Effect of High-dose Naloxone Following Third Molar Extraction (TME)

February 21, 2024 updated by: mads u werner

Effect of High-dose Target-controlled Naloxone Infusion on Pain and Hyperal-gesia in Patients Following Recovery From Impacted Mandibular Third Molar Extraction. A Randomized, Placebo-controlled, Double-blind Crossover Study.

Recent studies have focused on the role of endogenous opioids on central sensitization. Central sensitization is known to be impaired or altered in chronic pain conditions, as fibromyalgia or chronic tension headache.

Animal studies have shown reinstatement of mechanical hypersensitivity following naloxone administration after resolution of an injury. This suggests latent sensitization. In the present study, the investigators hypothesize that a high-dose target-controlled naloxone infusion (total dose: 3.25 mg/kg) can reinstate pain and hyperalgesia 6-8 weeks after a unilateral primary open groin hernia repair procedure. The investigators aim to show that latent sensitization is present in humans and is modulated by endogenous opioids.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Naloxone is a combined mu-opioid-receptor (MOR) inverse agonist and antagonist drug, which dose-dependently demonstrates hypoalgesic and hyperalgesic properties. Systemically administrated naloxone (3.0-10.0 mg/kg) and naltrexone (0.3-3.0 mg/kg) have been used in rodents to study the role of endogenous opioids on central processing of pain. It has been hypothesized that the endogenous opioid modulation of pain is impaired or altered in chronic pain conditions. Administration of naloxone and naltrexone following resolution of an inflammatory injury, have demonstrated a reinstatement of hypersensitivity to noxious stimuli, indicating a demasking of latent sensitization. It has thus been speculated that the endogenous opioid system may play an important role in the transition of acute to chronic pain in humans.

In an early human study using an electrical pain model, naloxone (21 microg/kg) increased the established area of secondary hyperalgesia (a measure of central sensitization).

In a previous translational placebo-controlled, double-blind, randomized, cross-over study in healthy humans, the investigators were unable to show naloxone-induced reinstatement of secondary hyperalgesia after resolution of a first-degree burn-injury (BI; H-2-2012-036). The investigators hypothesized, that the negative results were attributable to the low dose of naloxone (21 microg/kg) or perhaps insufficient tissue injury to generate latent sensitization.

The investigators therefore in a sequel study administered a higher dose of naloxone (2 mg/kg) 7 days after induction of a BI. The investigators demonstrated in 4 out of 12 subjects reinstatement of secondary hyperalgesia. The magnitude of reinstatement was more pronounced in high-sensitizers (subjects developing large secondary hyperalgesia areas immediately after the BI) The aims of the present clinical study in patients are first, to replicate our previous findings of naloxone-induced (3.25 mg/kg) unmasking of latent sensitization utilizing the impacted mandibular third molar extraction (TME) model with a more pronounced tissue injury than the BI-model. The endpoints are reinstatement of pain and hyperalgesia in the resolution-phase, 4 - 5 weeks after TME-surgery. Second, the study examines a potential dose-response relationship between three stable naloxone concentrations acquired by target controlled infusion (TCI).

Study Type

Interventional

Enrollment (Actual)

23

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Copenhagen, Denmark, 2200
        • Neuroscience Center, Copenhagen University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

INCLUSION CRITERIA:

  • Healthy male
  • Age, minimum 18 yrs and maximum 65 yrs
  • Signed informed consent
  • Participants submitted to unilateral, primary, impacted, uncomplicated mandibular third molar extraction 4 weeks (+ 3 days) prior to examination Day 1.
  • Standardized surgical procedure.
  • Urin-sample without traces of opioids (morphine, methadon, buprenorphine, codeine, tramadol, ketobemidone, oxycodone, hydromorphone, dextromethorphan)
  • ASA I-II
  • Body mass index (BMI): 18 < BMI < 30 kg/m2

EXCLUSION CRITERIA:

  • Participants, who do not speak or understand Danish
  • Participants, who cannot cooperate with the investigation
  • Participants, who have had previous surgery in the mandibular region
  • Participants with pain at rest > 3 (NRS [0: no pain; 10: worst perceivable pain])
  • Activity-related pain in the surgical field > 5 (NRS)
  • Allergic reaction against morphine or other opioids (including naloxone),
  • Abuse of alcohol or drugs - according to investigator's evaluation
  • Use of psychotropic drugs (exception of SSRI)
  • Neurologic or psychiatric disease
  • Chronic pain condition
  • Regular use of analgesic drugs
  • Skin lesions or tattoos in the assessment areas
  • Nerve lesions in the assessment sites (e.g., after trauma, dental surgery)
  • Use of prescription drugs one week before the trial
  • Use of over-the-counter (OTC) drugs 48 hours before the trial

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: High-dose naloxone
Naloxone 4 mg/ml i.v. infusion, total 3.25 mg/kg, target controlled infusion with three infusion rates (0.25 mg/kg; 0.75 mg/kg; 2.25 mg/kg) each of 25 min duration)
Drug: Naloxone
active drug infusion
Other Names:
  • Naloxon "B. Braun"
Placebo Comparator: Normal saline
0.9% physiological saline, i.v. infusion, total 0.81 ml/kg, target controlled infusion with three infusion rates (0.06 ml/kg; 0.19 ml/kg; 0.56 ml/kg) each of 25 min duration.
Drug: Normal Saline
placebo comparator
Other Names:
  • Physiologic Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in the composite measure of pain (numerical rating scale (NRS); 0 = no pain; 10 = worst perceivable pain)
Time Frame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.
during rest + masticatory pain + pain during external algometry (100 kPa) at the injury site
1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Secondary hyperalgesia/allodynia area at mandibular skin sites directly overlying surgical and contralateral side
Time Frame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.
Hyperalgesia/allodynia assessments with nylon monofilament (nominal value 4.93 [bending force: mean +/- SD = 69 +/- 14 mN]
1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.
Online Reaction Time
Time Frame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.
measured using http://getyourwebsiteherecom/jswb/rttest01.htm. This computer-application shows a red-green traffic light. Participants are instructed to press the button when the light changes from red to green. Three measurements are used and the median value is used as a representative estimate of reaction time.
1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.
Hospital Anxiety and Depression Scale (HADS)
Time Frame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. Only pre-infusion
HADS is used to assess anxiety and signs of depression. Based on 14 questions about the subject's status in the previous week, HADS measures agitation/anxiety and depression via two subscales (each containing seven questions). Participants have to answer each question on a scale of 0 to 3. The two subscales are summed separately. The maximum score of each subscale is 21 points and a score of 11 or more points suggests that the participant might be suffering from anxiety or depression. In case of score > 11 points in the depression subscale of the HADS, a physician will decide if there are clinical signs of depression. If there are signs of depression, this diagnosis will be told to the participant. The participant will be informed that the diagnosis of depression is based on clinical assessments - the HADS scale can be included in the diagnostic procedure. If it is the participants wish, he should visit his general practitioner for diagnosis and eventual treatment.
1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. Only pre-infusion
Pain Catastrophizing Scale (PCS)
Time Frame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. Only pre-infusion
PCS consists of 13 questions divided into three sections: rumination, exaggeration and helplessness. The questions are answered in accordance to a scale of 0 to 4. There is evidence of catastrophizing thoughts at a total score > 30 points.
1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. Only pre-infusion
Clinical Opiate Withdrawal Scale (COWS)
Time Frame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.
The Clinical Opiate Withdrawal Scale (COWS) is an examiner-based scale evaluating signs of opioid-withdrawal. Grading of symptoms, i.e. heart rate changes, sweating, restlessness, pupil size, bone or joint aches, running nose or tearing, nausea, vomiting, diarrhea, tremor, yawning, anxiety or irritability and "goose-flesh", are made in 11 categories. COWS-scores are divided into: 5-12 = mild; 13-24 = moderate; 25-36 = moderately severe ;> 36 = severe withdrawal reactions.
1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. At each session assessments are made at: -20 to -8 min; 15 to 25 min (TCI-step 1); 40 to 50 min (TCI-step 2); and 65 to 75 min (TCI-step 3) relative to start of TCI.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

mads u werner

Collaborators

University of Kentucky

Investigators

  • Principal Investigator: Mads U Werner, MD, DMSc, Neuroscience Center, Copenhagen University Hospital, Denmark
  • Study Chair: Bradley K Taylor, M.Sc., Ph.D., Department of Physiology, University of Kentucky Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 12, 2017

Primary Completion (Actual)

November 27, 2023

Study Completion (Actual)

December 27, 2023

Study Registration Dates

First Submitted

November 21, 2016

First Submitted That Met QC Criteria

November 23, 2016

First Posted (Estimated)

November 29, 2016

Study Record Updates

Last Update Posted (Estimated)

February 22, 2024

Last Update Submitted That Met QC Criteria

February 21, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H-15018869-TME

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Data will be made available as a supplementum to the published scientific article. Anticipated available in Spring 2018.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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