Opioids impact intensivists in multiple ways. While opioids form the cornerstone of managing pain and sedation in the intensive care unit (ICU), the significant increases in opioid use-related admissions in the wake of the opioid epidemic are concerning. Pain is ubiquitous in the ICU – almost every procedure performed in the ICU causes pain and patients often recall pain as one of the most common memories associated with their ICU stay. Acute pain in the ICU is attributed to prolonged immobility, indwelling devices and exposure to invasive procedures, among other etiologies. 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. The Society of Critical Care Medicine (SCCM) guidelines also stress upon managing pain first or providing analog-sedation to critically ill patients. However, pain management practices in the ICU are largely limited to intravenous (I.V.) and or oral opioid formulations.
The burgeoning opioid epidemic has led to a dramatic increase in deaths due to opioid overdoses in the community and a direct increase in opioid-related emergency room, hospital and ICU admissions. A recent study reviewing opioid-related hospital admissions from 162 hospital systems across 22 states and spread over six years, reported a significant increase in opioid overdose-associated ICU admissions over years, and the incidence and mortality associated with these admissions overtook overall ICU admissions during that time period. Simply stated – the intensivist is tasked with finding a balance between managing acute opioid overdose and possible acute withdrawal in opioid dependent patients while, at the same time providing sufficient analgesia. The risk of adding to the burden of opioid dependence in the community by creating new persistent opioid use amongst ICU survivors also remains a significant concern. The challenges in meeting the sedation and analgesia needs of an opioid-tolerant patient, management of acute opioid toxicity, along with the implications of opioid use in the ICU are discussed below.
Managing an opioid tolerant patient
The biggest challenge intensivists face in the aftermath of the opioid epidemic is managing analgesia and sedation in an opioid tolerant patient. The FDA defines a patient as opioid tolerant if, for at least one week, he or she has been receiving oral morphine 60 mg/day; transdermal fentanyl 25 mcg/hour; oral oxycodone 30 mg/day; oral hydromorphone 8 mg/day; oral oxymorphone 25 mg/day; or an equianalgesic dose of any other opioid. There has been a perceptible increase in the number of critically ill patients with opioid-tolerance patients, and the task of providing adequate analgesia while minimizing the risk of overdose and opioid dependence is daunting, with limited availability of appropriate resources. Identifying high-risk patients presents the opportunity to initiate interventions to reduce the risk of opioid withdrawal. Once these patients have been identified, monitoring for inadequate pain control and for early signs and symptoms of opioid withdrawal must be instituted. ICU patients with opioid dependence should continue their pre-existing opioid regimen, with supplemental analgesia as necessary. Multimodal treatment involving non-opioid medications (e.g., nonsteroidal anti-inflammatory agents, acetaminophen, etc.) can reduce the dose of supplemental opioids required and is recommended by the current SCCM guidelines. However, the lack of a standardized approach to pain management in ICU patients with OUD hampers clinical care and there is a dire need for research efforts targeted at optimizing safe and effective care to these patients.
A recent study reviewing opioid-related hospital admissions from 162 hospital systems across 22 states and spread over six years, reported a significant increase in opioid overdose-associated ICU admissions over years, and the incidence and mortality associated with these admissions overtook overall ICU admissions during that time period.
Acute Opioid Overdose
Opioid overdose is a preventable and potentially lethal condition resulting from improper prescribing practices, inadequate understanding on the patient’s part of the risks of medication misuse, errors in drug administration and pharmaceutical abuse. The number of ICU admissions and the associated mortality related to acute opioid overdose has increased significantly over the last decade. Opioid analgesic overdose encompasses myriad clinical findings (Table 1), and although the classic toxidrome of apnea, stupor and miosis strongly suggests opioid toxicity, all of these findings may not be consistently present. Respiratory depression (defined as a respiratory rate of 12 breaths per minute or less), the sine qua non of opioid toxicity, when accompanied by miosis or stupor and a suggestive history, strongly suggests acute opioid intoxication. Pharmacologic reversal with naloxone and supportive measures, including mechanical ventilation for respiratory depression and inotropic/vasopressor support for hemodynamic compromise, remain the mainstay of therapy in these patients.
Implications of opioid-based sedation
Iatrogenic opioid withdrawal
Iatrogenic opioid withdrawal is common in the ICU with reported incidence ranging from 16-32 percent in patients who receive opioids. Higher cumulative opioid doses and prolonged duration of use are primary risk factors. There is limited evidence regarding management of opioid withdrawal in the ICU and management should be individualized with careful monitoring for inadequate pain control as well as signs and symptoms of withdrawal. 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.11 However, further studies are required prior to recommending routine use of these agents in opioid dependent/tolerant patients in the ICU.
Opioid related complications
Opioids remain the mainstay of pain control and sedation in the ICU, despite substantial adverse consequences that continue to plague their use. Short term adverse effects include delirium, poor sleep quality and unintended sedation; this is particularly true in patients in the ICU, because of altered drug clearance, concomitant drug therapy and central metabolic dysfunction. In addition, long-term opioid use can lead to B and T cell-mediated immune dysfunction, opioid-induced hyperalgesia (OIH), tolerance (i.e., less susceptibility to the effects of the opioid, which can result in a need for higher and more frequent doses to achieve the same analgesic effect), physical dependence, opioid-withdrawal symptoms during weaning and the potential for physiological and psychological addiction. Strategies for mitigating opioid tolerance and opioid-induced hyperalgesia include reducing the dose of analgesics and the duration of treatment by interrupting infusions of sedative or analgesic agents daily or modulating infusions on the basis of analgesic assessment and sedation scores, by using multimodal analgesic agents (nerve blocks and nonopioid analgesics) and by rotating analgesic agents sequentially.
Chronic opioid use in ICU survivors
Opioid continuation following ICU admission is another concerning facet of opioid-based sedation in the ICU. In a retrospective, single-center study of medical and surgical ICU patients in Canada, it was reported that opioid use in ICU survivors was 12.2 percent following hospital discharge and 4.4 percent at 48 months. Prolonged hospital length of stay and pre-admission chronic opioid use were associated with this post-discharge chronic opioid use. Similarly, in a dataset of nearly a million opioid-naïve veterans requiring postoperative ICU care for greater than 24 hours, 4.1 percent developed new persistent OUD, defined as continuation of opioids for greater than three months following ICU discharge. These patients were significantly younger and had a history of substance use or alcohol use disorder. It is unclear if ICU-specific sedation practices may predispose patients to receiving a hospital discharge prescription for an opioid. A small, single center cohort of opioid-naïve 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.
In essence, opioids impact critical care providers in a number of ways especially in the aftermath of the opioid epidemic. Intensivists are variably tasked with 1) managing acute pain and sedation in patients variably affected by OUD, balancing the risk of opioid withdrawal with excessive sedation, 2) Aggressively treating acute pain to preventing the development of chronic pain while risking chronic opioid use in ICU survivors, and 3) Acutely managing patients with opioid toxicity and withdrawal. In order to achieve these daunting tasks, it is important that critical care providers have appropriate resources to manage this extremely complex patient population and research efforts are needed in this arena.