactic acid build-up, or electrolyte imbalance.

• Cramping likely originates from hyperexcitability of the alpha motor-neurons innervating the muscle.

• Cramping can be effectively inhibited by chemical neurostimulation of sensory neurons in the mouth using agents derived from natural products (TRP channel stimulation), through a pathway that reduces hyperexcitability of motor neurons.

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THE NEUROLOGY OF MUSCLE CRAMPS:FROM RESEARCH TO PRACTICE

Tom is the Chief Medical Officer at Flex Pharma and is a board certified neurologist with extensive drug development experience, including serving as the medical lead for three products approved in United States: RAZADYNE at Johnson & Johnson, LUNESTA at Sepracor, and AMPYRA at Acorda Therapeutics.

Prior to joining Flex Pharma, Dr. Wessel was an independent consultant to several biotechnology and large pharmaceutical companies, including Concert Pharmaceuticals, Alkermes, Sanofi and Novartis. Previously, Dr. Wessel was the Chief Medical Officer of Acorda Therapeutics from November 2008 until September 2011. Between March 2002 and October 2008, Dr. Wessel was employed in various leadership positions at Sepracor, including Senior Vice President of Clinical Research. Before joining Sepracor, Dr. Wessel worked on several CNS projects at Janssen Pharmaceuticals in Europe and the U.S. Before working in the pharmaceutical industry, Dr. Wessel held several academic and research positions.

Dr. Wessel received his M.D. from the University of Munich School of Medicine and completed his Ph.D. in experimental neurobiology at the Max-Planck-Institute for Psychiatry in Martinsried, Germany. He completed his residency in neurology at New York Hospital and Memorial Sloan-Kettering Cancer Center (Cornell University Medical Center).

Tom Wessel, MD, PhDChief Medical OfficerFlex Pharma, Inc.

2016 acsm eamc - murray

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