Clinically important analgesic effects

Abstract

Editor—Riddell and colleagues1Riddell J.M. Trummel J.M. Onakpoya I.J. Low-dose ketamine in painful orthopaedic surgery: a systematic review and meta-analysis.Br J Anaesth. 2019; 123: 325-334Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar reported on a systematic review and meta-analysis of low-dose ketamine in orthopaedic surgery, concluding that low-dose ketamine was an effective adjuvant that decreased pain and opioid requirements in painful orthopaedic procedures. I do not believe their data support such a conclusion. There were three nominated primary outcomes in their study: (i) total postoperative opioid consumption, (ii) time to the first dose of opioid after surgery (minutes), and (iii) pain scores at rest using the 10 cm visual analogue scale (VAS) at 12, 24, and 48 h. They included 20 studies in their meta-analysis and found that ketamine decreased total opioid use and pain VAS scores, and delayed the time to first opioid dose. These findings seem impressive and each were statistically significant. However, standardised mean difference and P-values tell us very little about clinical significance, the degree of statistical uncertainty, or both. In their meta-analysis, the standardised mean differences and 95% confidence intervals of the morphine (?) dose reduction were only 0.82 (0.40–1.24) mg at 24 h and 0.65 (0.27–1.03) at 48 h after surgery. These statistics reflect effect sizes but not actual clinical data about analgesic effectiveness or opioid- related side effects. The actual weighted mean reduction in pain VAS scores at 24 and 48 hours were not reported. Were they more than 1.0, previously defined by many investigators to be the minimal clinically important difference?2Myles P.S. Myles D.B. Galagher W. et al.Measuring acute postoperative pain using the visual analog scale: the minimal clinically important difference and patient acceptable symptom state.Br J Anaesth. 2017; 118: 424-429Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar Some authors have suggested that a 33% decrease,3Jensen M.P. Chen C. Brugger A.M. Interpretation of visual analog scale ratings and change scores: a reanalysis of two clinical trials of postoperative pain.J Pain. 2003; 4: 407-414Abstract Full Text Full Text PDF PubMed Scopus (752) Google Scholar or a change in VAS score of 1.5 to 2.0,4DeLoach L.J. Higgins M.S. Caplan A.B. Stiff J.L. The visual analog scale in the immediate postoperative period: intrasubject variability and correlation with a numeric scale.Anesth Analg. 1998; 86: 102-106Crossref PubMed Google Scholar, 5Campbell W.I. Patterson C.C. Quantifying meaningful changes in pain.Anaesthesia. 1998; 53: 121-125Crossref PubMed Scopus (55) Google Scholar, 6Myles P.S. Urquhart N. The linearity of the visual analogue scale in patients with severe acute pain.Anaesth Intensive Care. 2005; 33: 54-58Crossref PubMed Google Scholar would indicate a clinically important change in pain intensity. As it stands, and considering the marked heterogeneity of the patient populations and ketamine regimens, none of the findings presented by Riddell and colleagues suggests any clinically important analgesic benefits of low dose ketamine in orthopaedic surgery. The Standardised Endpoints in Perioperative Medicine (StEP) initiative undertook an extensive Delphi process to identify important, valid and reliable measures of patient comfort after surgery.7Myles P.S. Boney O. Botti M. et al.Systematic review and consensus definitions for the Standardised Endpoints in Perioperative Medicine (StEP) initiative: patient comfort.Br J Anaesth. 2018; 120: 705-711Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar Postoperative pain intensity at rest and on movement at 24 h, using a numerical rating scale (0–10), and (ideally) at least one other time point, were recommended. Opioid dose reduction, of itself (i.e. without a reduction in opioid-related side-effects), was not considered important, nor was time to the first dose of opioid after surgery. PM is an editor of the British Journal of Anaesthesia.