Pharmacological interventions for preventing opioid-induced hyperalgesia in adults after opioid-based anesthesia: a systematic review and network meta-analysis

Abstract

Background: Opioid-induced hyperalgesia (OIH) is an adverse event of prolonged opioid use that increases pain intensity. The optimal drug to prevent these adverse effects is still unknown. We aimed to conduct a network meta-analysis to compare different pharmacological interventions for preventing the increase in postoperative pain intensity caused by OIH. Methods: Several databases were searched independently for randomized controlled trials (RCTs) comparing various pharmacological interventions to prevent OIH. The primary outcomes were postoperative pain intensity at rest after 24 h and the incidence of postoperative nausea and vomiting (PONV). Secondary outcomes included pain threshold at 24 h after surgery, total morphine consumption over 24 h, time to first postoperative analgesic requirement, and shivering incidence. Results: In total, 33 RCTs with 1711 patients were identified. In terms of postoperative pain intensity, amantadine, magnesium sulphate, pregabalin, dexmedetomidine, ibuprofen, flurbiprofen plus dexmedetomidine, parecoxib, parecoxib plus dexmedetomidine, and S (+)-ketamine plus methadone were all associated with milder pain intensity than placebo, with amantadine being the most effective (SUCRA values = 96.2). Regarding PONV incidence, intervention with dexmedetomidine or flurbiprofen plus dexmedetomidine resulted in a lower incidence than placebo, with dexmedetomidine showing the best result (SUCRA values = 90.3). Conclusion: Amantadine was identified as the best in controlling postoperative pain intensity and non-inferior to placebo in the incidence of PONV. Dexmedetomidine was the only intervention that outperformed placebo in all indicators. Clinical Trial Registration: https://www.crd.york.ac. uk/prospero/display_record.php?, CRD42021225361.

Keywords: general anesthesia; network meta-analysis; opioid-induced hyperalgesia; pharmacological interventions; postoperative nausea and vomiting; postoperative pain.

FIGURE 1

Flow chart of search strategy to identify the eligible randomized controlled trials (RCTs).

FIGURE 2

Network meta-analysis of eligible comparisons for postoperative pain intensity at rest at 24 h (A) and the incidence of PONV (B).

FIGURE 3

Forest plots of network meta-analysis of all trials for postoperative pain intensity at rest at 24 h (A) and the incidence of PONV (B).

FIGURE 4

League table of head-to-head comparisons for postoperative pain intensity at rest at 24 h and the incidence of PONV of all pharmacological interventions and placebo. PLA = placebo. SKET = S (+)-ketamine. KET = ketamine. AMA = amantadine. MAG = magnesium sulphate. PRE = pregabalin. ADE = adenosine. DEX = dexmedetomidine. BUT = butorphanol. IBU = ibuprofen. FLU + DEX = flurbiprofen + dexmedetomidine. FLU + BUT = flurbiprofen + butorphanol. NALO = naloxone. BUP = buprenorphine. FLU = flurbiprofen. PAR = parecoxib. PAR + DEX = parecoxib + dexmedetomidine. NALB = nalbuphine. SKET + MET = S (+)-ketamine + methadone.

FIGURE 5

Two-dimensional graphs for postoperative pain intensity at rest at 24 h and the incidence of PONV. 1 = placebo; 2 = S (+)-ketamine; 3 = ketamine; 4 = amantadine; 5 = magnesium sulphate; 6 = pregabalin; 7 = dexmedetomidine; 8 = butorphanol; 9 = ibuprofen; 10 = flurbiprofen + dexmedetomidine; 11 = flurbiprofen + butorphanol; 12 = naloxone; 13 = buprenorphine; 14 = flurbiprofen; 15 = nalbuphine; 16 = S (+)-ketamine + methadone; 17 = ACTZ.