Treatment Of Traumatic Head Injury

In present days, the survival rate of head-trauma patients with neurological impairments and TBI affected disabilities increase with the better understanding of altered complex cascades of molecular and cellular events that developed after TBI and with modern as well as most advanced therapeutic management. There are several potential medications have been introduced that may prevent the occurrence or decline the effects of secondary brain insult, also helps in rapid recovery by increasing functions of neurological events without affecting others. Recently, the TBI-related revised medical treatment guidelines or regulatory alert or The U.S. Food and Drug Administration (FDA) warning are published by National Guideline Clearinghouse (NGC), which are as follows-

• According to FDA warning guideline published on December 14, 2016 – Recent studies suggest that general sedation and anaesthetic drugs that are widely used in case of surgical process may have a negative impact on brain function like behavioural or be learning changes in children (infants or toddlers); even very little exposure can be harmful in case of pregnant woman as the drugs can affect the child’s brain development.
• On August 31, 2016, another review was published by A.U.S. FDA which states that the commonly used pain and cough reliever opioid medicines in combination with benzodiazepines which usually affects the dejected central nervous system also share some serious side effects like reduced and stressful breathing even may lead to death also. Now, these drugs are prescribed with the prominently labeled warning.
• On May 10, 2016, the U.S. FDA include another warning for the antipsychotic Olanzapine drug that results in a severe and rare skin allergy that can impact on other body parts also. Drugs with olanzapine in composition now contain a warning label mentioning the fact of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
• On March 22, 2016, the U.S. FDA issued another warning measure for the pain reliever opioid drugs as it may cause deadly interactions with some specific medicines, also hampers the functioning of hormones like adrenaline and sex hormones. (Guideline.gov, 2017)

Plan for the use of Pharmacological Intervention in the treatment of TBI:  

The use of pharmacological interventions should be taken with great care and after discussing the pros and cons of the therapeutic medications like its adverse effects, ineffectiveness, overdose and several other details with the respective patient’s family members to avoid the further hazard in the treatment process.

Selection of target-based therapeutic agent is the most difficult decision that must be made after very precise and attentive analysis of the present disabilities and other associated factors like lesion nature and how much time passed after brain injury. (Bcmj.org, 2017)

The role of Psychostimulant drugs:

Attention deficit hyperactivity disorder (ADHD) is a condition that has almost similar symptoms and characterization to brain injury and also associated with aberrations of neurotransmitter can be treated with Psychostimulant drugs like methylpheni­date. (Evans and Gualtieri, 1987)

This drug usually thought to bind with dopamine receptor, thus prevent the reuptake and then enhancing the extracellular level of dopamine, specifically in frontal cortex area (Challman and Lipsky, 2000). It may also enhance the level of serotonin and norepinephrine. Several studies have revealed that the administered dose should be 10-15 mg or 0.3 mg/kg, twice in a day. ((Kaelin, Cifu and Matthies, 1996, Speech et al., 1993, Plenger et al., 1996, Mooney and Haas, 1993)

According to study, methylphenidate is more beneficial for the treatment of chronic stage after TBI than the acute phase of TBI; as the patients with chronic phase shows improvements in alertness, workability whereas evidence in acute phase patients after the TBI shows the improvements in concentration, task performance on motor memory within the first month of administration, but improvements did not last for long term basis. (Whyte et al., 1997) some studies revealed that methylphenidate is more effective for the treatment management of seizures and agitation (Wroblewski et al., 1992, Evans, Gualtieri and Patterson, 1987), whereas other studies suggest no such benefit involves for neurobehavioral performance. (Forsyth and Jayamoni, 2003)

But, recent studies concluded that presently there is not enough evidence is present that can support the beneficial role of methylphenidate or other amphetamines which thought to facilitate recovery from traumatic head injury. (Siddall, 2003) But other studies also demonstrated the clinical trials of methylpheni­date on patients surviving with TBI (acute and chronic) with specifically facing trouble for attention, cognitive processing, neurocognitive deficits, and speech.(Meythaler et al., 2001) Methylphenidate is consensus free stimulants for the treatment of motor activity and rapid in action with minor side effects and benefits for the treatment of chronic as well as the acute phase of traumatic head injury.

The role of Antidepressant drugs:

Post-TBI psychiatric events and other neurological deficits can be treated with antidepressants. The behavioural disorders in case of TBI patients in chronic and subacute phase can be managed with Selective serotonin reuptake inhibitors (SSRIs). Most studies revealed the fact that SSRIs are used for the improvements of neurocognitive, neurobehavioral and neuropsychiatric deficits, particularly depression, loss of memory, agitation etc.

A minimum of an 8-week duration of 100 mg average dose of Sertraline dose is required for the treatment of depression, agitation, psychomotor speed deficit; recent memory loss etc. (STENGLER-WENZKE and MÜLLER, 2002) In a similar way administration of fluoxetine 60 mg on a regular basis for about 3 months is useful for the treatment of TBI-related obsessive-compulsive disorder. (Muller et al., 1999) And also paroxetine or citalopram daily dose of 10-40 mg found to be beneficial to manage the pathological crying symptoms. (Teng et al., 2001) Other newly invented antidepressants like mirtazapine and venlafaxine can be effective on both norepinephrine and serotonin and are useful in the treatment of TBI. Bupropion enhances levels of dopamine and norepinephrine and 150 mg daily intake found to be useful for the treatment of restlessness. (Schneider, Jessie Drew-Cates, Tony, 1999)

The role of Antiparkinsonian drugs:

Bromocriptine, amantadine, levodopa in a combination with carbidopa all are known as antiparkinsonian drugs and possess a various target driven mechanism of action, also enhance the level of dopamine in the brain.

Usually, amantadine presynaptically acts for increasing the dopamine level or prevents its reuptake and also postsynaptically enhances the number or change the configuration of the dopamine receptor. (Kraus and Maki, 1997) It can serve as a NMDA receptor (non-competitive) and protect the excitotoxicity from the glutamate-mediated pathway in case of TBI. (Zafonte, Lexell, and Cullen, 2000) Bromocriptine is known as a dopamine receptor that affects D1 and D2 receptors.(22) The Levodopa and carbidopa both in a combination enhance the level of dopamine after decarboxylation and carbidopa also inhibit L-amino decarboxylase synthesis and by this way, levodopa makes its path towards the central nervous system. (Passler and Riggs, 2001)

Daily intake of amantadine about 100-300 mg found to be effective both in acute and chronic phases after traumatic head injury. Clinical demonstration study revealed that use of amantadine shows improvement in the case of motivation, attention, concentration, alertness and also effective to reduced processing time, agitation, fatigue, anxiety, and aggression issues.

Some cases with the use of bromocriptine (5-45 mg) daily and a combination of both bromocriptine (100mg) and ephedrine (100mg) also showed remarkable benefit in case of akinetic mutism. Bromocriptine in a combination with sensory stimulant also showed improvements in consciousness. (Karli et al., 1999)According to clinical study combined drug therapy like levodopa/carbidopa (25 mg/200 mg) thrice daily, amantadine/ bromocriptine (250/5mg) twice daily found to be effective for the improvement of neuropsychiatric deficits. (Wroblewski et al., 1997)

The role of Anticonvulsant drugs:

According to investigation use of Valproic acid (600-2250 mg) on daily basis showed positive result in neurocognitive actions also improve memory related troubles, reduces the neuropsychiatric and neuro­behavioral related symptoms like aggressive or destructive behaviour, mania, depression, impulsiveness, restlessness etc (25-29) by increasing the control mechanism for GABA neurotransmitter, also facilitating stabilization of central nervous system.

The role of Other Drugs:

Modafinil is known for the treatment of post-TBI related symptoms like inattention, reduced urge for social activity, sleepiness etc. The mechanism of action involves the inhibition of GABA or enhancement of glutamate levels in the hypothalamus. (Ferraro, Antonelli and Tanganelli, 1999, Saletu et al., 1993). According to study intake of modafinil daily, at 100-400 mg plays an important role in the improvement of attention and memory related issues along with daytime sleepiness. (Teitelman, 1993, Fleminger, Greenwood and Oliver, 2003)

Beta blockers like propranolol and pindolol are found to be useful for the treatment of chronic and subacute phase of post-TBI neurobehavioral and neuropsychiatric symptoms such as agitation, aggression. (Feeney, Gonzalez and Law, 1982) Neuroleptics are also used to change the level of neurotransmitter in brain tissues.(Goldstein.1995, Schallert, Hernandez and Barth,1986). But some evidence does not suggest the use of agents like benzodiazepines, trazodone, neuroleptics, prazosin etc. as they may cause adverse reaction even after recovery due to their effect on neurotransmitters like GABA, dopamine etc.(37-39) Donepezil known as cho­linesterase inhibitor which may effective for improvement of attention and memory at early phase but further use is strongly prohibited. (Walker et al., 2004, Levy et al., 2005)

Lastly, estrogens and progesterone or medroxyprogesterone known as antiandrogenic drugs are useful for the treatment of improper sexual behaviour in case of Traumatic head injury patients. (42)

Conclusion:

Pharmacological interventions regarding the improvement of certain behavioural, cognitive and psychiatric symptoms associated with traumatic head injury patients are still under investigation.

The proper administration of therapeutic agents after determining neurological deficits, associated symptoms, timing and interaction nature with other agents either in the acute or chronic stage after traumatic head injury is considered as an important factor. For the establishment of guideline regarding treatment process of traumatic head injury patient’s careful documentation regarding medications and their side effects along with effectiveness to overcome disabilities and recovery are necessary for future study.

References:

1. org. (2017). Pharmacological interventions for traumatic brain injury | BC Medical Journal. [online] Available at: http://www.bcmj.org/articles/pharmacological-interventions-traumatic-brain-injury [Accessed 3 Mar. 2017].
2. Beauchamp, K. and Mutlak, H. et al. (2017). Pharmacology of Traumatic Brain Injury: Where Is the “Golden Bullet”? | Available at: http://static.smallworldlabs.com/molmedcommunity/content/pdfstore/731_740.Beauchamp.00050.PDF [Accessed 4 Mar. 2017].
3. gov. (2017). Traumatic brain injury medical treatment guidelines. | National Guideline Clearinghouse. [online] Available at: https://www.guideline.gov/summaries/summary/43752/Traumatic-brain-injury-medical-treatment-guidelines [Accessed 4 Mar. 2017].
4. Evans, R. and Gualtieri, C. (1987). Psycho stimulant pharmacology in traumatic brain injury. Journal of Head Trauma Rehabilitation, 2(4), pp.29-33.
5. Challman, T. and Lipsky, J. (2000). Methylphenidate: Its Pharmacology and Uses. Mayo Clinic Proceedings, 75(7), pp.711-721.
6. Whyte, J., Hart, T., Schuster, K., Fleming, M., Polansky, M. and Coslett, H. (1997). EFFECTS OF METHYLPHENIDATE ON ATTENTIONAL FUNCTION AFTER TRAUMATIC BRAIN INJURY. American Journal of Physical Medicine & Rehabilitation, 76(6), pp.440-450.
7. Kaelin C, Cifu D, Matthies B. (1996). Methyl­phenidate effect on attention deficit in the acutely brain-injured adult. Arch Phys Med Rehabil, 77, pp.6-10.
8. Speech T, Rao S, Osmon D, et al. (1993). A double blind controlled study of methylphen­idate treatment in closed head injury. Brain Inj,7,pp.333-338
9. Plenger P, Dixon E, Castillo R, et al. (1996). Sub-acute methylphenidate treatment for moderate to moderately severe traumatic brain injury: A preliminary double-blind placebo-controlled study. Arch Phys Med Rehabil, 77, pp.536-540.
10. Mooney G, Haas L. (1993) Effect of methyl­phen­i­date on brain injury-related anger. Arch Phys Med Rehabil, 74, pp.153-160.
11. Wroblewski B, Leary J, Phelan A, et al. (1992) Methylphenidate and seizure frequency in brain injured patients with seizure disorders. J Clin Psychiatry, 53, pp.86-89.
12. Evans R, Gualtieri T, Patterson D. (1987) Treatment of chronic closed head injury with psychostimulant drugs: A controlled case study and an appropriate evaluation procedure. J Nerv Ment Dis, pp.175:110.
13. Forsyth R, Jayamoni B. (2003) Noradrenergic agonists for acute traumatic brain injury. Cochrane Database Syst Rev (1):CD003984
14. Siddall OM, (2005) Use of methylphedinate in traumatic brain injury. Ann Pharmacother, 39, pp.1309-1313.
15. Meythaler J, Lawrence D, Devivo M, et al. (2000) Sertraline to improve arousal and alertness in severe traumatic brain injury secondary to motor vehicle crashes. Brain Inj 15, pp.321-331.
16. STENGLER-WENZKE, K. and MÜLLER, U. (2002). Fluoxetine for OCD after Brain Injury. American Journal of Psychiatry, 159(5), pp.872-872.
17. Muller, U., Murai, T., Bauer-Wittmund, T. and Yves Von Cramon, D. (1999). Paroxetine versus citalopram treatment of pathological crying after brain injury. Brain Injury, 13(10), pp.808-811.
18. Teng, C., Bhalerao, S., Lee, A., et al (2001). The use of bupropion in the treatment of restlessness after a traumatic brain injury. Brain Injury, 15(5), pp.463-467.
19. Schneider, Jessie Drew-Cates, Tony, W. (1999). Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury: an initial double-blind placebo-controlled study. Brain Injury, 13(11), pp.863-872.
20. Kraus M, Maki P. (1997).The combined use of amantadine and l-dopa/carbidopa in the treatment of chronic brain injury. Brain Inj, 11, pp. 455-460.
21. Zafonte R, Lexell J, Cullen N. (2000).Possible applications for dopaminergic agents following traumatic brain injury: Part 1. J Head Trauma Rehabil, 15, pp.1179-1182.
22. Passler M, Riggs R. (2001).Positive outcomes in traumatic brain injury-vegetative state: Patients treated with bromocriptine. Arch Phys Med Rehabil, 82, pp.311-315.
23. Karli D, Burke D, Kim H, et al. (1999). Effects of dopaminergic combination therapy for frontal lobe dysfunction in traumatic brain injury rehabilitation. Brain Inj, 13, pp.63-68.
24. Wroblewski B, Joseph A, Kupfer J, et al. (1997). Effectiveness of valproic acid on destructive and aggressive behaviours in pa­tients with acquired brain injury. Brain Inj, 11, pp.37-47.
25. Massagli T. (1991). Neurobehavioral effects of phenytoin, carbamazepine, and valproic acid: Implications for use in traumatic brain injury. Arch Phys Med and Rehabil, 72, pp.219-225.
26. Dikmen S, Machamer J, Winn H, et al. (2000). Neuropsychological effects of valproate in traumatic brain injury. Neurology, 54, pp.895-902.
27. Chatham-Showalter P, Kimmel DN. (2000). Agitated symptom response to divalproex following acute brain injury. J Neuropsychiatry Clin Neurosci, 12, pp.395-397.
28. Kim E, Humaran T. (2002). Divalproex in the management of neuropsychiatric complications of remote acquired brain injury. J Neuropsychiatry Clin Neurosci, 14, pp.202-205.
29. Lin J, Hou Y, Jove M.(1996). Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-foes im­muno­cytochemistry in the cat. Proc Natl Acad Sci U S A, 93, pp.14128-14133.
30. Ferraro L, Antonelli T, Tanganelli S. (1999). The vigilance promoting drug modafinil in­creases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: Prevention by local GABAA receptor blockade. Neuropsychopharmacology, 20, pp. 346-356.
31. Saletu B, Saletu M, Grunberger J, et al. (1993).Treatment of the alcoholic organic brain syndrome: Double-blind, placebo-controlled clinical, psychometric and electroencephalographic mapping studies with modafinil. Neuropsychobiology, 27, pp.26-39.
32. Teitelman E. (2001). Off-label uses of modafinil. Is J Psychiatry, 158, 1341?
33. Fleming S, Greenwood RJ, Oliver DL. (2003). Pharmacological management for agitation and aggression in people with acquired brain injury. Cochrane Database Syst Rev ;( 1), CD003299.
34. Feeney DM, Gonzalez A, Law WA. (1982). Amphetamine, haloperidol and experience interact to affect the rate of recovery after motor cortex injury. Science, 217, pp.855-857.
35. Goldstein LB. (1995). Common drugs may influence motor recovery after stroke. Neurology, 45, pp.865-872.
36. Schallert T, Hernandez T, Barth T. (1986). Recovery of function after brain damage: Severe and chronic disruption by diaze­pam. Brain Res,379,pp.104-111.
37. Brailowsky S, Knight RT, Efron R. (1986). Phenytoin increases the severity of cortical hemiplegia in rats. Brain Res, 376, pp.71-77.
38. Goldstein LB. (1997). Influence of common drugs and related factors on stroke outcome. Curr Opin Neurol, 10, pp.52-57.
39. Zhang L, Plotkin RC, Wang G, et al. (2004). Cholinergic augmentation with donepezil enhances recovery in short-term memory and sustained attention after traumatic brain injury. Arch Phys Med Rehabil, 85, pp.1050-1055.
40. Walker W, Seel R, Gibellato M, et al. (2004). the effects of donepezil on traumatic brain injury acute rehabilitation outcomes. Brain Inj, 18, pp.739-750.
41. Levy M, Berson A, Cook T, et al. (2005). Treatment of agitation following traumatic brain injury: A review of the literature. NeuroRehabilitation, 20, pp.279-306.