Clinical trial NCT02976337: Effect of High-dose Naloxone Following Third Molar Extraction
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Healthy Subjects
Hyperalgesia
Inflammations, Endodontic
Pain, Acute
Sensitization, Central
Keywords: Central sensitization
Endogenous opioids
Humans
Latent sensitization
Mandibular third molar extraction
Naloxone
Pain
Pressure algometry
Randomized controlled trial
Secondary hyperalgesia
Target controlled infusion
Lead sponsor: University of Copenhagen
Sponsor class: OTHER
Collaborators: name: University of Kentucky
First posted: 2016-11-29
Enrollment: 23
Sex: MALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

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 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

Primary outcomes:
measure: Change in the composite measure of pain (numerical rating scale (NRS); 0 = no pain; 10 = worst perceivable pain)
timeFrame: 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 outcomes:
measure: Secondary hyperalgesia/allodynia area at mandibular skin sites directly overlying surgical and contralateral side
timeFrame: 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.
measure: Online Reaction Time
timeFrame: 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.
measure: Hospital Anxiety and Depression Scale (HADS)
timeFrame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. Only pre-infusion
measure: Pain Catastrophizing Scale (PCS)
timeFrame: 1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. Only pre-infusion
measure: Clinical Opiate Withdrawal Scale (COWS)
timeFrame: 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.
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Neuroscience Center, Copenhagen University Hospital
Study officials:
affiliation: Neuroscience Center, Copenhagen University Hospital, Denmark
name: Mads U Werner, MD, DMSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Physiology, University of Kentucky Medical Center
name: Bradley K Taylor, M.Sc., Ph.D.
role: STUDY_CHAIR
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