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Efficacy of Modafinil, Methylphenidate, Amantadine, and Zolpidem in Consciousness Recovery in Intensive Care Unit Patients with Traumatic Brain Injury

Jomi K. Oommen PharmD, PGY1 Pharmacy Practice Resident
Shan Wang PharmD, BCCCP, Critical Care Pharmacist
Alexander Axelrad MD, Department of Surgery
Adel Hanna MD, Department of Surgery
Rajanandini Muralidharan MD, Department of Neuroscience
Jules Osias MD, Department of Neuroscience
Melissa Fazzari PhD, Biostatistics Research Director
Fahd Ali MD, Department of Surgery

ABSTRACT

OBJECTIVE: Traumatic brain injury (TBI) is the most common cause of death and disability in persons between 15 and 30 years of age. Although various pharmacological agents have been reported to enhance consciousness recovery, few trials have studied these medications in patients with acute TBI. The objective of this study was to determine the effect of modafinil, methylphenidate, amantadine, and zolpidem in improving wakefulness in patients with TBI in an intensive care unit (ICU) setting and to identify any adverse drug reactions.

METHODS: Retrospective chart review identified all patients prescribed modafinil, methylphenidate, amantadine, or zolpidem; only patients older than 18 years with TBI in an ICU setting were further analyzed. The electronic medical record was used to retrieve clinical data including patient demographics, mechanism of TBI, drug dosage, treatment duration, Glasgow Coma Scale (GCS) score, length of time to improve GCS score, hospital length of stay, reported adverse drug reactions associated with above medications, and mortality. The primary outcome was the rate of positive response in the clinical neurological exam. Secondary outcomes included change in baseline and final GCS score, time to response, duration of treatment, change in GCS score over time, length of hospital stay, and in-hospital mortality. Descriptive statistics were used to analyze the data. 

RESULTS: The final analysis included a total of 53 patients. Median ages ranged from 44.0 to 61.5 years; 85% of patients were male. Baseline median GCS score was 8.0 in the amantadine group; 6.5, modafinil; 7.5, methylphenidate; and 7.0, zolpidem. The highest positive response rate was 90% in the amantadine group, followed by modafinil, 77%; methylphenidate, 50%; and zolpidem, 36%. The change in baseline GCS score and median final GCS score for amantadine, modafinil, methylphenidate, and zolpidem was 2.5, 3.0, 1.0, and 0, respectively (P = 0.20). The median time to response in days was 1.5, 1.0, 0.5, and 1.0, respectively. Change in GCS score over time for amantadine, modafinil, methylphenidate, and zolpidem was 0.16, 0.38, 0.12, and 0, respectively. Though rare, the most common adverse events were agitation, hypertension, and posturing. 

CONCLUSION: It remains to be determined if these medications have a role in reducing ICU and hospital length of stay, length of mechanical ventilation, tracheostomies, and overall medical costs in managing TBI patients. In our study amantadine was associated with the highest overall positive response rate when used as an awakening agent in TBI. Modafinil was associated with the largest change in GCS score over time.

BACKGROUND

Traumatic brain injury (TBI) is caused by an external force, such as a fall or a motor vehicle accident. It is the most common cause of death and disability in adults between the ages of 15 and 30 years.1 The estimated cost of TBI in the United States in 2010 was $76.5 billion, including direct and indirect medical costs. Ninety percent of total costs is related to severe TBI requiring hospitalization.2,3 

Clinicians commonly use the Glasgow Coma Scale (GCS) to express the level of consciousness of patients with TBI. The scale consists of three components (eye, verbal, and motor responsiveness) that are expressed as a single value ranging from 3 to 15 (see Table 1).4,5 Among patients whose GCS score is 3 between 6 and 48 hours after injury, 65% will die or remain in a vegetative state. When the GCS score is 7 to 13, however, only 10% to 15% will be expected to die or remain in a coma.6

Table 1 Glasgow Coma Scale4,5
  Points
Eye Response
Open before stimulus 4
Open after spoken or shouted request 3
Open after finger tip stimulus 2
No opening at any time, no interfering factor 1
Closed by local factor NT
Verbal Response  
Correctly gives name, place and date 5
Not oriented but communicates coherently 4
Intelligible single words 3
Only moans/groans 2
No audible response, no interfering factor 1
Factor interfering with communication NT
Best Motor Response  
Obeys two-part request 6
Brings hand above clavicle to stimulus on head, neck 5
Bends arm at elbow rapidly but features not predominantly abnormal 4
Bends arm at elbow, features clearly predominantly abnormal 3
Extends arm at elbow 2
No movement in arms/legs, no interfering factor 1
Paralyzed or other limiting factor NT
NT = Non-testable

Modafinil traditionally has been used to improve wakefulness in adult patients with narcolepsy, obstructive sleep apnea, and shift-work sleep disorder. The proposed mechanism of action of modafinil is related to its ability to inhibit the norepinephrine (NE) and dopamine transporters. Additionally, it indirectly affects extracellular levels of serotonin, glutamate, orexin, histamine, and gamma-Aminobutyric acid (GABA).7 Methylphenidate commonly is used for attention deficit hyperactivity disorder (ADHD) and narcolepsy. It blocks reuptake of NE and dopamine into presynaptic neurons.8 Amantadine is used to treat Parkinson’s disease and influenza. This drug appears to act as an N-methyl-D-aspartate receptor (NMDA) antagonist and indirect dopamine agonist.9 Zolpidem is often used for insomnia. Interactions with the benzodiazepine-1 (BZ1) binding site within the alpha subunit of the GABA receptor give zolpidem a unique side-effect profile, whereas the benzodiazepines nonspecifically bind to all BZ receptors.10

These agents are occasionally used off-label to improve the neurological status of comatose TBI patients in the inpatient setting. Few studies, however, have examined these medications’ role in the acute setting. The objective of this single-center retrospective study was to determine the effect of amantadine, methylphenidate, modafinil, and zolpidem in improving wakefulness in intensive care unit (ICU) TBI patients and to identify any adverse drug reactions.

METHODS

We conducted this study just outside New York City at NYU Winthrop Hospital, a 591-bed teaching hospital that serves as a level 1 trauma center. Eligible patients were at least 18 years old, had sustained a TBI and were admitted to an ICU, and had an order for amantadine, methylphenidate, modafinil, or zolpidem.

Exclusion criteria were hypersensitivity to any arousal agent, arousal agents ordered “as needed” or “one time,” patients treated for less than five days, and using the arousal agent for any indication other than TBI.

Because the study was retrospective, it received exempt status from the hospital’s institutional review board. The electronic medical record system identified patients who had been prescribed any dose of modafinil, methylphenidate, amantadine, or zolpidem between January 2013 and November 2017. Patients were further analyzed as per the aforementioned inclusion and exclusion criteria. The following data were collected: patient age, gender, ethnicity, nature of TBI, type of intracranial hemorrhage (ICH) or hematoma, drug dosage, treatment duration, GCS score, length of time to improve GCS score, hospital length of stay, reported adverse drug reactions associated with medications, and mortality (including cause of death). All data were collected, stored, and secured within a password-protected and encrypted computer at the hospital. The first and second authors designed the study. All the authors ensure the accuracy and completeness of the data and the analysis. 

The primary outcome was the rate of positive response in the clinical neurological exam, defined as an increase of at least one point in the GCS score. Other outcomes included change in baseline and final GCS score, time to response, duration of treatment, change in GCS score over time, length of hospital stay, and in-hospital mortality. Adverse events were documented for the duration of therapy.

Statistical Analysis

Summary statistics are presented as median (interquartile range [IQR]) for continuous variables, counts (percent) for categorical variables. A competing-risks analysis was performed to estimate the marginal probability of response and in-hospital mortality, given that a patient’s death would clearly prevent a subsequent response. All analyses were performed in R version 3.4.2. 

RESULTS

Study Participants

Of 843 patients admitted to an ICU for TBI, 53 met all eligibility criteria and were included in the final analysis (Figure 1). Ten patients received amantadine, 22 received modafinil, 10 received methylphenidate, and 11 received zolpidem (Table 2). Baseline characteristics are listed in Table 3

Figure 1 PRISMA Flow Diagram
Table 2 Medications
Medication Frequency Percent
Amantadine 10 19
Methylphenidate 10 19
Modafinil 22 42
Zolpidem 11 21
Table 3 Demographics
    Amantadine Methylphenidate Modafinil Zolpidem
Gender Male 9 (90%) 7 (70%) 20 (91%) 9 (82%)
Female 1 (10%) 3 (30%) 2 (9%) 2 (18%)
Ethnicity/race White 6 (60% ) 7 (70%) 14 (64%) 8 (73%)
Black, non-Hispanic 4 (40%) 1 (10%) 6 (28%) 1 (9%)
Hispanic 0 (0%) 1 (10%) 1 (5%) 0 (0%)
Asian 0 (0%) 1 (10%) 1 (5%) 2 (18%)
Age (median, IQR)   60.5 (47–74) 44 (33–53) 61.5 (41–71) 62 (77–79)
Baseline GCS (median, IQR)   8 (4–9) 7.5 (6–9) 6.5 (5–9) 7 (6–7)
Type ICH Subarachnoid 5 (63%) 5 (63%) 8 (50%) 4 (50%)
Other 3 (38%) 3 (37%) 8 (50%) 4 (50%)
Nature of TBI Fall 6 (60%) 5 (50%) 12 (55%) 8 (73%)
Other 4 (40%) 5 (50%) 10 (45%) 3 (27%)

Outcomes

The greatest positive response rate, 90%, was observed among patients receiving amantadine, followed by modafinil, 77%; methylphenidate, 50%; and zolpidem, 36%. The change from baseline GCS score to final GCS score for amantadine, modafinil, methylphenidate, and zolpidem was 2.5, 3.0, 1.0, and 0, respectively (P = 0.20). The mean time to positive response in days for amantadine, modafinil, methylphenidate, and zolpidem was 1.5, 1.0, 0.5, and 1.0, respectively. Change in GCS score over time for amantadine, modafinil, methylphenidate, and zolpidem was 0.16, 0.38, 0.12, and 0, respectively (Table 4).

Table 4 Outcomes*
  Amantadine Methylphenidate Modafinil Zolpidem
Response 90% 50% 77% 36%
Final GCS score 10.5 (9–11) 10 (6–14) 10.5 (9–13) 7 (3–10)
Change in GCS score 2.5 (2–4) 1 (0–6) 3 (0–5) 0 (-2–3)
Time to response (days) 1.5 (1–3) 0.5 (0–1) 1 (1–4) 1 (0–5)
Treatment length (days) 16 (7–25) 8.5 (5–16) 8 (5–13) 11 (5–14)
Change in GCS score/treatment length 0.16 0.12 0.38 0
Hospital length of stay (days) 37.5 (26.0–44.0) 42 (25.3–57.0) 35.5 (24.5–54.5) 30 (28.0–51.0)
In-hospital mortality 0% 20% 14% 9%
*Data are presented as median (interquartile range) unless otherwise specified

The majority of modafinil patients who had a positive response first responded to modafinil at a dose of 200 mg every 24 hours (six patients). The majority of amantadine patients (four) first responded at a dose of 200 mg every 24 hours. For methylphenidate, two patients started to respond at 5 mg every 24 hours, and another two patients at 10 mg every 24 hours. Finally, three patients who responded to zolpidem did so at 5 mg every 24 hours (Table 5)

Table 5 Response by Dose
  n
Modafinil Responders (n = 17)
Modafinil 100 mg every 24 hours 4
Modafinil 100 mg every 12 hours 3
Modafinil 200 mg every 24 hours 6
Modafinil 300 mg every 24 hours 1
Modafinil 400 mg every 24 hours 3
Amantadine Responders (n = 9)
Amantadine 50 mg every 12 hours 2
Amantadine 100 mg every 24 hours 1
Amantadine 100 mg every 8 hours 2
Amantadine 200 mg every 24 hours 4
Methylphenidate Responders (n = 5)
Methylphenidate 5 mg every 24 hours 2
Methylphenidate 5 mg every 12 hours 1
Methylphenidate 10 mg every 24 hours 2
Zolpidem Responders (n = 4)  
Zolpidem 5 mg every 24 hours 3
Zolpidem 10 mg every 24 hours 1

The overall cumulative incidence of response is presented in Figure 2. The estimated cumulative incidence of response at day 10 was 67%, and 71% at day 20. 

Figure 2 Cumulative Incidence of Response and Death

Adverse Events

The agents were associated with few adverse events. Posturing occurred in one patient on methylphenidate. Agitation occurred in two modafinil patients and one zolpidem patient. Hypertension occurred in one modafinil patient (Table 6). Five deaths occurred and were not attributable to the medications. Causes of death included aspiration pneumonia and acute respiratory distress syndrome, respiratory failure and cardiac arrest, and complications from ICH.

Table 6 Adverse Events
  Amantadine Modafinil Methylphenidate Zolpidem
Agitation 0 2 0 1
Hypertension 0 1 0 0
Posturing 0 0 1 0

DISCUSSION

In this single-center, retrospective cohort study of the use of arousal agents in the acute management of ICU TBI patients, we found that amantadine, followed by modafinil, had the highest positive response rate. The highest change in GCS score over time was with modafinil, followed by amantadine. The medications were associated with few adverse events. 

Previous studies have shown varying results for these medications in the long-term management of TBI-related disorders of consciousness. Jha et al. found there was no consistent and persistent clinically significant difference in fatigue or daytime wakefulness between treatment with modafinil and placebo; patients included in the final analysis were 5.77 years post-injury.11 However, Kaiser et al. reported modafinil to be effective and well tolerated in the treatment of post-traumatic excessive daytime sleepiness, but not of fatigue.12 Methylphenidate was found by Zhang et al. to significantly improve mental fatigue and cognitive functions in TBI patients (two weeks to one year after injury) with insignificant differences in safety compared to placebo.13 In patients who sustained a TBI four to 16 weeks before enrollment, exposure to amantadine was associated with more rapid recovery of cognitively mediated behaviors that serve as the foundation for functional independence.9 Cohen et al. described a case report of a 35-year-old male with anoxic brain injury who showed significant improvement in speech and gait after being given zolpidem twice daily.14

Similarly, a 31-year-old male who was in a permanent vegetative state for three years after a motor vehicle accident had a normal sleep/wake cycle, but no meaningful response to any stimuli by family. Once he was given zolpidem, he became able to awaken and greet his family. He was able to have meaningful conversations, eat food on his own, and perform simple calculations. Maximum arousal occurred one hour after zolpidem administration. His response to commands began to diminish after approximately 20 to 30 minutes. This awoken state terminated after approximately four hours. Since then, the authors report that the patient’s short- and long-term memory had been improving over six years of zolpidem therapy.15

Our study had several limitations. The study population was small and was limited to a single center. This may be a reason why we were unable to achieve statistically significant results. Individual responses were variable, and it is possible that certain subgroups may benefit more than others. The findings may not apply to the larger number of individuals with TBI. Also, the study’s retrospective nature yields many possible disadvantages, such as the difficulty to control bias and the accuracy of written records. Third, the generalizability of the results to nonwhites may be limited due to the underrepresentation of this population. Fourth, some patients received other psychoactive medications (e.g., sedatives and antipsychotics), which may have been confounding factors. Next, the exact time to start, change, or discontinue an awakening agent was never standardized. With this, ethical limitations may have only allowed for a short treatment and assessment period—caregivers were able to withdraw patients who were not responding to other trial modalities, such as intracranial pressure management, seizure prophylaxis, hyperosmolar therapy, and standard intensive care management, including ventilation and nutrition.16 Furthermore, it is not evident that the patients’ improvement in neurological status was a result of the medications alone or of spontaneous awakening. 

Finally, GCS is widely accepted as a tool for TBI classification due to the ease of measurement, reproducibility, and predictive value for prognosis.17 Nevertheless, in patients with a low GCS score, sedation and paralysis, endotracheal intubation, and intoxication may be confounding variables. Furthermore, although we used an increase in the GCS score of one point as a clinically significant difference, the scale is not purely linear, circumstances vary widely, and it is difficult to define rigid criteria for significant changes.5 The Full Outline of Unresponsiveness (FOUR) Score, on the other hand, has been developed to attempt to circumvent these issues, mainly by assessing brainstem function and respiration (Table 7). Unlike the GCS score, however, the FOUR score is more difficult to calculate and has not been studied extensively to predict prognosis.18

Table 7 Assessing Patients Using FOUR Score
  Points
Eye Responsea
Patient can track finer or blink on command, which indicates locked-in syndrome 4
Patient’s eyes open but not tracking 3
Eyes open in response to loud voice 2
Eyes open to pain stimulus 1
Eyes remain closed with pain 0
Motor Responseb  
Patient gives thumbs-up, makes fist, or displays peace sign on command with either hand 4
Patient touches the examiner’s hand after a painful stimulus 3
Flexion response to pain 2
Extensor response to pain 1
No response to pain or generalized myoclonus status epilepticus 0
Brainstem Reflexes
Pupil and corneal reflexes present 4
One pupil wide and fixed 3
Pupil or corneal reflexes absent 2
Both pupil and corneal reflexes absent 1
Absent pupil, corneal, and cough reflexes 0
Respiration
Patient not intubated and breathing regularly 4
Patient not intubated with Cheyne-Stokes breathing pattern 3
Not intubated with irregular breathing pattern 2
Intubated and breathing above ventilator rate 1
Intubated and breathing at the ventilator rate or
having apnea
0
aIf eyelids are closed, examiner should open them and examine tracking of finger. Tester should grade best response after three trials.
bTester should grade best possible response of the arms.

CONCLUSION

In our study, amantadine was associated with the highest overall positive response rate when used as an awakening agent in TBI. Modafinil was associated with the highest change in GCS score over time. Double-blind, randomized controlled trials are needed to confirm our findings. The awakening agents should be studied in acute, subacute, and chronic settings of TBI. It remains to be determined if these medications have a role in reducing ICU and hospital length of stay, length of mechanical ventilation, tracheostomies, and overall medical costs in managing TBI patients.

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