Pain is common in critically ill adults at both rest and during procedures. Opioids have remained the analgesic mainstay in the ICU for decades; 2013 guidelines recommend opioids as the first-line analgesic of choice for non-neuropathic pain (1). A recent 29-country ICU point prevalence study reported that 87% of patients received a scheduled IV opioid the prior day (2). In one Swedish cohort, 5% of ICU survivors not taking opioids at the time of admission were found to be chronic users of an opioid 1 year after discharge (3). As a class, traditional, full opioid (mu-receptor) agonists like fentanyl, morphine, and oxycodone are known to rapidly induce tolerance thereby increasing the risk for hyperalgesia and chronic pain syndromes (4). In the ICU, the pharmacokinetic parameters of full opioid agonists are complex, particularly when they are administered intermittently at high doses or as infusions, pharmacogenomic variability may result in unpredictable response and clearance (5), and opioid withdrawal reactions are common (6). Constipation, delirium, respiratory depression, and hemodynamic instability are frequent and are of particular concern in key ICU subgroups (7,8).

Despite these limitations, the critical care community has been slow to identify and evaluate analgesic alternatives to full opioid agonists, particularly for adults admitted to the ICU with urgent surgical or medical conditions. Although the multimodal ICU use of nonopioid analgesics like acetaminophen and low-dose ketamine is recommended as a strategy to reduce full opioid agonist use after elective surgery (9), data regarding their safety and efficacy in sicker ICU populations remain sparse. Characteristics of the ideal ICU analgesia include a rapid onset of activity, a reasonable duration of action, a predictable dose-response effect, minimal risk for accumulation, a clean safety profile (10), and the ability to be reliably administrated to patients without a functioning gastrointestinal tract. No currently marketed full opioid agonist or nonopioid analgesic meets all of these criteria.

Buprenorphine is a partial mu-receptor agonist and kappa-receptor antagonist that serves as a mainstay for the pharmacologic treatment of opioid use disorder (11). Compared with full opioid agonists, buprenorphine has higher mu-receptor affinity but lower intrinsic mu-receptor activity. In healthy patients, buprenorphine, when compared with full opioid agonists, has been reported to induce less euphoria, sedation, respiratory depression, and hyperalgesia (12,13). Generic sublingual (SL) buprenorphine (without naloxone) is currently marketed in the United States for the treatment of opioid use disorder. Buprenorphine has been extensively investigated for the treatment of both acute and chronic postsurgical pain given it may theoretically provide better pain control and result in fewer opioid-related adverse drug events (ORADEs) (11,14,15).

In this issue of Critical Care Medicine, the study by Patanwala et al (16) presents the results of a 4-year retrospective analysis comparing pain and opioid consumption in adult medical and general surgical ICU adults initiated on SL buprenorphine or oral/enteral oxycodone to wean IV full opioid agonists. In their nonrandomized study, the investigators used propensity scoring to match the SL buprenorphine and oxycodone groups by relevant baseline characteristics. Patients with missing pain scores, administered their first SL buprenorphine or oxycodone dose greater than 72 hours after ICU admission or receiving both agents were excluded. Of the 1,070 patients meeting study criteria, 288 buprenorphine patients were matched with 288 of the 782 oxycodone patients leaving 576 in the matched cohort. At baseline, the matched cohort had an average age of 64 ± 16, baseline Acute Physiology and Chronic Health Evaluation III score of 61 ± 23, was mostly surgical (62%), not invasively ventilated (63%), and not using opioids at the time of ICU admission (77%). On average, buprenorphine was initiated 33 hours after ICU admission for three doses totaling 0.8 mg and oxycodone was initiated 22 hours after ICU admission for four doses totaling 20 mg. Acetaminophen use was common (buprenorphine 76%, oxycodone 73%); use of other nonopioids was rare. The probability of significant pain over the first 5 ICU days was not significantly different between the buprenorphine (0.16) and oxycodone (0.17) groups (median difference 0.01; 95% CI, −0.02 to 0.04; p = 0.50). Median daily ICU opioid use was similar between the buprenorphine and oxycodone groups (median difference −1 mg morphine milliequivalent; 95% CI, −10 to 10 mg, p = 0.73). Ventilator days and ICU mortality were similar. No cases of opioid withdrawal syndrome or hyperalgesia were detected based on chart review. Subgroup analyses revealed the results to be similar across surgical, mechanical ventilation, and pre-ICU opioid use subgroups.

This pragmatic, retrospective evaluation suggests low-dose SL buprenorphine may work as well as oral/enteral oxycodone to wean IV full opioid agonists in a mixed population of medical-surgical ICU patients with a generally low baseline severity of illness (16). Although the two groups were well-matched, the lack of randomization has potential implications. Differences between groups, other than their perceived ability to be able to absorb oral/enteral oxycodone, may have existed and influenced SL buprenorphine use. Objective criteria to estimate GI absorption (e.g., enteral nutrition tolerance) were not used. The lack of an established IV-to-oral/enteral opioid protocol may have resulted in variable IV opioid transition practices. The retrospective nature of the study precluded a rigorous evaluation of buprenorphine’s safety. Although the safety of buprenorphine and full opioid agonist opioids appear to be similar in postsurgical adults not admitted to the ICU (11,14), safety concerns with buprenorphine may be greater in the ICU setting given the increased multimorbidity and organ dysfunction seen in this population, their greater exposure to other sedating drugs, and their higher exposure to full opioid agonists. Opioid withdrawal syndrome and hyperalgesia can only be rigorously evaluated prospectively and require evaluation in the post-ICU period. Although preliminary data suggests ICU patients will adequately respond to full opioid agonists after buprenorphine use (17), the clinical interaction between concomitant buprenorphine and full opioid agonists requires further evaluation. Lastly, it remains unclear if buprenorphine is as effective as methadone as an ICU strategy to reduce IV full opioid agonist infusion use (18).

The results reported in the study by Patanwala et al (18) highlight the importance of future prospective trials focused on evaluating the efficacy and safety of early SL buprenorphine use in the ICU as a strategy to reduce full opioid agonist use (16). Although prior buprenorphine randomized trials in non-ICU surgical patients have failed to demonstrate better pain control or reduced ORADE occurrence (11,14), these studies generally compared buprenorphine to either a full opioid agonist or a nonopioid analgesic, rather than placebo (11,14). Although SL buprenorphine has many of the ideal characteristics of an ICU analgesic, further prospective research is required to determine its role as a strategy to reduce full opioid agonist use in critically ill adults.

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