Evaluation of current post-concussion protocols

Abstract

The growing number of concussions and mild traumatic brain injuries (mTBI) with the lack of evidence-based treatment options is a continuous health concern. This creates problems when evaluating and providing efficacious symptom management to patients suffering from post-concussion syndrome (PCS). Numerous pharmacological and non-pharmacological agents have been utilized in an attempt to treat PCS. Some of these approaches include physical therapy, analgesics, antidepressants, and nutraceuticals. Although these treatments have had some success, there has been inconsistent outcomes, with some examples of patients’ symptoms worsening. Among pharmaceutical agents, fluoxetine has been a popular choice for the symptom management of PCS. Although some patients have had symptom resolution with the use of fluoxetine, there is still a lack of conclusive data. Of the several biochemical changes that occur in a patient’s brain following a concussion, an increase in reactive oxygen species (ROS) is of particular concern. In order to counteract the responses of the brain, antioxidants, such as ascorbic acid, have been utilized to reverse the damaging cellular effects. However, this may inadvertently cause an increase in ROS, rather than a reduction. Although there is a lack of consistency in exactly when each treatment was used in the post-injury interval, it is important that we analyze the strengths and weaknesses of the most commonly used agents due to the lack of a set protocol. The studies were chosen in a non-exhaustive manner and were not consistent in patients’ post-injury intervals, in addition to other baseline characteristics. However, over-arching claims that some treatments may benefit more than others can be made. This review evaluates both the pharmaceutical and non-pharmaceutical protocols that are most commonly utilized in post-concussive patients for their efficacy in treatment of post-concussive syndrome (PCS).

Full text

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Biomedicine & Pharmacotherapy
journal homepage: www.elsevier.com/locate/biopha
Review
Evaluation of current post-concussion protocols
Kristin Kim, Ronny Priefer*
Massachusetts College of Pharmacy and Health Sciences University, Boston, MA, United States
ARTICLE INFO
Keywords:
Concussion
Mild traumatic brain injury
Post-concussive syndrome
Electroencephalogram neurofeedback
Osteopathic medicine and physical therapy
Vitamin C
ABSTRACT
The growing number of concussions and mild traumatic brain injuries (mTBI) with the lack of evidence-based
treatment options is a continuous health concern. This creates problems when evaluating and providing effi-
cacious symptom management to patients suffering from post-concussion syndrome (PCS). Numerous pharma-
cological and non-pharmacological agents have been utilized in an attempt to treat PCS. Some of these ap-
proaches include physical therapy, analgesics, antidepressants, and nutraceuticals. Although these treatments
have had some success, there has been inconsistent outcomes, with some examples of patients’symptoms
worsening. Among pharmaceutical agents, fluoxetine has been a popular choice for the symptom management of
PCS. Although some patients have had symptom resolution with the use of fluoxetine, there is still a lack of
conclusive data. Of the several biochemical changes that occur in a patient’s brain following a concussion, an
increase in reactive oxygen species (ROS) is of particular concern. In order to counteract the responses of the
brain, antioxidants, such as ascorbic acid, have been utilized to reverse the damaging cellular effects. However,
this may inadvertently cause an increase in ROS, rather than a reduction. Although there is a lack of consistency
in exactly when each treatment was used in the post-injury interval, it is important that we analyze the strengths
and weaknesses of the most commonly used agents due to the lack of a set protocol. The studies were chosen in a
non-exhaustive manner and were not consistent in patients’post-injury intervals, in addition to other baseline
characteristics. However, over-arching claims that some treatments may benefit more than others can be made.
This review evaluates both the pharmaceutical and non-pharmaceutical protocols that are most commonly
utilized in post-concussive patients for their efficacy in treatment of post-concussive syndrome (PCS).
1. Introduction
Concussion, also known as mild traumatic brain injury (mTBI), is
defined as an alteration of the normal function of the brain caused by a
biomechanical force. According to the Centers for Disease Control and
Prevention (CDC), 2.87 million TBI-related emergency department
visits, hospitalizations, and deaths occurred in the United States in
2014, including over 837,000 of them occurring among children. With
rapidly increasing TBI related emergency department visits and no
universally established treatment, concussion is a public health crisis
and a growing concern [1]. Of the almost 3 million Americans that
encounter a traumatic brain injury (TBI) yearly, 290 000 were hospi-
talized and over 50 000 perished due to their injuries [2]. In late 2018,
the first CDC guidelines were established for the diagnosis and man-
agement of mTBI among children [3]. However, due to the lack of
evidence-based treatment options, post-concussion protocol mainly
consist of symptomatic treatment to prevent a recurring concussion and
to expedite the recovery process. Patients with a concussion history are
three times more likely to have an incidental concussion when
compared to those without a concussion history [4].
Acute post-concussion symptoms can be divided into two categories:
signs observed and signs reported. The most common signs observed
include loss of consciousness, confusion, and not being able to recall
events prior to or after the trauma. Among the signs reported from the
patient, headache, nausea, dizziness and light sensitivity are the most
common [5].
Without proper management, the concussion and the symptoms that
come along with the injury can develop into a chronic condition known
as post-concussive syndrome (PCS). Between 24%–84% of mTBI pa-
tients will develop this chronic condition [6] consisting of headaches,
dizziness, fatigue, sensitivity to light or sound, sleep disturbance, and/
or concentration difficulties [7]. These long-term effects of a concussion
can last up to months post-initial injury, leading to a decreased quality
of life. According to the DSM-V criteria, PCS is diagnosed as either mild
or major neurocognitive disorder (NCD) due to TBI. In order to have a
diagnosed NCD, a patient must have decline in cognitive ability, in-
cluding memory, concentration, and processing speed. Other specific
criteria include: 1) evidence of a traumatic brain injury, 2) NCD
https://doi.org/10.1016/j.biopha.2020.110406
Received 25 March 2020; Received in revised form 10 June 2020; Accepted 14 June 2020
⁎
Corresponding author.
E-mail address: ronny.priefer@mcphs.edu (R. Priefer).
Biomedicine & Pharmacotherapy 129 (2020) 110406
0753-3322/ © 2020 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/BY/4.0/).
T

presents immediately after the TBI or immediately after recovery of
consciousness and persists past the acute post-injury period [8].
Of those people who develop PCS, up to 25 % of them will experi-
ence prolonged PCS, where the symptoms continue for over six months
[9]. In addition, research has shown that 75 % of TBI patients suffer
from major depressive disorder (MDD) [10]. According to the National
Institute of Mental Health, depression (major depressive disorder or
clinical depression) is a mood disorder consisting of persistent symp-
toms ranging from sad and/or anxious mood to fatigue and restlessness
[10]. Of the total TBI patient population that suffer from depression, 35
% of them are classified as mild TBI patients, including concussions
[11]. The presence of these uncomfortable symptoms leads to under-
employment and productivity loss for a patient suffering from PCS [11].
Thus, it is important to recognize and manage symptoms in a timely and
vigorous manner. In order to understand the current treatment options
for PCS, understanding the pathophysiology is crucial.
2. Pathophysiology and symptom presentation
Following the physical injury to the head the brain undergoes vast
chemical and biological changes. The most common pathological
pathway when a mTBI occurs is through the tearing of neuron axons
and small blood vessels. This type of injury is known as diffuse axonal
injury (DAI). This leads to ischemia and hypoxia of the brain, along
with many different chemical changes that lead to inflammation and
edema [9]. The brain experiences a loss of regulation in the ion balance
of Na
+
/K
+
/Ca
2+
. Due to the loss of regulation, membrane depolar-
ization of the neuron causes an efflux of potassium out of the cells that
are responsible for the release of glutamate, an excitatory amino acid.
Glutamate and other excitatory neurotransmitters activate N-methyl-D-
aspartate (NMDA) receptors which consequently causes nonspecific
initiation of action potentials. In addition, NMDA activation opens the
ion-gated channels to allow a large influx of calcium into the neuron
[12]. This influx causes the breakdown of excitatory neurotransmitters,
causing the production of ROS [13]. Although ROS are produced by
essential biological and metabolic processes of the cell and does not
cause injury when levels are controlled, excessive amounts are toxic
and can cause cellular damage (Fig. 1). ROS can damage essential
proteins such as fragmentation and denaturation of collagen, albumin,
and others [14]. ROS overproduction is observed in mTBIs, including
concussions. These chemical changes can occur in the acute period
following the initial injury and can lead to secondary injury. In addition
to ROS, other neurotransmitters and inflammatory mechanisms un-
dergo changes leading to greater cellular damage, tissue damage, and
possibly brain cell death [13]. This pathophysiology has led to targeted
research in the usage of certain medications and nutraceuticals in the
treatment of concussions. However, there is yet to be enough evidence
to support the benefit of either classes.
While the aforementioned changes take place in the brain, the pa-
tient begins to feel the results of these effects through many different
symptoms. The symptoms can have a delayed presentation and may
occur days to weeks post initial injury. Each symptom falls under one or
more of the four domains including: physical, cognitive, emotional, and
sleep. Of these domains, the most commonly experienced symptoms,
such as headache and difficulty concentrating, fall under both the
physical and cognitive domains. The symptoms within these domains
are vastly non-specific ranging from headache, dizziness, and many
more.
Among the many symptoms a patient experiences post-concussion,
headache is the most common and long-lasting. Over 50 % of patients
will continue to experience this symptom even one year after the initial
injury. Headaches that worsen within seven days after a concussion are
known as posttraumatic headache (PTH) and very closely resembles a
migraine. Alongside a concussion, a PTH also does not have distinct
clinical features other than the fact that it occurs closely to the time of
initial injury. PTH is diagnosed and treated depending on factors such
as duration, severity, location of headache, and the patient’s medical
history [15]. Each patient’s symptoms may vary in both severity and
duration [4]. Harmon depicted the common post-concussion symptoms
and how many of the symptoms overlap with the different clinical
profiles, including the management of the symptoms in each profile
(Fig. 2). Fig. 2 depicts the correlation of patient reported symptoms to
the matching clinical profile, such as cognitive and ocular, and how
these symptoms present on a physical exam. As the figure illustrates,
many of the common symptoms a patient experiences overlap with each
other in both clinical profile and management [16].
In addition to headaches, the effect concussions have on a patient’s
mood and anxiety level is widely known. Aside from the various phy-
siological symptoms a patient may experience, there is growing re-
search on the development of long-term posttraumatic stress disorder
(PTSD) in patients who have had a mTBI. Several case reports have
shown the correlation of a mTBI and the presence of PTSD [17]. This
becomes relevant when discussing both the pharmaceutical and non-
pharmaceutical treatment methods that have been explored for PCS.
Despite the type of symptoms a patient experiences, treatment must be
actively sought to prevent worsening of severity.
3. Non-pharmaceutical therapy
Many different non-pharmaceutical therapies have been explored to
Fig. 1. Biochemical alteration process in the brain following a concussion.
K. Kim and R. Priefer Biomedicine & Pharmacotherapy 129 (2020) 110406
2

increase the rate of symptom resolution compared to pharmaceutical
options in post-concussion patients.
3.1. Electroencephalogram (EEG) Neurofeedback
The relationship between PTSD and mTBIs have been shown in
many studies. Studies have suggested that this relationship is largely
dependent on stress reactions that create a stressful environment for the
brain. Cortisol is a common biomarker used to measure stress levels and
is known to inhibit growth factors for neuroplasticity. Management of
cortisol and stress levels in a patient may be beneficial in PCS recovery.
Thus, the potential benefits of EEG neurofeedback in mTBI and PCS
treatment has been explored. Neurofeedback training works to help
change the patient’s irregular brain waves in amplitude, frequency, and
coherency. This treatment method works as a training procedure to
directly alter the biochemical and physiological response a mTBI pa-
tient has to a stressful environment. It has been shown that increasing
alpha levels increases relaxation levels, thus allowing a decrease in
anxiety and a more ideal recovery environment for the brain.
EEG neurofeedback could potentially expedite the initiation of the
relaxation state in patients who have PCS. A study evaluated 4 groups
of subjects experiencing TBI: 1) neurofeedback receiving group within
the spontaneous recovery period, 2) neurofeedback receiving group
post-spontaneous recovery period, 3) treatment as usual group within
the spontaneous recovery period, and 4) treatment as usual group post-
spontaneous recovery period. Both groups that received neurofeedback
treatment (NFT), either in the spontaneous recovery period or post-
spontaneous period, were all grouped as NFT. The remaining groups
that received standard treatment were grouped into as the “treatment
as usual group”(TAU). TAU consisted of routine treatment by the
neurosurgical team, ranging from various surgical procedures and
drugs to reduce edema of the brain. Post-assessment of patients’con-
ditions was conducted via the Perceived Stress Scale (PSS) and Visual
Analogue Scale (VAS) to rate the severity and presence of symptoms. In
addition to the two self-reported scales, serum analysis of cortisol using
ELISA was collected at 45–60 days post preassessment. The variables
observed included: 1) severity, 2) nausea, 3) seizures, 4) use of anti-
epileptic drugs, 5) ENT (ear, nose, and throat) bleeds, 6) loss of con-
sciousness, 7) amnesia, and 8) surgical intervention. The results showed
the NFT group had significantly more severe symptoms and more per-
ceived stress on the VAS and PSS scale. In addition, no significant dif-
ferences at baseline were found for biochemical variables, including
Fig. 2. Common post-concussive symptoms and their correlating treatments. (Harmon et al., 2019).
K. Kim and R. Priefer Biomedicine & Pharmacotherapy 129 (2020) 110406
3

cortisol levels. These results suggest that neurofeedback may not be an
effective treatment to reduce stress for injured patients. Although the
mechanism and benefits of neurofeedback sounds promising, there is
still a lack of favorable research to apply this treatment method to every
mTBI patient and may not be as effective or timely favorable compared
to other methods [18].
In addition, studies have been conducted to evaluate the efficacy of
neurofeedback treatment in patients with mTBIs and moderate closed
head injuries (CHI). In one particular study, twenty-one patients who
had experienced moderate CHIs with various injury-to-test intervals
were assigned to either receive NFT or participate in computer-based
attention training. Abnormalities in a PCS patient’s EEG included dif-
fuse slowing with an enhancement of slow theta (4−7 Hz) activity and
suppression of fast beta (13−20 Hz) activity. These changes in the EEG
represent axonal injuries due to the mTBI. The participants were
screened with computerized tomography (CT) scans to show any lesions
of the brain. Some of the patients in the sample showed the following
lesions: bilateral haematoma, frontoparietal haematoma, temporal lobe
contusions, frontotemporal contusions, and bilateral contusions.
Although there were differences in the presence of lesions in the
sample, the patients’level of brain damage was similar in severity. The
baseline-EEG pre-therapy and EEG post-therapy for the twelve CHI
patients receiving NFT were recorded. The main aim of NFT was to
increase the suppressed mean amplitude of 13−20 Hz EEG activity
through beta training. Patients either received ten NFT sessions, each
lasting thirty minutes, over the course of two weeks or ten computer-
based attention trainings, also lasting thirty minutes for two weeks.
Eight of the twelve NFT receiving patients that started with low beta
amplitudes had a statistically significant increase of 1 μV in the beta
activity post-treatment. In addition, these patients were able to main-
tain a statistically significant (p =0.012) increase in beta activity for a
longer duration. The computer-based attention training group also
showed improvements in beta activity acutely. However, their overall
beta amplitudes did not change over the entire course of treatment. In
addition, four of the twelve patients receiving NFT demonstrated a
decrease, rather than an increase, in beta activity following treatment.
The small sample size of the study and the difference in the overall beta
activity of the NFT receiving group prevent this study’sfindings to be
conclusive for all PCS and mTBI patients. [19]
3.2. Prescribed rest
The most common recommendation following a concussion is pre-
scribed rest. This rest consists of symptom-limited cognitive and phy-
sical rest for no less than 24−72 h post-injury. After this acute rest
period, moderate activity, both cognitive and physical, is recommended
to eventually reach pre-injury activity levels [16]. Rest is recommended
due to the sensitive condition of the brain following a concussion. Due
to the disturbance of the brain’s chemical homeostasis, especially in
glutamate and calcium levels, a concussed brain is more vulnerable to
additional injuries. This puts the brain at an increased risk to more
severe injuries if it were to encounter further trauma or stressful con-
ditions [20]. A study evaluated the difference in the level of brain in
male athletes who had a mTBI within 1–14 months prior to the study
and had persisting PCS. The athlete group was compared to a control
group consisting of subjects without a concussion history. Both the
athlete group and control group were matched in age and gender.
Through various verbal and visual working memory tasks, the level of
the subjects’brain activation was assessed with functional magnetic
resonance imaging (fMRI). The results demonstrated that PCS patients
had an activation level that was significantly higher compared to those
without PCS. The excessive activation is one of the brain’s compensa-
tory methods to make up for the loss of function post-concussion [21].
This excess activation leads to further production of ROS, potentially
leading to more cellular distress. This suggests that rest is necessary to
control the brain’s excessively activated cognitive activity.
In addition, another study was conducted to evaluate the relation-
ship between prescribed rest and the time to PCS symptom resolution.
The post-concussion symptom scale (PCSS), balance error scores, and
cognitive activity scale were used to evaluate the symptom recovery
duration in patients who had sustained a mTBI within three weeks of
the study. The PCSS scale rates the severity of the symptoms commonly
experienced by the patient, including headache, sensitivity to external
stimuli, and mood alterations. In addition to the PCSS, the cognitive
activity scale assigns a patient in categories zero to four, with zero
being complete cognitive rest and four being full cognitive activity. It
was demonstrated that patients with the highest level of cognitive ac-
tivity experienced longer times to symptom resolution, than those who
had controlled cognitive activity [22]. Similar results were found by
Majerske and coworkers when evaluating neurocognitive performance
in relation to activity intensity post-concussion. Athletes who were
prescribed rest and restricted cognitive activity performed the best on
neurocognitive tests and reported the lowest PCS symptom scores [23].
Prescribed rest has been the most popular and adapted protocol of
concussions for decades. However, other studies have shown that there
may be no benefit of cognitive activity restriction in PCS symptom re-
solution. Gibson et al. found no statistically significant relationship
between cognitive rest and the duration of PCS symptoms in athletes
post-concussion [24].
Furthermore, it has recently been reported that restricted activity
actually results in delayed recovery and more symptoms [16]. A study
evaluating children and adolescents post-concussion and the effects of
strict rest illustrated that these participants reported more post-con-
cussive symptoms overall. In addition, symptom resolution of the strict
rest group took several days longer compared to the participants who
had a higher activity level. Prolonged strict physical inactivity can lead
to further development of secondary symptoms, such as depression,
anxiety, and fatigue [6]. In a different study, patients who were pre-
scribed strict rest reported more symptoms 10 days after initial injury
than those who were not restricted from moderate cognitive and phy-
sical activity [25]. Early introduction of moderate exercise appeared to
improve symptomatic outcomes rather than delayed exercise in parti-
cipants [26]. Prescribed rest has been the primary treatment choice for
concussions, but like the other treatment options, the results and ben-
efits may be questionable.
Nevertheless, rest in the acute injury phase has its place in therapy,
as the brain is in a more vulnerable state and needs time to stabilize.
Certain studies have shown that in experimental animal data, there is a
lower concentration of ATP, as well as structural alterations of the
mitochondria in the brain. Lack of rest in the acute period may lead to
an increased metabolic demand of the brain before it has had a chance
to recover. Although post-concussion treatment is largely based on
specific patient characteristics, a period of prescribed rest may benefit
all post-concussion patients in the acute phase [27].
3.3. Osteopathic medicine and physical therapy
As the initial injury is caused by a biomechanical force, physical
rehabilitation has been utilized and researched for the therapeutic
benefits in PTH. Improvement has been shown with patients receiving
physical therapy (PT) when compared to those who have not. However,
these studies only evaluate PT as an adjunct to other medications and
treatments rather than monotherapy [28]. Osteopathic cranial manip-
ulative medicine (OCMM) is a non-pharmacologic method that has re-
cently been evaluated as a potential alternative treatment. OCMM is
based offof the idea that the anatomy of the cranium reflects the
human body as a whole. OCMM utilizes the primary respiratory me-
chanism as its main treatment component, which consists of the mo-
bility of the cranial bones, sacrum, dural membranes, central nervous
system, and cerebrospinal fluid [29]. This treatment aims to alleviate
cranial bony and myofascial dysfunctions that have resulted from var-
ious physical injuries [30]. A previous study showed that 95 % of
K. Kim and R. Priefer Biomedicine & Pharmacotherapy 129 (2020) 110406
4

patients who have had a TBI showed at least one pattern of cranial
strain and 87 % had at least one or more bony motion restrictions [31].
As PCS is a result of a mTBI, it is hypothesized that OCMM may benefit
these patients. Approximately 71 % of the participants who completed
the two treatment sessions of OCMM showed improvements in their
post-concussive symptoms with no adverse effects (worsened head-
aches, dizziness, and increased pain). However, the remaining portion
of the participants showed a significant worsening of PCS. The positive
findings in this study may be reflective of the natural recovery of the
patient, rather than the direct effects of OCMM treatment. OCMM may
have use as a potential adjunctive therapy, rather than a monotherapy
option, in PCS. However, with the small sample size of only nine-par-
ticipants in this study, more research is necessary to conclude any
therapeutic benefits [30].
Similar to OCMM, various PT treatments involving vestibular/ocu-
lomotor and cervical rehabilitation have been evaluated for efficacy as
PCS treatment. Although many of them are not aware, many PCS pa-
tients have concurrent injuries to the spine and other areas of the body
caused by the initial physical force. Potentially due to this reason, in
addition to other medical conditions the patient may have, very few
patients spontaneously recover from a concussion. In a recent retro-
spective cohort study, researchers have evaluated the efficacy of PT as a
treatment for PCS [6]. According to the type of symptoms, various
forms of PT including cardiovascular, vestibular/oculomotor, cervi-
cothoracic, and other areas of exercise were prescribed to patients.
Following an initial physical evaluation, a PCS phenotype was assigned
and the aligning treatment plan was designed. For example, if the pa-
tient’s primary symptoms included sensitivity to light, difficulty con-
centrating, and visual problems, the patient’s PCS phenotype correlated
to vestibular and oculomotor injury. Following this general assessment,
patients received a series of specific screening tests to evaluate the need
for PT prescribed by the sports physical therapist. The PT therapies
ranged from jogging, stationary cycling, repositioning procedures, and
joint and soft-tissue mobilization. After 4 PT visits over the course of the
3 months, patients’recovery of symptoms were assessed with the PCSS
[6]. An average improvement of 9 points on the PCSS, correlating to a
higher symptom recovery level than the minimum clinically important
difference of 6.8 points was reported. Despite the promising results, this
approach may not be applicable to the general PCS patient population.
Over 75 % of this study’s cohort only experienced either peripheral
vestibular disorder or cervicothoracic dysfunction. As peripheral ves-
tibular disorder and cervicothoracic dysfunction only represent two of
the PCS phenotypes, this study’sfindings can only be applied to those
particular patients. These results may also be influenced by the natural
recovery over time and not the direct effect of PT treatment. Ad-
ditionally, the small sample size of this study is another limitation in
stating PT as a treatment for the entire PCS patient population [6].
3.4. Hyperbaric oxygen therapy
By understanding the mechanism of DAIs in the brain, hyperbaric
oxygen therapy (HBOT) has been researched as a treatment method.
HBOT involves a chamber that is slowly pressurized to 1.5–3 times
higher than normal air pressure with pure oxygen. This method ideally
supplements the hypoxic brain with oxygen [34]. The proposed me-
chanism of action is through the promotion of angiogenesis. Angio-
genesis stimulated with hyperbaric oxygen can potentially increase
brain perfusion with better cerebral blood flow (CBF) and cerebral
blood volume (CBV). More introduction of blood to the areas of the
brain that have become ischemic or hypoxic from the tearing of blood
vessels could potentially expedite the recovery process. A study that
evaluated the neurotherapeutic effect of HBOT using brain perfusion
imaging and clinical cognitive functions demonstrated positive results
[9]. HBOT significantly improved cognitive functions, such as in-
formation processing, speed, and visual spatial processing. In addition,
CBF and CBV increased in regions of the brain that were responsible for
visual, sensory-motor, memory, and attention functions. However, de-
spite the promising results, there are limitations to this treatment op-
tion. In addition to the small study group, this treatment required nu-
merous hyperbaric oxygen sessions over the week. HBOT requires a
high level of compliancy and a substantial amount of time investment
as each session consists of 60 min. This treatment option is also not
easily accessible to the general mTBI patient population [9].
4. Pharmaceutical therapy
Several pharmacological and supplemental therapies for the treat-
ment of PCS have been explored. Currently, there are no established
guidelines for pharmaceutical therapy in the treatment of PCS and
mTBI symptoms. However, based on the symptom presentation, phar-
maceutical therapy, ranging from over-the-counter analgesics to pre-
scription antidepressants have been explored for potential benefits.
4.1. Anti-inflammatory and analgesic
Acute treatment for concussions is given early and is mostly
symptomatic treatment consisting of anti-inflammatory and analgesic
medications, including aspirin, ibuprofen, and acetaminophen.
Although acute aggressive therapy is needed, large amounts of medi-
cation consumption puts patients at a risk of developing medication-
overuse headache (MOH) [4]. To prevent the overuse and the devel-
opment of MOH, a preventative medication may be given if acute
treatment is needed for more than three days a week and/or if the
patient is at risk for delayed recovery. Similarly to acute treatment
selections, preventative treatments are also chosen based on symptom
presentation and the patient’s additional comorbidities. Some MOH
preventative agents include nutraceuticals, such as magnesium, ribo-
flavin, and coenzyme Q10, as well as a range of prescription medica-
tions including antidepressants, beta-blockers, anticonvulsants, and
neuropathic pain medications [4]. However, when the length of treat-
ment and side effects of these preventative treatments are taken into
account for, the level of prevention and protection these supplements
provides is questionable.
4.2. Antidepressants
Antidepressants are the most commonly prescribed medications for
PCS. Although they are not FDA approved for this use, some selective
serotonin reuptake inhibitors (SSRI) have an off-label use to address
PCS symptoms [35]. Patients with depression have a deficiency in brain
monoaminergic transmitters, including norepinephrine (NE), serotonin
(5-HT), and/or dopamine (DA) [10]. The balance and levels of these
neurotransmitters play a crucial role in many behavioral symptoms,
such as mood, fatigue, and psychomotor agitation [10]. Similarly, the
etiology of the comorbidity of depression in mTBI patients seems to
relate to the chemical imbalance of neurotransmitters in the brain post-
concussion. Studies have evaluated the therapeutic use of SSRI’s, spe-
cifically sertraline, in the treatment of depression in mTBI patients. A
particular study evaluated 15 ambulatory care patients that met the two
main inclusion criteria: 1) having sustained a TBI within the past 3–24
months and 2) suffering from MDD based on the Hamilton Depression
Rating Scale (HAM-D) and Diagnostic Interview Schedule (DIS) [36].
Patients received 8 weeks of sertraline, starting at a dose of 25 mg that
was titrated up to 200 mg a day, based on clinical response and toler-
ability. Results demonstrated a statistically significant improvement in
neuropsychological function and in depression scores on both the HAM-
D and DIS scale. In addition, ten participants had a complete remission
of depression. With these results, sertraline seems to be a viable treat-
ment option for PCS related symptoms. However, these results were
based offof a small subject size with several patients having normal
neuropsychological scores at the initial assessment, potentially de-
monstrating a ceiling effect in the results. Due to these limitations and
K. Kim and R. Priefer Biomedicine & Pharmacotherapy 129 (2020) 110406
5

lack of further studies, sertraline should not be concluded as a treat-
ment option to the general PCS patient population [36].
Furthermore, a different study evaluated the use of sertraline in
post-TBI patients and its effectiveness in reducing symptoms, including
post-TBI depression. The inclusion criteria included: eighteen years or
older, have a history of TBI with a documented loss of consciousness or
other evidence of a TBI, and be at least 6 months postinjury. In this ten-
week double-blinded randomized controlled study, patients received
either sertraline or a placebo. Patients’level of depression and anxiety
symptoms were assessed with the HAM-D scale at the beginning of the
trial, every two weeks throughout the treatment, and immediately at
the conclusion of the ten-week treatment. The sertraline-treated group
received a range of 25−100 mg daily. The results indicate that of the
forty-one patients that completed the trial for the entire ten weeks, 59
% of the sertraline-treated group and 32 % of the placebo-treated group
had a 50 % decrease in depression from baseline. Although there was a
decrease in severity of post-TBI depression and anxiety, the p-value of
0.15 demonstrates that the data was not statistically significant [37].
Additionally, amitriptyline, a tricyclic antidepressant, has been ex-
plored as a potential antidepressant that can be utilized for PCS and
post-TBI depression. In an open trial, twenty-two patients were ad-
ministered 200−300 mg of amitriptyline daily for a total of four weeks.
The control group of non-TBI patients with depression were compared
to mTBI patients with a high level of depression at baseline, based on
the HAM-D scale. The patients that did not respond to amitriptyline
were given a three to seven day treatment-free period, then switched to
phenelzine 60–65 mg/daily. As a monoamine oxidase inhibitor, phe-
nelzine increases levels of serotonin and dopamine within the brain. No
significant improvement was shown for both amitriptyline and phe-
nelzine treated post-TBI patients. The study’s small sample size and
inconclusive data makes it difficult to conclude the level of efficacy of
both amitriptyline and phenelzine for the treatment of PCS [38].
Another widely used SSRI in the treatment of depression and
symptom relief in PCS is fluoxetine. In an open-label pilot study, five
patients who have experienced mild to severe TBI were given fluoxetine
hydrochloride 20−60 mg/day. These patients had either no or mod-
erate depression and had no history of previous antidepressant use. The
participants were assessed for cognitive and memory function based on
the HAM-D scale at baseline and after eight months of fluoxetine
treatment. Although only a small size, there was a statistically sig-
nificant improvement in the severity of symptoms including mood and
memory with a p-value < 0.05. Improvements were also seen atten-
tional-motor speed tasks and a letter-number sequencing subtest, re-
flecting the level of a “working memory”of the patients. However, the
small sample size of five patients makes the application of these find-
ings difficult to be applied to all PCS patients [39].
4.3. Amantadine
Amantadine is a medication that has been researched specifically for
headaches in PCS. As a NMDA receptor antagonist, amantadine has
previously been studied for its use in other TBI symptoms, such as
impulsive behavior and disinhibition caused by frontal lobe disorders.
NMDA receptor activation following a concussion leads to non-specific
neuron activation leading to the production of ROS. By using NMDA
receptor antagonists, the firing of non-specific action potentials can be
stopped to prevent further cellular injury. In addition, NMDA receptor
antagonists are also used for its anesthetic and analgesic effects by
blocking the transfer of electric signals between neurons in the brain
and spinal column [40]. When studied for its analgesic effects in PTH,
the treatment course required an intake of 100 mg twice per day for 2
months. Although eighty-percent of patients showed improvement in
headache severity, one-third of the participants discontinued the course
due to side effects, including worsened headaches. Furthermore,
amantadine treatment did not show any improved response in the other
common symptoms of PCS, such as inattention and dizziness. While
amantadine seems to be a potential treatment, more studies are ne-
cessary to properly evaluate its benefits and risks in this patient po-
pulation [41].
4.4. OnabotulinumtoxinA (BOTOX®)
Regardless of the PTH phenotype, early and aggressive therapy is
important to prevent further worsening of the headache. Typically, if
the initial trauma does not result in a loss of consciousness or vomiting,
neuroimaging is not necessary. Due to the resemblance of PTH to mi-
graines and the lack of evidence-based PTH treatment options, patients
are often prescribed migraine treatments, such as triptans [4]. More
invasive procedures, such as BOTOX®and facet blocks, have gained
popularity. BOTOX®seems to be an ideal treatment as it is the only FDA
approved treatment for chronic migraines. As a neuromuscular blocker,
BOTOX®is thought to inhibit the peripheral signaling process to the
central nervous system, preventing central sensitization and therefore
decreasing the sensation of pain in both migraines and PTH [42].
Central sensitization is a protective mechanism that involves the en-
hancement in the function of neurons in nociceptive pathways. This
results in the perception of pain even in the absence of a noxious stimuli
and ultimately leads to pain hypersensitivity. Central sensitization can
be caused by continuous stimuli or by an intense noxious stimuli, in-
cluding the biomechanical force that causes a concussion [43]. When
the mechanism of action of BOTOX®and the resemblance of PTH to
migraines is taken into account, BOTOX®may be a reasonable treat-
ment method. A case study evaluated the effects of BOTOX®in a female
patient who had PTH for 5 years. The patient was given local BOTOX®
injections of 22 IU in the muscles of the facial area, including the
frontalis and corrugator supercilii muscles. The patient reported a de-
crease in pain on the pain scale after 5 days of the initial injection and
was completely symptom free after 10 days [44]. The results seem
promising, however, as this was only a single case study, BOTOX®
cannot be concluded as a single treatment option for PTH [44].
In a different retrospective consecutive case series, BOTOX®was
evaluated for its effectiveness in treating headaches in patients with a
history of mTBI. The study included 64 male subjects that had varying
post-injury times to the first BOTOX®injection. The patients were split
into different groups based on the type of headache: chronic migraine
(CM), cervical dystonia (CD), or mixed syndrome. Regardless of the
group patients were place in, all subjects had a diagnosed chronic PTH.
Patients in the CM group received 31, 5IU injections in fixed sites
(FSFD), while the CD group received injections based on the char-
acteristics of torticollis, a twisted and tilted neck with severe pain.
Patients with mixed syndrome received FSFD with either CD or “follow-
the-pain”(FTP) treatment where specific areas of discomfort was tar-
geted. The mean number of treatments for each patient ranged from 1
to 19 sessions, with intervals of 40–213 days. Clinical outcomes were
measured based on the global evaluation of change (GEC) scale through
patient report with options ranging from better, no difference, or worse.
Following the study, an improvement in symptoms were only reported
by CM patients. In addition, the patients in the study sample were all
white males, causing the effects of the agent to be confined to a certain
population. The limitations of this study makes it hard for these find-
ings to be applied to all mTBI patients experiencing PTH [45].
Epidural injections have also been explored as a treatment option
for patients with potential cervical spine injury due to the initial injury.
The ligaments and cervical muscles, among many other structures
within the cervical spine, can all be involved in triggering and
prolonging PTH. Ultimately, by focusing treatment on the cervical
spine, the triggering of PTH could potentially be reduced. Among the
interventional treatment options for PTH, peripheral nerve blocks are
most commonly used [44]. The theory is based offof the mechanism
that by administering anesthetics, such as bupivacaine and lidocaine to
the nerve, they can inhibit the feedback process of a headache, thus
stopping PTH. Administration of anesthetics at trigger points of the
K. Kim and R. Priefer Biomedicine & Pharmacotherapy 129 (2020) 110406
6

head and neck have also been used as interventional therapy for PTH
[44].
4.5. Nutraceutical supplements
Over the past few years the interest in nutraceutical supplements
and their benefits in many disease states have gained immense popu-
larity [16]. Antioxidants, certain B vitamins, omega-3 fatty acids, vi-
tamin D, progesterone, and some others have shown to provide pro-
tection and/or accelerate the post-concussion recovery process [16]. By
taking the pathophysiology of concussions into account, the effects of
antioxidants have been researched to inhibit NADPH oxidase to coun-
teract the secondary ROS production following the injury [46]. Among
these numerous antioxidants for the treatment of post-concussive
symptoms, melatonin has been a popular choice [46]. As a naturally
produced substance in our body, melatonin is well tolerated with few
side effects when taken as directed. Melatonin is a potent physiological
antioxidant that has neuroprotective, analgesic, and anxiolytic prop-
erties that could potentially be favorable to patients who have PCS. As
discussed earlier, excessive ROS production is one of the main pathways
that cause cellular and tissue damage in PCS. Melatonin could poten-
tially counteract the oxidative stress by acting as an antioxidant. In
addition, melatonin’s possible activity at the gamma aminobuteric acid
(GABA)-ergic system and opiate receptors give its analgesic properties
[46]. The analgesia may be beneficial to improve the common symp-
toms of PCS, such as headaches and pain. In the PLAYGAME pilot trial
data from 2013, melatonin showed a significant response compared to
other treatments for post-concussive symptoms in children with per-
sistent post-concussion symptoms (PPCS). 83 % of the children who
received melatonin showed improvement in PCS symptoms and
headaches with a p-value <0.05. However, with the lack of additional
data, further research is needed to conclude melatonin as a PCS treat-
ment option [46].
An important feature of cellular injury caused by excessive ROS
production is lipid peroxidation. Lipid peroxidation involves the
breakdown of the body’s structural lipids, including those that make up
the cellular membrane and the phospholipid bilayer arrangement.
Additionally, lipid peroxidation is a major source of the other by-
products that are cytotoxic, including aldehydes that are produced from
the breakdown of lipid hydroperoxides [14]. In order to counteract this
toxicity, antioxidants can theoretically be beneficial. Two of the most
accessible and well-known antioxidants are ascorbic acid (also known
as vitamin C) and vitamin E. Besides being an antioxidant itself, vitamin
C also transforms vitamin E, a potent lipid peroxidation inhibitor, into
its active form. A study conducted in rats showed the co-administration
of vitamin C and vitamin E led to a significant decrease in secondary
brain injury due to ROS stress compared to either alone [13]. However,
at high doses vitamin E can lead to serious side effects, including he-
morrhage [13]. Although these findings illustrate that both antioxidants
can be utilized as a treatment option for mTBI, this study’s results
cannot directly be applied to PCS patients, as this is not a human study
[13]. In addition, more research has shown that vitamin C actually
produces pro-oxidant effects. As indicated earlier, following a concus-
sion there is an excessive release of glutamate in the brain due to the
depolarization of neurons, leading to a cascade of reactions that causes
further cellular damage and ROS production [47]. A study utilizing
lipid peroxidation assays (LPOs) showed that vitamin C significantly
increases the oxidant effects of glutamate, leading to further ROS da-
mage [47]. Even without the presence of glutamate, vitamin C alone
induces lipid peroxidation in a dose-dependent manner. Statistically
significant oxidant effects were shown at all doses tested (from 25 to
200 μM) and when added together with glutamate, produced an ad-
ditive amount of ROS damage [47].
Excessive amounts of glutamate results in NMDA receptor activa-
tion, which ultimately leads to the breakdown of various neuro-
transmitters that produce ROS. In a particular study, the relationship
between vitamin C, including its oxidized form dehydroascorbate
(DHA), and NMDA receptor activation was evaluated. NMDA receptor
activity can be functionally measured by evaluating [3 H]MK-801
binding. This study showed that both vitamin C and DHA increased
[3 H]MK-801 binding, indicating that vitamin C directly correlates with
NMDA receptor activity (Fig. 3). Decreased uptake of D-aspartate allows
continuous activation of NMDA receptors, thus leading to further ROS
production. In addition, neurons treated with ascorbate for 30 min
showed decreased membrane surface excitatory amino acid transpor-
ters levels. As glutamate is removed from the synaptic cleft via ex-
citatory amino acid transporters (EAAT), the reduction in transporters
decreases the uptake of glutamate, causing further accumulation. In
addition, increased glutamate levels also led to a profound increase in
[3 H]MK-801 binding. These results show that ascorbate inhibits D-as-
partate uptake and causes extracellular glutamate accumulation,
Fig. 3. Model of vitamin C modulation of the glutamatergic system [47].
Fig. 4. Potential concerns of Vitamin C produces further cellular injury.
K. Kim and R. Priefer Biomedicine & Pharmacotherapy 129 (2020) 110406
7

suggesting that vitamin C increases the amount ROS production via
multiple mechanisms, leading to cellular injury (Fig. 4)[47].
5. Conclusion
Even with established guidelines by the CDC, the prevalence of
mTBIs and the lack of evidence-based treatments is a growing public
health concern. The neurochemical disturbances that occur due to this
injury lead to many symptoms, including headache and decreased
concentration. These symptoms not only decrease the quality of life of
the affected individual, but can continue to progress from acute
symptoms to chronic medical conditions, including PTH and PTSD.
Several different treatment options for these conditions in both the
acute and chronic phase have been researched. For non-pharmaceutical
options, treatments such as prescribed rest, PT, and EEG neurofeedback
have been trialed in patients with non-conclusive efficacy.
Pharmaceutical therapies, including antidepressants and analgesics,
have also shown little efficacy in mTBI patients. Among the pharma-
ceutical therapies, nutraceuticals have gained increasing interest for
their potential benefits in not just mTBIs, but in other health conditions.
Vitamin C has been one of the most widely used nutraceutical in mTBI
treatment. As the production of ROS vastly increases following a brain
injury, the use of vitamin C, an antioxidant, mechanistically makes
sense. However, recent studies suggest vitamin C may actually lead to
further cellular injury in the brain. These findings are concerning as the
number of mTBI incidences are increasing with very few options for
treatment and management of mTBI symptoms. The lack of evaluation
on the injury time of the patients and when each treatment was utilized
is the main downfall of this area, further requiring more studies.
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgements
The authors wish to thank the School of Pharmacy at the
Massachusetts College of Pharmacy and Health Sciences University for
financial support of this project.
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