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
T
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
RELATED CONCUSSION
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.
1
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.
2
The
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.
23
Each element of this
cascade has a different time window that
may have impor tant implications in
treating concussed individuals.
TREATMENT OPTIONS
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.
4–7
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
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.
8
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.
9
Free radical scavengers and
antioxidants
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
metabolism
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.
12
No specific
trials of this therapy have been per-
for med with mild traumatic brain injury.
Drugs that modify monoamine
function
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.
5
Glutamate receptor antagonists
Increased extracellular levels of glutamate
and aspartate correlate with brain injury
severity in animal models.
13
Treatment
with NMDA antagonists, AMPA antago-
nists, and magnesium have suggested a
protective benefit in animal and limited
human studies.
13
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
pharmacologically?
P McCrory
...................................................................................
The need for evidence based pharmacological treatment for
the concussed athlete
EDITORIALS
3
www.bjsportmed.com
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.
16
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
environment.
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.
21
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.
22
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.
23
The mode of
this action is likely via extracellular
signalling pathways that are involved in
both neuronal survival and axon
elongation.
Hypothermia
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
production.
24
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
underway.
4
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
months.
25
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
26
and
cytokines
5
have been proposed as well as
combination therapy directed at a
number of elements of the injury
cascade.
27
Even nutritional supplements,
such as creatine, have been proposed to
be of benefit in severe traumatic brain
injury.
28
Further randomised controlled
trials are necessary with all these agents
prior to consideration or their rec-
ommendation for widespread clinical
use.
CONCLUSION
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
2002;36:3–5
.....................
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;
pmccrory@compuserve.com
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4 EDITORIALS
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Beneficial effect of the non-selective opiate
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24 Goss J, Styren S, Miller P. Hypothermia
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EDUCATION PROGRAMME...........................................................................
British Association of Sport and Exercise Medicine in association with the National Sports
Medicine Institute
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.
Diploma Preparation
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.
Diploma Preparation
Location and date to be confirmed, October.
The Queen’s Golden Jubilee & Post Commonwealth Games BASEM
Congress
The Low Wood Hotel and Conference Centre, Windermere,
10–13 October.
Intermediate Sports Injury Management and Medicine—Lower Limb
Lilleshall National Sports Centre, 17–22 November.
Current Concepts
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
(Contact: r.m.bartlett@shu.ac.uk)
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:
barry.hill@nsmi.org.uk; www.nsmi.org.uk
EDITORIALS 5
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