The Conundrum of Pain, Opiate Use, and Delirium: Analgosedation or Analgesia-First Approach?

Critical illness, regardless of etiology, is a painful condition. Many mechanicallyventilatedpatientsthereforereceiveopioidstomanagethe discomfort of having an endotracheal tube or for procedures they undergo in line with the Society of Critical Care Medicine’s pain, agitation/sedation, delirium, immobility, and sleepdisruption (PADIS) guidelines (1). Theseguidelinesalsorecommendtargeting light levelsof sedation, thus minimizing overall sedative medication exposure (in particular, benzodiazepines). Specific recommendations in the PADIS guidelines were developed on the basis of well-conducted studies showinganassociationbetweendeep sedationandworseoutcomes (2), including the roleofbenzodiazepines indelirium(3). Recent large-scale implementation of theABCDEFbundle (assessment andmanagement of pain, both awakening and breathing trials, choice of sedation, delirium assessment andmanagement, exercise, family engagement), a pragmatic framework for operationalizing the PADIS guidelines, has shown significant improvements in patient outcomes, including delirium and mortality, yet found that patients were more awake and complained of pain more often (4). Unfortunately, pain is also associated with worse delirium outcomes (5), though this has not been clearly demonstrated in ICUpatients. Asmore focus is directed toward the assessment and treatment of pain in the critically ill while minimizing sedativemedications, it isnowmore important thanever to understand the role of opioids, and the pain they are used to treat, in delirium. Two approaches often recommended are an analgosedation approach, in which opioid medications are used for their sedative properties and often administered beyond what is needed for the management of pain, or the analgesia-first approach, in which pain is addressed first and only after it is treated are sedatives administered for agitation. Yet, it is unclear whether one approach is better or worse than the other. In this issue of the Journal, Duprey and colleagues (pp. 566–572) report on a large cohort of adult patients admitted to a mixed tertiarylevelmedical-surgical ICUintheNetherlands,wheretheauthorssought to understand the relationship between opioid use in the ICU and transitions from an awake, nondelirious state to delirium while accounting for the level of pain (6). As a secondary analysis, the authors also assessed the impact of pain on delirium, accounting for opiate use. Patients were assessed for level of pain, agitation and sedation, and delirium using well-validated instruments. Detailed patient demographic data and that of the ICU and hospital course, including exposure to opioid medications and their doses, were collected. Multinomial regression analyses, accounting for important confounders, including time-varying daily ICU variables, were used to study the associations of opioid use on a given day and the transition from being awake and nondelirious on that day to having delirium the followingday.Competingriskssuchascoma,discharge,ordeath,which would prevent a patient from being assessed for delirium, were accounted for in the modeling strategy. Sensitivity analyses were performed to address, among other variables, the long study duration and effect of changes in sedation and delirium practices over that time, implication of age, the impact of being on a surgical service, and whether the risk of delirium differed depending on the use of synthetic versus nonsynthetic opioids. Among almost 6,000 patients, 4,000 were included in the final analysis; themajority of those excluded had a neurological condition precluding delirium assessment. Of the almost 15,000 days patients were awake and nondelirious, the authors reported delirium occurring on 1,300 subsequent days. Opioid use was associated with 45% increased odds of this transition to delirium. Increased opioid dose was also associated with increased odds of this transition, though itwould require almost doublingof themediandaily dose administered (an additional 20.8 mg of intravenous morphine equivalents) to increase the risknominallyby5%. Thedosedependency varied by individual opioids; synthetic opioids were associated with lower odds of an increase compared with morphine (1.5% vs. 9% for every 10 mg of intravenous morphine equivalent). Surprisingly, the authors found an inverse association between the intensity of pain and delirium, which could relate to patients with better brain function more accurately reporting pain. The aforementioned sensitivity analyses did not result in any qualitative change in the associations, with opioids being associated with delirium across the entire study period, in younger and elderly patients, in both surgical and medical patients, and with both synthetic and nonsynthetic opioids. This study adds to the growing body of evidence showing an association between opioid administration and delirium (7, 8), with manymethodological advances. The large sample size, use of validated instruments, account of time-varying confounders and competing risks, and the additional exploratory sensitivity analysis all add to the strength of the study and the confidence in the results. On the contrary, the association of increasing pain with a lower probability of delirium belies any pathophysiological basis and raises concerns about bias and unmeasured confounders. Furthermore, up to 25%ofpain assessments were missing, rates of delirium (34%) were lower than those usually reported in tertiary ICUs with high severity of illness, and nonopiate painmanagement techniqueswerenot accounted for, limiting, to some extent, the generalizability of these findings. As healthcare providers reduce their dependency on sedative medications and patients are more awake and communicative, attention to appropriate pain management while avoiding overzealous opiate use is now the next challenge facing clinicians. Howcanweuse the resultsof this study to shapeourpractice? Although some have advocated analgosedation techniques to reduce the exposure to sedative medications, perhaps it is time to cautiously rethink this strategy; substituting one deliriogenic medication (e.g., a benzodiazepine) with another (opiate) may not appear to confer much benefit (thoughit likelydependsondosesrequired)ifyouextrapolatethe findings of this study. In particular, whenpain scoreswere not assessed, patients receivedmore opiates and were less arousable, supporting this This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern.