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Pilot Study: Postoperative Pain Reduction by Pre Emptive N-Acetylcysteine

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ClinicalTrials.gov Identifier: NCT03354572
Recruitment Status : Completed
First Posted : November 28, 2017
Last Update Posted : August 13, 2019
Sponsor:
Collaborator:
Maxima Medical Center
Information provided by (Responsible Party):
Radboud University

Brief Summary:
Despite current available analgesic drugs, post-surgical pain management remains challenging. A potential new target for analgesic drugs are group-II metabotropic glutamate receptors subtypes (mGlu2 and mGlu3 receptors), since growing evidence from animal models show that activation of these receptors produce s analgesic effects in inflammatory and in neuropathic pain states. . N-Acetylcysteine (NAC) is a safe agent and with little to no side effects. NAC can induce analgesia by activating the glutamate:cystein antiporter, causing endogenous activation of the mGlu 2/3 receptors. However, this has only been investigated once in the peri-operative setting, were it showed preliminary promising result of reduction in opiate necessity. In healthy subjects there was a significant reduction in pain ratings to laser stimuli and amplitudes of laser evoked potentials after NAC. Based on these promising results, we hypothesize that pre emptive intravenous NAC can reduce postoperative pain and thereby cause less necessity for escape analgesics like opiates.

Condition or disease Intervention/treatment Phase
Postoperative Pain Drug: Acetyl cysteine Drug: Placebos Phase 4

Detailed Description:

Currently approximately 240 million surgical procedures are done worldwide on a yearly basis. lnguinal hernia repair is one of the most performed surgeries in ambulatory setting. Despite currently available analgesic drugs, post surgical pain management remains challenging in this group of patients, as the pain score appears inadequate (mean VAS of 5.8 +/- 1 .22 cm) one day after surgery with the use of common analgesics. Beside accounting for patient discomfort, pain is also a major contributor to prolonged length of hospital stay and is a health care quality indicator. With multimodal pain management the intention is to reduce pain with less side effects of analgesics. Multimodal pain management is the combination of different pharmacologic mechanisms of action, which work by acting at different sites within the central and peripheral nervous system, thereby having an additive or synergistic effect and reducing the necessity of opiates. With this in mind, a potential new target for analgesic drugs are group- ll metabotropic glutamate receptors subtypes (mGlu2 and mGlu3 receptors) localized in the spinal cord and other regions of the nociceptive system. Growing evidence from animal models show that activation of these receptors occur via the glutamate:cystein antiporter and can induce analgesia in models of inflammatory and neuropathic pain. They depress pain transmission at synapses between primary afferent fibers and second order sensory neurons on the dorsal horn of the spinal cord.

N-Acetylcysteine (NAC) is on the market since 1968 and is an over the counter available agent, mostly known for its role as mucolytic agent in cystic fibrosis and for the treatment of acetaminophen intoxication. lt is a safe agent with little to no side effects. Recent studies have shown NAC can inhibit nociceptive transmission in rats and in healthy humans.NAC can induce analgesia by activating the glutamate:cystein antiporter, causing endogenous activation of the mGlu2/3 receptors. Therefore, NAC can potentially become a cheap and safe additive in the multimodal pain management. However, evidence for usage of NAC in the context of multimodal pain management is still lacking. Only one available study in humans evaluated the effect of NAC in the perioperative setting. Despite being a randomised controlled trial, there are several limitations in this study; the study arms are too small and only morphine consumption is presented. Also, blinding might have not as good as suggested since oral NAC has a typical flavour and the placebo was lemonade.

Due to these limitations, still no answer on the question whether NAC can be an additive in current multimodal pain management is provided.

Objective of the study:

Primary Objective:

To evaluate the efficacy of intravenous NAC in comparison with placebo in terms of pain relief after unilateral inguinal hernia repair measured by a visual analogue scale (VAS 0-100) at day 1 after surgery.

Secondary Objective(s):

  1. Difference in pain scores between NAC and placebo direct after surgery, before discharge and in following 3 days postoperative.
  2. Difference in time before first pain medication is administered postoperative between NAC and placebo.
  3. Difference in total consumption of opiates in the hospital (mg) between NAC and placebo.
  4. Difference in time from surgery to discharge between NAC and placebo.
  5. Difference in postoperative pain medication at home necessary to reach adequate pain relief between NAC and placebo (acetaminophen / NSAID's/ opiates).
  6. lf there is a difference in 5, is there also a difference in adverse effects of pain medication (like nausea, obstipation) between NAC and placebo.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The study will be a single centre double blinded randomized placebo controlled trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Pilot Study: Postoperative Pain Reduction by Pre Emptive N-Acetylcysteine
Actual Study Start Date : October 20, 2017
Actual Primary Completion Date : October 29, 2018
Actual Study Completion Date : October 29, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: NAC
receive 150 mg/kg acetylcysteïne in 200 ml saline (NaCl0,9%) prior to surgery
Drug: Acetyl cysteine
acetyl cysteine 150 mg/kg prior to surgery
Other Name: NAC

Placebo Comparator: placebo
receive only NaCl 0.9% prior to surgery (volume identical to active comparator)
Drug: Placebos
saline 0.9% prior to surgery
Other Name: Saline 0.9%




Primary Outcome Measures :
  1. pain score day 1 after surgery [ Time Frame: 24 hours ]
    To evaluate the efficacy of intravenous NAC in comparison with placebo in terms of pain relief after laparoscopic inguinal hernia repair measured by a visual analogue scale (VAS 0-100 millimeters) at day 1 after surgery. The higher the score, the more pain the patient has.


Secondary Outcome Measures :
  1. direct postoperative pain [ Time Frame: <1 hours ]
    Difference in pain scores between NAC and placebo direct after surgery (1 hour. Measurement in visual analogue scale (VAS 0-100 millimeters) at 1 hour after surgery. The higher the score, the more pain the patient has.

  2. time to first pain medication [ Time Frame: <4hours ]
    Difference in time before first pain medication is administered postoperative between NAC and placebo

  3. total consumption of opiates [ Time Frame: <4 hours ]
    Difference in total consumption of opiates in the hospital (mg) between NAC and placebo

  4. time to discharge [ Time Frame: 24 hours ]
    Difference in time from surgery to discharge between NAC and placebo.

  5. postoperative dosage of analgesics [ Time Frame: 72 hours ]
    Difference in postoperative pain medication at home necessary to reach adequate pain relief between NAC and placebo ( Acetaminophen /NSAID's/opiates).

  6. adverse effects of analgesics [ Time Frame: 72 hours ]
    is there also a difference in adverse effects of pain medication (like nausea, obstipation) between NAC and placebo

  7. Incidence of Treatment-Emergent Adverse Events (e.g. safety of acetylcystein) [ Time Frame: <4 hours ]
    adverse effects of acetylcysteine; do we see exanthema or breathing problems during administration of acetylcystein.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects scheduled for laparoscopic unilateral inguinal hernia repair
  • ASA 1 or2.
  • Age >18 years.

Exclusion Criteria:

  • Pregnancy or lactating
  • Allergy to NAC
  • History of chronic pain
  • Use of opioids or neuropathic analgesics
  • Use of NAC prior to trial (< 1 month of planned surgery)
  • Alcoholism
  • Diabetes Mellitus (insulin therapy)
  • Asthma or Chronic Obstructive pulmonary Disease
  • Known renal function disorders (MDRD <ô0)
  • Known liver failure (bilirubin >1.Sx upper limit of normal)
  • No written lC by patient

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03354572


Locations
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Netherlands
Maxima Medical Centre
Eindhoven, Noord Brabant, Netherlands, 5631BM
Sponsors and Collaborators
Radboud University
Maxima Medical Center
Investigators
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Principal Investigator: Kris Vissers, MD, PhD Chair
  Study Documents (Full-Text)

Documents provided by Radboud University:
Study Protocol  [PDF] September 8, 2017
Statistical Analysis Plan  [PDF] September 8, 2017


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Responsible Party: Radboud University
ClinicalTrials.gov Identifier: NCT03354572     History of Changes
Other Study ID Numbers: NAC.TEP
First Posted: November 28, 2017    Key Record Dates
Last Update Posted: August 13, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: not yet decided, if there is a question for data we will comply as much as possible

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Acetylcysteine
N-monoacetylcystine
Pain, Postoperative
Postoperative Complications
Pathologic Processes
Pain
Neurologic Manifestations
Signs and Symptoms
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes