TME: Effect of High-dose Naloxone Following Third Molar Extraction

Sponsor

mads u werner (Other)

Overall Status

Recruiting

CT.gov ID

NCT02976337

Collaborator

University of Kentucky (Other)

Enrollment

Location

Arms

70.5

Anticipated Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Healthy Subjects Hyperalgesia Inflammations, Endodontic Pain, Acute Sensitization, Central	Drug: Naloxone Drug: Normal Saline	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

14 participants

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.

Actual Study Start Date :

Oct 12, 2017

Anticipated Primary Completion Date :

Feb 28, 2023

Anticipated Study Completion Date :

Aug 28, 2023

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Change in the composite measure of pain (numerical rating scale (NRS); 0 = no pain; 10 = worst perceivable pain) [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 [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 [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) [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) [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) [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

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

Locations

	Site	City	State	Country	Postal Code
1	Neuroscience Center, Copenhagen University Hospital	Copenhagen		Denmark	2200

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