Effect of High-dose Naloxone Following Third Molar Extraction

NCT02976337 | Completed Phase 2

• 1 other identifier: H-15018869-TME
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (1)

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

  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 Outcomes (5)

• 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.

• 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.

• Hospital Anxiety and Depression Scale (HADS)

  1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. Only pre-infusion

• Pain Catastrophizing Scale (PCS)

  1st session: 4 weeks after TME-surgery; 2nd session: 1 week later. Only pre-infusion

• 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.

Study Arms (2)

High-dose naloxone

EXPERIMENTAL

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

Normal saline

PLACEBO COMPARATOR

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

Interventions

Naloxone DRUG

active drug infusion

Also known as: Naloxon "B. Braun"

High-dose naloxone

Normal Saline DRUG

placebo comparator

Also known as: Physiologic Saline

Normal saline

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• mads u werner: lead
• University of Kentucky: collaborator

Study Sites (1)

Neuroscience Center, Copenhagen University Hospital

Copenhagen, 2200, Denmark

Location

Related Publications (13)

• Brennum J, Kaiser F, Dahl JB. Effect of naloxone on primary and secondary hyperalgesia induced by the human burn injury model. Acta Anaesthesiol Scand. 2001 Sep;45(8):954-60. doi: 10.1034/j.1399-6576.2001.450806.x.

  PMID: 11576045 BACKGROUND

• Pielsticker A, Haag G, Zaudig M, Lautenbacher S. Impairment of pain inhibition in chronic tension-type headache. Pain. 2005 Nov;118(1-2):215-23. doi: 10.1016/j.pain.2005.08.019. Epub 2005 Oct 3.

  PMID: 16202520 BACKGROUND

• Price DD, Staud R, Robinson ME, Mauderli AP, Cannon R, Vierck CJ. Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain. 2002 Sep;99(1-2):49-59. doi: 10.1016/s0304-3959(02)00053-2.

  PMID: 12237183 BACKGROUND

• van Wilgen CP, Keizer D. The sensitization model to explain how chronic pain exists without tissue damage. Pain Manag Nurs. 2012 Mar;13(1):60-5. doi: 10.1016/j.pmn.2010.03.001. Epub 2010 Jul 22.

  PMID: 22341140 BACKGROUND

• Koppert W, Filitz J, Troster A, Ihmsen H, Angst M, Flor H, Schuttler J, Schmelz M. Activation of naloxone-sensitive and -insensitive inhibitory systems in a human pain model. J Pain. 2005 Nov;6(11):757-64. doi: 10.1016/j.jpain.2005.07.002.

  PMID: 16275600 RESULT

• Campillo A, Cabanero D, Romero A, Garcia-Nogales P, Puig MM. Delayed postoperative latent pain sensitization revealed by the systemic administration of opioid antagonists in mice. Eur J Pharmacol. 2011 Apr 25;657(1-3):89-96. doi: 10.1016/j.ejphar.2011.01.059. Epub 2011 Feb 4.

  PMID: 21300053 RESULT

• Taylor BK, Corder G. Endogenous analgesia, dependence, and latent pain sensitization. Curr Top Behav Neurosci. 2014;20:283-325. doi: 10.1007/7854_2014_351.

  PMID: 25227929 RESULT

• Corder G, Doolen S, Donahue RR, Winter MK, Jutras BL, He Y, Hu X, Wieskopf JS, Mogil JS, Storm DR, Wang ZJ, McCarson KE, Taylor BK. Constitutive mu-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science. 2013 Sep 20;341(6152):1394-9. doi: 10.1126/science.1239403.

  PMID: 24052307 RESULT

• Pereira MP, Werner MU, Ringsted TK, Rowbotham MC, Taylor BK, Dahl JB. Does naloxone reinstate secondary hyperalgesia in humans after resolution of a burn injury? A placebo-controlled, double-blind, randomized, cross-over study. PLoS One. 2013 May 31;8(5):e64608. doi: 10.1371/journal.pone.0064608. Print 2013.

  PMID: 23741350 RESULT

• Pereira MP, Donahue RR, Dahl JB, Werner M, Taylor BK, Werner MU. Endogenous Opioid-Masked Latent Pain Sensitization: Studies from Mouse to Human. PLoS One. 2015 Aug 25;10(8):e0134441. doi: 10.1371/journal.pone.0134441. eCollection 2015.

  PMID: 26305798 RESULT

• Edwards RR, Ness TJ, Fillingim RB. Endogenous opioids, blood pressure, and diffuse noxious inhibitory controls: a preliminary study. Percept Mot Skills. 2004 Oct;99(2):679-87. doi: 10.2466/pms.99.2.679-687.

  PMID: 15560360 RESULT

• Singla NK, Desjardins PJ, Chang PD. A comparison of the clinical and experimental characteristics of four acute surgical pain models: dental extraction, bunionectomy, joint replacement, and soft tissue surgery. Pain. 2014 Mar;155(3):441-456. doi: 10.1016/j.pain.2013.09.002. Epub 2013 Sep 6.

  PMID: 24012952 RESULT

• Glass PS, Jhaveri RM, Smith LR. Comparison of potency and duration of action of nalmefene and naloxone. Anesth Analg. 1994 Mar;78(3):536-41. doi: 10.1213/00000539-199403000-00021.

  PMID: 8109774 RESULT

MeSH Terms

Conditions

Hyperalgesia; Pulpitis; Acute Pain; Pain

Interventions

Naloxone; Saline Solution

Condition Hierarchy (Ancestors)

Somatosensory Disorders; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Dental Pulp Diseases; Tooth Diseases; Stomatognathic Diseases

Intervention Hierarchy (Ancestors)

Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Mads U Werner, MD, DMSc

  Neuroscience Center, Copenhagen University Hospital, Denmark

  PRINCIPAL INVESTIGATOR

• Bradley K Taylor, M.Sc., Ph.D.

  Department of Physiology, University of Kentucky Medical Center

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate professor

Study Record Dates

• First Submitted: November 21, 2016
• First Posted: November 29, 2016
• Study Start: October 12, 2017
• Primary Completion: November 27, 2023
• Study Completion: December 27, 2023
• Last Updated: February 22, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share

Locations

DK (1)