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10 Articles in Volume 17, Issue #10
A Guest Editorial on Counterfeit Pain Medication: The Other Epidemic
A Model to Incorporate Functional Medicine into Chronic Pain Care
Chronic Pain and Substance-Related Disorders
Getting at the Root of Opioid-Induced Constipation (OIC) with an Osteopathic Approach
Inside FDA's Guidance on Generic Abuse-Deterrent Opioids
Neural Pathway Pain — A Call for More Accurate Diagnoses
Pain Care in a Natural Disaster
Pharmacological Interventions in Sport-Related Concussion
The Internet of Medical Things
What Type of Withdrawal Symptoms from Tramadol Might a Patient Experience?

Pharmacological Interventions in Sport-Related Concussion

A review of treatment options and case examples provide insight into post-concussion management.

In recent years, there has been increasing attention paid to the impact of concussion and the potentially detrimental effects this type of injury may have.1,2 Langlois et al identified an approximate 1.6 to 3.8 million concussions occurring annually in the United States.3 In particular, sport-related concussion (SRC) is a type of injury that has seen a considerable increase in identification, understanding, and research. Estimates report that traumatic brain injury in youth athletes (ages 0 to 19) account for approximately 173,285 emergency room visits yearly, a trend that continues to rise.4 High-profile cases involving athletes with concussive injuries remain forefront in the news cycle, and SRC has been a major health concern in young adult and college-aged athletes as well, occurring at an incidence rate of 4.47 per 10,000 athletes exposures (AEs).5

Lincoln et al6 provided dramatic representation of the increase in rate of concussion in boys and girls youth athletics over 10 years. They noted an average yearly increase of 15.5%, from 0.12 per 1000 AEs in 1997-1998 to 0.49 per 1000 in 2007-2008.6 The findings of Zuckerman et al further suggested that overall incidence of concussion in NCAA athletes did not increase between the 2009-2010 and 2013-2014 seasons, although certain sports (eg, men’s football, women’s ice hockey, and men’s lacrosse) did show statistically significant increases.5 (see Table 1).

As the scope of the problem grows, efforts are aimed at further understanding the factors associated with SRC that impact treatment, time course, complications, and return-to-play (RTP) and return-to-learn (RTL) protocols.

As defined by the Concussion in Sport Group, sport-related concussion is a traumatic brain injury induced by biomechanical forces.6-8 Concussion may be caused by an impulsive force resulting from an impact to the head or transmitted to the head from another part of the body. There is typically a rapid onset of short-lived impairments in neurological function that resolve spontaneously. While in some cases there may be neuropathological changes, the acute symptoms likely reflect a functional impairment rather than a structural problem. A range of clinical signs and symptoms are typically resolved following a sequential course.7

The pathophysiology of concussion involves a complex cascade of biochemical processes that may lead to a dysregulation of ions and neurotransmitters, and increases in free radicals and inflammatory mediators.9 Common clinical presentations involve physical signs (loss of consciousness, amnesia), behavioral changes (irritability), cognitive impairment (slowed reaction times), sleep disturbance, and symptoms categorized as somatic (headache), cognitive (in a fog), and/or emotional symptoms (mood lability).7

The majority of sport-related concussions resolve within 14 days of initial injury.10 These cases often benefit from behavioral therapies (eg, physical and cognitive rest) and careful adherence to regulated RTP and RTL protocols, according to Meehan’s widely adhered-to recommendations in Medical Therapies for Concussion. 11 (Table 2 offers a summary of steps and goals.)

Both the RTP and RTL protocols are a graded set of activities designed to reintegrate athletes into physical and cognitive activity while mitigating the risk of symptom exacerbation after a concussion.12-14 RTP is a standardized strategy proposed by the Concussion in Sport Group,6 intended to be implemented following a 24- to 48-hour period of rest after initial insult. Once initiated, each stage (in youth and adolescents) is adhered to for no less than 24 hours before advancing to the next stage (some collegiate and professional RTP protocols do not mandate 24 hours per step). In the event of worsening of symptoms, the athlete is advised to cease activity; once symptoms have resolved, the athlete then returns to the previous step. If symptoms persist, referral to a clinician with expertise in the management of concussion may be warranted.14

However, approximately 10% of SRCs may persist longer than two to three weeks, at which point the symptoms may be classified as post-concussion syndrome (PCS).12-15 Patients suffering from PCS may benefit from pharmacological interventions. While there are relatively few standardized or evidence-based approaches to pharmacotherapy in concussed athletes, there are recommendations and treatments to consider. No medication to date has proven to speed recovery from traumatic brain injury, 16 and different categories of medication may be useful to target specific symptoms related to concussive injuries.

 

Case #1: Delayed Appearance of Concussion Symptoms in 10-Year-Old

A 10-year-old girl presented to a sports medicine specialty clinic approximately one month after sustaining a concussion while playing softball. This was her first lifetime concussion. There was no reported loss of consciousness or amnesia after the initial insult, and no other injuries were sustained at that time. Initial symptoms included headache, nausea, and dizziness. Shortly after, she began to experience more severe dizziness, nausea, and fatigue, as well as elevated distractibility, issues with memory, poor concentration, and mental fogginess. She also reported worsening in headaches, and it was noted that there was a strong family history of migraine. She missed 15 days of school before being able to gradually increase her attendance by several hours a day.

Her sports medicine physician referred her to a neurologist and occupational/physical therapists; with treatment, dizziness and related motor impairments gradually improved. Neurology initially recommended 10 mg of amitriptyline nightly to prevent headaches and naproxen to target acute symptoms. On follow up, the amitriptyline was deemed effective, but there were concerns of rebound headaches potentially occurring due to overuse of naproxen. She was switched to 300 mg of gabapentin nightly for the headache prevention, as well as 7.5 mg of meloxicam to target acute headache symptoms, and 25 mg of sumatriptan as needed when the meloxicam proved unsuccessful. She responded to this regimen without any side effects, and experienced a remission of headache symptoms. After six months, however, cognitive deficits included mental fogginess, inattention, and poor concentration persisted. Additionally, she began to experience symptoms of depression due to her inability to once again function at her baseline academic levels.

She was the referred for psychiatric evaluation of these cognitive deficits. At that visit, the prominent symptoms of mental fogginess, inattention, and poor concentration were addressed. After careful consideration of risks and benefits, as well as other treatment options, she was started on a daily morning dose of 20 mg of lisdexamphetamine. At follow up one month later, she and her family reported improvements in concentration and focus, and a decrease in overall anxiety as her cognitive function was nearing baseline. She did not experience any adverse effects from the medication. She was able to gradually increase her physical activity, but had not progressed to full sport participation.

 

This article provides an overview of these classes of medications, along with case examples that may be useful for practitioners in developing pharmacological treatment strategies for patients suffering from prolonged symptoms of sport-related concussion.

Standard of Care

Meehan recommended initiating pharmacological treatment for concussion only after the following conditions were met:11

  • The athlete’s symptoms have exceeded a typical recovery for a sport-related concussion
  • The symptoms negatively affect the patient’s life to such a degree that the possible benefit of treatment outweighs the potential risks of the medication being considered
  • The clinician caring for the athlete is knowledgeable and experienced in the general assessment and management of SRC or concussive brain injury.

Meehan also noted that initiation of psychiatric medication for the treatment of concussion-related symptoms should be withheld until other treatment options have proven unsuccessful.11 Patients and caregivers should, of course, be educated about potential side effects and the importance of titration. Medications that have potential for increasing confusion or causing sedation, fatigue, or drowsiness, should be avoided as they may mask underlying symptoms of concussion and make recovery monitoring difficult.11,17-20 Especially pertinent to the care of athletes is understanding that certain medications impact metabolism, which may be further affected by exertion and high rates of exercise.21-25

 

Case #2: Co-Occurrences of Anxiety and Depression with Concussion

A 17-year-old female presented at a sport concussion specialty clinic one month after sustaining a concussion; she had been elbowed in the head while playing basketball. At the time of injury, she reported dizziness and headache but continued to play. There was no reported loss of consciousness or amnesia. She eventually left the game due to these symptoms, and several nights later, she struck her head on the headboard of her bed. At the time of the clinic evaluation, she reported persistent nausea without vomiting or dizziness, heightened irritability, anxiety, and depression, the latter of which she attributed to the recent death of a friend. She was referred to pediatric neurologist and successfully treated for headaches with topiramate and riboflavin, as well as rizatriptan as a migraine abortive agent. Approximately 3 months after the concussion, she was asymptomatic and cleared to engage in the return-to-play protocol, which she completed successfully with no major setbacks.

Just over two years later, she returned to the clinic after her second lifetime concussion. At the time of the encounter, she reported that she had been hit in the face with a basketball 6 months earlier, which resulted in a fractured nose. Her initial symptoms included mild nausea, dizziness, imbalance, and decreased energy, all of which she reported as waxing and waning. She also reported experiencing persistent anxiety, emotionality, and panic attacks. When asked directly, she admitted to feeling depressed most of the time. She had received treatment for the nasal fracture, but had not sought treatment for the concussion and had not returned to any level of exertional physical activity. She was referred to psychiatry for additional treatment targeting mood symptoms.

At her psychiatric intake, it was noted that, while the mood symptoms were heightened after her second concussion, there was a significant history of baseline anxiety and depression. After careful deliberation and discussion with family, she was started on fluoxetine. She was followed closely for the next several months, and after showing mild response to a starting dose of 20 mg daily, she was increased to 30 and then 40 mg daily. After several weeks on 40 mg daily, she achieved near complete remission of the anxiety and mood related symptoms. She was able to successfully return to sports and eventually entered college where she was active in intramural basketball.

Cognitive Treatments

Dopamine has been well studied as a neurotransmitter involved in frontal lobe function,26-27 and multiple studies have demonstrated that dopamine antagonists may have a negative impact on recovery from concussion.28-29 Additionally, early studies have shown improvements in functional outcomes after brain injury when treated with medications that facilitate dopamine transmission.30-31

Amantadine

Amantadine leads to presynaptic release of dopamine and inhibits its reuptake, thereby increasing the amount of dopamine available in the synaptic cleft. Amantadine may also lead to increased density of postsynaptic dopamine receptors. Reddy et al32 studied the effects of amantadine treatment on a sample of adolescent subjects with sport-related concussion (25 male, 14 female, average age 15.54 years) who failed to recover after 21 days compared to a matched control group (25 male, 14 female, average age 15.68 years). The experimental group was given 100 mg amantadine twice a day for three to four weeks. Pre- and post-test performance comparisons using the Immediate Post Concussion Assessment and Cognitive Testing (ImPACT) found significantly greater improvements in the experimental group in the domains of symptoms, verbal memory, and reaction time. However, the experimental group had statistically greater symptoms and decreased neurocognitive performance prior to treatment; this group completed the study with similar symptom reporting and performance on all four ImPACT components, leading some to question potential treatment benefits.33

 

Case #3: Rebound Headaches and Rest Breaks in Post-Concussive 13-Year-Old

A 13-year-old girl presented at a specialty sports concussion clinic approximately one year after sustaining two hits to the head. The first involved bumping her head on a bedframe, which precipitated headaches. The second involved being hit in the head while playing basketball. Initial symptoms included headache, nausea, dizziness, blurry vision, and personality change. There was no reported loss of consciousness after either impact. Symptoms improved and her pediatrician cleared her to begin the return-to-play protocol, which she completed and resumed playing basketball within one month.

Approximately 9 months, symptoms recurred (impaired concentration and memory, and persistent headaches) without a definitive injury. Her pediatrician withheld her from further basketball. Electroencephalogram and computed tomography scans were negative; magnetic resonance imaging showed an incidental pineal cyst that would require serial monitoring by neurology. Her family had been giving her acetaminophen for the headaches with limited improvement, and avoiding ibuprofen due to concerns of rebound headaches.

On her initial visit to the clinic, the patient was encouraged to take 200 mg of magnesium and 200 mg of riboflavin, both twice a day, to target the ongoing headaches, as well as 1 mg of melatonin at bedtime to help with sleep; she was also advised to take 15-minute rest breaks at school as needed. At follow up two weeks later, she had started taking the magnesium and melatonin, but had not obtained the riboflavin. She had been engaging in light physical activity that was triggering headaches, and admitted that she was not utilizing rest breaks at school. There was no notable improvement in the headaches.

She was seen in clinic once again two weeks later. At that time, she was still taking magnesium and melatonin and had started riboflavin. She continued light exercise without provocation of her headaches, and was now taking rest breaks at school as needed. She noted that her headaches had resolved, and she was once again cleared to initiate a return-to-play protocol at a slowed rate. After completing the RTP, she was instructed to decrease the dose of the supplements by half, and after one week (and with no recurrence of symptoms at rest or with exertion), to discontinue them. She resumed basketball and remained asymptomatic.

 

Psychostimulants

Other studies have examined the role of stimulants, such as methylphenidate and amphetamine, in the treatment of concussion. Methylphenidate binds to and blocks dopamine (and a lesser extent norepinephrine) transporters, inhibiting reuptake and leading to an increase in availability of both catecholamines in the synaptic cleft. In a randomized, double-blind, placebo-controlled trial, Whyte et al34 were able to demonstrate that non-athlete adults with traumatic brain injury (TBI) who were prescribed methylphenidate had an improvement in performance speed on attention tasks compared to a control group. Follow-up studies demonstrated similar results while others have been unable to reproduce these findings, and research specific to athletes remains limited.33,35-36

Amphetamines, on the other hand, not only block the reuptake of dopamine and norepinephrine, but also directly promote the release of these neurotransmitters. Research conducted on the effect of these medications on traumatic brain injury, such as that of Tramontana et al,37 studied the impact of lisdexamphetamine on adults with non-sport related TBI in a 12-week randomized, double-blind, placebo-controlled, cross-over trial. Researchers found that positive treatment effects were found in the domains of sustained attention, working memory, response speed stability, endurance, and executive function. Although the study did not specifically target athletes, it is reasonable to consider that athletes who have suffered TBI may gain similar benefits.

Mood and Anxiety Treatments

Emotional disturbances are commonly experienced after a sport-related concussion. Many athletes report increased irritability.17 Other common symptoms include subjective sadness, depression, nervousness, and/or mood lability.38 Symptoms may heighten with pre-existing or family history of psychiatric illness.7,39 Higher baseline endorsement of depression and anxiety symptoms have been associated with increased likelihood of depressive and anxiety symptoms following a SRC.40  Other studies have demonstrated that pre-injury anxiety may predict development and incidence of post-concussion syndrome.41 When treating patients with PCS, it is important to screen for premorbid psychiatric illness.

Reddy et al17 recommended serotonin-selective reuptake inhibitors (SSRI) for emotional disturbance following concussion. Other studies have examined the use of sertraline, fluoxetine, and citalopram in non-athletes with brain injury.42-45

Since SSRIs may take several weeks or even months to reach full efficacy, Meehan11 recommended that management of these medications be left to clinicians with expertise in the treatment of depression. Other treatment options may include medications such as amitriptyline, nortriptyline, or trazodone (which may be sedating and therefore beneficial in cases of concomitant insomnia).25,29,33,46

Somatic Treatments

Although a common symptom occurring after sport-related concussion, headaches may be difficult to treat due to a myriad of potential underlying causes.47 In the aftermath of a concussion, headaches have been reported to be more common in individuals (both athletes and non-athletes) with a personal or family history of headaches or migraines.10,48 Nonsteroidal anti-inflammatory drugs may have a role in the short-term treatment of post-concussive headaches. However, long-term use of such medications may lead to rebound headaches that further complicate recovery.11

Several studies have found that amitriptyline (a tricyclic antidepressant) provides relief from post-traumatic headache.49-51 Reports examining a military population suffering from posttraumatic headaches, for example, suggested that daily treatment with topiramate may be effective.52 However, topiramate is known to have a cognitive blunting effect at higher doses and should be used with caution.53 Another study looked at 34 non-athletes with post-concussion headache and symptoms characteristic of post-concussion syndrome; after treatment with intravenous dihydroergotamine and metoclopramide, subjects reported improvement in headache (85%), memory (91%), sleep (94%), and dizziness (88%).54

Triptans may also be considered, often in conjunction with anti-nausea medications, to target migraine-like symptoms. While this family of medications does not prevent migraines, it may reduce symptoms.46,55 Valproate (Depakote) is an anticonvulsant that has been studied for the treatment of post-concussive headaches in military populations.56 This medication has considerable side effects and should be used with caution. Over-the-counter treatments that may be beneficial in preventing headaches include magnesium, butterbur, riboflavin, coenzyme Q10, and Feverfew, though further controlled research on these options is warranted.57

Sleep Treatments

Sleep disturbance is a well-documented and frustrating sequela of concussion.58 While some patients may experience hypersomnia in the immediate aftermath of a concussion, disturbance may develop into hyposomnia, trouble staying asleep, or disrupted sleep/wake patterns that can exacerbate other symptoms, such as fatigue, restlessness, and anxiety.58 After trialing behavioral interventions (eg, sleep hygiene, limiting caffeine and exposure to electronics at bedtime, and behavioral modification), pharmacotherapy may be considered.

Over-the-counter medicines such as melatonin may be offered initially, while medications such as trazodone or amitriptyline may be considered when OTC supplements are ineffective. As referenced above, amitriptyline has the added potential benefit of improving headache and depressive symptoms.11 Benzodiazepines and other sedative hypnotic agents may be discouraged due to potential amnestic properties and potential for worsening cognition.17

Conclusion

This review encompasses some the potential pharmacological and nonpharmacological treatments following sport-related concussion. Primary approaches may begin with behavioral interventions and a gradual return to play. The role of pharmacotherapy in the management of SRC continues to warrant empirical investigation. At this time, medication-based treatments are off-label, as evidence-based studies examining these interventions are lacking. However, studies are underway to determine the efficacy of current treatments. As practitioners’ ability to detect, diagnose, and manage concussion improves, so too will the ability to aid recovery from concussion.

 

Disclosures: Dr. Solomon reported receiving consulting fees from the Tennessee Titans (NFL), the Nashville Predators (NHL), and the athletic departments of several universities (fees paid to institution). He is a consultant to the Department of Health and Safety and the National Football League.

 
 
Last updated on: December 7, 2017
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