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

This study is currently recruiting participants.
Verified October 2017 by mads u werner, University of Copenhagen
Sponsor:
ClinicalTrials.gov Identifier:
NCT02976337
First Posted: November 29, 2016
Last Update Posted: October 18, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
University of Kentucky
Information provided by (Responsible Party):
mads u werner, University of Copenhagen
  Purpose

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.


Condition Intervention Phase
Healthy Subjects Hyperalgesia Inflammations, Endodontic Pain, Acute Sensitization, Central Drug: Naloxone Drug: Normal Saline Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by mads u werner, University of Copenhagen:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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]

  • 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.

  • 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.

  • 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.

  • 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.


Estimated Enrollment: 14
Actual Study Start Date: October 12, 2017
Estimated Study Completion Date: August 2018
Estimated Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: Physiologic Saline

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).

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
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): NCT02976337


Contacts
Contact: Mads U Werner, MD, DMSc. 28257703 ext +45 mads.u.werner@gmail.com

Locations
Denmark
Neuroscience Center, Copenhagen University Hospital Recruiting
Copenhagen, Denmark, 2200
Contact: Mads U Werner, MD, DMSc.    2825 7703 ext +45    mads.u.werner@gmail.com   
Sub-Investigator: Elisabeth K Jensen, MS         
Sub-Investigator: Anders D Springborg, MB         
Sponsors and Collaborators
mads u werner
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
  More Information

Publications:

Responsible Party: mads u werner, Associate professor, University of Copenhagen
ClinicalTrials.gov Identifier: NCT02976337     History of Changes
Other Study ID Numbers: H-15018869-TME
First Submitted: November 21, 2016
First Posted: November 29, 2016
Last Update Posted: October 18, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data will be made available as a supplementum to the published scientific article. Anticipated available in Spring 2018.

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by mads u werner, University of Copenhagen:
Central sensitization
Endogenous opioids
Humans
Latent sensitization
Mandibular third molar extraction
Naloxone
Pain
Pressure algometry
Randomized controlled trial
Secondary hyperalgesia
Target controlled infusion

Additional relevant MeSH terms:
Inflammation
Hyperalgesia
Acute Pain
Pulpitis
Pathologic Processes
Somatosensory Disorders
Sensation Disorders
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Pain
Dental Pulp Diseases
Tooth Diseases
Stomatognathic Diseases
Naloxone
Narcotic Antagonists
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents