[en] Survivors of severe brain injuries may end up in a state of 'wakeful unresponsiveness' or in a minimally conscious state. Pharmacological treatments of patients with disorders of consciousness aim to improve arousal levels and recovery of consciousness. We here provide a systematic overview of the therapeutic effects of amantadine, apomorphine and zolpidem in patients recovering from coma. Evidence from clinical trials using these commonly prescribed pharmacological agents suggests positive changes in the neurological status in patients, leading sometimes to dramatic improvements. These findings are discussed in the context of current hypotheses of these agents' therapeutic mechanisms on cerebral function. In order to enhance our understanding of the underlying pathophysiological mechanisms of these drugs, we suggest combining sensitive and specific behavioral tools with neuroimaging and electrophysiological measures in large randomized, double-blind, placebo-controlled experimental designs. We conclude that the pharmacokinetics and pharmacodynamics of amantadine, apomorphine and zolpidem need further exploration to determine which treatment would provide a better neurological outcome regarding the patient's etiology, diagnosis, time since injury and overall condition.
Research Center/Unit :
GIGA CRC (Cyclotron Research Center) In vivo Imaging-Aging & Memory - ULiège
Disciplines :
Neurology
Author, co-author :
Gosseries, Olivia ✱; Université de Liège - ULiège > Centre de recherches du cyclotron
Zafonte R, Hammond F, Dennison A, Chew E. Pharmacotherapy to enhance arousal: what is known and what is not. Prog Brain Res 2009; 177: 293-316.
Massucci JL, Kline AE, Ma X, Zafonte RD, Dixon CE. Time dependent alterations in dopamine tissue levels and metabolism after experimental traumatic brain injury in rats. Neurosci Lett 2004; 372(1-2): 127-31.
Adams JH, Graham DI, Murray LS, Scott G. Diffuse axonal injury due to nonmissile head injury in humans: an analysis of 45 cases. Ann Neurol 1982; 12(6): 557-63.
Yan HQ, Kline AE, Ma X, Li Y, Dixon CE. Traumatic brain injury reduces dopamine transporter protein expression in the rat frontal cortex. Neuroreport 2002; 13(15): 1899-901.
Wheaton P, Mathias JL, Vink R. Impact of early pharmacological treatment on cognitive and behavioral outcome after traumatic brain injury in adults: a meta-analysis. J Clin Psychopharmacol 2009; 29(5): 468-77.
van Woerkom TC, Minderhoud JM, Gottschal T, Nicolai G. Neurotransmitters in the treatment of patients with severe head injuries. Eur Neurol 1982; 21(4): 227-34.
Caine D, Watson JD. Neuropsychological and neuropathological sequelae of cerebral anoxia: a critical review. J Int Neuropsychol Soc 2000; 6(1): 86-99.
Chew E, Zafonte RD. Pharmacological management of neurobehavioral disorders following traumatic brain injury--a state-of-the-art review. J Rehabil Res Dev 2009; 46(6): 851-79.
Plum F, Posner JB. The diagnosis of stupor and coma. 3rd ed. FA D, editor. Philadelphia1983.
The multi-society task force on PVS. Medical aspects of the persistent vegetative state (1). N Engl J Med 1994; 330(21): 1499-508.
Laureys S, Celesia G, Cohadon F, et al. Unresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome. BMC Med 2010; 8(1): 68.
Gosseries O, Bruno MA, Chatelle C, et al. Disorders of consciousness: what's in a name? NeuroRehabilitation 2011; 28(1): 3-14.
Bruno MA, Vanhaudenhuyse A, Thibaut A, Moonen G, Laureys S. From unresponsive wakefulness to minimally conscious PLUS and functional locked-in syndromes: recent advances in our understanding of disorders of consciousness. J Neurol 2011; 258(7): 1373-84.
Giacino JT, Ashwal S, Childs N, et al. The minimally conscious state: definition and diagnostic criteria. Neurology 2002; 58(3): 349-53.
Majerus S, Gill-Thwaites H, Andrews K, Laureys S. Behavioral evaluation of consciousness in severe brain damage. Prog Brain Res 2005; 150: 397-413.
Laureys S. The neural correlate of (un)awareness: lessons from the vegetative state. Trends Cogn Sci 2005; 9(12): 556-9.
Jones BE. Arousal systems. Front Biosci 2003; 8: 438-51.
Schwartz J, Roth T. Neurophysiology of sleep and wakefulness: basic science and clinical implications. Curr Neuropharmacol 2008; 6(4): 367-78.
Laureys S, Faymonville ME, Luxen A, Lamy M, Franck G, Maquet P. Restoration of thalamocortical connectivity after recovery from persistent vegetative state. Lancet 2000; 355(9217): 1790-1.
Demertzi A, Soddu A, Laureys S. Consciousness supporting networks. Curr Opin Neurobiol 2013; 23(2): 239-44.
Vanhaudenhuyse A, Demertzi A, Schabus M, et al. Two distinct neuronal networks mediate the awareness of environment and of self. J Cogn Neurosci 2011; 23(3): 570-8.
U.S. Department of Health and Human Services-National Institutes of Health. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute; 2009 (v4.03: June 14, 2010); http: //evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
OCEBM Levels of Evidence Working Group. The Oxford Levels of Evidence 2 2011; http: //www.cebm.net/index.aspx?o=5653.
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974; 2(7872): 81-4.
Born JD. The Glasgow-Liege Scale. Prognostic value and evolution of motor response and brain stem reflexes after severe head injury. Acta Neurochir (Wien) 1988; 91(1-2): 1-11.
Wijdicks EF, Bamlet WR, Maramattom BV, Manno EM, McClelland RL. Validation of a new coma scale: The FOUR score. Ann Neurol 2005; 58(4): 585-93.
Rappaport M, Hall KM, Hopkins K, Belleza T, Cope DN. Disability rating scale for severe head trauma: coma to community. Arch Phys Med Rehabil 1982; 63(3): 118-23.
Rappaport M. The Coma/Near Coma Scale. The Center for Outcome Measurement in Brain Injury; 2000 [August 21, 2006]; Available from: http: //www.tbims.org/combi/cnc.
Ansell BJ, Keenan JE. The Western Neuro Sensory Stimulation Profile: a tool for assessing slow-to-recover head-injured patients. Arch Phys Med Rehabil 1989; 70(2): 104-8.
Gill-Thwaites H, Munday R. The sensory modality assessment and rehabilitation technique (SMART): a valid and reliable assessment for vegetative state and minimally conscious state patients. Brain Inj 2004; 18(12): 1255-69.
Shiel A, Horn SA, Wilson BA, Watson MJ, Campbell MJ, McLellan DL. The Wessex Head Injury Matrix (WHIM) main scale: a preliminary report on a scale to assess and monitor patient recovery after severe head injury. Clin Rehabil 2000; 14(4): 408-16.
Hagen C, Malkmus D, Durham P. Levels of cognitive functioning. Downey, editor. CA 1987.
Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery ScaleRevised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil 2004; 85(12): 2020-9.
Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet 1975; 1(7905): 480-4.
Jennett B, Snoek J, Bond M, Brooks N. Disability after severe head injury: observations on the use of the Glasgow Outcome Scale. J Neurol Neurosurg Psychiatry 1981; 44(4): 285-93.
Seel RT, Sherer M, Whyte J, et al. Assessment scales for disorders of consciousness: evidence-based recommendations for clinical practice and research. Arch Phys Med Rehabil 2010; 91(12): 1795-813.
Schnakers C, Vanhaudenhuyse A, Giacino J, et al. Diagnostic accuracy of the vegetative and minimally conscious state: clinical consensus versus standardized neurobehavioral assessment. BMC Neurol 2009; 9: 35.
DeMarchi R, Bansal V, Hung A, et al. Review of awakening agents. Can J Neurol Sci 2005; 32(4-17).
Hubsher G, Haider M, Okun M. Amantadine: the journey from fighting flu to treating Parkinson disease. Neurology 2012; 78(14): 1096-9.
Aoki F, Sitar D. Clinical pharmacokinetics of amantadine hydrochloride. Clin Pharmacokinet 1988; 14(1): 35-51.
Bleidner W, Harmon J, Hewes W, Lynes T, Hermann E. Absorption, distribution and excretion of amantadine hydrochloride. J Pharmacol Exp Ther 1965; 150(3): 484-90.
Schwab R, England A, Poskanzer D, Young R. Amantadine in the treatment of Parkinson's disease. JAMA 1969(208): 1168-70.
Millac P, Hasan I, Espir M, Slyfield D. Treatment of Parkinsonism with L-dopa and amantadine. Lancet 1970 2(7675): 720.
Fahn S, Isgreen W. Long-term evaluation of amantadine and levodopa combination in parkinsonism by double-blind crossover analyses. Neurology 1975; 25(8): 695-700.
Timberlake W, Vance M. Four-year treatment of patients with parkinsonism using amantadine alone or with levodopa. Ann Neurol 1978 3(2): 119-28.
Rezak M. Current pharmacotherapeutic treatment options in Parkinson's disease. Dis Mon 2007(53): 214-22.
Sawada H, Oeda T, Kuno S, et al. Amantadine for dyskinesias in Parkinson's disease: a randomized controlled trial. PLoS One 2010; 5(12): e15298.
Kraus M, Maki P. Effect of amantadine hydrochloride on symptoms of frontal lobe dysfunction in brain injury: case studies and review. J Neuropsychiatry Clin Neurosci 1997(9): 222-30.
Chandler M, Barnhill J, Gualtieri C. Amantadine for the agitated head injury patient. Brain Inj 1988(2): 309-11.
Gualtieri T, Chandler M, Coons T, Brown L. Amantadine: a new clinical profile for traumatic brain injury. Clin Neuropharmacol 1989; 12(4): 258-70.
Nickels J, Schneider W, Dombovy M, Wong T. Clinical use of amantadine in brain injury rehabilitation. Brain Inj 1994; 8(8): 709-18.
Saniova B, Drobny M, Kneslova L, Minarik M. The outcome of patients with severe head injuries treated with amantadine sulphate. J Neural Transm 2004; 111(4): 511-4.
Folstein M, Robins L, Helzer J. The Mini-Mental State Examination. Arch Gen Psychiatry 1983; 40(7): 812.
Davidoff G, Roth E, Haughton J, Ardner M. Cognitive dysfunction in spinal cord injury patients: sensitivity of the Functional Independence Measure subscales vs neuropsychologic assessment. Arch Phys Med Rehabil 1990; 71(5): 326-9.
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(4): 300-13
Whyte J, Katz D, Long D, et al. Predictors of outcome in prolonged posttraumatic disorders of consciousness and assessment of medication effects: a multicenter study. Arch Phys Med Rehabil 2005; 86(3): 453-62.
Zafonte R, Watanabe T, Mann N. Amantadine: a potential treatment for the minimally conscious state. Brain Inj 1998; 12(7): 617-21.
Patrick P, Patrick S, Poole J, Sharon H. Evaluation and treatment of the vegetative and minimally conscious child: a single subject design. Behavioral Interventions 2000 15: 225-42.
Patrick P, Blackman J, Mabry J, Buck M, Gurka M, Conaway M. Dopamine agonist therapy in low-response children following traumatic brain injury. J Child Neurol 2006; 21(10): 879-85.
McMahon M, Vargus-Adams J, Michaud L, 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(7): 525-32.
Vargus-Adams J, McMahon M, Michaud L, Bean J, Vinks A. Pharmacokinetics of amantadine in children with impaired consciousness due to acquired brain injury: preliminary findings using a sparse-sampling technique. PM R 2010; 2(1): 37-42.
Schneider W, Drew-Cates J, Wong T, Dombovy M. Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury: an initial double-blind placebo-controlled study. Brain Inj 1999; 13(11): 863-72.
Hughes S, Colantonio A, Santaguida P, Paton T. Amantadine to enhance readiness for rehabilitation following severe traumatic brain injury. Brain Inj 2005; 19(14): 1197-206.
Giacino JT, Whyte J, Bagiella E, et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med 2012; 366(9): 819-26.
Reynolds J, Rittenberger J, Callaway C. Methylphenidate and amantadine to stimulate reawakening in comatose patients resuscitated from cardiac arrest. Resuscitation 2013; 84(6): 818-24.
Horiguchi J, Inami Y, Shoda T. Effects of long-term amantadine treatment on clinical symptoms and EEG of a patient in a vegetative state. Clin Neuropharmacol 1990; 13(1): 84-8.
Schnakers C, Hustinx R, Vandewalle G, et al. Measuring the effect of amantadine in chronic anoxic minimally conscious state. J Neurol Neurosurg Psychiatry 2008; 79(2): 225-7.
Laureys S, Piret S, Ledoux D. Quantifying consciousness. Lancet Neurol 2005; 4(12): 789-90.
Ribarič S. The pharmacological properties and therapeutic use of apomorphine. Molecules 2012; 17(5): 5289-309.
Kolls B, Stacy M. Apomorphine: a rapid rescue agent for the management of motor fluctuations in advanced Parkinson disease. Clin Neuropharmacol 2006; 29: 292-301.
Katzenschlager R, Hughes A, Evans A, et al. Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: a prospective study using single-dose challenges. Mov Disord 2005; 20: 151-7.
Gee S. On the action of a new organic base, apomorphia. Trans Clin Soc Lond. 1869; 2: 166-9.
Weil E. De l'apomorphine dans certains troubles nerveux. Lyon Medicale. 1884; 48: 411-19.
Stern G. Apolaustic apomorphine. Pract Neurol 2013; 13(5): 335-7.
Stern G. A case of excessive smoking. London Hospital Gazette 1957: 144-5.
Corsini G, Del Zompo M, Gessa G, Mangoni A. Therapeutic efficacy of apomorphine combined with an extracerebral inhibitor of dopamine receptors in Parkinson's disease. Lancet 1979(1): 954-6.
Ossig C, Reichmann H. Treatment of Parkinson's disease in the advanced stage. J Neural Transm 2013; 120(4): 523-9.
Neef C, van Laar T. Pharmacokinetic-pharmacodynamic relationships of apomorphine in patients with Parkinson's disease. Clin Pharmacokinet 1999; 37: 257-71.
Dewhurst F, Lee M, Wood B. The pragmatic use of apomorphine at the end of life. Palliat Med 2009; 23(8): 777-9.
LeWitt P, Ondo W, Van Lunen B, Bottini P. Open-label study assessment of safety and adverse effects of subcutaneous apomorphine injections in treating "off" episodes in advanced Parkinson disease. Clin Neuropharmacol 2009; 32(2): 89-93.
Wojtecki L, Südmeyer M, Schnitzler A. Multiple subcutaneous abscesses and necroses due to apomorphine pump treatment. Parkinsonism Relat Disord 2012 18(8): 1002.
Struhal W, Guger M, Hödl S, Ung S, Bach M, Ransmayr G. Attempted suicide under high dose dopaminergic therapy including apomorphine. Wien Klin Wochenschr 2012; 124(13-14): 461-3.
Himeno E, Ohyagi Y, Ma L, et al. Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation. Ann Neurol 2011; 69(2): 248-56.
Mohee A, Bretsztajn L, Eardley I. The evaluation of apomorphine for the treatment of erectile dysfunction. Expert Opin Drug Metab Toxicol 2012; 8(11): 1447-53.
Riley A, Main M, Morgan F. Inhalation device allows novel administration of apomorphine in men with erectile dysfunctionefficacy and safety findings. J Sex Med 2010 7(4 Pt 1): 1508-17.
Fridman E, Calvar J, Bonetto M, et al. Fast awakening from minimally conscious state with apomorphine. Brain Inj 2009; 23(2): 172-7.
Fridman E, Krimchansky B, Bonetto M, et al. Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury. Brain Inj 2010; 24(4): 636-41.
Sawyer E, Mauro L, Ohlinger M. Amantadine enhancement of arousal and cognition after traumatic brain injury. Ann Pharmacother 2008; 42(2): 247-52.
Stahl S. Essential psychopharmacology: neuroscientific basis and practical applications. Press CU, editor. New York, 2000.
Oliveira L, Fregni F. Pharmacological and electrical stimulation in chronic disorders of consciousness: new insights and future directions. Brain Inj 2011; 25(4): 315-27.
Schiff ND. Central thalamic deep-brain stimulation in the severely injured brain: rationale and proposed mechanisms of action. Ann N Y Acad Sci 2009; 1157: 101-16.
Schiff ND. Recovery of consciousness after brain injury: a mesocircuit hypothesis. Trends Neurosci 2010; 33(1): 1-9.
Sawaguchi T. The effects of dopamine and its antagonists on directional delay-period activity of prefrontal neurons in monkeys during an oculomotor delayed-response task. Neurosci Res 2001; 41(2): 115-28.
Braver T, Cohen J. On the control of control: the role of dopamine in regulating prefrontal function and working memory: a cognitive neuroscience perspective. In: Struss DT, Knight RT, editors. Principles of frontal lobe function. Oxford: Oxford University Press; 2000. pp. 428-48.
Salva P, Costa J. Clinical pharmacokinetics and pharmacodynamics of zolpidem. Therapeutic implications. Clin Pharmacokinet 1995; 29(3): 142-53.
Daniele A, Albanese A, Gainotti G, Gregori B, Bartolomeo P. Zolpidem in Parkinson's disease. Lancet 1997; 349(9060): 1222-3.
Jackson CW, Pitner JK, Mintzer JE. Zolpidem for the treatment of agitation in elderly demented patients. J Clin Psychiatry 1996; 57(8): 372-3.
Chen L, Xie JX, Fung KS, Yung WH. Zolpidem modulates GABA(A) receptor function in subthalamic nucleus. Neurosci Res 2007; 58(1): 77-85.
Clauss RP, Guldenpfennig WM, Nel HW, Sathekge MM, Venkannagari RR. Extraordinary arousal from semi-comatose state on zolpidem. A case report. S Afr Med J 2000; 90(1): 68-72.
Sanger DJ, Griebel G, Perrault G, Claustre Y, Schoemaker H. Discriminative stimulus effects of drugs acting at GABA(A) receptors: differential profiles and receptor selectivity. Pharmacol Biochem Behav 1999; 64(2): 269-73.
Clauss RP, van der Merwe CE, Nel HW. Arousal from a semicomatose state on zolpidem. S Afr Med J 2001; 91(10): 788-9.
Clauss RP, Nel W. Drug induced arousal from the permanent vegetative state. NeuroRehabilitation 2006; 21(1): 23-8.
Snyman N, Egan JR, London K, et al. Zolpidem for persistent vegetative state-a placebo-controlled trial in pediatrics. Neuropediatrics 2010; 41(5): 223-7.
Singh R, McDonald C, Dawson K, et al. Zolpidem in a minimally conscious state. Brain Inj 2008; 22(1): 103-6.
Shames JL, Ring H. Transient reversal of anoxic brain injuryrelated minimally conscious state after zolpidem administration: a case report. Arch Phys Med Rehabil 2008; 89(2): 386-8.
Cohen SI, Duong TT. Increased arousal in a patient with anoxic brain injury after administration of zolpidem. Am J Phys Med Rehabil 2008; 87(3): 229-31.
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 2013; 347(3): 178-182
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(5): 410-8.
Machado C, Estévez M, Pérez-Nellar J, et al. Autonomic, EEG, and behavioral arousal signs in a PVS case after zolpidem intake. Can J Neurol Sci 2011; 38(2): 341-4.
Thonnard M, Gosseries O, Demertzi A, et al. Effect of zolpidem in chronic disorders of consciousness: a prospective open-label study. Funct Neurol 28(4): 259-64.
Chatelle C, Thibaut A, Gosseries O, et al. Zolpidem and recovery of consciousness: a FDG-PET study. European Neurology Society; 2013; Barcelona.
Cairns H, Oldfield RC, Pennybacker JB, Whitteridge D. Akinetic mutism with an epidermoid cyst of the third ventricle. Brain 1941; 64(4): 273-90.
Laureys S, Berré J, Goldman S. Cerebral function in coma, vegetative state, minimally conscious state, locked-in syndrome and brain death. In: Vincent JL, editor. Yearbook of Intensive Care and Emergency Medicine. Berlin: Springer-Verlag; 2001. pp. 386-96.
Giacino JT. Disorders of consciousness: differential diagnosis and neuropathologic features. Semin Neurol 1997; 17(2): 105-11.
Brefel-Courbon C, Payoux P, Ory F, et al. Clinical and imaging evidence of zolpidem effect in hypoxic encephalopathy. Ann Neurol 2007; 62(1): 102-5.
Lo YL, Tan EK, Ratnagopal P, Chan LL, Tan TE. Zolpidem and its effects on hypoxic encephalopathy. Ann Neurol 2008; 64(4): 477-8.
Schiff ND, Posner JB. Another "Awakenings". Ann Neurol 2007; 62(1): 5-7.
Chen L, Savio Chan C, Yung WH. Electrophysiological and behavioral effects of zolpidem in rat globus pallidus. Exp Neurol 2004; 186(2): 212-20.
Karkela JT. Critical evaluation of postmortem changes in human autopsy cisternal fluid. Enzymes, electrolytes, acid-base balance, glucose and glycolysis, free amino acids and ammonia. Correlation to total brain ischemia. J Forensic Sci 1993; 38(3): 603-16.
Palmer AM, Marion DW, Botscheller ML, Bowen DM, DeKosky ST. Increased transmitter amino acid concentration in human ventricular CSF after brain trauma. Neuroreport 1994; 6(1): 153-6.
Nuwer MR, Hovda DA, Schrader LM, Vespa PM. Routine and quantitative EEG in mild traumatic brain injury. Clin Neurophysiol 2005; 116(9): 2001-25.
Poza J, Hornero R, Abasolo D, Fernandez A, Escudero J. Analysis of spontaneous MEG activity in patients with Alzheimer's disease using spectral entropies. Conf Proc IEEE Eng Med Biol Soc 2007; 2007: 6180-3.
Hall SD, Yamawaki N, Fisher AE, Clauss RP, Woodhall GL, Stanford IM. GABA(A) alpha-1 subunit mediated desynchronization of elevated low frequency oscillations alleviates specific dysfunction in stroke-a case report. Clin Neurophysiol 2010; 121(4): 549-55.
Cohen L, Chaaban B, Habert MO. Transient improvement of aphasia with zolpidem. N Engl J Med 2004; 350(9): 949-50.
