Fentanyl Ultra Low Doses Effects on the Nociceptive Threshold - Full Text View

Sponsor:	University Hospital, Bordeaux
Information provided by:	University Hospital, Bordeaux
ClinicalTrials.gov Identifier:	NCT00454259

Purpose

Exaggerated pain and hyperalgesia are major issues after surgery and can lead to chronic pain. Opioid are parts of pain sensitization processes but remain absolutely necessary in the intraoperative period. NMDA receptor antagonists succeed in reducing this pain sensitization process. Recent studies show that in pain and opioid-experienced rats (POER) fentanyl ultra low doses do not induce analgesia, as observed in naive rats, but hyperalgesia. This is the first demonstration that a drug can induce opposite effect depending on individual history. We also observed a strong correlation between this hyperalgesic response in POER and the intensity of hyperalgesia they develop later, after inflammatory or surgical pain. The main aim of this study is to measure the dose effect response to fentanyl "ultra low doses" on human volunteer's nociceptive threshold, to determine if such an opposite response profile can be revealed.

Condition	Intervention	Phase
Pain, Postoperative	Drug: Fentanyl/Placebo injection	Phase IV

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Investigator, Outcomes Assessor) Primary Purpose: Health Services Research
Official Title:	Fentanyl Ultra Low Doses Effects on Human Volunteer's Nociceptive Threshold. Towards a Simple Pharmacological Test Able to Predict Pain Vulnerability, Post Operative Hyperalgesia Development Risk?

Resource links provided by NLM:

Drug Information available for: Fentanyl Fentanyl Citrate

U.S. FDA Resources

Further study details as provided by University Hospital, Bordeaux:

Primary Outcome Measures:

Nociceptive threshold evaluated with sternal electronical Von Frey mechanical stimulation. The stimulation will increase until the volunteer presses a trigger when the stimulation becomes painful. [ Time Frame: 5 min after injection, and every 15 min during 1 hour ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Non invasive blood pressure (SBP, DBP), heart rate, respiratory rate, pulse oxymetry and cognitive functions evaluation (sedation score). [ Time Frame: all along the experimentation ] [ Designated as safety issue: Yes ]

Enrollment:	48
Study Start Date:	March 2007
Study Completion Date:	August 2007
Primary Completion Date:	August 2007 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1 0,5 µg/kg	Drug: Fentanyl/Placebo injection Ultra low dose intravenous injection
Experimental: 2 0,05 µg/kg	Drug: Fentanyl/Placebo injection Ultra low dose intravenous injection
Experimental: 3 0,005 µg/kg	Drug: Fentanyl/Placebo injection Ultra low dose intravenous injection
Placebo Comparator: 4 NaCl 0,9 %	Drug: Fentanyl/Placebo injection Ultra low dose intravenous injection

Detailed Description:

Principal Objective : "Evaluate fentanyl "ultra low doses" effects on human volunteer's nociceptive threshold depending on their prior pain and opioid experience."
Secondary Objective : "Confirm the innocuousness of this test (the 3 "ultra low doses" used in this trial will be 10 to 1,000 fold lower than low doses use for anesthesia and analgesia) and to find the fentanyl ultra low dose that could be used to develop a pain sensitisation predictive test."
Study design : Bicentric, prospective, randomized, double-blind study.

Inclusion criteria :

In both groups:

18-40 years old male volunteer
weight: 60 to 85 kg
ASA score: 1
Informed consent obtained from the patient
Gender : Male

In "operated" group:

- At least one history of peripheral surgery under general anesthesia with opioid in the past five years

Exclusion criteria :

In both groups:

The patient do not accept inclusion to the study
Drug or alcohol abuse history
Chronic use of analgesic drugs or history of chronic pain
Analgesic or opioid consumption within the 12hs preceding the fentanyl or placebo injection
Neurological and/or psychiatric disorder, inability to give informed consent
Psychological trauma within the two year preceding the inclusion
Any contraindication to fentanyl use
Use of any medication interacting with fentanyl
Exclusion period from the national healthy volunteer register
Gender : Female

In "healthy" group:

- Any history of general anesthesia or surgery

Study plan: comparing two groups that only defer by their surgical and opioid prior experience and will receive three fentanyl ultra low doses (10 to 1,000 fold lower than low doses use for anesthesia and analgesia) and placebo (cross over administration, one week wash out period).
Number of subjects : 48

Eligibility

Ages Eligible for Study:	18 Years to 40 Years
Genders Eligible for Study:	Male
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

In both groups:

18-40 years old male volunteer
Weight: 60 to 85 kg
ASA score: 1
Informed consent obtained from the patient

In "operated" group:

At least one history of peripheral surgery under general anesthesia with opioid in the past five years.

Exclusion Criteria:

In both groups:

The patients do not accept inclusion to the study
Drug or alcohol abuse history
Chronic use of analgesic drugs or history of chronic pain
Analgesic or opioid consumption within the 12hs preceding the fentanyl or placebo injection
Neurological and/or psychiatric disorder, inability to give informed consent
Psychological trauma within the two year preceding the inclusion
Any contraindication to fentanyl use
Use of any medication interacting with fentanyl
Exclusion period from the national healthy volunteer register

In "healthy" group:

Any history of general anesthesia or surgery

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00454259

Locations

France
CHU de Bordeaux Département d'Anesthésie-Réanimation II
PESSAC Cedex, Hôpital cardiologique, France, 33604

Sponsors and Collaborators

University Hospital, Bordeaux

Investigators

Study Director:	Philippe RICHEBE, Dr	University Hospital, Bordeaux
Principal Investigator:	Gérard JANVIER, PHD	University Hospital, Bordeaux
Principal Investigator:	Claude DUBRAY, PHD	University Hospital, Bordeaux
Principal Investigator:	Alain ESCHALIER, PHD	University Hospital, Bordeaux
Principal Investigator:	jean DUALE CHRISTIAN, Dr	University Hospital, Bordeaux
Principal Investigator:	Gisèle PICKERING, Dr	University Hospital, Bordeaux

More Information

Publications:

Hsu YW, Somma J, Hung YC, Tsai PS, Yang CH, Chen CC. Predicting postoperative pain by preoperative pressure pain assessment. Anesthesiology. 2005 Sep;103(3):613-8.

Kalkman CJ, Visser K, Moen J, Bonsel GJ, Grobbee DE, Moons KG. Preoperative prediction of severe postoperative pain. Pain. 2003 Oct;105(3):415-23.

Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology. 2000 Oct;93(4):1123-33. Review. No abstract available.

Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006 May 13;367(9522):1618-25. Review.

Celerier E, Laulin JP, Corcuff JB, Le Moal M, Simonnet G. Progressive enhancement of delayed hyperalgesia induced by repeated heroin administration: a sensitization process. J Neurosci. 2001 Jun 1;21(11):4074-80.

Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain. 1993 Mar;52(3):259-85. Review.

Shen KF, Crain SM. Cholera toxin-B subunit blocks excitatory effects of opioids on sensory neuron action potentials indicating that GM1 ganglioside may regulate Gs-linked opioid receptor functions. Brain Res. 1990 Oct 29;531(1-2):1-7.

Crain SM, Shen KF. Modulation of opioid analgesia, tolerance and dependence by Gs-coupled, GM1 ganglioside-regulated opioid receptor functions. Trends Pharmacol Sci. 1998 Sep;19(9):358-65.

Richebe P, Rivat C, Laulin JP, Maurette P, Simonnet G. Ketamine improves the management of exaggerated postoperative pain observed in perioperative fentanyl-treated rats. Anesthesiology. 2005 Feb;102(2):421-8.

Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000 Jun 9;288(5472):1765-9. Review.

Rivat C, Laulin JP, Corcuff JB, Celerier E, Pain L, Simonnet G. Fentanyl enhancement of carrageenan-induced long-lasting hyperalgesia in rats: prevention by the N-methyl-D-aspartate receptor antagonist ketamine. Anesthesiology. 2002 Feb;96(2):381-91.

Simonnet G, Rivat C. Opioid-induced hyperalgesia: abnormal or normal pain? Neuroreport. 2003 Jan 20;14(1):1-7. Review. No abstract available.

Responsible Party:	Jean-Pierre LEROY / Clinical Research and Innovation Director, University Hospital, Bordeaux
ClinicalTrials.gov Identifier:	NCT00454259 History of Changes
Other Study ID Numbers:	CHUBX 2006/08
Study First Received:	March 29, 2007
Last Updated:	August 19, 2008
Health Authority:	France: Afssaps - French Health Products Safety Agency

Keywords provided by University Hospital, Bordeaux:

Postoperative Hyperalgesia
Human volunteer
Fentanyl

Randomized Controlled Trial
Pain chronicisation
Predictive test

Additional relevant MeSH terms:

Pain, Postoperative
Postoperative Complications
Pathologic Processes
Pain
Signs and Symptoms
Fentanyl
Adjuvants, Anesthesia
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions

Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Analgesics, Opioid

ClinicalTrials.gov processed this record on February 09, 2012