Pharmacologic Therapies to Promote Recovery of Consciousness

Megan E. Barra; Brian L. Edlow; Gretchen M. Brophy

doi:10.1055/s-0042-1755271

Seminars in Neurology, Table of Contents

Semin Neurol 2022; 42(03): 335-347
DOI: 10.1055/s-0042-1755271

Review Article

Pharmacologic Therapies to Promote Recovery of Consciousness

Authors

Megan E. Barra

¹Department of Pharmacy, Massachusetts General Hospital, Boston, Massachusetts

²Department of Neurology, Center for Neurotechnology and Neurorecovery (CNTR), Massachusetts General Hospital, Boston, Massachusetts
Brian L. Edlow

²Department of Neurology, Center for Neurotechnology and Neurorecovery (CNTR), Massachusetts General Hospital, Boston, Massachusetts

³Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts
Gretchen M. Brophy

⁴Department of Pharmacotherapy and Outcomes Science and Neurosurgery, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia

Abstract

Pharmacologic interventions are commonly used to support rehabilitation efforts of patients with disorders of consciousness (DoC). The 2018 practice guidelines recommend amantadine in adults with traumatic DoC to promote functional recovery, though several other stimulants are used off-label in clinical practice and trials, such as methylphenidate, bromocriptine, levodopa, and zolpidem. Differences in the mechanisms of action, adverse effects, pharmacokinetics, and drug–drug interactions should be considered when selecting the best agent for each individual patient. Overall, pharmacologic stimulants may provide a safe and inexpensive pathway to increased functionality and participation in rehabilitation. This article provides a concise summary of scientific evidence supporting the use of pharmacologic therapies to stimulate recovery of consciousness in patients with DoC.

Keywords

stimulant - brain injury - consciousness - recovery - neurotransmitter

Full Text

References

References
1 Schleissner LA. Glutethimide intoxication with prolonged coma and hyperpyrexia treated with methylphenidate. Calif Med 1966; 105 (01) 41-44
2 Powell JR. Treating the comatosed patient. Value of methylphenidate (Ritalin) hydrochloride. Tex State J Med 1960; 56: 363-366
3 Friedman HA, Harris SC. Massive doses of amphetamine as an adjuvant in the treatment of barbiturate intoxication. Am J Med Sci 1951; 221 (02) 133-136
4 Solomon H, Winter RE. Acute barbiturate intoxication treated by massive amphetamine therapy. N Y State J Med 1951; 51 (15) 1846-1847
5 Kondziella D, Stevens RD. Classifying disorders of consciousness: past, present, and future. Semin Neurol 2022. doi: 10.1055/a-1883-1021 (online ahead of print)
6 Brown EN, Lydic R, Schiff ND. General anesthesia, sleep, and coma. N Engl J Med 2010; 363 (27) 2638-2650
7 Edlow BL, Sanz LRD, Polizzotto L. et al; Curing Coma Campaign and Its Contributing Members. Therapies to restore consciousness in patients with severe brain injuries: a gap analysis and future directions. Neurocrit Care 2021; 35 (Suppl. 01) 68-85
8 Herrold AA, Pape TLB, Guernon A, Mallinson T, Collins E, Jordan N. Prescribing multiple neurostimulants during rehabilitation for severe brain injury. ScientificWorldJournal 2014; 2014: 964578
9 Königs M, Beurskens EA, Snoep L, Scherder EJ, Oosterlaan J. Effects of timing and intensity of neurorehabilitation on functional outcome after traumatic brain injury: a systematic review and meta-analysis. Arch Phys Med Rehabil 2018; 99 (06) 1149-1159 .e1
10 Giacino JT, Katz DI, Schiff ND. et al. Practice guideline update recommendations summary: disorders of consciousness: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research. Neurology 2018; 91 (10) 450-460
11 Giacino JT, Whyte J, Bagiella E. et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med 2012; 366 (09) 819-826
12 Danysz W, Dekundy A, Scheschonka A, Riederer P. Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials. J Neural Transm (Vienna) 2021; 128 (02) 127-169
13 Fridman EA, Osborne JR, Mozley PD, Victor JD, Schiff ND. Presynaptic dopamine deficit in minimally conscious state patients following traumatic brain injury. Brain 2019; 142 (07) 1887-1893
14 Donnemiller E, Brenneis C, Wissel J. et al. Impaired dopaminergic neurotransmission in patients with traumatic brain injury: a SPECT study using 123I-beta-CIT and 123I-IBZM. Eur J Nucl Med 2000; 27 (09) 1410-1414
15 Schiff ND. Recovery of consciousness after brain injury: a mesocircuit hypothesis. Trends Neurosci 2010; 33 (01) 1-9
16 Edlow BL, Claassen J, Schiff ND, Greer DM. Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies. Nat Rev Neurol 2021; 17 (03) 135-156
17 Wu TS, Garmel GM. Improved neurological function after Amantadine treatment in two patients with brain injury. J Emerg Med 2005; 28 (03) 289-292
18 Hughes S, Colantonio A, Santaguida PL, Paton T. Amantadine to enhance readiness for rehabilitation following severe traumatic brain injury. Brain Inj 2005; 19 (14) 1197-1206
19 Ghalaenovi H, Fattahi A, Koohpayehzadeh J. et al. The effects of amantadine on traumatic brain injury outcome: a double-blind, randomized, controlled, clinical trial. Brain Inj 2018; 32 (08) 1050-1055
20 Reynolds JC, Rittenberger JC, Callaway CW. Methylphenidate and amantadine to stimulate reawakening in comatose patients resuscitated from cardiac arrest. Resuscitation 2013; 84 (06) 818-824
21 Meythaler JM, Brunner RC, Johnson A, Novack TA. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil 2002; 17 (04) 300-313
22 Avecillas-Chasín JM, Barcia JA. Effect of amantadine in minimally conscious state of non-traumatic etiology. Acta Neurochir (Wien) 2014; 156 (07) 1375-1377
23 Lehnerer SM, Scheibe F, Buchert R, Kliesch S, Meisel A. Awakening with amantadine from a persistent vegetative state after subarachnoid haemorrhage. BMJ Case Rep 2017; 2017: bcr-2017–220305
24 Gao Y, Ma L, Liang F. et al. The use of amantadine in patients with unresponsive wakefulness syndrome after severe cerebral hemorrhage. Brain Inj 2020; 34 (08) 1084-1088
25 Zafonte RD, Watanabe T, Mann NR. Amantadine: a potential treatment for the minimally conscious state. Brain Inj 1998; 12 (07) 617-621
26 Abbasivash R, Valizade Hasanloei MA, Kazempour A, Mahdkhah A, Shaaf Ghoreishi MM, Akhavan Masoumi G. The effect of oral administration of amantadine on neurological outcome of patients with diffuse axonal injury in ICU. J Exp Neurosci 2019; 13: 1179069518824851
27 Sawyer E, Mauro LS, Ohlinger MJ. Amantadine enhancement of arousal and cognition after traumatic brain injury. Ann Pharmacother 2008; 42 (02) 247-252
28 Estraneo A, Pascarella A, Moretta P, Loreto V, Trojano L. Clinical and electroencephalographic on-off effect of amantadine in chronic non-traumatic minimally conscious state. J Neurol 2015; 262 (06) 1584-1586
29 Edby K, Larsson J, Eek M, von Wendt L, Ostergård B. Amantadine treatment of a patient with anoxic brain injury. Childs Nerv Syst 1995; 11 (10) 607-609
30 McMahon MA, Vargus-Adams JN, Michaud LJ, Bean J. Effects of amantadine in children with impaired consciousness caused by acquired brain injury: a pilot study. Am J Phys Med Rehabil 2009; 88 (07) 525-532
31 Seel RT, Sherer M, Whyte J. et al; American Congress of Rehabilitation Medicine, Brain Injury-Interdisciplinary Special Interest Group, Disorders of Consciousness Task Force. Assessment scales for disorders of consciousness: evidence-based recommendations for clinical practice and research. Arch Phys Med Rehabil 2010;91(12):1795–1813
32 Kondziella D, Bender A, Diserens K. et al; EAN Panel on Coma, Disorders of Consciousness. European Academy of Neurology guideline on the diagnosis of coma and other disorders of consciousness. Eur J Neurol 2020; 27 (05) 741-756
33 Alkhachroum A, Eliseyev A, Der-Nigoghossian CA. et al. EEG to detect early recovery of consciousness in amantadine-treated acute brain injury patients. J Neurol Neurosurg Psychiatry 2020; 91 (06) 675-676
34 Chen X, Tang C, Zhou H, Li Z. Effect of amantadine on vegetative state after traumatic brain injury: a functional magnetic resonance imaging study. J Int Med Res 2019; 47 (02) 1015-1024
35 Gale AS. The effect of methylphenidate (Ritalin) on thiopental recovery. Anesthesiology 1958; 19 (04) 521-531
36 Challman TD, Lipsky JJ. Methylphenidate: its pharmacology and uses. Mayo Clin Proc 2000; 75 (07) 711-721
37 Volkow ND, Wang GJ, Fowler JS. et al. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 1998; 155 (10) 1325-1331
38 Riddle EL, Hanson GR, Fleckenstein AE. Therapeutic doses of amphetamine and methylphenidate selectively redistribute the vesicular monoamine transporter-2. Eur J Pharmacol 2007; 571 (01) 25-28
39 Chien YJ, Chien YC, Liu CT, Wu HC, Chang CY, Wu MY. Effects of methylphenidate on cognitive function in adults with traumatic brain injury: a meta-analysis. Brain Sci 2019; 9 (11) E291
40 Barnett M, Reid L. The effectiveness of methylphenidate in improving cognition after brain injury in adults: a systematic review. Brain Inj 2020; 34 (01) 1-10
41 Dorer CL, Manktelow AE, Allanson J. et al. Methylphenidate-mediated motor control network enhancement in patients with traumatic brain injury. Brain Inj 2018; 32 (08) 1040-1049
42 Johansson B, Wentzel AP, Andréll P, Rönnbäck L, Mannheimer C. Long-term treatment with methylphenidate for fatigue after traumatic brain injury. Acta Neurol Scand 2017; 135 (01) 100-107
43 Johansson B, Andréll P, Rönnbäck L, Mannheimer C. Follow-up after 5.5 years of treatment with methylphenidate for mental fatigue and cognitive function after a mild traumatic brain injury. Brain Inj 2020; 34 (02) 229-235
44 Kim J, Whyte J, Patel S. et al. Methylphenidate modulates sustained attention and cortical activation in survivors of traumatic brain injury: a perfusion fMRI study. Psychopharmacology (Berl) 2012; 222 (01) 47-57
45 Kakehi S, Tompkins DM. A review of pharmacologic neurostimulant use during rehabilitation and recovery after brain injury. Ann Pharmacother 2021; 55 (10) 1254-1266
46 Edlow BL, Barra ME, Zhou DW. et al. Personalized connectome mapping to guide targeted therapy and promote recovery of consciousness in the intensive care unit. Neurocrit Care 2020; 33 (02) 364-375
47 Haddad F, Sawalha M, Khawaja Y, Najjar A, Karaman R. Dopamine and levodopa prodrugs for the treatment of Parkinson's disease. Molecules 2017; 23 (01) E40
48 Matsuda W, Komatsu Y, Yanaka K, Matsumura A. Levodopa treatment for patients in persistent vegetative or minimally conscious states. Neuropsychol Rehabil 2005; 15 (3-4): 414-427
49 Haig AJ, Ruess JM. Recovery from vegetative state of six months' duration associated with Sinemet (levodopa/carbidopa). Arch Phys Med Rehabil 1990; 71 (13) 1081-1083
50 Di Rocco C, Maira G, Meglio M, Rossi GF. L-DOPA treatment of comatose states due to cerebral lesions. Preliminary findings. J Neurosurg Sci 1974; 18 (03) 169-176
51 Chajek T, Berry EM, Friedman G, Abramsky O. Treatment of acute hepatic encephalopathy with L-dopa. Postgrad Med J 1977; 53 (619) 262-265
52 Matsuda W, Matsumura A, Komatsu Y, Yanaka K, Nose T. Awakenings from persistent vegetative state: report of three cases with parkinsonism and brain stem lesions on MRI. J Neurol Neurosurg Psychiatry 2003; 74 (11) 1571-1573
53 Freitas ME, Hess CW, Fox SH. Motor complications of dopaminergic medications in Parkinson's disease. Semin Neurol 2017; 37 (02) 147-157
54 Fridman EA, Schiff ND. Organizing a rational approach to treatments of disorders of consciousness using the Anterior Forebrain Mesocircuit Model. J Clin Neurophysiol 2022; 39 (01) 40-48
55 Sanz LRD, Lejeune N, Blandiaux S. et al. Treating disorders of consciousness with apomorphine: protocol for a double-blind randomized controlled trial using multimodal assessments. Front Neurol 2019; 10: 248
56 Fridman EA, Krimchansky BZ, Bonetto M. et al. Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury. Brain Inj 2010; 24 (04) 636-641
57 Sanger GJ, Andrews PLR. A history of drug discovery for treatment of nausea and vomiting and the implications for future research. Front Pharmacol 2018; 9: 913
58 Hauser RA, Isaacson S, Clinch T. Tigan/Apokyn Study Investigators. Randomized, placebo-controlled trial of trimethobenzamide to control nausea and vomiting during initiation and continued treatment with subcutaneous apomorphine injection. Parkinsonism Relat Disord 2014; 20 (11) 1171-1176
59 Arnold G, Schwarz J, Macher C, Oertel WH. Domperidone is superior to ondansetron in acute apomorphine challenge in previously untreated parkinsonian patients - a double blind study. Parkinsonism Relat Disord 1997; 3 (04) 191-193
60 Passler MA, Riggs RV. Positive outcomes in traumatic brain injury-vegetative state: patients treated with bromocriptine. Arch Phys Med Rehabil 2001; 82 (03) 311-315
61 Munakomi S, Bhattarai B, Mohan Kumar B. Role of bromocriptine in multi-spectral manifestations of traumatic brain injury. Chin J Traumatol 2017; 20 (02) 84-86
62 Clauss RP, Güldenpfennig WM, Nel HW, Sathekge MM, Venkannagari RR. Extraordinary arousal from semi-comatose state on zolpidem: a case report. S Afr Med J 2000; 90 (01) 68-72
63 Cohen SI, Duong TT. Increased arousal in a patient with anoxic brain injury after administration of zolpidem. Am J Phys Med Rehabil 2008; 87 (03) 229-231
64 Clauss R, Nel W. Drug induced arousal from the permanent vegetative state. NeuroRehabilitation 2006; 21 (01) 23-28
65 Kim C, Kwon BS, Nam KY, Park JW, Lee HJ. Zolpidem-induced arousal by paradoxical GABAergic stimulation: a case report with F-18 flumazenil positron emission tomography and single photon emission computed tomography study. Ann Rehabil Med 2016; 40 (01) 177-181
66 Crestani F, Martin JR, Möhler H, Rudolph U. Mechanism of action of the hypnotic zolpidem in vivo. Br J Pharmacol 2000; 131 (07) 1251-1254
67 Tucker C, Sandhu K. The effectiveness of zolpidem for the treatment of disorders of consciousness. Neurocrit Care 2016; 24 (03) 488-493
68 Chattopadhyay AC, Shukla L, Kandasamy A, Benegal V. High-dose zolpidem dependence - psychostimulant effects? A case report and literature review. Ind Psychiatry J 2016; 25 (02) 222-224
69 Sabe M, Kashef H, Gironi C, Sentissi O. Zolpidem stimulant effect: induced mania case report and systematic review of cases. Prog Neuropsychopharmacol Biol Psychiatry 2019; 94: 109643
70 Ohshima H, Kotorii N, Takii M. et al. Polysomnographic sleep disturbances due to high-dose zolpidem use: a case report. J Clin Sleep Med 2018; 14 (11) 1949-1952
71 Zhang B, O'Brien K, Won W, Li S. A retrospective analysis on clinical practice-based approaches using zolpidem and lorazepam in disorders of consciousness. Brain Sci 2021; 11 (06) 726
72 Lo YL, Tan EK, Ratnagopal P, Chan LL, Tan TE. Zolpidem and its effects on hypoxic encephalopathy. Ann Neurol 2008; 64 (04) 477-478
73 Shames JL, Ring H. Transient reversal of anoxic brain injury-related minimally conscious state after zolpidem administration: a case report. Arch Phys Med Rehabil 2008; 89 (02) 386-388
74 Thonnard M, Gosseries O, Demertzi A. et al. Effect of zolpidem in chronic disorders of consciousness: a prospective open-label study. Funct Neurol 2013; 28 (04) 259-264
75 Whyte J, Myers R. Incidence of clinically significant responses to zolpidem among patients with disorders of consciousness: a preliminary placebo controlled trial. Am J Phys Med Rehabil 2009; 88 (05) 410-418
76 Whyte J, Rajan R, Rosenbaum A. et al. Zolpidem and restoration of consciousness. Am J Phys Med Rehabil 2014; 93 (02) 101-113
77 Du B, Shan A, Zhang Y, Zhong X, Chen D, Cai K. Zolpidem arouses patients in vegetative state after brain injury: quantitative evaluation and indications. Am J Med Sci 2014; 347 (03) 178-182
78 Calabrò RS, Aricò I, De Salvo S, Conti-Nibali V, Bramanti P. Transient awakening from vegetative state: is high-dose zolpidem more effective?. Psychiatry Clin Neurosci 2015; 69 (02) 122-123
79 Carboncini MC, Piarulli A, Virgillito A. et al. A case of post-traumatic minimally conscious state reversed by midazolam: clinical aspects and neurophysiological correlates. Restor Neurol Neurosci 2014; 32 (06) 767-787
80 Margetis K, Korfias SI, Gatzonis S. et al. Intrathecal baclofen associated with improvement of consciousness disorders in spasticity patients. Neuromodulation 2014; 17 (07) 699-704 , discussion 704
81 Nardone R, Sebastianelli L, Brigo F. et al. Effects of intrathecal baclofen therapy in subjects with disorders of consciousness: a reappraisal. J Neural Transm (Vienna) 2020; 127 (09) 1209-1215
82 Gerrard P, Malcolm R. Mechanisms of modafinil: a review of current research. Neuropsychiatr Dis Treat 2007; 3 (03) 349-364
83 Dhamapurkar SK, Wilson BA, Rose A, Watson P, Shiel A. Does Modafinil improve the level of consciousness for people with a prolonged disorder of consciousness? a retrospective pilot study. Disabil Rehabil 2017; 39 (26) 2633-2639
84 Formica F, Pozzi M, Avantaggiato P. et al. Disordered consciousness or disordered wakefulness? The importance of prolonged polysomnography for the diagnosis, drug therapy, and rehabilitation of an unresponsive patient with brain injury. J Clin Sleep Med 2017; 13 (12) 1477-1481
85 Leclerc AM, Riker RR, Brown CS. et al. Amantadine and modafinil as neurostimulants following acute stroke: a retrospective study of intensive care unit patients. Neurocrit Care 2021; 34 (01) 102-111
86 Scott G, Carhart-Harris RL. Psychedelics as a treatment for disorders of consciousness. Neurosci Conscious 2019; 2019 (01) niz003
87 Kunieda K, Shigematsu T, Fujishima I. Case reports describing amantadine intoxication in a rehabilitation hospital. Prog Rehabil Med 2017; 2: 20170017
88 Cattoni J, Parekh R. Acute respiratory distress syndrome: a rare presentation of amantadine toxicity. Am J Case Rep 2014; 15: 1-3
89 Schwartz M, Patel M, Kazzi Z, Morgan B. Cardiotoxicity after massive amantadine overdose. J Med Toxicol 2008; 4 (03) 173-179
90 Carbone F, Djamshidian A, Seppi K, Poewe W. Apomorphine for Parkinson's disease: efficacy and safety of current and new formulations. CNS Drugs 2019; 33 (09) 905-918
91 Sherer M, Katz DI, Bodien YG. et al. Post-traumatic confusional state: a case definition and diagnostic criteria. Arch Phys Med Rehabil 2020; 101 (11) 2041-2050
92 Hammond FM, Malec JF, Zafonte RD. et al. Potential impact of amantadine on aggression in chronic traumatic brain injury. J Head Trauma Rehabil 2017; 32 (05) 308-318
93 Gramish JA, Kopp BJ, Patanwala AE. Effect of amantadine on agitation in critically ill patients with traumatic brain injury. Clin Neuropharmacol 2017; 40 (05) 212-216
94 Barra ME, Izzy S, Sarro-Schwartz A, Hirschberg RE, Mazwi N, Edlow BL. Stimulant therapy in acute traumatic brain injury: prescribing patterns and adverse event rates at 2 level 1 trauma centers. J Intensive Care Med 2020; 35 (11) 1196-1202
95 Ter Mors BJ, Backx APM, Spauwen P, Ponds RWHM, Van Harten PN, Van Heugten CM. Efficacy of amantadine on behavioural problems due to acquired brain injury: a systematic review. Brain Inj 2019; 33 (09) 1137-1150
96 Claassen J, Akbari Y, Alexander S. et al. Proceedings of the first curing coma campaign NIH symposium: challenging the future of research for coma and disorders of consciousness. Neurocrit Care 2021;35(Suppl 1):4–23
97 Forslund MV, Perrin PB, Røe C. et al. Global outcome trajectories up to 10 years after moderate to severe traumatic brain injury. Front Neurol 2019; 10: 219 Doi: 9
98 Hammond FM, Giacino JT, Nakase Richardson R. et al. Disorders of consciousness due to traumatic brain injury: functional status ten years post-injury. J Neurotrauma 2019; 36 (07) 1136-1146
99 Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson disease. Arch Neurol 2010; 67 (01) 58-63
100 Moein H, Khalili HA, Keramatian K. Effect of methylphenidate on ICU and hospital length of stay in patients with severe and moderate traumatic brain injury. Clin Neurol Neurosurg 2006; 108 (06) 539-542
101 Koneski JAS, Casella EB, Agertt F, Ferreira MG. Efficacy and safety of methylphenidate in treating ADHD symptoms in children and adolescents with uncontrolled seizures: a Brazilian sample study and literature review. Epilepsy Behav 2011; 21 (03) 228-232
102 Brikell I, Chen Q, Kuja-Halkola R. et al. Medication treatment for attention-deficit/hyperactivity disorder and the risk of acute seizures in individuals with epilepsy. Epilepsia 2019; 60 (02) 284-293
103 Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke 2007; 38 (03) 1091-1096
104 Shukla D, Devi BI, Agrawal A. Outcome measures for traumatic brain injury. Clin Neurol Neurosurg 2011; 113 (06) 435-441
105 Ganti L, Daneshvar Y, Ayala S, Bodhit AN, Peters KR. The value of neurocognitive testing for acute outcomes after mild traumatic brain injury. Mil Med Res 2016; 3: 23
106 Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil 2004; 85 (12) 2020-2029