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

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    mads u werner
Updated on 25 March 2022
body mass index
chronic pain
tension headache
Accepts healthy volunteers


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.


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).

Condition Healthy Subjects, Hyperalgesia, Inflammations, Endodontic, Pain, Acute, Sensitization, Central
Treatment Normal saline, naloxone
Clinical Study IdentifierNCT02976337
Sponsormads u werner
Last Modified on25 March 2022


Yes No Not Sure

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)
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
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