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

Ketamine

Brief Summary

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.

Intervention / Treatment

We will randomize patients in a 1:1:1:1 fashion to receive; 1) NMDA active + dexamethasone placebo, 2) dexamethasone active + NMDA placebo, 3) NMDA active + dexamethasone active, and 4) NMDA placebo + dexamethasone placebo.
  • NMDA active (DRUG)
    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 \[following three weeks\]).
  • Steroid active (DRUG)
    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.
  • NMDA placebo (DRUG)
    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 \[following three weeks\]).
  • Steroid placebo (DRUG)
    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.

Condition or Disease

  • Pain, Postoperative

Phase

  • Phase 3

    • Study Design

    Study type: INTERVENTIONAL
    Status: Terminated
    Study results: No Results Available
    Age: 18 Years to 75 Years
    Enrollment: 27 (ACTUAL)
    Funded by: Other
    Allocation: Randomized
    Primary Purpose: Treatment

    Masking

    Patients, health care providers, data collectors, outcome adjudicators, and Investigators (e.g., Steering Committee Members) will all be blind to treatment allocation.

    QUADRUPLE:
    • Participant
    • Care Provider
    • Investigator
    • Outcomes Assessor

    Clinical Trial Dates

    Start date: May 04, 2017 ACTUAL
    Primary Completion: Dec 31, 2018 ACTUAL
    Completion Date: Mar 31, 2019 ACTUAL
    Study First Posted: Nov 01, 2016 ESTIMATED
    Results First Posted: Aug 31, 2020
    Last Updated: Jan 13, 2020

    Sponsors / Collaborators

    Lead Sponsor: Population Health Research Institute
    Lead sponsor is responsible party
    Responsible Party: N/A

    Location

    Cleveland, Ohio, USA
    Hamilton, Ontario, Canada

    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.

    Participant Groups

    • 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.

    • 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.

    • 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.

    • 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.

    Eligibility Criteria

    Sex: All
    Minimum Age: 18
    Maximum Age: 75
    Age Groups: Adult / Older Adult
    Healthy Volunteers: Yes

    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.

    Primary Outcomes

    • Ability to recruit 90% of eligible patients.

    • Ability to recruit at least 4 patients per month per site, and complete the recruitment over a 6-month period.

    • Ability to obtain follow-up in \>90% of enrolled patients, at three months.

    Secondary Outcomes

    • Intensity of PPSP on a scale of 0-10, at 3 months after randomization \[0-10 numerical rating scale (NRS) - where 0=no pain, 10=maximum pain\].

    • 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.

    • The rate of change of postoperative pain intensity measured over time (pain trajectory).

    • Use of narcotic analgesic medication \> 3 days/week beyond 4 weeks and up to 3 months after randomization.

    • Presence of NP as \> 3 out 7 items using DN4 scale, at measured at 3 months after randomization.

    • Difference in interference with activities of daily living measured using Brief Pain Inventory interference score, measured at 3 months after randomization.

    • Difference in thoracic surgery specific activity limitations, measured at 3 months after randomization.

    • Change in global health status measured using global impression of change (GIC) scale at 3 months after randomization.

    • Difference in Quality of Life (QoL) using European Organization for Research and Treatment of Cancer (EORTC) QoL-30 at 3 months after randomization.

    Other Outcomes

    • Incidence of myocardial infarction and myocardial injury after noncardiac surgery (MINS)

    • Incidence of postoperative pneumonia

    • Incidence of prolonged air-leak

    • Incidence of new intubation and positive pressure ventilation

    • Incidence of surgical site infection

    More Details

    NCT Number: NCT02950233
    Acronym: PAIN-STOP
    Other IDs: 2016-001-PS
    Study URL: https://clinicaltrials.gov/study/NCT02950233
    Last updated: Sep 29, 2023