N-Methyl-D-Aspartate Antagonists and Steroids for the Prevention of Persisting Post-Surgical Pain After Thoracoscopic Surgeries: A Randomized Controlled, Factorial Design, International, Multicenter Pilot Trial

Harsha Shanthanna, Alparslan Turan, Jessica Vincent, Remie Saab, Yaron Shargall, Turlough O'Hare, Kimberly Davis, Sylvanus Fonguh, Kumar Balasubramaniam, James Paul, Ian Gilron, Henrik Kehlet, Daniel I Sessler, Mohit Bhandari, Lehana Thabane, P J Devereaux, Harsha Shanthanna, Alparslan Turan, Jessica Vincent, Remie Saab, Yaron Shargall, Turlough O'Hare, Kimberly Davis, Sylvanus Fonguh, Kumar Balasubramaniam, James Paul, Ian Gilron, Henrik Kehlet, Daniel I Sessler, Mohit Bhandari, Lehana Thabane, P J Devereaux

Abstract

Purpose: We conducted a feasibility 2×2 factorial trial comparing N-methyl-D-aspartate (NMDA) antagonists (intravenous ketamine and oral memantine) versus placebo and intravenous steroids versus placebo, in patients having elective video-assisted thoracic surgery lobectomies, at St. Joseph's Hamilton, Canada, and Cleveland Clinic, Cleveland, USA. Our feasibility objectives were: 1) recruitment rate/week; 2) recruitment of ≥90% of eligible patients; and 3) >90% follow-up. Secondary objectives were incidence and intensity of persistent post-surgical pain (PPSP) and other clinical and safety outcomes.

Methods: Using computerized randomization, patients were allocated to one of four groups: NMDA active with steroid placebo; NMDA placebo with steroid active; both NMDA and steroid active; both NMDA and steroid placebo. Patients, health providers, and data analysts were blinded to allocation. Patients were followed for 3 months after randomization.

Results: The trial was initiated in May 2017 at Hamilton and, after subsequent regulatory and ethics approval, in April 2018 at Cleveland. The trial had to be stopped after only 1 month of recruitment in Cleveland because the packaged study medications (memantine) expired and we were unable to procure the dosage required. Among 41 eligible patients, 27 (66%) were randomized. The recruitment rate/week was 0.63, 95% confidence interval (CI): 0.47-0.79 in Hamilton; and 1, 95% CI: 0.83-1.17 in Cleveland. Follow-up was complete for all 24 patients (100%) in Hamilton, and 3 of 4 patients in Cleveland. In total, only 4 patients (15%), and 2 patients (7%) had persistent pain at rest and with movement, respectively. There were no significant differences between groups for other outcomes.

Conclusion: The trial had to be stopped prematurely due to non-availability of study medications. Trial feasibility objectives of recruiting 90% of eligible patients and recruiting at least one patient/week per site were not met. Consideration for protocol changes will be necessary for the full trial.

Trial registration: NCT02950233.

Keywords: NMDA antagonists; chronic pain; ketamine; persisting pain; prevention; steroids.

Conflict of interest statement

Dr. Philip J. Devereaux reports grants from Abbott Diagnostics, Boehringer Ingelheim, Philips Healthcare, Roche Diagnostics, and Siemens, outside the submitted work. The authors report no other conflicts of interest in this work.

© 2020 Shanthanna et al.

Figures

Figure 1
Figure 1
CONSORT 2010 Flow Diagram.
Figure 2
Figure 2
Rate of change in postoperative pain intensity since surgery up to 3 months after randomization. (A) Resolution of postoperative pain over time in the NMDA group; (B) Resolution of postoperative pain over time in the steroid group.

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