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Healthy SubjectsPhase 2TMENCT02976337

Effect of High-dose Naloxone Following Third Molar Extraction

A Phase 2 study testing Naloxone and Normal Saline in people with Healthy Subjects and Hyperalgesia, run by mads u werner at 1 site in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 65 years, men onlyHealthy volunteers can take part
What is being tested?
Naloxone and Normal Saline
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
23 participants
Where
1 siteDenmark
Study dates
12 Oct 2017to 27 Dec 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • Men only
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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),
Show all 15Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

Denmark1 site

  • Neuroscience Center, Copenhagen University Hospital

    Copenhagen, 2200

Other trials in Denmark

About this study

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.

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.

Read the 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).

Being tested
Naloxone, Normal Saline
Keywords
Central sensitization, Endogenous opioids, Humans, Latent sensitization, Mandibular third molar extraction, Naloxone, Pain, Pressure algometry, Randomized controlled trial, Secondary hyperalgesia, Target controlled infusion
Medical subject headings
Hyperalgesia, Pulpitis, Acute Pain, Pain

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NaloxoneDrug

    Also called Naloxon "B. Braun"

    active drug infusion

  • Normal SalineDrug

    Also called Physiologic Saline

    placebo comparator

Study groups in NCT02976337
Study groupRoleWhat they receive
High-dose naloxoneExperimentalNaloxone 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)
Receives: Drug: Naloxone
Normal salinePlacebo comparator0.9% 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.
Receives: Drug: Normal Saline

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: 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)

  1. Secondary hyperalgesia/allodynia area at mandibular skin sites directly overlying surgical and contralateral side

    Hyperalgesia/allodynia assessments with nylon monofilament (nominal value 4.93 [bending force: mean +/- SD = 69 +/- 14 mN]

    Measured: 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.

  2. Online Reaction Time

    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.

    Measured: 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.

  3. Hospital Anxiety and Depression Scale (HADS)

    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.

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

  4. Pain Catastrophizing Scale (PCS)

    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.

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

  5. Clinical Opiate Withdrawal Scale (COWS)

    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.

    Measured: 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.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Nov 2016 (estimated)
  2. Study start12 Oct 2017
  3. Primary completion27 Nov 2023
  4. Study completion27 Dec 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Crossover
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
23 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02976337
Sponsor's protocol ID
H-15018869-TME
Acronym
TME
Status last verified
Feb 2024
First submitted
21 Nov 2016
Last updated
22 Feb 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Data will be made available as a supplementum to the published scientific article. Anticipated available in Spring 2018.

Publications

  • 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.

    PubMed 11576045

  • 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.

    PubMed 16202520

  • 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.

    PubMed 12237183

  • 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.

    PubMed 22341140

  • 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.

    PubMed 16275600

  • 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.

    PubMed 21300053

  • 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.

    PubMed 25227929

  • 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.

    PubMed 24052307

  • 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.

    PubMed 23741350

  • 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.

    PubMed 26305798

  • 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.

    PubMed 15560360

  • 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.

    PubMed 24012952

  • 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.

    PubMed 8109774

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Naloxone and Normal Saline in people with Healthy Subjects and Hyperalgesia, run by mads u werner at 1 site in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in the composite measure of pain (numerical rating scale (NRS); 0 = no pain; 10 = worst perceivable pain) (time frame: 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.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02976337, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Feb 2024.

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