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, 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

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.

Conflict of interest statement

Dr. Rochwerg is supported by a Hamilton Health Sciences Early Career Research Award. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.

Figures

Figure 1.
Figure 1.
Study flow diagram. RCT = randomized controlled trial.
Figure 2.
Figure 2.
Forest plot of pain scores at 24 hr after intervention. df = degrees of freedom, NSAIDs = nonsteroidal anti-inflammatory drugs.
Figure 3.
Figure 3.
Forest plot of opioid consumption in first 24 hr of intervention. df = degrees of freedom, OME = oral morphine equivalents.

References

    1. Burry LD, Williamson DR, Perreault MM, et al. Analgesic, sedative, antipsychotic, and neuromuscular blocker use in Canadian intensive care units: A prospective, multicentre, observational study. Can J Anaesth. 2014; 61:619–630
    1. Pattinson KT. Opioids and the control of respiration. Br J Anaesth. 2008; 100:747–758
    1. Chappell D, Rehm M, Conzen P. Opioid-induced constipation in intensive care patients: Relief in sight? Crit Care. 2008; 12:161.
    1. Wei G, Moss J, Yuan CS. Opioid-induced immunosuppression: Is it centrally mediated or peripherally mediated? Biochem Pharmacol. 2003; 65:1761–1766
    1. Luchting B, Azad SC. Pain therapy for the elderly patient: Is opioid-free an option? Curr Opin Anaesthesiol. 2019; 32:86–91
    1. Marra A, Pandharipande PP, Patel MB. Intensive care unit delirium and intensive care unit-related posttraumatic stress disorder. Surg Clin North Am. 2017; 97:1215–1235
    1. Stamenkovic DM, Laycock H, Karanikolas M, et al. Chronic pain and chronic opioid use after intensive care discharge - is it time to change practice? Front Pharmacol. 2019; 10:23.
    1. Puntillo KA, Naidu R. Chronic pain disorders after critical illness and ICU-acquired opioid dependence: Two clinical conundra. Curr Opin Crit Care. 2016; 22:506–512
    1. Abdolrazaghnejad A, Banaie M, Tavakoli N, et al. Pain management in the emergency department: A review article on options and methods. Adv J Emerg Med. 2018; 2:e45.
    1. Wick EC, Grant MC, Wu CL. Postoperative multimodal analgesia pain management with nonopioid analgesics and techniques: A review. JAMA Surg. 2017; 152:691–697
    1. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018; 46:e825–e873
    1. Weightman AL, Williamson J; Library & Knowledge Development Network (LKDN) Quality and Statistics Group. The value and impact of information provided through library services for patient care: A systematic review. Health Info Libr J. 2005; 22:4–25
    1. Nielsen S, Degenhardt L, Hoban B, et al. A synthesis of oral morphine equivalents (OME) for opioid utilisation studies. Pharmacoepidemiol Drug Saf. 2016; 25:733–737
    1. Higgins JP, Altman DG, Gøtzsche PC, et al. ; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011; 343:d5928.
    1. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011; 64:383–394
    1. The Nordic Cochrane Centre, The Cochrane Collaboration Review Manager (RevMan). 2014, Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration
    1. Higgins JPT, Green SE. Cochrane Handbook for Systematic Reviews of Interventions. 2011. Copenhagen, The Cochrane Collaboration
    1. Huwaldt J. Source Forge: Plot Digitizer. 2013 Available at: . Accessed October 16, 2018.
    1. Abu-Halaweh S, Obeidat F, Absalom AR, et al. Dexmedetomidine versus morphine infusion following laparoscopic bariatric surgery: Effect on supplemental narcotic requirement during the first 24 h. Surg Endosc. 2016; 30:3368–3374
    1. Anvaripour A, Ashkpour H, Marashian M, et al. The efficacy and side effects of dexmedetomidine and morphine in patient-controlled analgesia method after coronary artery bypass grafting surgery. Int J Pharm Res. 2018; 10:251–256
    1. Azeem TMA, Yosif NE, Alansary AM, et al. Dexmedetomidine vs morphine and midazolam in the prevention and treatment of delirium after adult cardiac surgery; a randomized, double-blinded clinical trial. Saudi J Anaesth. 2018; 12:190–197
    1. Cheng M, Shi J, Gao T, et al. The addition of dexmedetomidine to analgesia for patients after abdominal operations: A prospective randomized clinical trial. World J Surg. 2017; 41:39–46
    1. Korkmaz Dişli Z, Çelebi N, Canbay Ö, et al. Comparison of morphine and dexmedetomidine delivered by patient-controlled analgesia device during the postoperative period of coronary artery bypass surgery. Anestezi Dergisi. 2013; 21:29–36
    1. Martin E, Ramsay G, Mantz J, et al. The role of the alpha2-adrenoceptor agonist dexmedetomidine in postsurgical sedation in the intensive care unit. J Intensive Care Med. 2003; 18:29–41
    1. Priye S, Jagannath S, Singh D, et al. Dexmedetomidine as an adjunct in postoperative analgesia following cardiac surgery: A randomized, double-blind study. Saudi J Anaesth. 2015; 9:353–358
    1. Skrobik Y, Duprey MS, Hill NS, et al. Low-dose nocturnal dexmedetomidine prevents ICU delirium. A randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2018; 197:1147–1156
    1. Su X, Meng ZT, Wu XH, et al. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: A randomised, double-blind, placebo-controlled trial. Lancet. 2016; 388:1893–1902
    1. Venn RM, Bradshaw CJ, Spencer R, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 1999; 54:1136–1142
    1. Zhao LH, Shi ZH, Chen GQ, et al. Use of dexmedetomidine for prophylactic analgesia and sedation in patients with delayed extubation after craniotomy: A randomized controlled trial. J Neurosurg Anesthesiol. 2017; 29:132–139
    1. Arslan Y, Kudsioglu T, Yapici N, et al. Administration of paracetamol, diclofenac sodium, and tramadol for postoperative analgesia after coronary artery bypass surgery. GKDA Derg. 2018; 24:23–28
    1. Bameshki A, Peivandi Yazdi A, Sheybani S, et al. The assessment of addition of either intravenous paracetamol or diclofenac suppositories to patient-controlled morphine analgesia for postgastrectomy pain control. Anesth Pain Med. 2015; 5:e29688.
    1. Eremenko AA, Kuslieva EV. Analgesic and opioid-sparing effects of intravenous paracetamol in the early period after aortocoronary bypass surgery. Anesteziol Reanimatol. 200811–14
    1. Fayaz MK, Abel RJ, Pugh SC, et al. Opioid-sparing effects of diclofenac and paracetamol lead to improved outcomes after cardiac surgery. J Cardiothorac Vasc Anesth. 2004; 18:742–747
    1. Memis D, Inal MT, Kavalci G, et al. Intravenous paracetamol reduced the use of opioids and extubation time after major surgery in intensive care unit. Intensive Care Med. 2009; 35:S136
    1. Shaikh N, Kettern MA, Ali Ahmed AH, et al. Morphine sparing effect of proparacetamol in surgical and trauma intensive care. Middle East J Emergency Med. 2006; 6:28–30
    1. Subramaniam B, Shankar P, Mueller A. Intravenous acetaminophen for postoperative delirium-reply. JAMA. 2019; 322:272
    1. Eremenko A, Sorokina L, Pavlov M. Ketoprophen and nefopam combination for postoperative analgesia with minimal use of narcotic analgesics in cardio-surgical patients. Anesteziol Reanimatol. 201311–15
    1. Hynninen MS, Cheng DC, Hossain I, et al. Non-steroidal anti-inflammatory drugs in treatment of postoperative pain after cardiac surgery. Can J Anaesth. 2000; 47:1182–1187
    1. Rapanos T, Murphy P, Szalai JP, et al. Rectal indomethacin reduces postoperative pain and morphine use after cardiac surgery. Can J Anaesth. 1999; 46:725–730
    1. Guillou N, Tanguy M, Seguin P, et al. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Anesth Analg. 2003; 97:843–847
    1. Joachimsson PO, Hedstrand U, Eklund A. Low-dose ketamine infusion for analgesia during postoperative ventilator treatment. Acta Anaesthesiol Scand. 1986; 30:697–702
    1. Perbet S, Verdonk F, Godet T, et al. Low doses of ketamine reduce delirium but not opiate consumption in mechanically ventilated and sedated ICU patients: A randomised double-blind control trial. Anaesth Crit Care Pain Med. 2018; 37:589–595
    1. Takieddine SC, Droege CA, Ernst N, et al. Ketamine versus hydromorphone patient-controlled analgesia for acute pain in trauma patients. J Surg Res. 2018; 225:6–14
    1. Eremenko AA, Sorokina LS, Pavlov MV. The use of central acting analgesic nefopam in postoperative analgesia in cardiac surgery patients. Anesteziol Reanimatol. 201378–82
    1. Kim K, Kim WJ, Choi DK, et al. The analgesic efficacy and safety of nefopam in patient-controlled analgesia after cardiac surgery: A randomized, double-blind, prospective study. J Int Med Res. 2014; 42:684–692
    1. But AK, Erdil F, Yucel A, et al. The effects of single-dose tramadol on post-operative pain and morphine requirements after coronary artery bypass surgery. Acta Anaesthesiol Scand. 2007; 51:601–606
    1. Moskowitz EE, Garabedian L, Hardin K, et al. A double-blind, randomized controlled trial of gabapentin vs. placebo for acute pain management in critically ill patients with rib fractures. Injury. 2018; 49:1693–1698
    1. Pandey CK, Raza M, Tripathi M, et al. The comparative evaluation of gabapentin and carbamazepine for pain management in Guillain-Barré syndrome patients in the intensive care unit. Anesth Analg. 2005; 101:220–225, table of contents
    1. Tripathi M, Kaushik S. Carbamezapine for pain management in Guillain-Barré syndrome patients in the intensive care unit. Crit Care Med. 2000; 28:655–658
    1. Farasatinasab M, Kouchek M, Sistanizad M, et al. A randomized placebo-controlled trial of clonidine impact on sedation of mechanically ventilated ICU patients. Iran J Pharm Res. 2015; 14:167–175
    1. Memiş D, Turan A, Karamanlioglu B, et al. Comparison of sufentanil with sufentanil plus magnesium sulphate for sedation in the intensive care unit using bispectral index. Crit Care. 2003; 7:R123–R128
    1. Meurant F, Bodart A. Sparing analgesic effect using pregabaline in postsurgical trauma patients in the ICU. Crit Care. 2006; 10:P439
    1. Zhao H, Yang S, Wang H, et al. Non-opioid analgesics as adjuvants to opioid for pain management in adult patients in the ICU: A systematic review and meta-analysis. J Crit Care. 2019; 54:136–144
    1. Cantais A, Schnell D, Vincent F, et al. Acetaminophen-induced changes in systemic blood pressure in critically ill patients: Results of a multicenter cohort study. Crit Care Med. 2016; 44:2192–2198
    1. VanderWeide LA, Foster CJ, MacLaren R, et al. Evaluation of early dexmedetomidine addition to the standard of care for severe alcohol withdrawal in the ICU: A retrospective controlled cohort study. J Intensive Care Med. 2016; 31:198–204
    1. Keating GM. Dexmedetomidine: A review of its use for sedation in the intensive care setting. Drugs. 2015; 75:1119–1130
    1. Chanques G, Sebbane M, Constantin JM, et al. Analgesic efficacy and haemodynamic effects of nefopam in critically ill patients. Br J Anaesth. 2011; 106:336–343
    1. Vazzana M, Andreani T, Fangueiro J, et al. Tramadol hydrochloride: Pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomed Pharmacother. 2015; 70:234–238
    1. Shehabi Y, Howe BD, Bellomo R, et al. ; ANZICS Clinical Trials Group and the SPICE III Investigators. Early sedation with dexmedetomidine in critically ill patients. N Engl J Med. 2019; 380:2506–2517
    1. Hall JE, Uhrich TD, Barney JA, et al. Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg. 2000; 90:699–705
    1. Weerink MAS, Struys MMRF, Hannivoort LN, et al. Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine. Clin Pharmacokinet. 2017; 56:893–913

Source: PubMed

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