nach oben

Drugs

Erschienen in:

01.11.2013 | Leading Article

Pharmacotherapy for Disorders of Consciousness: Are ‘Awakening’ Drugs Really a Possibility?

verfasst von: Rosella Ciurleo, Placido Bramanti, Rocco Salvatore Calabrò

Erschienen in: Drugs | Ausgabe 17/2013

Einloggen, um Zugang zu erhalten

Abstract

Disorders of consciousness, including the coma state, vegetative state and minimally conscious state, are among the least understood and least curable conditions in modern neurology. Structural or functional injuries may produce impairments in the neuronal circuits (the ascending reticular activating system and thalamocortical loops) responsible for maintaining the wakefulness state and awareness, associated with a change in neurotransmitter concentrations. Pharmacological agents that are able to restore the levels of neurotransmitters and, consequently, neural synaptic plasticity and functional connectivity of consciousness networks, may play an important role as drugs useful in improving the consciousness state. Currently, there is growing interest in the scientific community with regard to pharmacological agents that act on the gamma amino-butyric acid (GABA) system, such as zolpidem and baclofen, and monoamine systems, such as dopaminergic agents and some antidepressants. The purpose of this article is to provide a comprehensive overview of these potential ‘awakening’ drugs in patients with disorders of consciousness. The possible mechanisms by which these drugs may exert their effects in promoting recovery of consciousness are discussed, highlighting how many findings are often the result of sporadic events rather than prospective controlled trials or implementation of standard treatment guidelines.

Zeman A. Consciousness. Brain. 2001;124(Pt 7):1263–89.PubMedCrossRef

Vanhaudenhuyse A, Demertzi A, Schabus M, Noirhomme Q, Bredart S, Boly M, et al. Two distinct neuronal networks mediate the awareness of environment and of self. J Cogn Neurosci. 2011;23(3):570–8.PubMedCrossRef

Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol. 1949;1(4):455–73.PubMed

Neylan TC. Physiology of arousal: Moruzzi and Magoun’s ascending reticular activating system. J Neuropsychiatry Clin Neurosci. 1995;7(2):250.PubMed

Edlow BL, Takahashi E, Wu O, Benner T, Dai G, Bu L, et al. Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. J Neuropathol Exp Neurol. 2012;71(6):531–46.PubMedCrossRef

Laureys S. The neural correlate of (un)awareness: lessons from the vegetative state. Trends Cogn Sci. 2005;9(12):556–9.PubMedCrossRef

Palmiter RD. Dopamine signaling as a neural correlate of consciousness. Neuroscience. 2011;198:213–20.PubMedCrossRef

Lau HC, Rogers RD, Ramnani N, Passingham RE. Willed action and attention to the selection of action. NeuroImage. 2004;21:1407–15.PubMedCrossRef

Paus T, Koski L, Caramanos Z, Westbury C. Regional differences in the effects of task difficulty and motor output on blood flow response in the human anterior cingulated cortex: a review of 107 PET activation studies. Neuroreport. 1998;9(9):R37–47.PubMedCrossRef

10.

Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci. 2000;4(6):215–22.PubMedCrossRef

11.

Goldfine AM, Schiff ND. Consciousness: its neurobiology and the major classes of impairment. Neurol Clin. 2011;29:723–37.PubMedCrossRef

12.

Schiff ND. Recovery of consciousness after brain injury: a mesocircuit hypothesis. Trend Neurosci. 2010;33(1):1–9.PubMedCrossRef

13.

Laureys S. Functional neuroimaging in the vegetative state. NeuroRehab. 2004;19(4):335–41.

14.

Giacino JT, Ashwal S, Childs N, Cranford R, Jennett B, Katz DI, et al. The minimally conscious state: definition and diagnostic criteria. Neurology. 2002;58(3):349–53.PubMedCrossRef

15.

Adams JH, Graham DI, Jennett B. The neuropathology of the vegetative state after an acute brain insult. Brain. 2000;123(7):1327–38.PubMedCrossRef

16.

Maxwell WL, MacKinnon MA, Smith DH, McIntosh TK, Graham DI. Thalamic nuclei after human blunt head injury. J Neuropathol Exp Neurol. 2006;65(5):478–88.PubMedCrossRef

17.

Johnson VE, Stewart W, Smith DH. Axonal pathology in traumatic brain injury. Exp Neurol. 2013;246:35–43.PubMedCrossRef

18.

Thibaut A, Bruno MA, Chatelle C, Gosseries O, Vanhaudenhuyse A, Demertzi A, et al. Matabolic activity in external and internal awareness network in severely brain-damaged patients. J Rehabil Med. 2012;44(6):487–94.PubMedCrossRef

19.

Yi JH, Hazell AS. Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochem Int. 2006;48(5):394–403.PubMedCrossRef

20.

Clauss RP. Neurotrasmitters in coma, vegetative and minimally conscious state, pharmacological interventions. Med Hypotheses. 2010;75(3):287–90.PubMedCrossRef

21.

Clauss RP. Neurotrasmitters in disorders of consciousness and brain damage. Med Hypotheses. 2011;77(2):209–13.PubMedCrossRef

22.

Clauss R, Nel W. Drug induced arousal from the permanent vegetative state. NeuroRehab. 2006;21(1):23–8.

23.

Kao CQ, Goforth PB, Ellis EF, Santin LS. Potentiation of GABA(A) currents after mechanical injury of cortical neurons. J Neurotrauma. 2004;21(3):259–70.PubMedCrossRef

24.

The Multi-Society Task Force Report on PVS. Medical aspects of the persistent vegetative state. N Engl J Med. 1994;330:1499–508.CrossRef

25.

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.PubMedCrossRef

26.

Laureys S, Lemaire C, Maquet P, Phillips C, Franck G. Cerebral metabolism during vegetative state and after recovery to consciousness. J Neurol Neurosurg Psychiatry. 1999;67(1):121.PubMedCrossRef

27.

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.PubMedCrossRef

28.

Fernandez-Espejo D, Junque C, Cruse D, Bernabeu M, Roig-Rovira T, Fabregas N, et al. Combination of diffusion tensor and functional magnetic resonance imaging during recovery from vegetative state. BMC Neurol. 2010;10:77.PubMedCrossRef

29.

Drover DR. Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone. Clin Pharmacokinet. 2004;43(4):227–38.PubMedCrossRef

30.

Lioresal^® intrathecal (baclofen injection): full prescribing information. Medtronic Inc. Minneapolis, MN. http://professional.medtronic.com/pt/neuro/itb/fpi/#.UkP28lPDVz0. Accessed 23 Sep 2013.

31.

Deleu D, Northway MG, Hanssens Y. Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson’s disease. Clin Pharmacokinet. 2002;41(4):261–309.PubMedCrossRef

32.

Bryson HM, Wilde MI. Amitriptyline. A review of its pharmacological properties and therapeutic use in chronic pain states. Drugs Aging. 1996;8(6):459–76.PubMedCrossRef

33.

Dorwald FZ. Lead optimization for medicinal chemists: pharmacokinetic properties of functional groups and organic compounds. Wiley, New York. http://books.google.it/books?id=YTeY9ZEfNccC (2013). Accessed 23 Sep 2013.

34.

Hiemke C, Härtter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther. 2000;85(1):11–28.PubMedCrossRef

35.

Kimko HC, Cross JT, Abernethy DR. Pharmacokinetics and clinical effectiveness of methylphenidate. Clin Pharmacokinet. 1999;37(6):457–70.PubMedCrossRef

36.

Ramback B, Wolf P. Lamotrigine clinical pharmacokinetics. Clin Pharmacokinet. 1993;25(6):433–43.CrossRef

37.

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.PubMedCrossRef

38.

Sanger DJ, Benavides J, Perrault G, Morel E, Cohen C, Joly D, et al. Recent developments in the behavioral pharmacology of benzodiazepine (ω) receptors: evidence for the functional significance of receptor subtypes. Neurosci Biobehav Rev. 1994;18(3):355–72.PubMedCrossRef

39.

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(1):68–72.PubMed

40.

Brefel-Courbon C, Payoux P, Ory F, Sommet A, Slaoui T, Raboyeau G, et al. Clinical and imaging evidence of zolpidem effect in hypoxic encephalopathy. An Neurol. 2007;62(1):102–5.CrossRef

41.

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(2):386–8.PubMedCrossRef

42.

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.PubMedCrossRef

43.

Cohen L, Chaaban B, Habert MO. Transient improvement of aphasia with zolpidem. N Engl J Med. 2004;350(9):949–50.PubMedCrossRef

44.

Clauss RP, Nel WH. Effect of zolpidem on brain injury and diaschisis as detected by 99 m Tc HMPAO brain SPECT in humans. Arzneimittelforschung. 2004;54(10):641–6.PubMed

45.

Clauss R, Sathekge M, Nel W. Transient improvement of spinocerebellar ataxia with zolpidem. N Engl J Med. 2004;351(5):511–2.PubMedCrossRef

46.

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. doi:10.1097/MAJ.0b013e318287c79c.

47.

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.PubMedCrossRef

48.

Snyman N, Egan JR, London K, Howman-Giles R, Gill D, Gillis J, et al. Zolpidem for persistent vegetative state—a placebo-controlled trial in pediatrics. Neuropediatrics. 2010;41(5):223–7.PubMedCrossRef

49.

Singh R, McDonald C, Dawson K, Lewis S, Pringle AM, Smith S, et al. Zolpidem in a minimally conscious state. Brain Inj. 2008;22(1):103–6.PubMedCrossRef

50.

Sarà M, Sacco S, Cipolla F, Onorati P, Scoppetta C, Albertini G, et al. An unexpected recovery from permanent vegetative state. Brain Inj. 2007;21(1):101–3.PubMedCrossRef

51.

Taira T, Hori T. Intrathecal baclofen in the treatment of post-stroke central pain, dystonia, and persistent vegetative state. Acta Neurochir Suppl. 2007;97(Pt 1):227–9.PubMed

52.

Taira T. Intrathecal administration of GABA agonists in the vegetative state. Prog Brain Res. 2009;177:317–28.PubMedCrossRef

53.

Sarà M, Pistoia F, Mura E, Onorati P, Govoni S. Intrathecal baclofen in patients with persistent vegetative state: 2 hypotheses. Arch Phys Med Rehabil. 2009;90(7):1245–9.PubMedCrossRef

54.

Morita I, Keith MW, Kanno T. Dorsal column stimulation for persistent vegetative state. Acta Neurochir Suppl. 2007;97(Pt 1):455–9.PubMed

55.

Liu JT, Tan WC, Liao WJ. Effects of electrical cervical spinal cord stimulation on cerebral blood perfusion, cerebrospinal fluid catecholamine levels, and oxidative stress in comatose patients. Acta Neurochir Suppl. 2008;101:71–6.PubMedCrossRef

56.

Smits H, van Kleef M, Holsheimer J, Joosten EA. Experimental spinal cord stimulation and neuropathic pain: mechanism of action, technical aspects, and effectiveness. Pain Pract. 2013;13(2):154–68.PubMedCrossRef

57.

Fridman EA, Calvar J, Bonetto M, Gamzu E, Krimchansky BZ, Meli F, et al. Fast awakening from minimally conscious state with apomorphine. Brain Inj. 2009;23(2):172–7.PubMedCrossRef

58.

Fridman EA, Krimchansky BZ, Bonetto M, Galperin T, Gamzu E, Leiguarda RC, et al. Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury. Brain Inj. 2010;24(4):636–41.PubMedCrossRef

59.

Haig AJ, Ruess JM. Recovery from vegetative state of six months’ duration associated with Sinemet (levodopa/carbidopa). Arch Phys Med Rehabil. 1990;71(13):1081–3.PubMed

60.

Koeda T, Takeshita K. A case report of remarkable improvement of motor disturbances with l-Dopa in a patient with post-diffuse axonal injury. Brain Dev. 1998;20(2):124–6.PubMedCrossRef

61.

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):1571–3.PubMedCrossRef

62.

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):414–27.PubMedCrossRef

63.

Krimchansky BZ, Keren O, Sazbon L, Groswasser Z. Differential time and related appearance of signs, indicating improvement in the state of consciousness in vegetative state traumatic brain injury (VS-TBI) patients after initiation of dopamine treatment. Brain Inj. 2004;18(11):1099–105.PubMedCrossRef

64.

Passler MA, Riggs RV. Positive outcomes in traumatic brain injury-vegetative state: patients treated, with bromocriptine. Arch Phys Med Rehabil. 2001;82(3):311–5.PubMedCrossRef

65.

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.PubMedCrossRef

66.

Zafonte RD, Watanabe T, Mann NR. Amantadine: a potential treatment for the minimally conscious state. Brain Inj. 1998;12(7):617–21.PubMedCrossRef

67.

Schnakers C, Hustinx R, Vandewalle G, Majerus S, Moonen G, Boly M, et al. Measuring the effect of amantadine in chronic anoxic minimally conscious state. J Neurol Neurosurg Psychiatry. 2008;79(2):225–7.PubMedCrossRef

68.

Giacino JT, Whyte J, Bagiella E, Kalmar K, Childs N, Khademi A, et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med. 2012;366(9):819–26.PubMedCrossRef

69.

Reinhard DL, Whyte J, Sandel ME. Improved arousal and initiation following tricyclic antidepressant use in severe brain injury. Arch Phys Med Rehabil. 1996;77(1):80–3.PubMedCrossRef

70.

Wroblewski B, Glenn MB, Cornblatt R, Joseph AB, Suduikis S. Protriptyline as an alternative stimulant medication in patients with brain injury: a series of case reports. Brain Inj. 1993;7(4):353–62.PubMedCrossRef

71.

DeMarchi R, Bansal V, Hung A, Wroblewski K, Dua H, Sockalingam S, et al. Review of awakening agents. Can J Neurol Sci. 2005;32:4–17.PubMed

72.

Meythaler JM, Depalma L, Devivo MJ, Guin-Renfroe S, Novack TA. Sertraline to improve arousal and alertness in severe TBI secondary to motor vehicle crashes. Brain Inj. 2001;15(4):321–31.PubMedCrossRef

73.

Leonard BE, McCartan D, White J, King DJ. Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects. Hum Psychopharmacol. 2004;19:151–80.PubMedCrossRef

74.

Worzniak M, Fetters MD, Comfort M. Methylphenidate in the treatment of coma. J Fam Pract. 1997;44(5):495–8.PubMed

75.

Reynolds JC, Rittenberger JC, Callaway CW. Methylphenidate and amantadine to stimulate reawakening in comatose patients resuscitated from cardiac arrest. Resuscitation. 2013;84(6):818–24.PubMedCrossRef

76.

Kim YW, Shin JC, An YS. Effects of methylphenidate on cerebral glucose metabolism in patients with impaired consciousness after acquired brain injury. Clin Neuropharmacol. 2009;32(6):335–9.PubMedCrossRef

77.

Bagnato S, Boccagni C, Sant’Angelo A, Galardi G. A range of antiepileptic drugs do not affect the recovery of consciousness in vegetative and minimally conscious states. Epilepsy Behav. 2013;27:365–70.PubMedCrossRef

78.

Showalter PE, Kimmel DN. Stimulating consciousness and cognition following severe brain injury: a new potential clinical use for lamotrigine. Brain Inj. 2000;14(11):997–1001.PubMedCrossRef

79.

Stefan H, Feuerstein TJ. Novel anticonvulsant drugs. Pharmacol Ther. 2007;113(165–8):3.

80.

Whyte J. Treatment to enhance recovery from the vegetative and minimally conscious state: ethical issue surrounding efficacy studies. Am J Phys Med Rehabil. 2007;86:86–92.PubMedCrossRef

Titel: Pharmacotherapy for Disorders of Consciousness: Are ‘Awakening’ Drugs Really a Possibility?
verfasst von: Rosella Ciurleo
Placido Bramanti
Rocco Salvatore Calabrò
Publikationsdatum: 01.11.2013
Verlag: Springer International Publishing
Erschienen in: Drugs / Ausgabe 17/2013
Print ISSN: 0012-6667
Elektronische ISSN: 1179-1950
DOI: https://doi.org/10.1007/s40265-013-0138-8

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 17/2013

Efinaconazole: First Global Approval

Fosfomycin Trometamol: A Review of Its Use as a Single-Dose Oral Treatment for Patients with Acute Lower Urinary Tract Infections and Pregnant Women with Asymptomatic Bacteriuria

Riociguat: First Global Approval

Therapeutic Options for Old World Cutaneous Leishmaniasis and New World Cutaneous and Mucocutaneous Leishmaniasis

Therapeutic Options for Visceral Leishmaniasis

Gender Differences in Cardiovascular Therapy: Focus on Antithrombotic Therapy and Percutaneous Coronary Intervention