Preventing pAIn With NMDA Antagonists - Steroids in Thoracoscopic lObectomy Procedures (PAIN-STOP) Pilot Trial (PAIN-STOP)

NMDA Antagonists and Steroids for the Prevention of Persisting Post-Surgical Pain After Thoracoscopic Surgeries: A Randomized Controlled, Factorial Design, International, Multicentre Pilot Study

The objective of the PAIN-STOP trial is to assess the feasibility of a larger randomized controlled trial (RCT) evaluating NMDA antagonists and IV steroids, as compared to placebo, in decreasing the chances of clinically significant persistent post-surgical pain (PPSP) after video assisted thoracoscopic surgeries (VATS). This is a multi-centre randomized, controlled clinical trial with a 2 x 2 factorial design. The pilot phase of the trial will recruit 48 patients and follow them for 3 months. Patients will be randomized to one of four groups: 1) NMDA active + Steroid placebo; 2) Steroid active + NMDA placebo; 3) NMDA active + Steroid active; 4) NMDA placebo + Steroid placebo.

Study Overview

• Status: Terminated
• Conditions: Pain, Postoperative
• Intervention / Treatment: Drug: NMDA active; Drug: Steroid placebo; Drug: Steroid active; Drug: NMDA placebo

Detailed Description

Persistent Post-Surgical Pain (PPSP) after Video Assisted Thoracic Surgery (VATS) lobectomy procedures is an important health problem for which there is no effective method of prevention. NMDA antagonists and steroids can modify pain signaling-sensitization pathways, and inflammatory-immune pathways, and hence can potentially prevent the development of PPSP. These agents have been safely used in thoracic surgeries to obtain many perioperative benefits, without increasing the harmful effects. Since these agents act by different biological mechanisms, it is appropriate to study their effects in a factorial design to increase the trial efficiency. Before conducting a large multicenter trial, we propose to establish the feasibility by carrying out this feasibility trial.

The objective of the PAIN-STOP trial is to assess the feasibility of a larger randomized controlled trial (RCT) evaluating NMDA antagonists and IV steroids, as compared to placebo, in decreasing the chances of clinically significant persistent post-surgical pain (PPSP) after video assisted thoracoscopic surgeries (VATS). This is a multi-centre randomized, controlled clinical trial with a 2 x 2 factorial design. The pilot phase of the trial will recruit 48 patients and follow them for 3 months. Patients will be randomized to one of four groups: 1) NMDA active + Steroid placebo; 2) Steroid active + NMDA placebo; 3) NMDA active + Steroid active; 4) NMDA placebo + Steroid placebo. Follow-up visit will be conducted in hospital; day 8 and month 2 by a phone call; and in person follow-up visits at 30 days and 3 months post-randomization; for patients who cannot attend in person, a telephone follow up will be done.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N4A6
      • St. Joseph's Healthcare
• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18-75 years of age,
• Planned elective VATS pulmonary lobectomy,
• Provide written informed consent to participate.

Exclusion Criteria:

• Current pain on the same side of the chest of moderate to severe intensity (>3/10 in 0-10 numerical rating scale (NRS) - where 0=no pain, 10=maximum pain),
• Known intracranial mass or cerebral aneurysm or raised intraocular pressure,
• Severe renal impairment (creatinine clearance based GFR of <30ml/min),
• Allergies to one or more of the study medications,
• Steroid treatment > 10mg/day of Prednisolone or its equivalent for > 3 weeks within the last 3 months,
• History of schizophrenia or bipolar disorder,
• History of drug addiction (prescription or non-prescription drug addiction diagnosed by a physician, excluding alcohol),
• Current diagnosis of Cushing's syndrome,
• Pregnancy,
• Previous participation in the PAIN-STOP trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NMDA active + Steroid placebo; NMDA active: ketamine (0.5 mg/kg IV bolus pre-incision and 0.1 mg/kg/hr infusion postoperatively up to 24 hours) and oral memantine (5 mg BID [first week]; 10 mg BID [following three weeks]). Steroid placebo: two doses of normal saline; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.	Drug: NMDA active; NMDA active group will involve ketamine (0.5 mg/kg IV bolus pre-incision and 0.1 mg/kg/hr infusion postoperatively up to 24 hours) and oral memantine (5 mg BID [first week]; 10 mg BID [following three weeks]).; Drug: Steroid placebo; Steroid placebo group will involve two doses of normal saline; one dose given prior to starting surgery and one dose given on the morning of second postoperative day.
Experimental: Steroid active + NMDA placebo; NMDA placebo: normal saline (IV bolus pre-incision and infusion postoperatively up to 24 hours) and oral matching placebo to memantine (one capsule BID [first week]; one capsule BID [following three weeks]). Steroid active: two doses of dexamethasone; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.	Drug: Steroid active; Steroid active group will involve two doses of dexamethasone; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.; Drug: NMDA placebo; NMDA active group will involve normal saline (IV bolus pre-incision and infusion postoperatively up to 24 hours) and oral matching placebo to memantine (1 capsule BID [first week]; 1 capsule BID [following three weeks]).
Experimental: NMDA active + Steroid active; NMDA active: ketamine (0.5 mg/kg IV bolus pre-incision and 0.1 mg/kg/hr infusion postoperatively up to 24 hours) and oral memantine (5 mg BID [first week]; 10 mg BID [following three weeks]). Steroid active: two doses of dexamethasone; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.	Drug: NMDA active; NMDA active group will involve ketamine (0.5 mg/kg IV bolus pre-incision and 0.1 mg/kg/hr infusion postoperatively up to 24 hours) and oral memantine (5 mg BID [first week]; 10 mg BID [following three weeks]).; Drug: Steroid active; Steroid active group will involve two doses of dexamethasone; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.
Placebo Comparator: NMDA placebo + Steroid placebo; NMDA placebo: normal saline (IV bolus pre-incision and infusion postoperatively up to 24 hours) and oral matching placebo to memantine (one capsule BID [first week]; one capsule BID [following three weeks]). Steroid placebo: two doses of normal saline; 25 mg given prior to starting surgery and 25 mg given on the morning of second postoperative day.	Drug: Steroid placebo; Steroid placebo group will involve two doses of normal saline; one dose given prior to starting surgery and one dose given on the morning of second postoperative day.; Drug: NMDA placebo; NMDA active group will involve normal saline (IV bolus pre-incision and infusion postoperatively up to 24 hours) and oral matching placebo to memantine (1 capsule BID [first week]; 1 capsule BID [following three weeks]).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment	Ability to recruit 90% of eligible patients.	6 months
Recruitment	Ability to recruit at least 4 patients per month per site, and complete the recruitment over a 6-month period.	6 months
Follow-up	Ability to obtain follow-up in >90% of enrolled patients, at three months.	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NRS - Incidence of PPSP	Intensity of PPSP on a scale of 0-10, at 3 months after randomization [0-10 numerical rating scale (NRS) - where 0=no pain, 10=maximum pain].	3 months
NRS - Incidence of PPSP with movement evoked	Incidence of PPSP (in and/or around the surgical scar) at 3 months after randomization, as the presence of movement evoked pain > 3/10 in 0-10 NRS.	3 months
Rate of change of postoperative pain intensity	The rate of change of postoperative pain intensity measured over time (pain trajectory).	3 months
Use of narcotic analgesic medication	Use of narcotic analgesic medication > 3 days/week beyond 4 weeks and up to 3 months after randomization.	3 months
Presence of NP	Presence of NP as > 3 out 7 items using DN4 scale, at measured at 3 months after randomization.	3 months
BPI score	Difference in interference with activities of daily living measured using Brief Pain Inventory interference score, measured at 3 months after randomization.	3 months
Thoracic surgery specific activity limitations	Difference in thoracic surgery specific activity limitations, measured at 3 months after randomization.	3 months
Change in global health status	Change in global health status measured using global impression of change (GIC) scale at 3 months after randomization.	3 months
Difference in Quality of Life	Difference in Quality of Life (QoL) using European Organization for Research and Treatment of Cancer (EORTC) QoL-30 at 3 months after randomization.	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of myocardial infarction and injury	Incidence of myocardial infarction and myocardial injury after noncardiac surgery (MINS)	3 months
Incidence of postoperative pneumonia	Incidence of postoperative pneumonia	3 months
Incidence of prolonged air-leak	Incidence of prolonged air-leak	3 months
Incidence of new intubation and positive pressure ventilation	Incidence of new intubation and positive pressure ventilation	3 months
Incidence of surgical site infection	Incidence of surgical site infection	3 months

Collaborators and Investigators

• Sponsor: Population Health Research Institute
• Investigators: Study Chair: PJ Devereaux, MD, PhD, McMaster University

Publications and helpful links

General Publications

• Shanthanna H, Turan A, Vincent J, Saab R, Shargall Y, O'Hare T, Davis K, Fonguh S, Balasubramaniam K, Paul J, Gilron I, Kehlet H, Sessler DI, Bhandari M, Thabane L, Devereaux PJ. 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. J Pain Res. 2020 Feb 12;13:377-387. doi: 10.2147/JPR.S237058. eCollection 2020.

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2017
• Primary Completion (Actual): December 31, 2018
• Study Completion (Actual): March 31, 2019

Study Registration Dates

• First Submitted: October 28, 2016
• First Submitted That Met QC Criteria: October 31, 2016
• First Posted (Estimate): November 1, 2016

Study Record Updates

• Last Update Posted (Actual): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 13, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: quality of life; activities of daily living; postoperative pain; VATS
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Excitatory Amino Acid Agents; Excitatory Amino Acid Agonists; N-Methylaspartate
• Other Study ID Numbers: 2016-001-PS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No