Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Pain control in the critically ill adult patient

Pratik Pandharipande, MD, MSCI
Stuart McGrane, MBChB
Section Editors
Polly E Parsons, MD
Michael Avidan, MD
Deputy Editors
Geraldine Finlay, MD
Nancy A Nussmeier, MD, FAHA


Many critically ill patients experience pain due to underlying illness or injury, a recent surgical or other invasive procedure, or noxious stimuli caused by interventions in the intensive care unit (ICU; eg, mechanical ventilation, routine nursing care such as repositioning). In this topic, we review the physiology, assessment, and treatment of pain in the critical care setting. Other topics present a broader discussion of the use of sedative-analgesic medications to alleviate distress due to multiple causes (eg, anxiety, dyspnea, pain) or manage delirium with agitation in critically ill patients.

(See "Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal".)

(See "Sedative-analgesic medications in critically ill adults: Properties, dosage regimens, and adverse effects".)

(See "Delirium and acute confusional states: Prevention, treatment, and prognosis".)


Physiology of pain and pain control — Pain is sensed through the afferent pain pathway (figure 1) [1,2]. Recent tissue damage due to illness, injury, or surgery initiates the release of local inflammatory mediators (eg, bradykinin, substance P, prostaglandins, potassium, histamine, and serotonin) (figure 2). These mediators may cause primary hyperalgesia (augmented sensitivity to painful stimuli) or allodynia (misperception of pain with stimuli that are not noxious) (figure 3) [3,4]. Increased excitability of neurons in the central nervous system due to glutamate activation of the spinal N-methyl-D-aspartate (NMDA) receptors may exacerbate pain perception (secondary hyperalgesia) [4]. Patients with a preexisting chronic pain syndrome, neuropathy, or myopathy may develop exacerbation of baseline pain due to hyperalgesia or allodynia [5].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Sep 20, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Argoff C. Mechanisms of pain transmission and pharmacologic management. Curr Med Res Opin 2011; 27:2019.
  2. Lewis KS, Whipple JK, Michael KA, Quebbeman EJ. Effect of analgesic treatment on the physiological consequences of acute pain. Am J Hosp Pharm 1994; 51:1539.
  3. Kelly DJ, Ahmad M, Brull SJ. Preemptive analgesia I: physiological pathways and pharmacological modalities. Can J Anaesth 2001; 48:1000.
  4. Bruehl S. Complex regional pain syndrome. BMJ 2015; 351:h2730.
  5. Jensen TS, Finnerup NB. Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms. Lancet Neurol 2014; 13:924.
  6. Payen JF, Bosson JL, Chanques G, et al. Pain assessment is associated with decreased duration of mechanical ventilation in the intensive care unit: a post Hoc analysis of the DOLOREA study. Anesthesiology 2009; 111:1308.
  7. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain 2016; 17:131.
  8. A controlled trial to improve care for seriously ill hospitalized patients. The study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). The SUPPORT Principal Investigators. JAMA 1995; 274:1591.
  9. Mularski RA. Pain management in the intensive care unit. Crit Care Clin 2004; 20:381.
  10. van de Leur JP, van der Schans CP, Loef BG, et al. Discomfort and factual recollection in intensive care unit patients. Crit Care 2004; 8:R467.
  11. Rijkenberg S, Stilma W, Endeman H, et al. Pain measurement in mechanically ventilated critically ill patients: Behavioral Pain Scale versus Critical-Care Pain Observation Tool. J Crit Care 2015; 30:167.
  12. Schweickert WD, Kress JP. Strategies to optimize analgesia and sedation. Crit Care 2008; 12 Suppl 3:S6.
  13. Chanques G, Pohlman A, Kress JP, et al. Psychometric comparison of three behavioural scales for the assessment of pain in critically ill patients unable to self-report. Crit Care 2014; 18:R160.
  14. Chanques G, Viel E, Constantin JM, et al. The measurement of pain in intensive care unit: comparison of 5 self-report intensity scales. Pain 2010; 151:711.
  15. Joffe AM, Hallman M, Gélinas C, et al. Evaluation and treatment of pain in critically ill adults. Semin Respir Crit Care Med 2013; 34:189.
  16. Erstad BL, Puntillo K, Gilbert HC, et al. Pain management principles in the critically ill. Chest 2009; 135:1075.
  17. Gélinas C, Puntillo KA, Joffe AM, Barr J. A validated approach to evaluating psychometric properties of pain assessment tools for use in nonverbal critically ill adults. Semin Respir Crit Care Med 2013; 34:153.
  18. Ahlers SJ, van der Veen AM, van Dijk M, et al. The use of the Behavioral Pain Scale to assess pain in conscious sedated patients. Anesth Analg 2010; 110:127.
  19. Chanques G, Payen JF, Mercier G, et al. Assessing pain in non-intubated critically ill patients unable to self report: an adaptation of the Behavioral Pain Scale. Intensive Care Med 2009; 35:2060.
  20. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41:263.
  21. Hylén M, Akerman E, Alm-Roijer C, Idvall E. Behavioral Pain Scale - translation, reliability, and validity in a Swedish context. Acta Anaesthesiol Scand 2016; 60:821.
  22. Frandsen JB, O'Reilly Poulsen KS, Laerkner E, Stroem T. Validation of the Danish version of the Critical Care Pain Observation Tool. Acta Anaesthesiol Scand 2016; 60:1314.
  23. Battle CE, Lovett S, Hutchings H. Chronic pain in survivors of critical illness: a retrospective analysis of incidence and risk factors. Crit Care 2013; 17:R101.
  24. Kyranou M, Puntillo K. The transition from acute to chronic pain: might intensive care unit patients be at risk? Ann Intensive Care 2012; 2:36.
  25. Korosec Jagodic H, Jagodic K, Podbregar M. Long-term outcome and quality of life of patients treated in surgical intensive care: a comparison between sepsis and trauma. Crit Care 2006; 10:R134.
  26. Timmers TK, Verhofstad MH, Moons KG, et al. Long-term quality of life after surgical intensive care admission. Arch Surg 2011; 146:412.
  27. Cuthbertson BH, Roughton S, Jenkinson D, et al. Quality of life in the five years after intensive care: a cohort study. Crit Care 2010; 14:R6.
  28. Barr J, Pandharipande PP. The pain, agitation, and delirium care bundle: synergistic benefits of implementing the 2013 Pain, Agitation, and Delirium Guidelines in an integrated and interdisciplinary fashion. Crit Care Med 2013; 41:S99.
  29. Costantini R, Affaitati G, Fabrizio A, Giamberardino MA. Controlling pain in the post-operative setting. Int J Clin Pharmacol Ther 2011; 49:116.
  30. Gilron I, Orr E, Tu D, et al. A randomized, double-blind, controlled trial of perioperative administration of gabapentin, meloxicam and their combination for spontaneous and movement-evoked pain after ambulatory laparoscopic cholecystectomy. Anesth Analg 2009; 108:623.
  31. Lee BH, Park JO, Suk KS, et al. Pre-emptive and multi-modal perioperative pain management may improve quality of life in patients undergoing spinal surgery. Pain Physician 2013; 16:E217.
  32. Memis D, Inal MT, Kavalci G, et al. Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit. J Crit Care 2010; 25:458.
  33. Brodner G, Pogatzki E, Van Aken H, et al. A multimodal approach to control postoperative pathophysiology and rehabilitation in patients undergoing abdominothoracic esophagectomy. Anesth Analg 1998; 86:228.
  34. Smith JE, Rockett M, Creanor S, et al. PAin SoluTions In the Emergency Setting (PASTIES)--patient controlled analgesia versus routine care in emergency department patients with non-traumatic abdominal pain: randomised trial. BMJ 2015; 350:h3147.
  35. Chumbley GM, Hall GM, Salmon P. Patient-controlled analgesia: an assessment by 200 patients. Anaesthesia 1998; 53:216.
  36. Sessler CN, Varney K. Patient-focused sedation and analgesia in the ICU. Chest 2008; 133:552.
  37. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 2008; 371:126.
  38. Devlin JW, Roberts RJ. Pharmacology of commonly used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids. Crit Care Clin 2009; 25:431.
  39. Agarwal V, O'Neill PJ, Cotton BA, et al. Prevalence and risk factors for development of delirium in burn intensive care unit patients. J Burn Care Res 2010; 31:706.
  40. Flacke JW, Flacke WE, Bloor BC, et al. Histamine release by four narcotics: a double-blind study in humans. Anesth Analg 1987; 66:723.
  41. Baldo BA, Pham NH. Histamine-releasing and allergenic properties of opioid analgesic drugs: resolving the two. Anaesth Intensive Care 2012; 40:216.
  42. Sullivan SR, Friedrich JB, Engrav LH, et al. "Opioid creep" is real and may be the cause of "fluid creep". Burns 2004; 30:583.
  43. Wibbenmeyer L, Sevier A, Liao J, et al. The impact of opioid administration on resuscitation volumes in thermally injured patients. J Burn Care Res 2010; 31:48.
  44. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs 2003; 63:649.
  45. Reich A, Szepietowski JC. Opioid-induced pruritus: an update. Clin Exp Dermatol 2010; 35:2.
  46. Tarcatu D, Tamasdan C, Moryl N, Obbens E. Are we still scratching the surface? A case of intractable pruritus following systemic opioid analgesia. J Opioid Manag 2007; 3:167.
  47. Roberts DJ, Hall RI, Kramer AH, et al. Sedation for critically ill adults with severe traumatic brain injury: a systematic review of randomized controlled trials. Crit Care Med 2011; 39:2743.
  48. Hocker SE, Fogelson J, Rabinstein AA. Refractory intracranial hypertension due to fentanyl administration following closed head injury. Front Neurol 2013; 4:3.
  49. de Nadal M, Munar F, Poca MA, et al. Cerebral hemodynamic effects of morphine and fentanyl in patients with severe head injury: absence of correlation to cerebral autoregulation. Anesthesiology 2000; 92:11.
  50. Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth 2011; 58:911.
  51. De Pinto M, Jelacic J, Edwards WT. Very-low-dose ketamine for the management of pain and sedation in the ICU. J Opioid Manag 2008; 4:54.
  52. Cammarano WB, Pittet JF, Weitz S, et al. Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients. Crit Care Med 1998; 26:676.
  53. Honey BL, Benefield RJ, Miller JL, Johnson PN. Alpha2-receptor agonists for treatment and prevention of iatrogenic opioid abstinence syndrome in critically ill patients. Ann Pharmacother 2009; 43:1506.
  54. Awissi DK, Lebrun G, Fagnan M, et al. Alcohol, nicotine, and iatrogenic withdrawals in the ICU. Crit Care Med 2013; 41:S57.
  55. Kress JP, Pohlman AS, Hall JB. Sedation and analgesia in the intensive care unit. Am J Respir Crit Care Med 2002; 166:1024.
  56. Lee M, Silverman SM, Hansen H, et al. A comprehensive review of opioid-induced hyperalgesia. Pain Physician 2011; 14:145.
  57. Paul D, Standifer KM, Inturrisi CE, Pasternak GW. Pharmacological characterization of morphine-6 beta-glucuronide, a very potent morphine metabolite. J Pharmacol Exp Ther 1989; 251:477.
  58. Peterson GM, Randall CT, Paterson J. Plasma levels of morphine and morphine glucuronides in the treatment of cancer pain: relationship to renal function and route of administration. Eur J Clin Pharmacol 1990; 38:121.
  59. Björkman S, Stanski DR, Harashima H, et al. Tissue distribution of fentanyl and alfentanil in the rat cannot be described by a blood flow limited model. J Pharmacokinet Biopharm 1993; 21:255.
  60. Dahaba AA, Grabner T, Rehak PH, et al. Remifentanil versus morphine analgesia and sedation for mechanically ventilated critically ill patients: a randomized double blind study. Anesthesiology 2004; 101:640.
  61. Karabinis A, Mandragos K, Stergiopoulos S, et al. Safety and efficacy of analgesia-based sedation with remifentanil versus standard hypnotic-based regimens in intensive care unit patients with brain injuries: a randomised, controlled trial [ISRCTN50308308]. Crit Care 2004; 8:R268.
  62. Breen D, Karabinis A, Malbrain M, et al. Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: a randomised trial [ISRCTN47583497]. Crit Care 2005; 9:R200.
  63. Tan JA, Ho KM. Use of remifentanil as a sedative agent in critically ill adult patients: a meta-analysis. Anaesthesia 2009; 64:1342.
  64. Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005; 103:147.
  65. Beers RA, Calimlim JR, Uddoh E, et al. A comparison of the cost-effectiveness of remifentanil versus fentanyl as an adjuvant to general anesthesia for outpatient gynecologic surgery. Anesth Analg 2000; 91:1420.
  66. Guignard B, Bossard AE, Coste C, et al. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000; 93:409.
  67. Davison SN, Mayo PR. Pain management in chronic kidney disease: the pharmacokinetics and pharmacodynamics of hydromorphone and hydromorphone-3-glucuronide in hemodialysis patients. J Opioid Manag 2008; 4:335.
  68. Al-Qadheeb NS, Roberts RJ, Griffin R, et al. Impact of enteral methadone on the ability to wean off continuously infused opioids in critically ill, mechanically ventilated adults: a case-control study. Ann Pharmacother 2012; 46:1160.
  69. Meyer MM, Berens RJ. Efficacy of an enteral 10-day methadone wean to prevent opioid withdrawal in fentanyl-tolerant pediatric intensive care unit patients. Pediatr Crit Care Med 2001; 2:329.
  70. Wanzuita R, Poli-de-Figueiredo LF, Pfuetzenreiter F, et al. Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial. Crit Care 2012; 16:R49.
  71. Drew BJ, Ackerman MJ, Funk M, et al. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. Circulation 2010; 121:1047.
  72. Avellaneda C, Gómez A, Martos F, et al. The effect of a single intravenous dose of metamizol 2 g, ketorolac 30 mg and propacetamol 1 g on haemodynamic parameters and postoperative pain after heart surgery. Eur J Anaesthesiol 2000; 17:85.
  73. de Maat MM, Tijssen TA, Brüggemann RJ, Ponssen HH. Paracetamol for intravenous use in medium--and intensive care patients: pharmacokinetics and tolerance. Eur J Clin Pharmacol 2010; 66:713.
  74. Duggan ST, Scott LJ. Intravenous paracetamol (acetaminophen). Drugs 2009; 69:101.
  75. Gozzoli V, Treggiari MM, Kleger GR, et al. Randomized trial of the effect of antipyresis by metamizol, propacetamol or external cooling on metabolism, hemodynamics and inflammatory response. Intensive Care Med 2004; 30:401.
  76. Hersch M, Raveh D, Izbicki G. Effect of intravenous propacetamol on blood pressure in febrile critically ill patients. Pharmacotherapy 2008; 28:1205.
  77. Edrich T, Friedrich AD, Eltzschig HK, Felbinger TW. Ketamine for long-term sedation and analgesia of a burn patient. Anesth Analg 2004; 99:893.
  78. McGuinness SK, Wasiak J, Cleland H, et al. A systematic review of ketamine as an analgesic agent in adult burn injuries. Pain Med 2011; 12:1551.
  79. Holtman JR Jr, Jellish WS. Opioid-induced hyperalgesia and burn pain. J Burn Care Res 2012; 33:692.
  80. Hughes RA, Wijdicks EF, Benson E, et al. Supportive care for patients with Guillain-Barré syndrome. Arch Neurol 2005; 62:1194.
  81. Pandey CK, Bose N, Garg G, et al. Gabapentin for the treatment of pain in guillain-barré syndrome: a double-blinded, placebo-controlled, crossover study. Anesth Analg 2002; 95:1719.
  82. Pandey CK, Raza M, Tripathi M, et al. The comparative evaluation of gabapentin and carbamazepine for pain management in Guillain-Barré syndrome patients in the intensive care unit. Anesth Analg 2005; 101:220.
  83. Liu J, Wang LN, McNicol ED. Pharmacological treatment for pain in Guillain-Barré syndrome. Cochrane Database Syst Rev 2015; :CD009950.
  84. Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev 2009; :CD007076.
  85. Chaparro LE, Smith SA, Moore RA, et al. Pharmacotherapy for the prevention of chronic pain after surgery in adults. Cochrane Database Syst Rev 2013; :CD008307.
  86. McNicol ED, Schumann R, Haroutounian S. A systematic review and meta-analysis of ketamine for the prevention of persistent post-surgical pain. Acta Anaesthesiol Scand 2014; 58:1199.
  87. Clarke H, Bonin RP, Orser BA, et al. The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis. Anesth Analg 2012; 115:428.
  88. Mamoun NF, Lin P, Zimmerman NM, et al. Intravenous acetaminophen analgesia after cardiac surgery: A randomized, blinded, controlled superiority trial. J Thorac Cardiovasc Surg 2016; 152:881.
  89. McDaid C, Maund E, Rice S, et al. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review. Health Technol Assess 2010; 14:1.
  90. Ong CK, Seymour RA, Lirk P, Merry AF. Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesth Analg 2010; 110:1170.
  91. Kelly SJ, Moran JL, Williams PJ, et al. Haemodynamic effects of parenteral vs. enteral paracetamol in critically ill patients: a randomised controlled trial. Anaesthesia 2016; 71:1153.
  92. Malchow RJ, Black IH. The evolution of pain management in the critically ill trauma patient: Emerging concepts from the global war on terrorism. Crit Care Med 2008; 36:S346.
  93. Quibell R, Prommer EE, Mihalyo M, et al. Ketamine*. J Pain Symptom Manage 2011; 41:640.
  94. Himmelseher S, Durieux ME. Ketamine for perioperative pain management. Anesthesiology 2005; 102:211.
  95. Tucker AP, Kim YI, Nadeson R, Goodchild CS. Investigation of the potentiation of the analgesic effects of fentanyl by ketamine in humans: a double-blinded, randomised, placebo controlled, crossover study of experimental pain[ISRCTN83088383]. BMC Anesthesiol 2005; 5:2.
  96. De Kock M, Crochet B, Morimont C, Scholtes JL. Intravenous or epidural clonidine for intra- and postoperative analgesia. Anesthesiology 1993; 79:525.
  97. Omote K, Kitahata LM, Collins JG, et al. Interaction between opiate subtype and alpha-2 adrenergic agonists in suppression of noxiously evoked activity of WDR neurons in the spinal dorsal horn. Anesthesiology 1991; 74:737.
  98. Krachman SL, D'Alonzo GE, Criner GJ. Sleep in the intensive care unit. Chest 1995; 107:1713.
  99. Tembo AC, Parker V. Factors that impact on sleep in intensive care patients. Intensive Crit Care Nurs 2009; 25:314.
  100. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002; 30:119.
  101. Carr DB, Goudas LC. Acute pain. Lancet 1999; 353:2051.
  102. Bradt J, Dileo C. Music interventions for mechanically ventilated patients. Cochrane Database Syst Rev 2014; :CD006902.
  103. Chlan LL, Weinert CR, Heiderscheit A, et al. Effects of patient-directed music intervention on anxiety and sedative exposure in critically ill patients receiving mechanical ventilatory support: a randomized clinical trial. JAMA 2013; 309:2335.
  104. Richardson S. Effects of relaxation and imagery on the sleep of critically ill adults. Dimens Crit Care Nurs 2003; 22:182.
  105. Wang AT, Sundt TM 3rd, Cutshall SM, Bauer BA. Massage therapy after cardiac surgery. Semin Thorac Cardiovasc Surg 2010; 22:225.