ETIOLOGY AND TREATMENT OF
EXERCISE-ASSOCIATED MUSCLE CRAMPS:
EMERGING RESEARCH
1
SYMPOSIUM AGENDA
▪
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
2
• Bob Murray - consultant
• Kevin Miller - research funding, 2014
• Bruce Bean - company co-founder
• Tom Wessel - chief medical officer
3
CASE STUDY: EAMCs IN
AN EXPERIENCED CYCLIST
▪
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]
4
DIFFERENTIATING
MUSCLE CRAMPS
• 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
Katzberg HD. Neurogenic muscle cramps. J Neurol 262:1814-1821, 2015.
5
DIFFERENTIATING
MUSCLE CRAMPS
✓• 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
Katzberg HD. Neurogenic muscle cramps. J Neurol 262:1814-1821, 2015.
6
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.”
Minetto MA et al. (2013) Origin and development of muscle cramps. Exerc Sports Sci Rev 41(1):3-10.
EXTENT
▪ Fasciculations / twitches
▪ One muscle or part of it
▪ A muscle group
▪ Whole-body
7
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.
8
WHAT DO WE KNOW ABOUT EAMCs?
▪
▪
▪
▪
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
9
3 THEORIES OF
EAMC ETIOLOGY
Fatigue, hyperthermia, dehydration, and/or other factors ...
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.
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.
10
A CRAMP IS A FAILURE OF NORMAL
NEUROMUSCULAR FUNCTION
11
WHAT TRIGGERS
EAMCs?
12
PREDISPOSITION TO EAMCs
Exercise
- fatigue (central, peripheral)
- intensity (competition)
- duration
Nutrition
- muscle length
- low muscle glycogen
- environment (Ta, RH)
- chronic dehydration
- hydration status
- mineral deficiencies
- sweat loss
Disease
- mineral loss
- exertional sickling
- muscle ischemia
- diabetes
Individual
- parathyroid dysfunction
- cramp Hx
- recent muscle injury/damage
- fitness
- medications (e.g., statins)
- agonist imbalances
13
Hyper-excited
alpha motor
neurons
8 CHALLENGES WITH
EAMC RESEARCH
14
8 CHALLENGES WITH
EAMC RESEARCH
1. No animal model for cramping
2. Difficult to study spontaneous cramping
3. Tough to isolate central mechanisms
4. Challenging to study motor nerves
5. Strong placebo effect
6. Difficult to find suitable placebos
7. Influence of ingrained misconceptions
8. Research approaches crude, but useful
15
EAMC RESEARCH
OPTIONS
• Electrically induced muscle cramps
• Isometrically induced muscle cramps
• Field/survey studies
• Observation and anecdotes
16
WHAT STOPS
EAMCs?
… in some people, some of the time …
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
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)
17
EAMCs: CHARACTERISTICS
& CURES
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
ACTIVATING SENSORY NEURONS
TO 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.
49
Activating Sensory Neurons
to Inhibit Muscle Cramping
Bruce P. Bean, PhD
Department of Neurobiology
Harvard Medical School
50
Overview
• Most muscle cramping is NOT caused by dehydration, lactic acid
build-up, or electrolyte imbalance.
• Cramping likely originates from hyperexcitability of the alpha motorneurons 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.
51
Muscle cramping is poorly understood
Rod MacKinnon, MD
Rockefeller University
2003 Nobel Prize in Chemistry
52
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.
53
Cramping is not caused by dehydration or electrolyte
imbalance
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
Significant and serious dehydration does not affect skeletal
muscle cramp threshold frequency
Braulick KW, Miller KC, Albrecht JM, et al. Br J Sports Med 2013;47:710–714.
54
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.
55
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.
56
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.
57
Human cramps likely also reflect bistable behavior of
motor neuron firing
58
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.
59
60
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
61
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.
62
How?
• 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.
63
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.
64
Drinking a beverage containing natural TRPV1 and TRPA activators
produces long-lasting inhibition of electrically-induced muscle
cramping
65
Hypothesized mechanism of action:
chemical neurostimulation via TRP channels
Activation of a trigeminal sensory
neuron by TRPA1 and TRPV1 agonists.
66
Hypothesized mechanism of action:
chemical neurostimulation via TRP channels
TRPV1
TRPA1
AA
A
A
AA
AA
A
A
A
A
AA
A
AA
A
Brian Davis, U Pittsburgh
67
Summary
• Most muscle cramping is NOT caused by dehydration, lactic acid
build-up, or electrolyte imbalance.
• Cramping likely originates from hyperexcitability of the alpha motorneurons 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.
68
THE NEUROLOGY OF MUSCLE CRAMPS:
FROM RESEARCH TO PRACTICE
Tom Wessel, MD, PhD
Chief Medical Officer
Flex Pharma, Inc.
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). 69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84