Gabapentin in the management of postconcussion symptoms: Rationale for use and case series

 

Authors:   Marilyn F. Kraus, Mark P. Burns

 

Epidemiologic data from the CDC estimates that approximately 1.7 traumatic brain injuries (TBI) occur annually in the United States.  Of these, approximately 75% of TBI cases each year consist of mild TBI/concussion [1]. However, well-controlled treatment studies in concussion are lacking [2].

Symptoms after concussion can occur for a variable period of time ranging from days to months, or even longer in some cases. This represents a clinical and public health challenge.  Headaches are the most common symptom, along with vestibular problems (e.g., dizziness), insomnia, mood and cognitive disorders.  In terms of neuropharmacologic management, there are no comprehensive guidelines based on well-controlled clinical studies, and symptomatic treatment is often based primarily on the individual clinician’s experience. There has to date been minimal translation from basic science research to actual patient care in concussion management.  There is a need for controlled clinical trials, as well as basic research to better understand the mechanism of neuropharmacologic agents in concussion, both in regards to potential neurorestorative/recovery issues, as well as symptom management.  But the reality is that those are difficult studies to complete, and we need to care for those that come into our clinics.  There is a rational way to approach neuropharmacologic management after concussion, even with current limitations of hard data.

Neuropharmacology after Concussion: The Current Reality

The majority of agents used to treat TBI are used for off-label purposes.  This is the rule in the field of brain injury medicine, not the exception, so it is important to consider how we approach drug usage. In a paper published on off-label use in medicine [3], Dr Kraus was asked to address the issues in the arena of brain injury medicine.  Based on her contribution to that paper, we propose the following guidelines for choice of off-label agents in traumatic brain injury, including concussion:

  1. The physician making the recommendation should ideally be a recognized specialist in the area of brain injury medicine, which is rapidly evolving and has developed into a recognized subspecialty.
  1. There should be a robust literature on clinical use in the same or related conditions that support the rationale for use (e.g., an agent that is helpful in attention deficit disorder may be helpful for attention problems after TBI).
  1. A basic science literature that supports the use of the treatment from an etiologic or pathologic standpoint supplies even stronger support. An example is of agents that may be used for agitation in a patient with a brain injury but also may have a role in neurorecovery: for example, gabapentin or amantadine, agents that have preclinical support for a potential neurorestorative or neuroprotective role.
  1. The risk-benefit ratio should be reasonable based on the available literature and clinical experience. There should ideally be enough safety and tolerability data to assess this in the same or related conditions

Gabapentin: A potential off-label role in managing post-concussion symptoms as a multi-task agent: In this paper we are going to focus on gabapentin as an example of a multi-tasking agent that shows potential when used in concussion. In our experience it can be used to manage several aspects of post concussion symptoms – headache, pain, poor sleep, and neurobehavioral features such as moodiness, irritability and anxiety.  We present a  review of the preclinical and clinical literature that  supports a rational for its use. . We then present a case series as an example of this clinical experience,  although well-controlled clinical  studies in TBI are currently lacking. 

Gabapentin was introduced in 1993 as an adjuvant treatment for refractory partial seizures, and has since been widely used for chronic pain, headaches, and neurobehavioral issues such as anxiety and sleep.  It is a structural analogue of the neurotransmitter γ-aminobutyric acid (GABA), and there have been multiple clinical and preclinical studies that help explain why we believe that gabapentin is efficacious after mTBI.

Gabapentin in pain and sleep quality: Headache and poor sleep are most common complaint after concussion.  Controlled studies using gabapentin in post TBI headache are lacking, but evidence from the pain literature is supportive [4,5]. In a mouse model Takemura and colleagues assessed the effect of gabapentin on neuronal activity and sleep disturbance in an animal model of neuropathic pain [4]. Sciatic nerve-ligated animals showed a significant increase in wakefulness and a decrease in non-rapid eye movement (NREM) sleep during the light phase, and the sleep disturbance was almost completely alleviated by a higher dose of gabapentin [4]. These findings suggest that gabapentin may improve the quality of sleep as well as control pain. It also may help reduce spasticity and pain in spinal cord injury [6, 7]. Use of gabapentin has been shown to reduce morphine requirements and increase norepinephrine levels in CSF after surgery in patients with chronic pain [6, 7].

Gabapentin in mood and behavior:  Mood disturbances are common in mTBI, and gabapentin has been shown to have neurobehavioral benefit in humans and animals [8-10]. In humans, gabapentin was shown to have significant benefit in treating presurgical anxiety in a placebo controlled trial [10] and in reducing anxiety in chemotherapy patients [9]. Small scale, open label trials of gabapentin have shown that it can reduce depression in epilepsy patients [11], however large-scale double blind studies have not been conducted. In animals, the modeling of neuropathic pain by constriction of the sciatic nerve results not only in pain, but also in anxiety-like, depression-like and memory deficits in rats. In a 2012 study, Gregoire et al [8] looked at the role of gabapentin in the treatment of chronic pain as a multidimensional experience. Injured rats exhibited mechanical hypersensitivity, which was reduced by gabapentin (10-30 mg/kg). Pain-induced cognitive impairments in the social recognition memory test, and anxiety-like behavior in the open field test were reduced dose-dependently by gabapentin.

The pathway between central amygdala and ventrolateral periaqueductal gray (vlPAG) is implicated in both pain and anxiety, and it has been shown that gabapentin suppresses activity in this pathway, which may lend to its efficacy [12].

Effect of gabapentin on neuroplasticity, neurorecovery and repair in preclinical models:In experimental ischemia and spinal cord injury, gabapentin has shown significant neuroprotection, however the mechanisms of action are still unclear [13, 14]. Studies suggest that GBP enhanced hippocampal neurogenesis via a NF-κB mediated pathway may be involved in enhanced cognitive and emotional outcome after restraint stress [15].

Autonomic Dysfunction after TBI: By interfering with glutamate neurotransmission, GBP may moderate autonomic dysreflexia (AD), which can result from high spinal cord injury.  Gabapentin has shown benefit in managing paroxysmal autonomic instability with dystonia after severe TBI [15]. There is evidence of autonomic dysregulation observed even after concussion. The resting heart rate can be increased after concussion, and has been shown to accelerate more rapidly with exertion [16, 17]. Clinically, this can be associated with an increase in post concussive symptoms.  Autonomic over activity may contribute to symptomology such as increased heart rate, light sensitivity, pupillary dilation, sleep disturbances, and anxiety [18].

A key issue in the day-to-day management of the cognitive, mood and behavioral sequelae of TBI of any severity is finding treatments that make sense in the setting of TBI. This means rational choices based on what we know of the mechanisms, neuropathology and neurochemical disruptions after TBI, and what we know of their potential relationships to clinical symptoms and impairments. Choice of an agent to use in treatment requires that we use the most current clinical experience (our own as well as the literature) with the agent for certain symptoms or deficits, as well as considering knowledge of an agent’s potential effects on recovery (positive or negative) which may not be immediately apparent.  Gabapentin is an example of a multi-tasking agent with potential in this regard. 

In this case series we assess the use of gabapentin to ameliorate post-concussion symptoms in a cohort of patients presenting to the concussion clinic, with a focus on headache, one of the most common presenting complaints.

Methods

The files of 19 patients who were treated in our concussion clinic, and who were treated with gabapentin, were reviewed and the results reported here. The treating physician was one of the authors (MFK).

The main symptom that gabapentin was used to treat was headache (HA). In these cases, the patients presented with either continuous HA, or significant HA greater than four times per week. Secondary symptoms targeted with gabapentin included sleep problems, and agitation/anxiety. In terms of time out from injury, we generally are conservative with using any medication in the early phase of concussion (e.g., less than 2-3 weeks out), unless symptoms are severe and strongly impacting function. We do not have hard and fast guidelines for who receives gabapentin: it is an individualized clinical call.

Based on the authors experience (MFK) gabapentin was started at 300mg at night and tapered up weekly as tolerated and as effective, generally keeping the largest dose at night to help with sleep and minimize daytime sedation. Most patients did well with only a single nightly dose up to 1200 mg, with others prescribed additional daytime doses if necessary.

The patients also received other standard care, not just medication. For our clinic, which is fairly comprehensive, that can include physical therapy (PT), vestibular rehabilitation, cognitive rehabilitation through a speech language pathologist (SLP), and other therapies as indicated in each individual case.  We attempted to limit the assessment period to a time period in which gabapentin was the only medication for post-concussion symptoms being used.

Outcomes measures: We report Neurobehavioral Symptom Inventory scores (NSI) [19] pre- and post-treatment for patients. The NSI consists of 22 self-report items for symptoms that can occur following concussion. These items include symptoms such as  headache, sleep, and  dizziness, as well as cognitive and mood/behavioral symptoms. Each item is scaled from 0-4, with 4 being the worst, reflecting symptom severity that significantly impacts ability to function.

Results   

The demographics and patient characteristics are presented in Table 1. The outcomes are presented in Table 2.  Duration of treatment was limited to the time during which gabapentin was the only medication being used for post concussive symptoms, and the average of this length of treatment was eight weeks.  It is not uncommon to use more than one medication in TBI management, but we attempted to assess the time period during which only gabapentin was being used.  In reviewing the cases, we could not find a correlation between time from injury and outcome, such that even patients many months out from injury could still report benefit.  We did not see any apparent relationship between demographics and outcome, or injury descriptors such as LOC and outcome.  We report the total NSI scores, and the individual score for headache. But of note, sleep most often was also improved along with headache.

gab_table_1.png

 

gab_table_2.png

 

Adverse events:  Of the 19 patients, 7 reported potential side effects.  Most were mild,    and the patient did not elect to stop the medication.  Sedation or fatigue was reported in 4, worsened sleep was reported in 2, and in 1 case there was an extremity rash that resolved on discontinuation. One patent elected to stop medication due to fatigue.

An overall clinical global impression score (CGI) was assigned to each patient, rated from 0-3. This was based on a thorough review of the chart, including a review of the NSI items, as well as more detailed information obtained during the examination by the physician (MFK):  no response or worse = 0, minimal positive response =1, moderate response = 2 , and a marked response =3 (this was reserved for reported resolution of headache as well as improvement in other symptoms). We found that 10 patients reported a moderate improvement (CGI = 2), 6 patients reported a minimal improvement (CGI = 1), and 3 patients reported no improvement (CGI = 0).

Conclusions

Most pharmacologic treatment used after concussion is off label, and well controlled treatment studies are still lacking. However, a rational approach to the choice of neuropharmacologic agents after concussion can be applied, and we focus on the example of  gabapentin. We supply a rationale for this multi-tasking agent, based on the available literature, and present a small case series as an example. The limits of the case series are well known.  There is always the risk of bias, and the outcome measures are not exact.  We only intend to provide these cases as examples of what is seen in our clinic.  The patients were also receiving other standard care, not just medication. For our clinic, which is fairly comprehensive, that can include PT, vestibular rehabilitation, cognitive rehabilitation through SLP, and other therapies as indicated in each individual case.  We attempted to limit the assessment period to a time period in which gabapentin was the only medication for post-concussion being used. We cannot assert how much improvement is due to these other treatments, or to recovery due to time.  But time out from injury did not appear to correlate with reported response in our limited sample. The patient who was 2 years out from injury reported a good response to gabapentin.  We did not see any obvious relationship between demographics or TBI variables such as LOC and response. We reasonably feel that the results we see are due to comprehensive care, which includes neuropharmacology.  Gabapentin may be contributing to positive outcomes, and appears to be fairly well tolerated. We found it to be helpful for headaches, and other symptoms such as sleep were also often improved. 

There is a role in our treatment decision making for clinical experience, including the case series and open label studies, even though they are not at the level of gold standard controlled trials. Our hope is to eventually complete a more controlled clinical trial. In the meantime, we have to treat our patients to the best of our abilities and help them get back to their previous level of function if possible. As part of a comprehensive approach to the management of concussion, neuropharmacology plays a role, and we feel that gabapentin is a rational option.

References

1. Faul, M.D., et al., Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths, 2002-2006. Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, 2010.

2. Meehan, W.P., 3rd, Medical therapies for concussion. Clinics in sports medicine, 2011. 30(1): p. 115-24, ix.

3. Vox, F., et al., Balancing burdens and benefits: ethical issues of off-label prescription pharmaceutical use. PM R, 2013. 5(10): p. 882-9.

4.         Takemura, Y., et al., Effects of gabapentin on brain hyperactivity related to pain and sleep disturbance under a neuropathic pain-like state using fMRI and brain wave analysis. Synapse, 2011. 65(7): p. 668-76.

5.  Hayashida, K., et al., Gabapentin acts within the locus coeruleus to alleviate neuropathic pain. Anesthesiology, 2008. 109(6): p. 1077-84.

6. Gruenthal, M., et al., Gabapentin for the treatment of spasticity in patients with spinal cord injury. Spinal cord, 1997. 35(10): p. 686-9.

7. Priebe, M.M., et al., Effectiveness of gabapentin in controlling spasticity: a quantitative study. Spinal cord, 1997. 35(3): p. 171-5.

8. Gregoire, S., et al., Study of emotional and cognitive impairments in mononeuropathic rats: effect of duloxetine and gabapentin. Pain, 2012. 153(8): p. 1657-63.

9. Lavigne, J.E., et al., A randomized, controlled, double-blinded clinical trial of gabapentin 300 versus 900 mg versus placebo for anxiety symptoms in breast cancer survivors. Breast cancer research and treatment, 2012. 136(2): p. 479-86.

10. Clarke, H., et al., Gabapentin reduces preoperative anxiety and pain catastrophizing in highly anxious patients prior to major surgery: a blinded randomized placebo-controlled trial. Canadian journal of anaesthesia = Journal canadien d'anesthesie, 2013. 60(5): p. 432-43.

11. Miller, J.M., et al., Depressive symptoms in epilepsy: prevalence, impact, aetiology, biological correlates and effect of treatment with antiepileptic drugs. Drugs, 2008. 68(11): p. 1493-509.

12. Tupal, S. and C.L. Faingold, The amygdala to periaqueductal gray pathway: plastic changes induced by audiogenic kindling and reversal by gabapentin. Brain research, 2012. 1475: p. 71-9.

13. Kale, A., et al., Neuroprotective effects of gabapentin on spinal cord ischemia-reperfusion injury in rabbits. Journal of neurosurgery. Spine, 2011. 15(3): p. 228-37.

14.  Traa, B.S., et al., Gabapentin neuroprotection and seizure suppression in immature mouse brain ischemia. Pediatric research, 2008. 64(1): p. 81-5.

15.  Valente, M.M., et al., alpha2delta ligands act as positive modulators of adult hippocampal neurogenesis and prevent depression-like behavior induced by chronic restraint stress. Molecular pharmacology, 2012. 82(2): p. 271-80.

16. King, M.L., et al., Heart-rate variability in chronic traumatic brain injury. Brain injury : [BI], 1997. 11(6): p. 445-53.

17. Gall, B., W. Parkhouse, and D. Goodman, Heart rate variability of recently concussed athletes at rest and exercise. Medicine and science in sports and exercise, 2004. 36(8): p. 1269-74.

18.  Hanna-Pladdy, B., et al., Stress as a diagnostic challenge for postconcussive symptoms: sequelae of mild traumatic brain injury or physiological stress response. The Clinical neuropsychologist, 2001. 15(3): p. 289-304.

19. Cicerone, K. and K. Kalmar, Persistent postconcussion syndrome: The structure and subjective complaints after mild traumatic brain injury. The Jounral of Head Trauma Rehabilitation, 1995. 10(3).


About the Authors: 

1MedStar National Rehabilitation Hospital, Washington, DC 20010, Georgetown University Medical Center, Departments of Physical Medicine and Rehabilitation, Psychiatry and Neurology
2Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057

Acknowledgements: This work was supported by a MedStar/Georgetown Univeristy Partnership Award to MFK and MPB, and R01 NS067417 from the National Institute for Neurological Disorders and Stroke to MPB.

Keywords: 

mild brain injury, concussion, gabapentin, headache, postconcussion syndrome, PCS

Address correspondence to:

Marilyn F. Kraus, M.D.,
MedStar National Rehabilitation Hospital,  
102 Irving Street, NW,
Washington, DC 20010, 
Ph: 202-877-1686 
e-mail: Marilyn.Kraus@medstar.net