Effect of High-dose Naloxone Following Third Molar Extraction
NCT ID: NCT02976337
Last Updated: 2024-02-22
Study Results
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Basic Information
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COMPLETED
PHASE2
23 participants
INTERVENTIONAL
2017-10-12
2023-12-27
Brief Summary
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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.
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Detailed Description
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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).
Conditions
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Study Design
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RANDOMIZED
CROSSOVER
BASIC_SCIENCE
QUADRUPLE
Study Groups
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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)
Naloxone
active drug infusion
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.
Normal Saline
placebo comparator
Interventions
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Naloxone
active drug infusion
Normal Saline
placebo comparator
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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 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
18 Years
65 Years
MALE
Yes
Sponsors
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University of Kentucky
OTHER
mads u werner
OTHER
Responsible Party
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mads u werner
Associate professor
Principal Investigators
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Mads U Werner, MD, DMSc
Role: PRINCIPAL_INVESTIGATOR
Neuroscience Center, Copenhagen University Hospital, Denmark
Bradley K Taylor, M.Sc., Ph.D.
Role: STUDY_CHAIR
Department of Physiology, University of Kentucky Medical Center
Locations
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Neuroscience Center, Copenhagen University Hospital
Copenhagen, , Denmark
Countries
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References
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Other Identifiers
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H-15018869-TME
Identifier Type: -
Identifier Source: org_study_id
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