Fentanyl Ultra Low Doses Effects on the Nociceptive Threshold

Pain, Postoperative Clinical Trial

— FENTANULD  

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?

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00454259
• Other study ID #: CHUBX 2006/08
• Status: Completed
• Phase: Phase 4
• First received: March 29, 2007
• Last updated: June 2, 2015
• Start date: March 2007
• Est. completion date: August 2007

Study information

• Verified date: March 2007
• Source: University Hospital, Bordeaux
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial Summary

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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: August 2007
• Est. primary completion date: August 2007
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 40 Years

Eligibility

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

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

Related Conditions & MeSH terms

• Pain, Postoperative

Intervention

Drug:
• Fentanyl/Placebo injection
Ultra low dose intravenous injection

Locations

Country	Name	City	State
France	CHU de Bordeaux Département d'Anesthésie-Réanimation II	PESSAC Cedex	Hôpital cardiologique

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Bordeaux

Country where clinical trial is conducted

France, 

References & Publications (12)

Célèrier 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology. 2000 Oct;93(4):1123-33. Review. — View Citation

Richebé 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. — View Citation

Rivat C, Laulin JP, Corcuff JB, Célèrier 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. — View Citation

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. — View Citation

Simonnet G, Rivat C. Opioid-induced hyperalgesia: abnormal or normal pain? Neuroreport. 2003 Jan 20;14(1):1-7. Review. — View Citation

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

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.		5 min after injection, and every 15 min during 1 hour	No
Secondary	Non invasive blood pressure (SBP, DBP), heart rate, respiratory rate, pulse oxymetry and cognitive functions evaluation (sedation score).		all along the experimentation	Yes