Persistent Post-Concussive Symptoms: Pharmacology
Author: Andrew Schleihauf
After covering introduction, imaging and treatment strategies of persistent post-concussive symptoms (PPCS), also termed post-concussion syndrome, we continue by examining the evidence behind commonly used pharmacologic agents. There are some providers that manage concussions without prescribing any medications and only recommend over-the-counter acetaminophen or ibuprofen. Other providers may try to treat symptoms of concussion with pharmacologic agents. Management likely depends on how many concussions the individual sees, treatment options available and region of practice. It is important to note that there is still no medications that is FDA approved to specifically treat persistent post-concussion symptoms. Many of the medications used are off label and approved for other conditions and some medications used require close monitoring and follow up. Attempts should be made to wean patients off of any medications used to treat PPCS symptoms after they have recovered.
A 2013 survey reported that 89% of 220 providers managing pediatric concussions reported the majority manage symptoms with medications with acetaminophen most common (62%), followed by NSAIDs (54%). The next most commonly prescribed medications were tricyclic antidepressants (23%), amantadine (10%) and methylphenidate (10%). It was also more common for providers to use these types of medications if they see more than 16 concussions per year (1). The most recent position statement from AMSSM breaks down post-concussive symptoms into vestibular, ocular, cognitive, fatigue, anxiety/mood and headache/migraine (2). The vestibular and ocular categories were previously covered. The other symptoms are more likely to be treated pharmacologically.
Headaches are the most common symptom associated with concussions and many providers will treat post concussive headaches with medications besides acetaminophen or NSAIDs. Headaches related to concussions are sometimes separated into tension-type headaches and migraine-type headaches (3). Tricyclic antidepressants, such as amitriptyline and nortriptyline, are commonly used. Amitriptyline has been used for migraine prophylaxis and it was shown to be effective during randomized trials in the 1970s, 80s and 90s (4-7). One specific retrospective study in 1980 showed 90% or patients suffering from post traumatic headaches had an excellent or good recovery (8). It was more recently also shown to be more effective in decreasing headache frequency compared to placebo at 8 weeks in a 2011 trial (9). Because it has been shown to treat both tension-type headache and migraine type headaches and has sedating effects that can aid with sleep disturbance, it remains a popular choice today.
Other medications commonly used are topiramate, triptans and beta-blockers. One retrospective study in 2011 in 100 military members undergoing treatment for post-traumatic headache showed topiramate to be superior to tricyclics for headache prophylaxis. Triptan medications were shown to have efficacy in aborting headaches (10). Another prospective, nonrandomized, uncontrolled study using prophylactic medications for severe post-traumatic migraine (propranolol and amitriptyline) revealed satisfactory results in 21 of 30 patients (11). Propranolol has been shown to decrease mortality after moderate to severe TBI and crosses the blood brain barrier. However, most studies conducted are for patients with moderate to severe TBI and in the hospital setting (12). Other pharmacologic therapies used for headaches with limited data include botulinum toxin injections, occipital nerve blocks, manual therapy and acupuncture.
Cognitive symptoms commonly associated with PPCS include slowed processing speed and difficulty with memory and concentration. The use of neuropsychological testing as part of collaborative care has been spreading in recent years and helps reveal deficits in this area. Methylphenidate has been studied more than most agents and has been shown in randomized controlled trials to treat deficits in attention, speed of processing and general cognitive functioning (13-15). The decision to start a stimulant such as methylphenidate needs to be done on a case by case basis and the provider should be comfortable with medication interactions, side effects and provide close follow up.
The second most common medication used to treat cognitive deficits is amantadine, a dopaminergic agent. Studies have mostly been after a range of traumatic brain injury and the evidence is mixed. It has been shown to be safe in both pediatric and adult populations (16). A retrospective case series involving 25 patients showed improvement in neuropsychiatric testing scores and decreased cognitive symptoms (17). One case-controlled trial on 54 patients aged 3-18 showed an increase in a cognitive functioning scale in 63 percent of patients treated (18). A 2019 retrospective review in 33 patients with PPCS treated with amantadine showed a significant decrease in headaches for 80% of patients, but up to one-third of the patients in the study stopped amantadine due to side effects. There was little improvement in memory, dizziness or personality changes (19). Other trials showing little or no improvement include a randomized controlled trial showed no significant difference on neuropsychological measurements (20). One study in 27 pediatric patients suggested cognition may be improved, but differences were not shown to be statistically significant (16). A more recent randomized controlled trial in 2018 with 168 patients with chronic TBI (greater than 6 months) showed no improvement in cognitive functioning (21). A similar medication, memantine, is a medication that has shown some promise in rodent studies and early studies in human in regards to protection of neurons and possibly cognitive function. Other medications that may be used with limited evidence include bromocriptine and donepezil.
Sleep-wake disorders are another common symptom that is potentially amenable to pharmacologic therapy. Both hypersomnia and insomnia have been reported in patients following concussion (22) and may affect patients two to three years after their initial injury (23). Discussion should always begin with sleep hygiene and limiting stimulation before bedtime. Melatonin is the most commonly used agent and has minimal side effects. A 2018 randomized controlled trial in patients with mild to severe TBI showed an increase in subjective sleep quality (24). Another randomized controlled trial is set to finish in 2019 in patients with PPCS (25). Trazodone is a heterocyclic antidepressant and one of the most frequently prescribed drugs for treatment of insomnia in TBI patients and is generally well tolerated. For insomnia in the general population, trazodone increased sleep duration compared to placebo and in patients with comorbid depression was also found to increase total sleep time (26). There are no clinical trials published investigating concussion and trazodone use, but it may be an option in a patient with sleep disturbance and co-existing depression. Other medications such as zolpidem and zapleplon are used in some cases but there is very limited data in patients with concussion or TBI.
Anxiety and mood symptoms related to chronic TBI occur in 20-50 percent of this population (27). SSRIs are commonly used in the general population to treat depressive or anxiety symptoms, but data is limited in regards to treating PPCS symptoms. Sertraline and citalopram are the most commonly studied medications. A double-blind study comparing methylphenidate, sertraline and placebo showed significant decreases in depressive symptoms when compared to placebo and the methylphenidate group also showed an improvement in cognitive symptoms (28). Two randomized trials have been conducted in patients with mild to moderate TBI that criteria for major depressive disorder (MDD). A ten week randomized double blind trial showed significant time effect for improvement compared to placebo (29). Another single blind nine week trial in patients treated with sertraline resulted in significantly less depressive symptoms and 67% of the patients had full remission of major depressive symptoms (30). A prospective cohort study found a significant decrease in depressive symptoms after 6 weeks of treatment with citalopram in patients suffering from PPCS (31). Other medications that are used with more limited evidence include other SSRIs such as fluoxetine and SNRIs such as venlafaxine.
Treating emotional or psychological symptoms can be challenging due to the natural course of mood symptoms as the brain recovers. SSRIs may be used prior to their injury and providers may able to adjust the dosage. This should be done in collaboration with any psychiatrists or neuropsychiatrists if they already treating the patient. Mood disorders can also develop as a result of prolonged concussion symptoms and referrals and treatment need to be made when appropriate.
In summary, there are no FDA approved medications to specifically treat persistent post-concussive symptoms, but many medications used to treat symptoms. Prolonged headache symptoms are often treated prophylactically with tricyclic antidepressants and topiramate and have a few studies that show benefit for migraines. Cognitive symptoms have been shown to improve with methylphenidate following TBI, but should be used with caution. Amantadine is commonly used and has conflicting evidence. Melatonin is used for sleep wake disorders following concussion with a recent study showing promise, with another trial pending. Lastly, mood symptoms are commonly treated with SSRIs with a moderate amount of evidence following mild TBI. Medications should be weaned as the patient recovers, collaborative care should be utilized and paired with more evidence based therapies covered previously.
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