Adjuvant Analgesic Use in the Critically Ill: A Systematic Review and Meta-Analysis

Kathleen E Wheeler; Ryan Grilli; John E Centofanti; Janet Martin; Celine Gelinas; Paul M Szumita; John W Devlin; Gerald Chanques; Waleed Alhazzani; Yoanna Skrobik; Michelle E Kho; Mark E Nunnally; Andre Gagarine; Begum A Ergan; Shannon Fernando; Carrie Price; John Lewin; Bram Rochwerg

doi:10.1097/CCE.0000000000000157

Adjuvant Analgesic Use in the Critically Ill: A Systematic Review and Meta-Analysis

Crit Care Explor. 2020 Jul 6;2(7):e0157. doi: 10.1097/CCE.0000000000000157. eCollection 2020 Jul.

Authors

Kathleen E Wheeler¹, Ryan Grilli², John E Centofanti^{1

2}, Janet Martin³, Celine Gelinas⁴, Paul M Szumita⁵, John W Devlin⁶, Gerald Chanques^{7

8}, Waleed Alhazzani³, Yoanna Skrobik⁹, Michelle E Kho³, Mark E Nunnally¹⁰, Andre Gagarine¹, Begum A Ergan¹¹, Shannon Fernando¹², Carrie Price¹³, John Lewin¹⁴, Bram Rochwerg^{3

15}

Affiliations

¹ Department of Anesthesia, McMaster University, Hamilton, ON, Canada.
² Division of Critical Care, McMaster University, Hamilton, ON, Canada.
³ Department of Medicine, McMaster University, Hamilton, ON, Canada.
⁴ Ingram School of Nursing, McGill University, Montreal, QC, Canada.
⁵ Department of Pharmacy, Brigham and Women's Hospital, Boston, MA.
⁶ School of Pharmacy, Northeastern University, Boston, MA.
⁷ Department of Anaesthesia and Intensive Care, University of Montpellier Saint Eloi Hospital, Montpellier, France.
⁸ PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.
⁹ Faculty of Medicine, McGill University, Montreal, QC, Canada.
¹⁰ Division of Anesthesiology, Perioperative Care and Pain Medicine, New York University Langone Health, New York, NY.
¹¹ Department of Pulmonary and Critical Care, Dokuz Eylul University, Izmir, Turkey.
¹² University of Ottawa, Ottawa, ON, Canada.
¹³ Welch Medical Library, Johns Hopkins University, Baltimore, MD.
¹⁴ Johns Hopkins Medical Institutions, Baltimore, MD.
¹⁵ Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.

Abstract

This systematic review and meta-analysis addresses the efficacy and safety of nonopioid adjunctive analgesics for patients in the ICU.

Data sources: We searched PubMed, Embase, the Cochrane Library, CINAHL Plus, and Web of Science.

Study selection: Two independent reviewers screened citations. Eligible studies included randomized controlled trials comparing efficacy and safety of an adjuvant-plus-opioid regimen to opioids alone in adult ICU patients.

Data extraction: We conducted duplicate screening of citations and data abstraction.

Data synthesis: Of 10,949 initial citations, we identified 34 eligible trials. These trials examined acetaminophen, carbamazepine, clonidine, dexmedetomidine, gabapentin, ketamine, magnesium sulfate, nefopam, nonsteroidal anti-inflammatory drugs (including diclofenac, indomethacin, and ketoprofen), pregabalin, and tramadol as adjunctive analgesics. Use of any adjuvant in addition to an opioid as compared to an opioid alone led to reductions in patient-reported pain scores at 24 hours (standard mean difference, -0.88; 95% CI, -1.29 to -0.47; low certainty) and decreased opioid consumption (in oral morphine equivalents over 24 hr; mean difference, 25.89 mg less; 95% CI, 19.97-31.81 mg less; low certainty). In terms of individual medications, reductions in opioid use were demonstrated with acetaminophen (mean difference, 36.17 mg less; 95% CI, 7.86-64.47 mg less; low certainty), carbamazepine (mean difference, 54.69 mg less; 95% CI, 40.39-to 68.99 mg less; moderate certainty), dexmedetomidine (mean difference, 10.21 mg less; 95% CI, 1.06-19.37 mg less; low certainty), ketamine (mean difference, 36.81 mg less; 95% CI, 27.32-46.30 mg less; low certainty), nefopam (mean difference, 70.89 mg less; 95% CI, 64.46-77.32 mg less; low certainty), nonsteroidal anti-inflammatory drugs (mean difference, 11.07 mg less; 95% CI, 2.7-19.44 mg less; low certainty), and tramadol (mean difference, 22.14 mg less; 95% CI, 6.67-37.61 mg less; moderate certainty).

Conclusions: Clinicians should consider using adjunct agents to limit opioid exposure and improve pain scores in critically ill patients.

Keywords: acute pain; analgesics; critical illness; meta-analysis; nonnarcotic; opioid; pain management.