The Ethics of Pain Clinical Trials on Persons Lacking Judgment Ability: Much to Improve

Pain Medicine

Volumn 13, Issue 3, 2012, Pages 427-433

  Bellieni, Carlo V ^a   Rocchi, Raffaele ^a   Buonocore, Giuseppe ^a  

^a UNIVERSITY OF SIENA   (Italy)

Author keywords

Alzheimer disease; Autism; Clinical trial; Dementia; Depression; Down syndrome; Ethics; Newborns; Pain

Indexed keywords

ALZHEIMER DISEASE; ANALGESIA; ARM MOVEMENT; AUTISM; CLINICAL TRIAL (TOPIC); DECISION MAKING; DEMENTIA; DEPRESSION; DOWN SYNDROME; ELECTRICITY; HEAT; HUMAN; MEDICAL ETHICS; MEDICAL PROCEDURES; MENTAL DISEASE; NEWBORN; PAIN; PATIENT RIGHT; REVIEW; VEIN PUNCTURE;

EID: 84858613812     PISSN: 15262375     EISSN: 15264637     Source Type: Journal    
DOI: 10.1111/j.1526-4637.2011.01325.x     Document Type: Article

References (98)

1. MENCAP. Death by indifference. Report about institutional discrimination within the NHS, and people with a learning disability getting poor healthcare. 2007. Available at: (accessed January 6, 2012).
2. Lago P, Guadagni A, Merazzi D, etal. Pain Study Group of the Italian Society of Neonatology. Pain management in the neonatal intensive care unit: A national survey in Italy. Paediatr Anaesth 2005;15(11):925-31.
3. Byrd PJ, Gonzales I, Parsons V. Exploring barriers to pain management in newborn intensive care units: A pilot survey of NICU nurses. Adv Neonatal Care 2009;9(6):299-306.
4. Tyebkhan G. Declaration of Helsinki: The ethical cornerstone of human clinical research. Indian J Dermatol Venereol Leprol 2003;6(3):245-7.
5. Shavit I, Hadash A, Knaani-Levinz H, Shachor-Meyouhas Y, Kassis I. Lidocaine-based topical anesthetic with disinfectant (LidoDin) versus EMLA for venipuncture: A randomized controlled trial. Clin J Pain 2009;25(8):711-4.
6. Brochard S, Blajan V, Lempereur M, etal. Effectiveness of nitrous oxide and analgesic cream (lidocaine and prilocaine) for prevention of pain during intramuscular botulinum toxin injections in children. Ann Phys Rehabil Med 2009;52(10):704-16.
7. Weise KL, Nahata MC. EMLA for painful procedures in infants. J Pediatr Health Care 2005;19(1):42-7.
8. Holsti L, Grunau RE. Considerations for using sucrose to reduce procedural pain in preterm infants. Pediatrics 2010;125(5):1042-7.
9. Bellieni CV, Bagnoli F, Perrone S, etal. Effect of multisensory stimulation on analgesia in term neonates: A randomized controlled trial. Pediatr Res 2002;51(4):460-3.
10. Gomes Chermont A, Magno Falcão LF, de Souza Silva EHL, etal. Skin-to-skin contact and/or oral 25% dextrose for procedural pain relief for term newborn infants. Pediatrics 2009;124:e1101-7.
11. Bellieni CV, Burroni A, Perrone S, etal. Intracranial pressure during procedural pain. Biol Neonate 2003;84(3):202-5.
12. Bellieni CV, Iantorno L, Perrone S, etal. Even routine painful procedures can be harmful for the newborn. Pain 2009;147(1-3):128-31.
13. Marceau JR, Murray H, Nanan RK. Efficacy of oral sucrose in infants of methadone-maintained mothers. Neonatology 2009;97(1):67-70.
14. Milesi C, Cambonie G, Jacquot A, etal. Validation of a neonatal pain scale without facial items. Arch Dis Child Fetal Neonatal Ed 2009;95(4):F263-6.
15. Cignacco E, Denhaerynck K, Nelle M, Bührer C, Engberg S. Variability in pain response to a non-pharmacological intervention across repeated routine pain exposure in preterm infants: A feasibility study. Acta Paediatr 2009;98(5):842-6.
16. Harrison D, Loughnan P, Manias E, Gordon I, Johnston L. Repeated doses of sucrose in infants continue to reduce procedural pain during prolonged hospitalizations. Nurs Res 2009;58(6):427-34.
17. Leite AM, Linhares MB, Lander J, etal. Effects of breastfeeding on pain relief in full-term newborns. Clin J Pain 2009;25(9):827-32.
18. Weissman A, Aranovitch M, Blazer S, Zimmer EZ. Heel-lancing in newborns: Behavioral and spectral analysis assessment of pain control methods. Pediatrics 2009;124(5):e921-6.
19. Slater R, Cantarella A, Yoxen J, etal. Latency to facial expression change following noxious stimulation in infants is dependent on postmenstrual age. Pain 2009;146(1-2):177-82.
20. Cong X, Ludington-Hoe SM, McCain G, Fu P. Kangaroo Care modifies preterm infant heart rate variability in response to heel stick pain: Pilot study. Early Hum Dev 2009;85(9):561-7.
21. Slater R, Worley A, Fabrizi L, etal. Evoked potentials generated by noxious stimulation in the human infant brain. Eur J Pain 2009;14(3):321-6.
22. Taddio A, Crosdale B, Hogan ME, etal. Safety of morphine in nonintubated infants in the neonatal intensive care unit. Clin J Pain 2009;25(5):418-22.
23. Elserafy FA, Alsaedi SA, Louwrens J, Bin Sadiq B, Mersal AY. Oral sucrose and a pacifier for pain relief during simple procedures in preterm infants: A randomized controlled trial. Ann Saudi Med 2009;29(3):184-8.
24. Schäffer L, Luzi F, Burkhardt T, Rauh M, Beinder E. Antenatal betamethasone administration alters stress physiology in healthy neonates. Obstet Gynecol 2009;113(5):1082-8.
25. Akcan E, Yiǧit R, Atici A. The effect of kangaroo care on pain in premature infants during invasive procedures. Turk J Pediatr 2009;51(1):14-8.
26. Axelin A, Salanterä S, Kirjavainen J, Lehtonen L. Oral glucose and parental holding preferable to opioid in pain management in preterm infants. Clin J Pain 2009;25(2):138-45.
27. Taddio A, Shah V, Atenafu E, Katz J. Influence of repeated painful procedures and sucrose analgesia on the development of hyperalgesia in newborn infants. Pain 2009;144(1-2):43-8.
28. Taddio A, Shah V, Katz J. Reduced infant response to a routine care procedure after sucrose analgesia. Pediatrics 2009;123(3):e425-9.
29. Kashaninia Z, Sajedi F, Rahgozar M, Noghabi FA. The effect of Kangaroo Care on behavioral responses to pain of an intramuscular injection in neonates. J Spec Pediatr Nurs 2008;13(4):275-80.
30. Williams AL, Khattak AZ, Garza CN, Lasky RE. The behavioral pain response to heelstick in preterm neonates studied longitudinally: Description, development, determinants, and components. Early Hum Dev 2009;85(6):369-74.
31. Chimello JT, Gaspardo CM, Cugler TS, Martinez FE, Linhares MB. Pain reactivity and recovery in preterm neonates: Latency, magnitude, and duration of behavioral responses. Early Hum Dev 2009;85(5):313-8.
32. France CR, Taddio A, Shah VS, Pagé MG, Katz J. Maternal family history of hypertension attenuates neonatal pain response. Pain 2009;142(3):189-93.
33. Ahola Kohut S, Pillai Riddell R. Does the Neonatal Facial Coding System differentiate between infants experiencing pain-related and non-pain-related distress? J Pain 2009;10(2):214-20.
34. Stevens B, McGrath P, Dupuis A, etal. Indicators of pain in neonates at risk for neurological impairment. J Adv Nurs 2009;65(2):285-96.
35. Nishitani S, Miyamura T, Tagawa M, etal. The calming effect of a maternal breast milk odor on the human newborn infant. Neurosci Res 2009;63(1):66-71.
36. Schäffer L, Müller-Vizentini D, Burkhardt T, etal. Blunted stress response in small for gestational age neonates. Pediatr Res 2009;65(2):231-5.
37. Badiee Z, Torcan N. Effects of high dose orally administered paracetamol for heel prick pain in premature infants. Saudi Med J 2009;30(11):1450-3.
38. Joung KH, Cho SC. The effect of sucrose on infants during a painful procedure. Korean J Pediatr 2010;53(8):790-4.
39. Yilmaz F, Arikan D. The effects of various interventions to newborns on pain and duration of crying. J Clin Nurs 2010;20(7-8):1008-17.
40. O'Sullivan A, O'Connor M, Brosnahan D, McCreery K, Dempsey EM. Sweeten, soother and swaddle for retinopathy of prematurity screening: A randomized placebo controlled trial. Arch Dis Child Fetal Neonatal Ed 2010;95(6):F419-22.
41. Liaw JJ, Yang L, Ti Y, etal. Non-nutritive sucking relieves pain for preterm infants during heel stick procedures in Taiwan. J Clin Nurs 2010;19(19-20):2741-51.
42. Slater R, Cornelissen L, Fabrizi L, etal. Oral sucrose as an analgesic drug for procedural pain in newborn infants: A randomised controlled trial. Lancet 2010;376(9748):1225-32.
43. Badr LK, Abdallah B, Hawari M, etal. Determinants of premature infant pain responses to heel sticks. Pediatr Nurs 2010;36(3):129-36.
44. Dilen B, Elseviers M. Oral glucose solution as pain relief in newborns: Results of a clinical trial. Birth 2010;37(2):98-105.
45. Michel F, Vialet R, Hassid S, etal. Sevoflurane for central catheter placement in neonatal intensive care: A randomized trial. Paediatr Anaesth 2010;20(8):712-9.
46. Okan F, Ozdil A, Bulbul A, Yapici Z, Nuhoglu A. Analgesic effects of skin-to-skin contact and breastfeeding in procedural pain in healthy term neonates. Ann Trop Paediatr 2010;30(2):119-28.
47. El-Naggar W, Yiu A, Mohamed A, etal. Comparison of pain during two methods of urine collection in preterm infants. Pediatrics 2010;125(6):1224-9.
48. Slater R, Fabrizi L, Worley A, etal. Premature infants display increased noxious-evoked neuronal activity in the brain compared to healthy age-matched term-born infants. Neuroimage 2010;52(2):583-9.
49. Liu MF, Lin KC, Chou YH, Lee TY. Using non-nutritive sucking and oral glucose solution with neonates to relieve pain: A randomised controlled trial. J Clin Nurs 2010;19(11-12):1604-11.
50. Jong JT, Kao T, Lee LY, etal. Can temperament be understood at birth? The relationship between neonatal pain cry and their temperament: A preliminary study. Infant Behav Dev 2010;33(3):266-72.
51. Silva M, Mijovic B, Van den Bergh BR, etal. Decoupling between fundamental frequency and energy envelope of neonate cries. Early Hum Dev 2010;86(1):35-40.
52. Axelin A, Kirjavainen J, Salanterä S, Lehtonen L. Effects of pain management on sleep in preterm infants. Eur J Pain 2010;14(7):752-8.
53. Baba LR, McGrath JM, Liu J. The efficacy of mechanical vibration analgesia for relief of heel stick pain in neonates: A novel approach. J Perinat Neonatal Nurs 2010;24(3):274-83.
54. Tordjman S, Anderson GM, Botbol M, etal. Pain reactivity and plasma beta-endorphin in children and adolescents with autistic disorder. PLoS ONE 2009;4(8):e5289.
55. Euteneuer F, Schwarz MJ, Hennings A, etal. Depression, cytokines and experimental pain: Evidence for sex-related association patterns. J Affect Disord 2011;131(1-3):143-9. [Epub ahead of print].
56. Terhaar J, Boettger MK, Schwier C, etal. Increased sensitivity to heat pain after sad mood induction in female patients with major depression. Eur J Pain 2010;14(5):559-63.
57. de la Fuente-Sandoval C, Favila R, Gómez-Martin D, Pellicer F, Graff-Guerrero A. Functional magnetic resonance imaging response to experimental pain in drug-free patients with schizophrenia. Psychiatry Res 2010;183(2):99-104.
58. Carlino E, Benedetti F, Rainero I, etal. Pain perception and tolerance in patients with frontotemporal dementia. Pain 2010;151(3):783-9.
59. Kunz M, Mylius V, Schepelmann K, Lautenbacher S. Effects of age and mild cognitive impairment on the pain response system. Gerontology 2009;55(6):674-82.
60. Nandhagopal R, Troiano AR, Mak E, etal. Response to heat pain stimulation in idiopathic Parkinson's disease. Pain Med 2010;11(6):834-40.
61. Schnakers C, Chatelle C, Vanhaudenhuyse A, etal. The Nociception Coma Scale: A new tool to assess nociception in disorders of consciousness. Pain 2010;148(2):215-9.
62. Pesonen A, Kauppila T, Tarkkila P, etal. Evaluation of easily applicable pain measurement tools for the assessment of pain in demented patients. Acta Anaesthesiol Scand 2009;53(5):657-64.
63. Ersek M, Herr K, Neradilek MB, Buck HG, Black B. Comparing the psychometric properties of the Checklist of Nonverbal Pain Behaviors (CNPI) and the Pain Assessment in Advanced Dementia (PAIN-AD) instruments. Pain Med 2010;11(3):395-404. Epub 2010 Jan 15.
64. Husebo BS, Strand LI, Moe-Nilssen R, Husebo SB, Ljunggren AE. Pain in older persons with severe dementia. Psychometric properties of the Mobilization-Observation-Behaviour-Intensity-Dementia (MOBID-2) Pain Scale in a clinical setting. Scand J Caring Sci 2010;24(2):380-91.
65. Husebø BS. [Pain assessment in dementia]. Tidsskr Nor Laegeforen 2009;129(19):1996-8.
66. Cervo FA, Bruckenthal P, Chen JJ, etal. Pain assessment in nursing home residents with dementia: Psychometric properties and clinical utility of the CNA Pain Assessment Tool (CPAT). J Am Med Dir Assoc 2009;10(7):505-10.
67. Husebo BS, Strand LI, Moe-Nilssen R, Husebo SB, Ljunggren AE. Pain behaviour and pain intensity in older persons with severe dementia: Reliability of the MOBID Pain Scale by video uptake. Scand J Caring Sci 2009;23(1):180-9. Epub 2009 Jan 20.
68. Valkenburg AJ, van Dijk M, de Klein A, van den Anker JN, Tibboel D. Pain management in intellectually disabled children: Assessment, treatment, and translational research. Dev Disabil Res Rev 2010;16(3):248-57.
69. Scarpinato N, Bradley J, Kurbjun K, etal. Caring for the child with an autism spectrum disorder in the acute care setting. J Spec Pediatr Nurs 2010;15(3):244-54.
70. Solomowitz BH. Treatment of mentally disabled patients with intravenous sedation in a dental clinic outpatient setting. Dent Clin North Am 2009;53(2):231-42, viii.
71. Banicek J. How to ensure acute pain in older people is appropriately assessed and managed. Nurs Times 2010;106(29):14-7.
72. Hauer J. Identifying and managing sources of pain and distress in children with neurological impairment. Pediatr Ann 2010;39(4):198-205.
73. Autism Canada Foundation. Characteristics. 2011. Available at: (accessed January 6, 2012).
74. Nader R, Oberlander TF, Chambers CT, Craig KD. Expression of pain in children with autism. Clin J Pain 2004;20(2):88-97.
75. Harrison D, Bueno M, Yamada J, Adams-Webber T, Stevens B. Analgesic effects of sweet-tasting solutions for infants: Current state of equipoise. Pediatrics 2010;126(5):894-902.
76. Van Howe RS, Svoboda JS. Neonatal pain relief and the Helsinki Declaration. J Law Med Ethics 2008;36(4):803-23, 611.
77. Brady-Fryer B, Wiebe N, Lander JA. Pain relief for neonatal circumcision. Cochrane Database Syst Rev 2004;(4):CD004217.
78. World Medical Association. Declaration of Helsinki-Ethical principles for medical research involving human subjects. 1964. Available at: (accessed January 6, 2012).
79. Whitfield MF, Grunau RE. Behavior, pain perception, and the extremely low-birth weight survivor. Clin Perinatol 2000;27(2):363-79.
80. Simons SH, van Dijk M, Anand KS, etal. Do we still hurt newborn babies? A prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med 2003;157(11):1058-64.
81. Stevens B, Franck L, Gibbins S, etal. Determining the structure of acute pain responses in vulnerable neonates. Can J Nurs Res 2007;39(2):32-47.
82. Mainous RO, Looney S. A pilot study of changes in cerebral blood flow velocity, resistance, and vital signs following a painful stimulus in the premature infant. Adv Neonatal Care 2007;7(2):88-104.
83. Wing J. Ethics and psychiatric research. In: Bloch S, Chodoff P, eds. Psychiatric Ethics. Oxford, UK: Oxford University Press; 1981:279-94.
84. Schuklenk U. Protecting the vulnerable: Testing times for clinical research ethics. Soc Sci Med 2000;51:969-77.
85. Capron A. Ethical and human-rights issues in research on mental disorders that may affect decision-making capacity. N Engl J Med 1999;340:1430-4.
86. National institutes for health. Regulations and ethical guidelines. 2005. Available at: (accessed January 6, 2010).
87. Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst Rev 2004;(3):CD001069. Update in: Cochrane Database Syst Rev 2010;(1):CD001069.
88. Smith M, Gray SM, Ingram S, Jewkes DA. Double-blind comparison of topical lignocaine-prilocaine cream (EMLA) and lignocaine infiltration for arterial cannulation in adults. Br J Anaesth 1990;65:240-2.
89. Selby IM, Bowles BJ. Analgesia for venous cannulation: A comparison of EMLA (5 minutes application), lignocaine, ethyl chloride, and nothing. J R Soc Med 1995;88:264-7.
90. Nott MR, Peacock JL. Relief of injection pain in adults. EMLA cream for 5 minutes before venepuncture. Anaesthesia 1990;45:772-4.
91. Harrison N, Langham BT, Bogod DG. Appropriate use of local anaesthetic for venous cannulation. Anaesthesia 1992;47:210-2.
92. Anand KJ, Scalzo FM. Can adverse neonatal experiences alter brain development and subsequent behavior? Biol Neonate 2000;77(2):69-82.
93. Bhutta AT, Anand KJ. Vulnerability of the developing brain. Neuronal mechanisms. Clin Perinatol 2002;29(3):357-72.
94. Fries JF, Krishnan E. Equipoise, design bias, and randomized controlled trials: The elusive ethics of new drug development. Arthritis Res Ther 2004;6(3):R250-5.
95. Verhoeven J. Precaution principle, international law and international relations. A few remarks AFRI, volume III. 2002. Available at: (accessed January 6, 2012).
96. Bellieni CV, Buonocore G. Recommendations for an ethical treatment of newborns involved in clinical trials. Acta Paediatr 2010;99(1):30-2.
97. NBAC. Research Involving Persons with Mental Disorders that May Affect Decision Making Capacity. Rockville, MD: National Bioethics Advisory Commission; 1998.
98. Annas GJ. The dominance of American law and market values over American bioethics. In: Grodin MA, ed. Meta Medical Ethics: The Philosophical Foundations of Bioethics. Dordrecht: Kluwer; 1995:83-96.