Impact Factor 3.508

Frontiers journals are at the top of citation and impact metrics

Opinion ARTICLE

Front. Neurol., 16 November 2016 | https://doi.org/10.3389/fneur.2016.00202

Pain Perception in Unresponsive Wakefulness Syndrome May Challenge the Interruption of Artificial Nutrition and Hydration: Neuroethics in Action

imageFrancesco Riganello1*, imageSimone Macrì2, imageEnrico Alleva2, imageCarlo Petrini3, imageAndrea Soddu4, imageJosè Leòn-Carriòn5 and imageGiuliano Dolce1
  • 1Research in Advanced Neurorehabilitation, Istituto S. Anna, Crotone, Italy
  • 2Section of Behavioral Neuroscience, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy
  • 3Office of the President, Bioethics Unit, Istituto Superiore di Sanità, Rome, Italy
  • 4Department of Physics and Astronomy, Brain and Mind Institute, The University of Western Ontario, London, ON, Canada
  • 5Human Neuropsychology Laboratory, Department of Experimental Psychology, School of Psychology, University of Seville, Seville, Spain

Introduction

The voluntary withdrawal of artificial nutrition and hydration (ANH) in patients with severe disorders of consciousness (DoC, e.g., permanent vegetative states) constitutes a fundamental ethical issue extending beyond the boundaries of end-of-life decisions. The term “Vegetative State” was originally adopted to define “an organic body capable of growth and development but devoid of sensation and thought” (1). In this frame, the traditional approach toward the suspension of ANH rested upon the view that patients in the Vegetative State had no residual capability to perceive pain (2, 3). However, over the past few decades, an increasing number of studies (411) have shown that strong claims about awareness in patients without behavioral responses to commands are unwarranted. Furthermore, there is again a high percentage of misdiagnoses in the assessment of these patients (1214).

Recently it was proposed the alternative name “unresponsive wakefulness syndrome” (VS/UWS) (15), to define a condition characterized by the absence of response to commands or oriented voluntary movements in the presence of wakefulness. Neuroimaging studies demonstrated the existence of distinctive cerebral responses to noxious stimuli in conditions like VS/UWS and minimally conscious state (MCS) (1618). Yet, there is no univocal consensus about pain perception in patients with DoC. In a study by Demertzi and colleagues (19), 2,059 medical and paramedical professionals from 32 European countries were asked the following question: “can a patient in vegetative state feel pain?” Over 40% of those surveyed replied that these patients do not feel pain. The percentage was higher among medical doctors compared to paramedical caregivers (54 and 32%, respectively). This view was substantiated by the idea that, in the absence of consciousness, patients were not capable of experiencing and reporting a painful experience. However, recent advances in the pathophysiology of DoC, debunking the original tenet that patients with DoC do not perceive pain, suggest a reconsideration of the voluntary withdrawal of ANH (20).

In this manuscript, we will briefly review the recent literature indicating that some patients with DoC reveal a form of residual awareness (21) and that they are capable of perceiving painful stimuli and exhibiting consistent responses to them. Furthermore, empirical evidence in the literature suggests that, when tested with the appropriate tools, these patients can exhibit consistent reactions to emotionally salient stimuli (5, 10, 2227). Based on these findings, we propose that the voluntary withdrawal of ANH should be carefully reconsidered on medical and ethical grounding.

Pain: Definition and Neuroanatomical Substrates

Pain is defined as “… an unpleasant sensory and emotional experience arising from actual or potential tissue damage or described in terms of such damage…” (28). Likewise, McCaffrey and Pasero (29) reported that “Pain is whatever the experiencing person says it is, existing whenever the experiencing person says it does.” Such subjectivity implies that pain may only be detected when a patient reports its manifestation. Therefore, the presence of consciousness would seem to constitute a fundamental prerequisite in the individual appraisal and experience of pain. Analogous considerations may be applied to the concept of suffering, defined as “the state of severe distress associated with events that threaten the intactness of the person” (30). Furthermore, Turk and Wilson (31) proposed that “a person might experience significant pain-related suffering from a relatively low-level noxious stimulation if she or he believes the implications are ominous, interminable, and beyond their control” (31). Within this framework, both pain and suffering seem to require the presence of consciousness.

Several authors have shown that nociceptive stimuli elicit the activation of an extensive cortical network including somatosensory, insular, and cingulate areas, as well as frontal and parietal areas (32, 33). In particular, nociception refers to the perception (conscious or not) of nociceptive stimuli (28). The stimulation of nociceptors leads to the transmission of information via the spinothalamic tract to the thalamus and on to the cortex, with the midbrain and thalamus thought to be involved in the modulation of reflex response to nociceptive stimuli (34). The cortical nociceptive network entails the secondary somatosensory (S2) cortex, with the posterior insula (lateral network), taking part in the sensory–discriminative features of the pain processing (35, 36). However, the generation of a conscious experience of pain requires the activation of a more complex network. This network is often referred to as the “pain matrix.” The pain matrix entails two main subsystems (37): the lateral neuronal network [secondary somatosensory (S2) cortex, lateral thalamus, and posterior insula], encoding sensory–discriminative information (38), and the medial network [anterior cingulate cortex (ACC) and prefrontal cortex], encoding affective–cognitive information (39). Also, the cerebellum plays a major role in processing aversive stimuli including pain (40), contributing to the sensory–discriminative part of the pain processing network. Finally, motor-related areas (e.g., the striatum, cerebellum, and the supplementary motor area) are involved in pain perception and processing (41). In addition to identifying the neuroanatomical structures involved in pain perception, these studies investigated the dynamics of activation (connectivity) of the pain matrix. Thus, results on cortical potential suggest that nociceptive input is first processed in the posterior insula, wherein it is coded in terms of intensity and anatomical location, and then conveyed to the anterior insula, where the emotional reaction to pain is elaborated (36, 42, 43).

Furthermore, several authors demonstrated the existence in humans of multiple somatotopic representations of pain within the operculo-insular region. This mechanism may constitute a sensory-integration site that selectively targets emotional responses toward the specific injured body-site (44). Finally, the pain matrix has been shown to vary with age and in response to the onset of pathologies. Some authors have suggested that structural deficits in regions involved in the modulation of pain, and in their connectivity, occur in chronic pain syndromes (45).

Pain in Patients with DOC

Pioneering studies attempting to quantify nociception in patients with DoC (46) systematically measured physiological variables like eye opening, breathing, heart rate, and blood pressure, and occasionally grimace-like or crying-like behavior (47). However, notwithstanding their heuristic value, these signs are considered to be of subcortical origin, not necessarily reflecting a conscious perception of pain. Additional quantitative measurements of nociception in patients with DoC reported stereotyped responses (i.e., slow generalized flexion or extension of the upper and lower extremities), flexion withdrawal (i.e., withdrawal of the limb away from the point of the stimulation), and localization responses (i.e., the non-stimulated limb locates and makes contact with the stimulated body part at the point of stimulation), all of which were linked, respectively, to brainstem, subcortical, or cortical activity (nociceptive network or pain matrix) (32, 46, 48).

Other studies investigated the extent to which the pain matrix responded to nociceptive stimuli in patients with DoC. For example, Boly et al. (16) observed that, in response to a noxious stimulus, patients in MCS showed “pain matrix” activation similar to that seen in normal controls (16). Patients in VS/UWS also showed activation in the pain matrix, although this activation was much less prominent compared to controls (16). An independent study performed by Markl et al. (49) observed the presence of significant activation in the sensory and affective components of the pain matrix in patients characterized by severe DoC (49). In a study adopting laser-evoked potentials, the authors observed that painful stimuli may be processed even in patients with severe brain damage (50). Functional magnetic resonance imaging (fMRI) has also been used to investigate brain mechanisms underlying the perception of pain in patients with DoC. Using this paradigm, Monti et al. (20) demonstrated that patients with a diagnosis of “unresponsive wakefulness syndrome” (UWS), evaluated at the bedside, exhibited measurable awareness. Therefore, the authors proposed that negative results in clinical trials or activation protocols do not necessarily imply the absence of cognitive processes in these patients (20). Alternatively, it may be suggested that these patients were misdiagnosed due to the technical constraints of the bedside evaluation. Retrospective reports of patients surviving intensive care constitute an additional indication that patients with DoC may exhibit some form of appraisal of noxious stimuli. These individuals report vivid memories of pain, noise, sleep deprivation, thirst, hunger, heat, cold, fear, anxiety, isolation, physical restraint, lack of information, and absence of daylight (51).

These empirical data corroborate the view that although patients with DoC may not be capable of exhibiting a detectable reaction to painful stimuli, they may nonetheless be capable of perceiving them (52). These data do not demonstrate that all patients with severe disorders of consciousness perceive and/or exhibit pain; yet, they demonstrate that several patients, deemed incapable of experiencing pain, showed a consistent response to noxious stimuli. Regardless of whether this is due to misdiagnosis or technical limitations, these data contravene the tenet that all patients with severe disorders of consciousness do not experience pain.

Conclusion

For patients with severe pathologies (e.g., terminally ill), the dehydration and starvation may have benefits (patients could be intolerant of enteral feeding because of abdominal distension, vomiting, diarrhea, or fluid overload) and to refuse food and fluids and to have relief of distress through provision of medicine may be a right (53). However, most patients in VS/UWS are unlikely to be intolerant of nutrition and hydration that are considered basic compassionate care because they promote physical and emotional well-being (54, 55). Withdrawal of ANH has biologic consequences including distress and pain (56).

Neurophysiological and fMRI studies are finding ways to assess awareness in VS/UWS patients (57, 58). The identification of the “pain matrix” along with the design of experimental tools capable of detecting consistent patterns of brain activation in response to noxious stimuli allowed us to integrate the original definitions of pain, which rested largely upon subjective experiences with objective measurements.

These data, which bestow a heuristic advancement in the study of pain and consciousness, may also foster a reconsideration of the general attitude toward the management of pain in patients with DoC. Herein, our main interest is directed toward the withdrawal of ANH in these patients. With respect to the latter, Ogino and collaborators (59) demonstrated that dehydration, in control subjects, leads to increased brain activity in the anatomical structures involved in pain perception (ACC, insula, and thalamus). Thus, dehydration may per se constitute a source of pain in healthy subjects (60). Furthermore, Perry et al. (60) reported that hydration status is an important modulator of the cerebrovascular response to cold pressor tests, which are commonly used to investigate cerebrovascular regulation. Therefore, dehydration may not only constitute a source of pain but also interfere with the ability to assess a nociceptive response in the patient. Ultimately, current experimental knowledge supports the notion that voluntary withdrawal of hydration may, under specific conditions, constitute a source of pain. Given the empirical data reported above, concerning pain perception in patients with DoC, it is tenable that the primary ethical, clinical, and deontological concerns shall relate to the suffering of the patient. Within this framework, the voluntary withdrawal of ANH may raise ethical concerns worth being addressed.

Author Contributions

All the authors have contributed to the drafting and revisions of the manuscript and have approved the submitted version.

Note

From the meeting “Voluntary withdrawal of Nutrition and Hydration in Patients with severe Disorders of Consciousness: Clinical and Ethical aspects.” 23-11-2015 Rome (Italy).

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1. Jennett B, Plum F. Persistent vegetative state after brain damage. A syndrome in search of a name. Lancet Lond Engl (1972) 1:734–7. doi: 10.1016/S0140-6736(72)90242-5

CrossRef Full Text | Google Scholar

2. Andrews K. Medical decision making in the vegetative state: withdrawal of nutrition and hydration. NeuroRehabilitation (2004) 19:299–304.

PubMed Abstract | Google Scholar

3. Jennett B. Thirty years of the vegetative state: clinical, ethical and legal problems. In: Laureys S, editor. Progress in Brain Research. The Boundaries of Consciousness: Neurobiology and Neuropathology. Elsevier (2005). p. 537–43. Available from: http://www.sciencedirect.com/science/article/pii/S0079612305500372

Google Scholar

4. Bruno MA, Vanhaudenhuyse A, Schnakers C, Boly M, Gosseries O, Demertzi A, et al. Visual fixation in the vegetative state: an observational case series PET study. BMC Neurol (2010) 10:35. doi:10.1186/1471-2377-10-35

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Dolce G, Riganello F, Quintieri M, Candelieri A, Conforti D. Personal interaction in the vegetative state: a data-mining study. J Psychophysiol (2008) 22:150–6. doi:10.1027/0269-8803.22.3.150

CrossRef Full Text | Google Scholar

6. Gutiérrez J, Machado C, Estévez M, Olivares A, Hernández H, Perez J, et al. Heart rate variability changes induced by auditory stimulation in persistent vegetative state. Int J Disabil Hum Dev (2010) 9:357–62. doi:10.1515/IJDHD.2010.041

CrossRef Full Text | Google Scholar

7. Laureys S, Perrin F, Brédart S. Self-consciousness in non-communicative patients. Conscious Cogn (2007) 16:722–41. doi:10.1016/j.concog.2007.04.004

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Leon-Carrion J, Leon-Dominguez U, Halper J, Pollonini L, Zouridakis G, Dominguez-Morales M, et al. Restoring cortical connectivity directionality and synchronization is essential to treating disorder of consciousness. Curr Pharm Des (2013) 999:17–8. doi:10.2174/13816128113196660651

CrossRef Full Text | Google Scholar

9. Monti MM. Cognition in the vegetative state. Annu Rev Clin Psychol (2012) 8:431–54. doi:10.1146/annurev-clinpsy-032511-143050

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Riganello F, Candelieri A, Dolce G, Sannita WG. Residual emotional processing in the vegetative state: a scientific issue? Clin Neurophysiol (2011) 122:1061–2. doi:10.1016/j.clinph.2010.09.006

CrossRef Full Text | Google Scholar

11. Riganello F, Cortese MD, Dolce G, Sannita WG. Visual pursuit response in the severe disorder of consciousness: modulation by the central autonomic system and a predictive model. BMC Neurol (2013) 13:164. doi:10.1186/1471-2377-13-164

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Andrews K, Murphy L, Munday R, Littlewood C. Misdiagnosis of the vegetative state: retrospective study in a rehabilitation unit. BMJ (1996) 313:13–6. doi:10.1136/bmj.313.7048.13

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Bosco A, Lancioni GE, Belardinelli MO, Singh NN, O’Reilly MF, Sigafoos J. Vegetative state: efforts to curb misdiagnosis. Cogn Process (2010) 11:87–90. doi:10.1007/s10339-009-0355-y

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Gill-Thwaites H. Lotteries, loopholes and luck: misdiagnosis in the vegetative state patient. Brain Inj (2006) 20:1321–8. doi:10.1080/02699050601081802

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Laureys S, Celesia GG, Cohadon F, Lavrijsen J, León-Carrión J, Sannita WG, et al. Unresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome. BMC Med (2010) 8:68. doi:10.1186/1741-7015-8-68

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Boly M, Faymonville ME, Schnakers C, Peigneux P, Lambermont B, Phillips C, et al. Perception of pain in the minimally conscious state with PET activation: an observational study. Lancet Neurol (2008) 7:1013–20. doi:10.1016/S1474-4422(08)70219-9

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Laureys S. Death, unconsciousness and the brain. Nat Rev Neurosci (2005) 6:899–909. doi:10.1038/nrn1789

CrossRef Full Text | Google Scholar

18. Laureys S, Faymonville ME, Peigneux P, Damas P, Lambermont B, Del Fiore G, et al. Cortical processing of noxious somatosensory stimuli in the persistent vegetative state. Neuroimage (2002) 17:732–41. doi:10.1006/nimg.2002.1236

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Demertzi A, Schnakers C, Ledoux D, Chatelle C, Bruno MA, Vanhaudenhuyse A, et al. Different beliefs about pain perception in the vegetative and minimally conscious states: a European survey of medical and paramedical professionals. Progress in Brain Research. Elsevier (2009). p. 329–38. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0079612309177221

Google Scholar

20. Monti MM, Laureys S, Owen AM. The vegetative state. BMJ (2010) 341:c3765–3765. doi:10.1136/bmj.c3765

CrossRef Full Text | Google Scholar

21. Chennu S, Finoia P, Kamau E, Allanson J, Williams GB, Monti MM, et al. Spectral signatures of reorganised brain networks in disorders of consciousness. PLoS Comput Biol (2014) 10:e1003887. doi:10.1371/journal.pcbi.1003887

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Bekinschtein T, Niklison J, Sigman L, Manes F, Leiguarda R, Armony J, et al. Emotion processing in the minimally conscious state. J Neurol Neurosurg Psychiatry (2004) 75:788–788. doi:10.1136/jnnp.2003.034876

CrossRef Full Text | Google Scholar

23. Fiacconi CM, Owen AM. Using Facial Electromyography to Detect Preserved Emotional Processing in the Vegetative State in Psychophysiology. Hoboken, NJ: Wiley-Blackwell (2015). p. S35–35.

Google Scholar

24. Machado C, Korein J, Aubert E, Bosch J, Alvarez MA, Rodríguez R, et al. Recognizing a mother’s voice in the persistent vegetative state. Clin EEG Neurosci (2007) 38:124–6. doi:10.1177/155005940703800306

CrossRef Full Text | Google Scholar

25. O’Kelly J, James L, Palaniappan R, Taborin J, Fachner J, Magee WL. Neurophysiological and behavioral responses to music therapy in vegetative and minimally conscious states. Front Hum Neurosci (2013) 7:884. doi:10.3389/fnhum.2013.00884

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Riganello F, Candelieri A, Quintieri M, Conforti D, Dolce G. Heart rate variability: an index of brain processing in vegetative state? An artificial intelligence, data mining study. Clin Neurophysiol (2010) 121:2024–34. doi:10.1016/j.clinph.2010.05.010

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Sharon H, Pasternak Y, Ben Simon E, Gruberger M, Giladi N, Krimchanski BZ, et al. Emotional processing of personally familiar faces in the vegetative state. PLoS One (2013) 8:e74711. doi:10.1371/journal.pone.0074711

PubMed Abstract | CrossRef Full Text | Google Scholar

28. IASP. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. Seattle, WA: IASP Press (1994).

Google Scholar

29. McCaffrey M, Pasero C. Pain: Clinical manual. St Louis, MO: Mosby (1999).

Google Scholar

30. Cassell EJ. Recognizing suffering. Hastings Cent Rep (1991) 21:24–24. doi:10.2307/3563319

CrossRef Full Text | Google Scholar

31. Turk DC, Wilson HD. Pain, suffering, pain-related suffering – are these constructs inextricably linked? Clin J Pain (2009) 25:353–5. doi:10.1097/AJP.0b013e31819c62e7

CrossRef Full Text | Google Scholar

32. Chatelle C, Thibaut A, Bruno MA, Boly M, Bernard C, Hustinx R, et al. Nociception coma scale-revised scores correlate with metabolism in the anterior cingulate cortex. J Neurol Rehabil (2014) 28:149–52. doi:10.1177/1545968313503220

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Coghill RC, McHaffie JG, Yen Y-F. Neural correlates of interindividual differences in the subjective experience of pain. Proc Natl Acad Sci U S A (2003) 100:8538–42. doi:10.1073/pnas.1430684100

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Loeser JD, Treede R-D. The Kyoto protocol of IASP basic pain terminology. Pain (2008) 137:473–7. doi:10.1016/j.pain.2008.04.025

CrossRef Full Text | Google Scholar

35. Lockwood PL, Iannetti GD, Haggard P. Transcranial magnetic stimulation over human secondary somatosensory cortex disrupts perception of pain intensity. Cortex (2013) 49:2201–9. doi:10.1016/j.cortex.2012.10.006

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Ploner M, Gross J, Timmermann L, Schnitzler A. Cortical representation of first and second pain sensation in humans. Proc Natl Acad Sci U S A (2002) 99:12444–8. doi:10.1073/pnas.182272899

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Brooks J, Tracey I. From nociception to pain perception: imaging the spinal and supraspinal pathways. J Anat (2005) 207:19. doi:10.1111/j.1469-7580.2005.00428.x

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Mutschler I, Wankerl J, Seifritz E, Ball T. P02-405 – the role of the human insular cortex in pain processing. Eur Psychiatry (2011) 26(Suppl 1):1001. doi:10.1016/S0924-9338(11)72706-7

CrossRef Full Text | Google Scholar

39. Medford N, Critchley HD. Conjoint activity of anterior insular and anterior cingulate cortex: awareness and response. Brain Struct Funct (2010) 214:535–49. doi:10.1007/s00429-010-0265-x

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Moulton EA, Elman I, Pendse G, Schmahmann J, Becerra L, Borsook D. Aversion-related circuitry in the cerebellum: responses to noxious heat and unpleasant images. J Neurosci (2011) 31:3795–804. doi:10.1523/JNEUROSCI.6709-10.2011

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Barceló AC, Filippini B, Pazo JH. The striatum and pain modulation. Cell Mol Neurobiol (2012) 32:1–12. doi:10.1007/s10571-011-9737-7

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Frot M, Faillenot I, Mauguière F. Processing of nociceptive input from posterior to anterior insula in humans. Hum Brain Mapp (2014) 35:5486–99. doi:10.1002/hbm.22565

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Tracey I. Imaging pain. Br J Anaesth (2008) 101:32–9. doi:10.1093/bja/aen102

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Baumgärtner U, Iannetti GD, Zambreanu L, Stoeter P, Treede R-D, Tracey I. Multiple somatotopic representations of heat and mechanical pain in the operculo-insular cortex: a high-resolution fMRI study. J Neurophysiol (2010) 104:2863–72. doi:10.1152/jn.00253.2010

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Hadjipavlou G, Dunckley P, Behrens TE, Tracey I. Determining anatomical connectivities between cortical and brainstem pain processing regions in humans: a diffusion tensor imaging study in healthy controls. Pain (2006) 123:169–78. doi:10.1016/j.pain.2006.02.027

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Schnakers C, Chatelle C, Vanhaudenhuyse A, Majerus S, Ledoux D, Boly M, et al. The Nociception Coma Scale: a new tool to assess nociception in disorders of consciousness. Pain (2010) 148:215–9. doi:10.1016/j.pain.2009.09.028

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Schnakers C, Zasler ND. Pain assessment and management in disorders of consciousness. Curr Opin Neurol (2007) 20:620–6. doi:10.1097/WCO.0b013e3282f169d9

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Riganello F, Cortese MD, Arcuri F, Candelieri A, Guglielmino F, Dolce G, et al. A study of the reliability of the Nociception Coma Scale. Clin Rehabil (2014) 29:388–93. doi:10.1177/0269215514546767

CrossRef Full Text | Google Scholar

49. Markl A, Yu T, Vogel D, Müller F, Kotchoubey B, Lang S. Brain processing of pain in patients with unresponsive wakefulness syndrome. Brain Behav (2013) 3:95–103. doi:10.1002/brb3.110

PubMed Abstract | CrossRef Full Text | Google Scholar

50. de Tommaso M, Navarro J, Lanzillotti C, Ricci K, Buonocunto F, Livrea P, et al. Cortical responses to salient nociceptive and not nociceptive stimuli in vegetative and minimal conscious state. Front Hum Neurosci (2015) 9:17. doi:10.3389/fnhum.2015.00017

CrossRef Full Text | Google Scholar

51. Simini B. Patients’ perceptions of intensive care. Lancet (1999) 354:571–2. doi:10.1016/S0140-6736(99)02728-2

CrossRef Full Text | Google Scholar

52. Naro A, Leo A, Bramanti P, Calabrò RS. Moving toward conscious pain processing detection in chronic disorders of consciousness: anterior cingulate cortex neuromodulation. J Pain (2015) 16:1022–31. doi:10.1016/j.jpain.2015.06.014

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Savulescu J. A simple solution to the puzzles of end of life? Voluntary palliated starvation. J Med Ethics (2013) 2013:101379. doi:10.1136/medethics-2013-101379

CrossRef Full Text | Google Scholar

54. Amano K, Morita T, Baba M, Kawasaki M, Nakajima S, Uemura M, et al. Effect of nutritional support on terminally ill patients with cancer in a palliative care unit. Am J Hosp Palliat Care (2013) 30:730–3. doi:10.1177/1049909112469273

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Cohen MZ, Torres-Vigil I, Burbach BE, de la Rosa A, Bruera E. The meaning of parenteral hydration to family caregivers and patients with advanced cancer receiving hospice care. J Pain Symptom Manage (2012) 43:855–65. doi:10.1016/j.jpainsymman.2011.06.016

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Rady MY, Verheijde JL. Nonconsensual withdrawal of nutrition and hydration in prolonged disorders of consciousness: authoritarianism and trustworthiness in medicine. Philos Ethics Humanit Med (2014) 9:16. doi:10.1186/1747-5341-9-16

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Gosseries O, Di H, Laureys S, Boly M. Measuring consciousness in severely damaged brains. Annu Rev Neurosci (2014) 37:457–78. doi:10.1146/annurev-neuro-062012-170339

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Jox RJ, Bernat JL, Laureys S, Racine E. Disorders of consciousness: responding to requests for novel diagnostic and therapeutic interventions. Lancet Neurol (2012) 11:732–8. doi:10.1016/S1474-4422(12)70154-0

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Ogino Y, Kakeda T, Nakamura K, Saito S. Dehydration enhances pain-evoked activation in the human brain compared with rehydration. Anesth Analg (2014) 118:1317–25. doi:10.1213/ANE.0b013e3182a9b028

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Perry BG, Bear TLK, Lucas SJE, Mündel T. Mild dehydration modifies the cerebrovascular response to the cold pressor test: hydration status and the cold pressor test. Exp Physiol (2016) 101(1):135–42. doi:10.1113/EP085449

CrossRef Full Text | Google Scholar

Keywords: unresponsive wakefulness syndrome, vegetative state, pain, consciousness, withdrawal of artificial nutrition and hydration, neuroethics

Citation: Riganello F, Macrì S, Alleva E, Petrini C, Soddu A, Leòn-Carriòn J and Dolce G (2016) Pain Perception in Unresponsive Wakefulness Syndrome May Challenge the Interruption of Artificial Nutrition and Hydration: Neuroethics in Action. Front. Neurol. 7:202. doi: 10.3389/fneur.2016.00202

Received: 02 August 2016; Accepted: 01 November 2016;
Published: 16 November 2016

Edited by:

Barak Bar, Loyola University Medical Center, USA

Reviewed by:

Torrey Ann Boland, Rush University, USA
Michael Adam Rubin, University of Texas Southwestern Medical Center, USA

Copyright: © 2016 Riganello, Macrì, Alleva, Petrini, Soddu, Leòn-Carriòn and Dolce. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Francesco Riganello, f.riganello@istitutosantanna.it