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.
PATHOPHYSIOLOGY OF SPORT
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
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.
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.
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.
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
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
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
Should we treat concussion
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.
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
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.
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
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
OTHER TREATMENT STRATEGIES
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
P McCrory, Centre for Sports Medicine
Research & Education and Brain Research
Institute, University of Melbourne, Melbourne,
Correspondence to: Dr P McCrory, PO Box 93,
Shoreham, Vic 3916, Australia;
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11 Yoshida S, Busto R, Ginsberg M.
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Changes incortical extracellular levels of
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vasospasm following severe head injury.
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(S)-emopamil attenuates acute reduction in
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administration on recovery of segmental and
long tract neurological function in NASCIS2.
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A randomised controlled trial of
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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.
21 Sinson G, Perri B, Trojanowski J,
Improvement of cognitive deficits and
decreased cholinergic neuronal cell loss and
apoptotic cell death following neurotrophin
infusion after experimental traumatic brain
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.
23 Chen D, Schneider G, Martinou J,
promotes regeneration of severed axons in the
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.
25 Rockswold G, Ford S, Anderson D. Results of
a prospective randomised trial for the
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British Association of Sport and Exercise Medicine in association with the National Sports
Education programme 2002
Intermediate Sports Injury Management and Medicine—Head,
Neck, & Upper Limb
Lilleshall National Sports Centre, 17–22 February.
General Sports Medicine
Lilleshall National Sports Centre, 21–26 April.
Shefﬁeld Centre of Sports Medicine, April–May.
Current Concepts: Lower Limb Rehabilitation
DSMRC Headley Court, Surrey, 10–11 May .
Intermediate Sports Injury Management and Medicine—Lumbar
Spine, Thorax, Groin, Pelvis, & Hip
Lilleshall National Sports Centre, 7–12 July .
General Sports Medicine
Lilleshall National Sports Centre, 22–27 September.
Practical Sport and Medicine Meeting
Club La Santa, Lanzarote (families & non-delegates welcome;
deadline 17 July, 2002), 3–10 October.
Location and date to be conﬁrmed, October.
The Queen’s Golden Jubilee & Post Commonwealth Games BASEM
The Low Wood Hotel and Conference Centre, Windermere,
Intermediate Sports Injury Management and Medicine—Lower Limb
Lilleshall National Sports Centre, 17–22 November.
Topic, location, and date to be conﬁrmed, December.
Education programme 2003
Intermediate Sports Injury Management and Medicine—Head, Neck,
and Upper Limb
Lilleshall National Sports Centre, 16–21 February.
General Sports Medicine
Lilleshall National Sports Centre, 27 April–2 May.
The Cutting Edge
Shefﬁeld, 3–7 September
For further details of these courses please contact Mr Barry Hill, The
National Sports Medicine Institute, 32 Devonshire Street, London
W1G 6PX, UK. Tel: 020 7486 3974; Fax:020 7935 0402; email: