By Elaine Chen, MD
Associate Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Section of Palliative Medicine, Rush University Medical Center, Chicago
SYNOPSIS: In a small, single-center, retrospective, propensity-matched cohort study examining enteral oxycodone vs. sublingual buprenorphine in a critically ill population, pain control was equivalent, indicating that sublingual buprenorphine may be an effective and appropriate alternative.
SOURCE: Patanwala AE, Moran B, Johnstone C, et al. Effectiveness of sublingual buprenorphine for pain control in the ICU. Crit Care Med 2023;51:1650-1658.
Pain is common in the critically ill patient population, and parenteral opioids remain the mainstay of analgesia when patients are critically ill. As patients recover, parenteral opioids generally are transitioned to enteral opioids, most commonly oxycodone, but this may be limited by issues such as enteral absorption. Sublingual buprenorphine has some potential benefits over enteral opioids due to bypassing the gastrointestinal tract via the sublingual delivery route, as well as pharmacological benefits as a partial mu-opioid agonist and kappa receptor antagonist. This study aimed to evaluate pain control and opioid consumption in a population of critically ill patients treated with either sublingual buprenorphine or oral/enteral oxycodone.
This retrospective, parallel, cohort study was completed in one 30-bed medical/surgical intensive care unit (ICU) at a single quaternary care institution in Sydney, Australia, in a four-year period from 2019 to 2022. The choice of analgesic was at the discretion of the treating physician. In the opinion of the clinician investigators, there was equipoise in selecting either choice. All adult patients in the study ICU were included if they received either buprenorphine or oxycodone (but not both) during their ICU stay, and if they met other specified inclusion and exclusion criteria. Data were obtained via electronic query with additional manual abstraction of selected text searches of notes.
The primary outcome was the presence of significant pain during the hospital stay, with secondary outcomes including opioid consumption during ICU stay in oral morphine milligram equivalents (MMEs) and durations of mechanical ventilation and ICU stay. As a reference, daily MMEs were calculated with 1.5 mg of oral oxycodone and 40 mg of buprenorphine as equivalent to 1 mg of morphine. Propensity score matching was employed to match the groups using logistic regression of baseline variables, followed by statistical analyses such as Wilcoxon rank-sum (medians) due to non-normal distribution of outcomes.
Of 2,247 patients who received either buprenorphine or oxycodone in the study period, 1,070 met selection criteria, with 288 in the buprenorphine group and 782 in the oxycodone group. After propensity score matching, there were 288 patients in each group. Before propensity score matching, the buprenorphine group was older, had higher Acute Physiology and Chronic Health Evaluation (APACHE) III scores, and were more likely to have a surgical diagnosis, have metastatic cancer, and receive renal replacement therapy (RRT) and mechanical ventilation. In the matched groups, the mean age was 64 years, 51% were male, 62% had a surgical diagnosis, mean APACHE III score was 61, 37% received mechanical ventilation, and 23% had a history of opioid use prior to hospitalization.
Buprenorphine was initiated a median of 33 (interquartile range [IQR], 17-45) hours and oxycodone was initiated at 22 (IQR, 9-41) hours after ICU admission. Initial buprenorphine dose was 0.2 mg (IQR, 0.2 mg to 0.2 mg), with three cumulative doses (IQR, 2-6) and a cumulative dose of 0.8 mg (IQR, 0.4 mg to 1.6 mg). Initial dose of oxycodone was 5 mg (IQR, 5 mg to 5 mg), with four cumulative doses (IQR, 2-6) and a cumulative dose of 20 mg (IQR, 10 mg to 40 mg). Median reported total MME was 65 (IQR, 25-200) in the buprenorphine group and 70 (IQR, 30-201) in the oxycodone group (P = 0.730). Median daily MME was 22 (IQR, 8-50) in the buprenorphine group and 22 (IQR, 10-58) in the oxycodone group (P = 0.38).
The median probability of significant pain was 0.16 in the buprenorphine group and 0.17 in the oxycodone group (median difference 0.01; 95% confidence interval [CI], –0.02 to 0.04; P = 0.50). Ventilator days and ICU lengths of stay were similar; exploratory outcomes of hospital mortality and Richmond Agitation and Sedation Scale (RASS) scores also were similar. No cases of opioid withdrawal or hyperalgesia were reported in either cohort.
The authors concluded that their key finding is that buprenorphine appears to be a suitable alternative to oxycodone for pain control in the ICU when transitioning from a parenteral formulation to facilitate discharge out of an ICU. In particular, this can be considered when the gastrointestinal tract is not a feasible option for analgesia. They noted that the groups were well-matched.
COMMENTARY
Optimizing sedation and analgesia remain important components of ICU care. Routes of delivery are important in the ICU since many patients may have difficulties with using the gastrointestinal tract but do not require intravenous formulations. Additionally, given the worldwide opioid crisis and global health concerns, minimizing administration of opioids in previously opioid-naïve patients is important.1
The authors issued a strong conclusion statement in both their abstract and the body of their manuscript, that buprenorphine sublingual is as effective as enteral oxycodone regarding pain control in the ICU, and that buprenorphine sublingual is an appropriate option for patients who are unable to take enteral opioids. I find this a bit of a generous conclusion in this limited cohort study in a single ICU. Strengths include strongly matched cohorts and a relatively sick population. Limitations include a short time frame and overall low doses of medications. Upon review of the opioid calculation reference and the MME calculations, the numbers either include the parenteral opioid prior to transition (which was not explicitly reported) or may not reflect the reference cited.2 Additionally, it generally is not recommended to convert buprenorphine to MMEs. Buprenorphine MME calculations can be inaccurate due to its pharmacokinetics, including partial agonism effects, strong affinity to the receptors, long half-life, slow dissociation, and partial antagonism.3
I agree that the results of this study should spark consideration of buprenorphine in the ICU population, particularly when transitioning from a parenteral infusion to more intermittent dosing in a population at high risk for significant pain. However, these results are exploratory and hypothesis-generating at best, and further study of buprenorphine in the ICU should be undertaken. Prospective studies would be ideal, given the current growing interest in and enthusiasm about buprenorphine. Having not previously used buprenorphine in the ICU outside of opioid use disorder, this paper will lead me to consider its use in ICU patients who no longer need intravenous opioid medication but are unable to use the gastrointestinal tract or may be at risk for opioid misuse. It is important for intensive care clinicians to pursue education about and gain comfort with buprenorphine.
REFERENCES
- The Lancet Regional Health - Americas. Opioid crisis: Addiction, overprescription, and insufficient primary prevention. The Lancet Regional Health – Americas 2023;23:100557. doi:10.1016/j.lana.2023.100557
- Opioid Dose Equivalence: Faculty of Pain Medicine of the Australian and New Zealand College of Anaesthetists. 2021. https://www.anzca.edu.au/getattachment/6892fb13-47fc-446b-a7a2-11cdfe1c9902/PS01(PM)-(Appendix)-Opioid-Dose-Equivalence-Calculation-Table#page=
- Coe MA, Lofwall MR, Walsh SL. Buprenorphine pharmacology review: Update on transmucosal and long-acting formulations. J Addict Med 2019;13:93-103.
In a small, single-center, retrospective, propensity-matched cohort study examining enteral oxycodone vs. sublingual buprenorphine in a critically ill population, pain control was equivalent, indicating that sublingual buprenorphine may be an effective and appropriate alternative.
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