Pain, Analgesic Effectiveness, and Long-Term Opioid Dependency

  • Yoanna SkrobikEmail author
  • Pamela Flood
Part of the Lessons from the ICU book series (LEICU)


Routine pain assessment and the procurement of effective analgesics are of paramount importance to critical care patients. Constant evaluation underpins the important balance between pain relief and the pharmacological side effects of administered agents. The significance of these issues was highlighted during the production of the most recent Society of Critical Medicine’s (SCCM) Pain, Agitation, Delirium, Immobility, and Sleep (PADIS) Guidelines [1]. Patients who partnered as authors and contributors in the SCCM PADIS effort ranked this dimension of clinical care as essential to their well-being, leading to its prioritization for these guidelines [2].


  1. 1.
    Devlin JW, Skrobik Y, Gelinas C, Needham DM, Slooter AJC, Pandharipande PP, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825–e73.PubMedCrossRefGoogle Scholar
  2. 2.
    Devlin JW, Skrobik Y, Rochwerg B, Nunnally ME, Needham DM, Gelinas C, et al. Methodologic innovation in creating clinical practice guidelines: insights from the 2018 society of critical care medicine pain, agitation/sedation, delirium, immobility, and sleep disruption guideline effort. Crit Care Med. 2018;46(9):1457–63.PubMedCrossRefGoogle Scholar
  3. 3.
    Cousins MJ, Lynch ME. The Declaration Montreal: access to pain management is a fundamental human right. Pain. 2011;152(12):2673–4.PubMedCrossRefGoogle Scholar
  4. 4.
    Potera C. Joint commission reassesses pain management. Am J Nurs. 2017;117(11):13.PubMedCrossRefGoogle Scholar
  5. 5.
    Barr J, Fraser GL, Puntillo K, Ely EW, Gelinas C, Dasta JF, 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(1):263–306.PubMedCrossRefGoogle Scholar
  6. 6.
    Kotfis K, Strzelbicka M, Zegan-Baranska M, Safranow K, Brykczynski M, Zukowski M, et al. Validation of the behavioral pain scale to assess pain intensity in adult, intubated postcardiac surgery patients: a cohort observational study – POL-BPS. Medicine. 2018;97(38):e12443.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Chanques G, Pohlman A, Kress JP, Molinari N, de Jong A, Jaber S, 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(5):R160.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Chanques G, Sebbane M, Barbotte E, Viel E, Eledjam JJ, Jaber S. A prospective study of pain at rest: incidence and characteristics of an unrecognized symptom in surgical and trauma versus medical intensive care unit patients. Anesthesiology. 2007;107(5):858–60.PubMedCrossRefGoogle Scholar
  9. 9.
    Puntillo KA, Morris AB, Thompson CL, Stanik-Hutt J, White CA, Wild LR. Pain behaviors observed during six common procedures: results from thunder project II. Crit Care Med. 2004;32(2):421–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Puntillo KA, Max A, Timsit JF, Ruckly S, Chanques G, Robleda G, et al. Pain distress: the negative emotion associated with procedures in ICU patients. Intensive Care Med. 2018;44(9):1493–501.PubMedCrossRefGoogle Scholar
  11. 11.
    Puntillo KA, Max A, Timsit JF, Vignoud L, Chanques G, Robleda G, et al. Determinants of procedural pain intensity in the intensive care unit. The Europain(R) study. Am J Respir Crit Care Med. 2014;189(1):39–47.PubMedGoogle Scholar
  12. 12.
    van der Woude MC, Bormans L, Hofhuis JG, Spronk PE. Current use of pain scores in Dutch intensive care units: a postal survey in the Netherlands. Anesth Analg. 2016;122(2):456–61.PubMedCrossRefGoogle Scholar
  13. 13.
    Payen JF, Bru O, Bosson JL, Lagrasta A, Novel E, Deschaux I, et al. Assessing pain in critically ill sedated patients by using a behavioral pain scale. Crit Care Med. 2001;29(12):2258–63.PubMedCrossRefGoogle Scholar
  14. 14.
    Aissaoui Y, Zeggwagh AA, Zekraoui A, Abidi K, Abouqal R. Validation of a behavioral pain scale in critically ill, sedated, and mechanically ventilated patients. Anesth Analg. 2005;101(5):1470–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Cade CH. Clinical tools for the assessment of pain in sedated critically ill adults. Nurs Crit Care. 2008;13(6):288–97.PubMedCrossRefGoogle Scholar
  16. 16.
    Topolovec-Vranic J, Canzian S, Innis J, Pollmann-Mudryj MA, McFarlan AW, Baker AJ. Patient satisfaction and documentation of pain assessments and management after implementing the adult nonverbal pain scale. Am J Crit Care. 2010;19(4):345–54; quiz 55PubMedCrossRefGoogle Scholar
  17. 17.
    Rose L, Smith O, Gelinas C, Haslam L, Dale C, Luk E, et al. Critical care nurses’ pain assessment and management practices: a survey in Canada. Am J Crit Care. 2012;21(4):251–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Watt-Watson J, Stevens B, Garfinkel P, Streiner D, Gallop R. Relationship between nurses’ pain knowledge and pain management outcomes for their postoperative cardiac patients. J Adv Nurs. 2001;36(4):535–45.PubMedCrossRefGoogle Scholar
  19. 19.
    Glynn G, Ahern M. Determinants of critical care nurses’ pain management behaviour. Aust Crit Care. 2000;13(4):144–51.PubMedCrossRefGoogle Scholar
  20. 20.
    Robinson BR, Mueller EW, Henson K, Branson RD, Barsoum S, Tsuei BJ. An analgesia-delirium-sedation protocol for critically ill trauma patients reduces ventilator days and hospital length of stay. J Trauma. 2008;65(3):517–26.PubMedCrossRefGoogle Scholar
  21. 21.
    Skrobik Y, Ahern S, Leblanc M, Marquis F, Awissi DK, Kavanagh BP. Protocolized intensive care unit management of analgesia, sedation, and delirium improves analgesia and subsyndromal delirium rates. Anesth Analg. 2010;111(2):451–63.PubMedCrossRefGoogle Scholar
  22. 22.
    Awissi DK, Begin C, Moisan J, Lachaine J, Skrobik Y. I-SAVE study: impact of sedation, analgesia, and delirium protocols evaluated in the intensive care unit: an economic evaluation. Ann Pharmacother. 2012;46(1):21–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Kanji S, MacPhee H, Singh A, Johanson C, Fairbairn J, Lloyd T, et al. Validation of the critical care pain observation tool in critically ill patients with delirium: a prospective cohort study. Crit Care Med. 2016;44(5):943–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, et al. GRADE evidence to decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: clinical practice guidelines. BMJ. 2016;353:i2089.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Kavanagh BP. The GRADE system for rating clinical guidelines. PLoS Med. 2009;6(9):e1000094.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Kumar A, Miladinovic B, Guyatt GH, Schunemann HJ, Djulbegovic B. GRADE guidelines system is reproducible when instructions are clearly operationalized even among the guidelines panel members with limited experience with GRADE. J Clin Epidemiol. 2016;75:115–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Payen JF, Chanques G, Mantz J, Hercule C, Auriant I, Leguillou JL, et al. Current practices in sedation and analgesia for mechanically ventilated critically ill patients: a prospective multicenter patient-based study. Anesthesiology. 2007;106(4):687–95; quiz 891–2PubMedCrossRefGoogle Scholar
  28. 28.
    Mehta S, Burry L, Fischer S, Martinez-Motta JC, Hallett D, Bowman D, et al. Canadian survey of the use of sedatives, analgesics, and neuromuscular blocking agents in critically ill patients. Crit Care Med. 2006;34(2):374–80.PubMedCrossRefGoogle Scholar
  29. 29.
    Richards-Belle A, Canter RR, Power GS, Robinson EJ, Reschreiter H, Wunsch H, et al. National survey and point prevalence study of sedation practice in UK critical care. Crit Care. 2016;20(1):355.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Chawla R, Myatra SN, Ramakrishnan N, Todi S, Kansal S, Dash SK. Current practices of mobilization, analgesia, relaxants and sedation in Indian ICUs: a survey conducted by the Indian Society of Critical Care Medicine. Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care. Medicine. 2014;18(9):575–84.Google Scholar
  31. 31.
    Wang J, Peng ZY, Zhou WH, Hu B, Rao X, Li JG. A national multicenter survey on management of pain, agitation, and delirium in intensive care units in China. Chin Med J. 2017;130(10):1182–8.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Devlin JW, Roberts RJ. Pharmacology of commonly used analgesics and sedatives in the ICU: benzodiazepines, propofol, and opioids. Crit Care Clin. 2009;25(3):431–49, viiPubMedCrossRefGoogle Scholar
  33. 33.
    Muellejans B, Lopez A, Cross MH, Bonome C, Morrison L, Kirkham AJ. Remifentanil versus fentanyl for analgesia based sedation to provide patient comfort in the intensive care unit: a randomized, double-blind controlled trial [ISRCTN43755713]. Crit Care. 2004;8(1):R1–r11.PubMedCrossRefGoogle Scholar
  34. 34.
    Karabinis A, Mandragos K, Stergiopoulos S, Komnos A, Soukup J, Speelberg B, 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(4):R268–80.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Dumas EO, Pollack GM. Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J. 2008;10(4):537–51.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Allouche S, Noble F, Marie N. Opioid receptor desensitization: mechanisms and its link to tolerance. Front Pharmacol. 2014;5:280.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Gaveriaux-Ruff C, Kieffer BL. Delta opioid receptor analgesia: recent contributions from pharmacology and molecular approaches. Behav Pharmacol. 2011;22(5–6):405–14.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Stein C. Opioid receptors. Annu Rev Med. 2016;67:433–51.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhang X, Bao L, Li S. Opioid receptor trafficking and interaction in nociceptors. Br J Pharmacol. 2015;172(2):364–74.PubMedCrossRefGoogle Scholar
  40. 40.
    Anand KJ, Willson DF, Berger J, Harrison R, Meert KL, Zimmerman J, et al. Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics. 2010;125(5):e1208–25.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Wiesenfeld-Hallin Z. Sex differences in pain perception. Gend Med. 2005;2(3):137–45.PubMedCrossRefGoogle Scholar
  42. 42.
    Mogil JS, Bailey AL. Sex and gender differences in pain and analgesia. Prog Brain Res. 2010;186:141–57.PubMedGoogle Scholar
  43. 43.
    Skrobik Y, Leger C, Cossette M, Michaud V, Turgeon J. Factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors. Crit Care Med. 2013;41(4):999–1008.PubMedCrossRefGoogle Scholar
  44. 44.
    Kieffer BL, Befort K, Gaveriaux-Ruff C, Hirth CG. The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci USA. 1992;89(24):12048–52.PubMedCrossRefGoogle Scholar
  45. 45.
    Contet C, Kieffer BL, Befort K. Mu opioid receptor: a gateway to drug addiction. Curr Opin Neurobiol. 2004;14(3):370–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Lavand’homme P, Steyaert A. Opioid-free anesthesia opioid side effects: tolerance and hyperalgesia. Best Pract Res Clin Anaesthesiol. 2017;31(4):487–98.PubMedCrossRefGoogle Scholar
  47. 47.
    Yu EH, Tran DH, Lam SW, Irwin MG. Remifentanil tolerance and hyperalgesia: short-term gain, long-term pain? Anaesthesia. 2016;71(11):1347–62.PubMedCrossRefGoogle Scholar
  48. 48.
    Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011;14(2):145–61.PubMedGoogle Scholar
  49. 49.
    Oh E, Ahn HJ, Sim WS, Lee JY. Synergistic effect of intravenous ibuprofen and hydromorphone for postoperative pain: prospective randomized controlled trial. Pain Physician. 2016;19(6):341–8.PubMedGoogle Scholar
  50. 50.
    Chabot-Dore AJ, Schuster DJ, Stone LS, Wilcox GL. Analgesic synergy between opioid and alpha2-adrenoceptors. Br J Pharmacol. 2015;172(2):388–402.PubMedCrossRefGoogle Scholar
  51. 51.
    Pacreu S, Fernandez Candil J, Molto L, Carazo J, Fernandez Galinski S. The perioperative combination of methadone and ketamine reduces post-operative opioid usage compared with methadone alone. Acta Anaesthesiol Scand. 2012;56(10):1250–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Raffa R. Pharmacological aspects of successful long-term analgesia. Clin Rheumatol. 2006;25(Suppl 1):S9–15.PubMedCrossRefGoogle Scholar
  53. 53.
    Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Twenty-four years of experience. Can Fam Physician. 2010;56(6):514–7, e202–5.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Hanks F, McKenzie C. Paracetamol in intensive care - intravenous, oral or not at all? Anaesthesia. 2016;71(10):1136–40.PubMedCrossRefGoogle Scholar
  55. 55.
    Suzuki S, Eastwood GM, Bailey M, Gattas D, Kruger P, Saxena M, et al. Paracetamol therapy and outcome of critically ill patients: a multicenter retrospective observational study. Crit Care. 2015;19:162.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Perbet S, Verdonk F, Godet T, Jabaudon M, Chartier C, Cayot S, et al. Low doses of ketamine reduce delirium but not opiate consumption in mechanically ventilated and sedated ICU patients: a randomised double-blind control trial. Anaesthesia Crit Care Pain Med. 2018;37(6):589–95.CrossRefGoogle Scholar
  57. 57.
    Wong I, St John-Green C, Walker SM. Opioid-sparing effects of perioperative paracetamol and nonsteroidal anti-inflammatory drugs(NSAIDs) in children. Paediatr Anaesth. 2013;23(6):475–95.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Shehabi Y, Grant P, Wolfenden H, Hammond N, Bass F, Campbell M, et al. Prevalence of delirium with dexmedetomidine compared with morphine based therapy after cardiac surgery: a randomized controlled trial (DEXmedetomidine COmpared to morphine-DEXCOM study). Anesthesiology. 2009;111(5):1075–84.PubMedCrossRefGoogle Scholar
  59. 59.
    Zhao LH, Shi ZH, Chen GQ, Yin NN, Chen H, Yuan Y, et al. Use of dexmedetomidine for prophylactic analgesia and sedation in patients with delayed extubation after craniotomy: a randomized controlled trial. J Neurosurg Anesthesiol. 2017;29(2):132–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Ruokonen E, Parviainen I, Jakob SM, Nunes S, Kaukonen M, Shepherd ST, et al. Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation. Intensive Care Med. 2009;35(2):282–90.PubMedCrossRefGoogle Scholar
  61. 61.
    Djaiani G, Silverton N, Fedorko L, Carroll J, Styra R, Rao V, et al. Dexmedetomidine versus propofol sedation reduces delirium after cardiac surgery: a randomized controlled trial. Anesthesiology. 2016;124(2):362–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Papathanassoglou ED, Mpouzika MD. Interpersonal touch: physiological effects in critical care. Biol Res Nurs. 2012;14(4):431–43.PubMedCrossRefGoogle Scholar
  63. 63.
    Myhren H, Toien K, Ekeberg O, Karlsson S, Sandvik L, Stokland O. Patients’ memory and psychological distress after ICU stay compared with expectations of the relatives. Intensive Care Med. 2009;35(12):2078–86.PubMedCrossRefGoogle Scholar
  64. 64.
    Kapfhammer HP, Rothenhausler HB, Krauseneck T, Stoll C, Schelling G. Posttraumatic stress disorder and health-related quality of life in long-term survivors of acute respiratory distress syndrome. Am J Psychiatry. 2004;161(1):45–52.PubMedCrossRefGoogle Scholar
  65. 65.
    Myhren H, Ekeberg O, Toien K, Karlsson S, Stokland O. Posttraumatic stress, anxiety and depression symptoms in patients during the first year post intensive care unit discharge. Crit Care. 2010;14(1):R14.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Duceppe MA, Perreault MM, Frenette AJ, Burry LD, Rico P, Lavoie A, et al. Frequency, risk factors and symptomatology of iatrogenic withdrawal from opioids and benzodiazepines in critically ill neonates, children and adults: a systematic review of clinical studies. J Clin Pharm Ther. 2018;44(2):148–56.PubMedCrossRefGoogle Scholar
  67. 67.
    Arroyo-Novoa CMF-RM, Puntillo K. Identifying opioid and benzodiazepine withdrawal in trauma intensive care unit (TICU) patients. Crit Care Med. 2018;46(Suppl 1):791.CrossRefGoogle Scholar
  68. 68.
    Clark J, Endicott J, Menon P, McMillian W. 919: incidence of prescribing opioids at hospital discharge after admission to a medical ICU. Crit Care Med. 2018;46(1):443.CrossRefGoogle Scholar

Copyright information

© European Society of Intensive Care Medicine 2020

Authors and Affiliations

  1. 1.McGill UniversityMontrealCanada
  2. 2.Stanford UniversitySan FranciscoUSA

Personalised recommendations