Should we treat concussion pharmacologically? The need for evidence based pharmacological treatment for the concussed athlete

Article · March 2002with29 Reads
Source: PubMed
  • Paul McCrory at The Florey Institute of Neuroscience and Mental Health
    • 48.8
    • The Florey Institute of Neuroscience and Mental Health
he medical management of concus-
sion in sport has traditionally inv olved
close observation and “masterly inac-
tivity”. With the use of clinical assessment
and neuropsychological testing we hav e
the ability to individualise patient man-
agement and determine safe and appro-
priate return to play strategies. At the
present time, the sports physician has no
evidence based pharmacological treat-
ment to offer the concussed athlete. The
ability to treat concussion with specific
drug therapy requires an understanding
of the pathoph ysiological changes that
accompany concussive injuries.
Concussive brain injury has long been
thought to evoke immediate and irre-
versible damage to the brain. While this
may be true in moderate to severe
traumatic brain injury, the evidence that
this occurs in milder injuries such as
concussion is not compelling. Recent
experimental evidence suggests that the
pathogenesis of axonal dysfunction re-
sulting from head trauma is complex.
In addition, studies of moderate to
severe traumatic brain injury have re-
vealed that a cascade of neurochemical,
ionic, and metabolic changes occur fol-
lowing experimental brain injury.
assumption is that similar changes occur
in milder injury although this remains
controversial. Most notably, an injury
induced ionic flux across the cell mem-
brane due to the release of the excitatory
amino acids, has been shown to increase
glycolysis that results in a state of meta-
bolic depression due to a decrease in
both glucose and oxidative metabolism
accompanied by a decrease in cerebral
blood flow.
Each element of this
cascade has a different time window that
may have impor tant implications in
treating concussed individuals.
There are many pharmacological man-
agement options that have been pro-
posed for all grades of brain injury.
Readers are referred to some of the larger
texts and recent reviews on these topics
for more complete discussion.
The list
below outlines some of the recent devel-
opments and areas where treatment may
have a role. In many cases, the evidence
is based upon studies of severe brain
injury and readers need to interpret this
in light of the discussion above. These
treatments are summarised in table 1.
Corticosteroids have been utilised for
many years in experimental neuro-
trauma, initially based upon their ability
to stabilise lysosomal membranes and
reduce tissue oedema. There are a
number of studies that suggest both
positive and negative benefits of using
corticosteroids in severe brain injury.
Other steroid compounds, particularly
the lazaroids or 21-amino steroids, that
inhibit lipid peroxidation also have pro-
tective benefit in neurotrauma models.
One such compound, tirilazad mesylate
has been shown to improve behavioural
recovery in mice.
Free radical scavengers and
Treatment with vitamin C or E, if admin-
istered pre-injury, has been shown to pro-
vide protection in various models of
central nervous system (CNS) trauma
where free radicals are generated.
10 11
Some concern howev er has been raised by
the large epidemiological studies of anti-
oxidant use for cardiovascular disease
where antioxidant therapy was associated
with an increase in cancer incidence. The
mechanism for this in not known.
Drugs inhibiting arachidonic acid
Toxic breakdown products of arachidonic
acid metabolism may exacerbate CNS
injury. These include thromboxanes,
peptidyl leukotrienes, and free radicals.
Studies of cyclo-oxgenase inhibitors (for
example, ibuprofen) and mixed cyclo-
oxygenase-lipoxygenase inhibitors have
shown therapeutic benefit in animal
models of spinal cord injury.
No specific
trials of this therapy have been per-
for med with mild traumatic brain injury.
Drugs that modify monoamine
There is a well documented sympatho-
adrenal response following traumatic
brain injury, however, whether blocking
this response has a therapeutic benefit is
unknown. It has been known anecdotally
since the Second World War, that cholin-
ergic antagonists such as scopolamine
can reduce the behavioural deficits fol-
lowing moderate to severe brain injury. A
recent randomised trial however was ter-
minated prematurely because of unac-
ceptable psychomimetic side effects sug-
gesting that this agent may not be a
practical treatment option.
Glutamate receptor antagonists
Increased extracellular levels of glutamate
and aspartate correlate with brain injury
severity in animal models.
with NMDA antagonists, AMPA antago-
nists, and magnesium have suggested a
protective benefit in animal and limited
human studies.
These agents may be of
increasing importance once safety and
other issues are dealt with.
Calcium channel antagonists
It has been proposed that the entry of
calcium through voltage-dependent
channels may contribute to secondary
brain injury. Despite the intuitive logic of
Abbreviations: CNS, central nervous system;
TRH, thyrotrophin releasing hormone
Table 1 Summary of treatment options
Treatments that are possibly effective Treatments unlikely to be effective
Treatments that may place the athlete at risk of
adverse events
Drugs inhibiting arachidonic acid metabolism Neurotrophic factors Free-radical scavengers
Calcium channel antagonists TRH/TRH analogues Antioxidants
Corticosteroids Drugs that modify monoamine function
Hyperbaric oxygen therapy
Concussion treatment
Should we treat concussion
P McCrory
The need for evidence based pharmacological treatment for
the concussed athlete
treatment with calcium channel antago-
nists, a number of randomised trials of
various agents have failed to demon-
strate protective benefit.
14 15
Recently a
novel calcium channel agent,
S-emopamil, has been shown to be ben-
eficial in experimental injury.
Opiate receptor antagonists
Endogenous opioids contribute to sec-
ondary damage following CNS trauma.
Studies have suggested that the kappa
opioid receptor or its isoforms may be
significant in the modification of these
injuries. Reanalysis of data from ran-
domised trials of spinal cord injury have
suggested a benefit from naloxone al-
though the dose studied may have been
too high.
17 18
TRH and TRH analogues
Thyrotrophin releasing hormone (TRH)
was initially used in the treatment of
acute spinal cord injury because of its
ability to antagonise many of the actions
of endogenous opioids. This agent may
also have effects on platelet function,
leukotriene activation, and excitatory
amino acid release. Protective effects in
CNS injury are dose-related and are
found even when treatment is delayed
up to 24 hours.
19 20
Neurotrophic factors
The ability of injured neurons in the
adult brain to recover from injury de-
pends on the expression of growth
related genes and the responsiveness to
survival and growth signals in the
Nerve growth factor: The neuroprotec-
tive efficacy of intracerebral nerve
growth factor infusion has been demon-
strated during the acute phase of experi-
mental head injury. This beneficial effect
of nerve growth factor may be related to
its ability to attenuate traumatically
induced apoptotic cell death.
Insulin-like growth factor-1: Intra-
venous insulin-like growth factor-1 has
been evaluated for the treatment of
moderate to severe head injury in a
phase II safety and efficacy trial.
Bcl-2: This proto-oncogene has actions
similar to those of brain-derived neuro-
trophic factor in promoting the regen-
eration of severed CNS axons in the
mammalian CNS.
The mode of
this action is likely via extracellular
signalling pathways that are involved in
both neuronal survival and axon
Significant morbidity and mortality of
patients with traumatic brain injury is
associated with post-traumatic inflam-
matory complications. Hypothermia has
been suggested as a treatment to lessen
these inflammatory reactions. Hypother-
mia, applied immediately after severe
traumatic brain injury, reduces the post
traumatic increase in interleukin-1 beta-
mediated nerve growth factor
Thus, hypothermia, while
reducing the inflammatory response,
may also hinder the brain’s intrinsic
repair mechanism. In phase 1 and phase
2 trials, short (<48 hours) periods of
moderate (32–33°C) hypothermia are
well tolerated and provide limited evi-
dence of a beneficial effect on the
outcome following moderate to severe
traumatic brain injury. Phase 3 ran-
domised controlled trials are currently
Hyperbaric oxygen therapy
The delivery of high concentrations of
oxygen under pressure has been pro-
posed as a means of enhancing cerebral
oxygenation and hence injury recovery
post-injury. Possible mechanisms of ac-
tion include cerebral vasoconstriction,
improvement in glucose metabolism and
reduction of cerebral oedema. Hyper-
baric oxygen may also have a potentially
har mful effect on the injured brain by
supplying oxygen for free radical reac-
tions that result in iron-catalysed lipid
peroxidation. In severe brain injuries,
randomised trials have demonstrated an
improved mortality rate with hyperbaric
therapy however there was no improve-
ment in functional outcome at 12
There are a number of other agents that
have been utilised either in small clinical
trials, experimental studies or reported
anecdotally to be of benefit. Agents such
as anion transport inhibitors
have been proposed as well as
combination therapy directed at a
number of elements of the injury
Even nutritional supplements,
such as creatine, have been proposed to
be of benefit in severe traumatic brain
Further randomised controlled
trials are necessary with all these agents
prior to consideration or their rec-
ommendation for widespread clinical
In summary, at the present time the cli-
nician has no evidence based pharmaco-
logical treatment to offer the concussed
athlete. Although as physicians we often
feel the need to treat “something” rather
than sit idly by and observe the clinical
state, it is critical that we bear in mind
the Hippocratic aphorism Primum non
nocere”. And to paraphrase Hippocrates
further; Life is short, the art is
long, opportunity fleeting, experience
deceiving, and judgment difficult. Thus
medicine was almost three millennia ago
and remains true today.
Br J Sports Med
Author’s affiliation
P McCrory, Centre for Sports Medicine
Research & Education and Brain Research
Institute, University of Melbourne, Melbourne,
Australia 3004
Correspondence to: Dr P McCrory, PO Box 93,
Shoreham, Vic 3916, Australia;
1 Povishlok J, Pettus E. Traumatically induced
axonal damage: evidence for enduring
changes in axolemmal permeability with
associated cytoskeletal change.
Neurochir Suppl
2 Hovda D, Lee S, Smith M,
et al
neurochemical and metabolic cascade
following brain injury: moving from animal
models to man.
J Neurotrauma
3 Takayama Y, Maeda T, Koshinaga K. Role of
excitatory amino acids-mediated ionic fluxes
in traumatic brain injury.
Brain Pathol
4 Narayan R, Wilberger J, Povishlok J.
. New York: McGraw-Hill,
5 McIntosh T. Novel pharmacological therapies
in the treatment of experimental traumatic
brain injury: a review.
J Neurotrauma
6 McCrory P, Johnston K, Meeuwisse W,
et al
Evidence based review of sport related
concussion—basic science.
Clin J Sport Med
7 Johnston K, McCrory P, Mohtadi N,
et al
Evidence based review of sport-related
concussion—clinical science.
Clin J Sport Med
8 Braughler J, Hall E. High dose methyl
prednisolone and CNS injury.
J Neurosurg
9 Hall E, Yonkers P, McCall J,
et al
. Effect of the
21-amino steroid U-74006F on experimental
head injury in mice.
J Neurosurg
10 Clifton G, Lyeth B, Jenkins L. Effect of D1
alpha tocepherol succinate and polyethelene
glycol on performance tests after fluid
percussion brain injury.
J Neurotrauma
11 Yoshida S, Busto R, Ginsberg M.
Compression induced brain edema:
modificaion by prior depletion and
supplementation of vitamin E.
12 Hallenbeck J, Jacobs T, Faden A. Combined
PGI2, indomethacin and heparin improves
neurological recovery after spinal trauma in
J Neurosurg
13 Nilsson P, Hillered L, Ponten U,
et al
Changes incortical extracellular levels of
energy related metabolites and amino acids
following concussive brain injury in rats.
J Cereb Blood Flow Metab
14 Teasdale G. A randomised trial of
nimodipine in severe head injury.
J Neurotrauma
15 Compton J, Lee T, Jones N. A double blind
placebo controlled trial of the calcium entry
blocking drug nicardipine in the treatment of
vasospasm following severe head injury.
Br J
16 Okiyama K, Rosenkrantz TS, Smith DH,
et al
(S)-emopamil attenuates acute reduction in
regional cerebral blood flow following
experimental brain injury.
J Neurotrauma
17 Bracken M, Holford T. Effects of timing of
methyl prednisolone or naloxone
administration on recovery of segmental and
long tract neurological function in NASCIS2.
J Neurosurg
18 Bracken M, Shepard M, Collins W.
A randomised controlled trial of
methylprednisolone or naloxone in the
treatment of acute spinal cord injury.
Eng J Med
19 Faden A, Jacobs T, Smith M. TRH in
experimental spinal cord injury.
20 McIntosh T, Fernyak S, Hayes R,
et al
Beneficial effect of the non-selective opiate
antagonist naloxone hydrochloride and the
TRH analogue YM-14673 on long-term
neurobehavioural outcome following
experimental brain injury in the rat.
J Neurotrauma
21 Sinson G, Perri B, Trojanowski J,
et al
Improvement of cognitive deficits and
decreased cholinergic neuronal cell loss and
apoptotic cell death following neurotrophin
infusion after experimental traumatic brain
J Neurosurg
22 Hatton J, Rapp R, Kudsk K. Intravenous
insulin-like growth factor-1 (IGF-1) in
moderate-to-severe head injury: a phase II
safety and efficacy trial.
J Neurosurg
23 Chen D, Schneider G, Martinou J,
et al
. Bcl-2
promotes regeneration of severed axons in the
mammalian CNS.
24 Goss J, Styren S, Miller P. Hypothermia
accentuates the normal increase in interleukin
1 beta RNA and nerve growth factor
following traumatic brain injury in the rat.
J Neurotrauma
25 Rockswold G, Ford S, Anderson D. Results of
a prospective randomised trial for the
treatment of severely brain injured patients
with hyperbaric oxygen.
J Neurosurg
26 Kimelberg H, Cragoe E, LR N. Improved
recovery from a traumatic-hypoxic brain injury
in cats by intracisternal injection of an anion
transport inhibitor.
CNS Trauma
27 Faden A. Comparison of single versus
combination drug strategies in experimental
brain trauma.
J Neurotrauma
28 Sullivan P. Dietary supplement creatine
protects against traumatic brain injury.
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