Kunal Karamchandani, MD, FCCP; Bridgette L. Kram, PharmD, BCPS, BCCCP; Ashish K. Khanna, MD, FCCP, FCCM
Opioids impact critical care in multiple ways. Not only do they form the backbone of managing pain and sedation in the intensive care unit (ICU), the burgeoning opioid epidemic also feeds into opioid-related ICU admissions. While managing acute opioid overdose and acute withdrawal is vital, providing sufficient analgesia to critically ill patients and preventing opioid dependence challenges critical care providers. ICU-acquired opioid dependence and chronic pain disorders after critical illness contribute to post-intensive care syndrome (PICS), and preventing them provides ICU caregivers an opportunity to improve outcomes in ICU survivors.
Pain is one of the most common memories associated with patients’ ICU stays.1 Acute pain in the ICU is attributed to prolonged immobility, indwelling devices, and exposure to invasive procedures, among other etiologies.2 If left untreated, this can lead to hemodynamic and neurobehavioral changes impacting short- and long-term outcomes such as agitation, delirium, and chronic pain syndromes.3 Management of pain in critically ill patients is also prioritized by consensus guidelines, which recommend treating pain first or using analgosedation (ie, analgesia first or analgesia-based treatment) with opioids as the mainstay of pain management.3 Consequently, there is concern for the development of opioid tolerance, dependence, and persistent opioid use in ICU survivors. In this article, we discuss the challenges of meeting the sedation and analgesia needs of an opioid-tolerant patient, critical care management of acute opioid toxicity and withdrawal, and the implications of opioid use in the ICU.
The Opioid-Tolerant Patient
The U.S. Food and Drug Administration defines a patient as opioid tolerant if, for at least 1 week, the patient has been receiving oral morphine, 60 mg/day; transdermal fentanyl, 25 µg/hour; oral oxycodone, 30 mg/day; oral hydromorphone, 8 mg/day; oral oxymorphone, 25 mg/day; or an equianalgesic dose of any other opioid.4 Critical care admission of opioid-tolerant patients seems to be increasing in the wake of the opioid epidemic. The task of providing adequate analgesia while minimizing the risk of overdose and opioid dependence in these patients is daunting, and educational resources are limited. While well-written reviews are available to practitioners to help manage postsurgical or posttraumatic pain,5,6 explicit guidelines are lacking. In a survey of a random sampling of ICU clinicians at acute care hospitals in the United States, only 7% had specific guidelines to address titratable sedative analgesic needs for patients with opioid use disorder (OUD). Additionally, 66% of respondents reported not having access to pain or addiction specialists.7 The lack of a standardized approach to pain management in ICU patients with OUD hampers clinical care. There is a dire need for research efforts targeted at optimizing safe and effective care of these patients.
Some critically ill patients may have a history of OUD while being maintained on medication-assisted therapy (MAT) with drugs such as methadone or buprenorphine. These patients with OUD on MAT should continue their preexisting opioid regimen with supplemental analgesia as necessary.8 Because MAT does not provide sustained analgesia, doses should not be increased for acute pain control. Instead, short-acting opioid analgesics should be combined with MAT to achieve adequate pain control in the acute setting. Multimodal treatment involving nonopioid medications (eg, nonsteroidal anti-inflammatory agents, acetaminophen, gabapentin) can reduce opioid requirements and is suggested by the current guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU (PADIS).3
Acute opioid toxicity is one of the most common reasons for ICU admission related to OUD. A nearly 34% increase in ICU admissions for opioid overdose was reported from January 2009 to September 2015, with an associated ICU mortality rate of 7% (95% CI, 7.0-7.6%).9 Acute opioid toxicity manifests with a broad range of clinical findings. The hallmark of opioid intoxication, respiratory depression (defined as a respiratory rate of 12 breaths/min or less), when accompanied by miosis or stupor and a suggestive history, strongly suggests acute opioid intoxication.10 Pharmacologic reversal with naloxone and supportive measures, including mechanical ventilation for respiratory depression and inotropic/vasopressor support to counteract the cardiovascular effects of opioids, remain the tenets of management. Dosing of naloxone is empiric and titrated to effect. The effective dose is dependent on the amount of opioid the patient has taken, the type of opioid, the patient’s weight, and the degree of opioid penetrance into the central nervous system.11 The initial dose of naloxone for adults is 0.04 mg and the dose is increased every 2-3 minutes in a stepwise manner to achieve a respiratory rate of more than 12 breaths/min. Since the half-life of naloxone is short, a continuous naloxone infusion may be warranted, particularly for opioids with a long half-life (eg, methadone, extended-release formulations) to prevent recurrent respiratory depression.
Iatrogenic opioid withdrawal in the ICU has been reported to occur in 16%-32% of critically ill patients who receive opioids.12 Higher cumulative opioid doses and prolonged duration of use in the ICU are primary risk factors. There is a paucity of evidence regarding management of opioid withdrawal in the ICU. No specific opioid tapering strategy has been evaluated to prevent iatrogenic withdrawal in adults; thus, management should be individualized, with careful monitoring for inadequate pain control, anxiety, restlessness, lacrimation, rhinorrhea, mydriasis, piloerection, diarrhea, and elevations in heart rate, blood pressure, and respiratory rate.13 N-methyl-d-aspartate (NMDA) receptor antagonists, such as ketamine, and alpha-2 agonists, such as clonidine and dexmedetomidine, may have potential for managing the symptoms of opioid withdrawal.14 However, further studies are required before recommending routine use of these agents in opioid-dependent or opioid-tolerant patients in the ICU.
Implications of Opioid Use in the ICU
Opioids are administered to most critically ill patients for analgosedation as well as for acute pain management, as an important preventive mechanism against the development of chronic pain. Unfortunately, chronic pain has been described in multiple patient populations following ICU admission.15-17 The reported rates of chronic pain following ICU admission range from 12% to 73%. This wide variation is due to widely variable patient populations, severity of illness, pain assessment tool used, timing since ICU discharge, and evaluation of preexisting chronic pain.16-19 While risk of chronic pain in ICU survivors is apparent, opioid continuation following ICU admission has not been well characterized.
In a retrospective, single-center study of medical and surgical ICU patients in Canada, Yaffe et al found that opioid use in ICU survivors was 12.2% following hospital discharge and 4.4% at 48 months.20 Prolonged hospital length of stay and pre-admission chronic opioid use were associated with post-discharge chronic opioid use. In a dataset of nearly 350 million opioid-naive veterans requiring postoperative ICU care for more than 24 hours, 4.1% developed new persistent OUD, defined as continuation of opioids for more than 3 months following ICU discharge.21 These patients were significantly younger and had a history of substance use or alcohol use disorder. Interestingly, the trends of new persistent opioid use in these ICU survivors decreased over time, attributable in part to better ICU pain management.
ICU-specific sedation practices may predispose patients to receiving a hospital discharge prescription for an opioid. A small, single-center cohort of opioid-naive mechanically ventilated patients reported that, when scheduled enteral opioids were administered as part of a weaning strategy from continuous intravenous opioid infusions, nearly one-third of patients received a discharge prescription for scheduled opioids at hospital discharge. Lack of breakthrough pain medication use and low pain scores prior to discharge indicate potentially inappropriate prescribing practices.22 Similarly, a multidisciplinary panel retrospectively adjudicated opioids as the most common inappropriate medications prescribed on hospital discharge in elderly ICU survivors, with 73% initiated in the ICU setting.23
Management of acute pain in critically ill patients is a cornerstone of excellent ICU care; however, opioid stewardship in the ICU is imperative. Frequent pain assessment, use of the lowest effective opioid dose, a multimodal approach to pain management, ongoing evaluation of medication appropriateness, and vigilance at transitions of care are key strategies in preventing development of potential OUD in ICU survivors.
- Stein-Parbury J, McKinley S. Patients’ experiences of being in an intensive care unit: a select literature review. Am J Crit Care. 2000 Jan;9(1):20-27.
- Puntillo KA, Max A, Timsit JF, et al. Determinants of procedural pain intensity in the intensive care unit. The Europain® study. Am J Respir Crit Care Med. 2014 Jan 1;189(1):39-47.
- Devlin JW, Skrobik Y, Gélinas C, et al. Executive summary: 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 Sep;46(9):1532-1548.
- U.S. Food and Drug Administration. Extended-Release (ER) and Long-Acting (LA) Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS). Washington, DC: U.S. Food and Drug Administration; 2014. www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm311290.pdf. Accessed January 7, 2019.
- Karamchandani K, Carr ZJ, Bonavia A, Tung A. Critical care pain management in patients affected by the opioid epidemic: a review. Ann Am Thorac Soc. 2018 Sep;15(9):1016-1023.
- Karamchandani K, Klick JC, Linskey Dougherty M, Bonavia A, Allen SR, Carr ZJ. Pain management in trauma patients affected by the opioid epidemic: a narrative review. J Trauma Acute Care Surg. 2019 Aug;87(2):430-439.
- Reichheld AM, Hills-Evans K, Sheehan JK, et al. A national survey of approaches to manage the ICU patient with opioid use disorder. J Crit Care. 2019 Jun 29;54:42-47.
- Mehta V, Langford RM. Acute pain management for opioid dependent patients. Anaesthesia. 2006 Mar;61(3):269-276.
- Stevens JP, Wall MJ, Novack L, Marshall J, Hsu DJ, Howell MD. The critical care crisis of opioid overdoses in the United States. Ann Am Thorac Soc. 2017 Dec;14(12):1803-1809.
- Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with altered mental status: a reappraisal. Ann Emerg Med. 1991 Mar;20(3):246-252.
- Berkowitz BA. The relationship of pharmacokinetics to pharmacological activity: morphine, methadone and naloxone. Clin Pharmacokinet. 1976;1(3):219-230.
- Cammarano WB, Pittet JF, Weitz S, Schlobohm RM, Marks JD. Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients. Crit Care Med. 1998 Apr;26(4):676-684.
- Jenkins DH. Substance abuse and withdrawal in the intensive care unit. Contemporary issues. Surg Clin North Am. 2000 Jun;80(3):1033-1053.
- Puntillo KA, Naidu R. Chronic pain disorders after critical illness and ICU-acquired opioid dependence: two clinical conundra. Curr Opin Crit Care. 2016 Oct;22(5):506-512.
- Battle CE, Lovett S, Hutchings H. Chronic pain in survivors of critical illness: a retrospective analysis of incidence and risk factors. Crit Care. 2013 May 29;17(3):R101.
- Baumbach P, Götz T, Gunther A, Weiss T, Meissner W. Prevalence and characteristics of chronic intensive care-related pain: the role of severe sepsis and septic shock. Crit Care Med. 2016 Jun;44(6):1129-1137.
- Choinière M, Watt-Watson J, Victor JC, et al. Prevalence of and risk factors for persistent postoperative nonanginal pain after cardiac surgery: a 2-year prospective multicentre study. CMAJ. 2014 Apr 15;186(7):E213-E223.
- Dowdy DW, Eid MP, Dennison CR, et al. Quality of life after acute respiratory distress syndrome: a meta-analysis. Intensive Care Med. 2006 Aug;32(8):1115-1124.
- Van der Schaaf M, Beelen A, Dongelmans DA, Vroom MB, Nollet F. Poor functional recovery after a critical illness: a longitudinal study. J Rehabil Med. 2009 Nov;41(13):1041-1048.
- Yaffe PB, Green RS, Butler MB, Witter T. Is admission to the intensive care unit associated with chronic opioid use? A 4-year follow-up of intensive care unit survivors. J Intensive Care Med. 2017 Aug;32(7):429-435.
- Karamchandani K, Pyati S, Bryan W, et al. New persistent opioid use after postoperative intensive care in US veterans. JAMA Surg. 2019 Jun 5. [Epub ahead of print].
- Kram B, Weigel KM, Kuhrt M, Gilstrap DL. Discharge prescribing of enteral opioids after initiation as a weaning strategy from continuous opioid infusions in the Intensive Care Unit. J Opioid Manag. 2018 Jan/Feb;14(1):35-42.
- Morandi A, Vasilevskis E, Pandharipande PP, et al. Inappropriate medication prescriptions in elderly adults surviving an intensive care unit hospitalization. J Am Geriatr Soc. 2013 Jul;61(7):1128-1134.