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The need for evidence based pharmacological treatment for the concussed athlete
The medical management of concussion in sport has traditionally involved close observation and “masterly inactivity”. With the use of clinical assessment and neuropsychological testing we have the ability to individualise patient management and determine safe and appropriate return to play strategies. At the present time, the sports physician has no evidence based pharmacological treatment to offer the concussed athlete. The ability to treat concussion with specific drug therapy requires an understanding of the pathophysiological changes that accompany concussive injuries.
PATHOPHYSIOLOGY OF SPORT RELATED CONCUSSION
Concussive brain injury has long been thought to evoke immediate and irreversible 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 resulting from head trauma is complex.1
In addition, studies of moderate to severe traumatic brain injury have revealed that a cascade of neurochemical, ionic, and metabolic changes occur following 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 membrane due to the release of the excitatory amino acids, has been shown to increase glycolysis that results in a state of metabolic depression due to a decrease in both glucose and oxidative metabolism accompanied by a decrease in cerebral blood flow.2, 3 Each element of this cascade has a different time window that may have important implications in treating concussed individuals.
There are many pharmacological management options that have been proposed 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 developments 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 neurotrauma, 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 protective 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 administered pre-injury, has been shown to provide protection in various models of central nervous system (CNS) trauma where free radicals are generated.10, 11 Some concern however has been raised by the large epidemiological studies of antioxidant 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 performed 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 cholinergic antagonists such as scopolamine can reduce the behavioural deficits following moderate to severe brain injury. A recent randomised trial however was terminated prematurely because of unacceptable psychomimetic side effects suggesting 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 antagonists, 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 treatment with calcium channel antagonists, a number of randomised trials of various agents have failed to demonstrate protective benefit.14, 15 Recently a novel calcium channel agent, S-emopamil, has been shown to be beneficial in experimental injury.16
Opiate receptor antagonists
Endogenous opioids contribute to secondary 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 randomised trials of spinal cord injury have suggested a benefit from naloxone although 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
The ability of injured neurons in the adult brain to recover from injury depends on the expression of growth related genes and the responsiveness to survival and growth signals in the environment.
Nerve growth factor: The neuroprotective efficacy of intracerebral nerve growth factor infusion has been demonstrated during the acute phase of experimental 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: Intravenous 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 neurotrophic factor in promoting the regeneration 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.
Significant morbidity and mortality of patients with traumatic brain injury is associated with post-traumatic inflammatory complications. Hypothermia has been suggested as a treatment to lessen these inflammatory reactions. Hypothermia, 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 evidence of a beneficial effect on the outcome following moderate to severe traumatic brain injury. Phase 3 randomised controlled trials are currently underway.4
Hyperbaric oxygen therapy
The delivery of high concentrations of oxygen under pressure has been proposed as a means of enhancing cerebral oxygenation and hence injury recovery post-injury. Possible mechanisms of action include cerebral vasoconstriction, improvement in glucose metabolism and reduction of cerebral oedema. Hyperbaric oxygen may also have a potentially harmful effect on the injured brain by supplying oxygen for free radical reactions 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 improvement 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 inhibitors26 and cytokines5 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 recommendation for widespread clinical use.
In summary, at the present time the clinician has no evidence based pharmacological 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.
The need for evidence based pharmacological treatment for the concussed athlete