Administration of Acetazolamide to Prevent Remifentanil Induced Hyperalgesia

Administration of Acetazolamide to Prevent Remifentanil Induced Hyperalgesia: Randomize Double Blind Clinical Trial

Remifentanil is a potent opioid widely used during the administration of general anesthesia. There is a lot of evidence that suggest that the used of remifentanil is associated with the development of hyperalgesia (a reduction of nociceptive thresholds). However, the mechanism of this hyperalgesia is not fully understood.

Recently, it was demonstrated that the disruption of the Cl- homeostasis could be involved. Interestingly, this was prevented in a murine model with the administration of Acetazolamide, a carbonic anhydrase inhibitor. In our clinical trial we will try to determine if the preoperative administration of acetazolamide could prevent the hyperalgesia induced by remifentanil in patients scheduled for thyroidectomy with general anesthesia.

Study Overview

• Status: Completed
• Conditions: Opioid-Related Disorders; Hyperalgesia
• Intervention / Treatment: Drug: Placebo Oral Tablet; Drug: Acetazolamide

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• Chile
  • Metropolitana
    • Santiago, Metropolitana, Chile, 7563215
      • Faculty of Medicine, University of Chile

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients scheduled for thyroidectomy with general anesthesia in the University of Chile Clinical Hospital

Exclusion Criteria:

• Patients ASA III y IV
• Chronic pain history
• Drug and alcohol abuse
• Chronic use of opioid and sedatives
• Neuropsychiatric illness
• NSAID and other analgesics used the 48 hours previous to the surgery
• CMI > 30

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Acetazolamide; 250 mg VO of acetazolamide will be administered the day of the surgery 2 hours before anesthesia induction	Drug: Acetazolamide
Placebo Comparator: Placebo; An oral tablet without active principle acetazolamide but with the same physical characteristics will be administered the day of the surgery 2 hours before anesthesia induction	Drug: Placebo Oral Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the mechanical pain threshold in an area distant to the site of the injury	The threshold will be determine using von Frey monofilaments before the surgery and will be compared 12-18 hours after the end of the surgery	12-18 hours after the end of the surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the mechanical pain threshold in an area distant to the site of the injury		2 hours after the end of the surgery
Postoperative pain	A visual analogue scale (VAS; 0, no pain; 100, worst poss- ible pain) will be used to assess pain	The first postoperative day
Morphine consumption	Morphine consumption with a patient controlled analgesia (PCA) in mg	The first postoperative day

Collaborators and Investigators

• Sponsor: University of Chile
• Investigators: Principal Investigator: Rodrigo Gutierrez, MD, Anesthesia Department, University of Chile; Principal Investigator: Antonello Penna, MD PhD, Anesthesia Department, University of Chile

Publications and helpful links

General Publications

• Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, Chauvin M. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005 Jul;103(1):147-55. doi: 10.1097/00000542-200507000-00022.
• Ferrini F, Trang T, Mattioli TA, Laffray S, Del'Guidice T, Lorenzo LE, Castonguay A, Doyon N, Zhang W, Godin AG, Mohr D, Beggs S, Vandal K, Beaulieu JM, Cahill CM, Salter MW, De Koninck Y. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl(-) homeostasis. Nat Neurosci. 2013 Feb;16(2):183-92. doi: 10.1038/nn.3295. Epub 2013 Jan 6.
• Echevarria G, Elgueta F, Fierro C, Bugedo D, Faba G, Iniguez-Cuadra R, Munoz HR, Cortinez LI. Nitrous oxide (N(2)O) reduces postoperative opioid-induced hyperalgesia after remifentanil-propofol anaesthesia in humans. Br J Anaesth. 2011 Dec;107(6):959-65. doi: 10.1093/bja/aer323. Epub 2011 Sep 28.
• Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain. 2003 Nov;106(1-2):49-57. doi: 10.1016/s0304-3959(03)00276-8.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2016
• Primary Completion (Actual): September 28, 2018
• Study Completion (Actual): September 28, 2018

Study Registration Dates

• First Submitted: December 11, 2016
• First Submitted That Met QC Criteria: December 13, 2016
• First Posted (Estimate): December 14, 2016

Study Record Updates

• Last Update Posted (Actual): December 31, 2018
• Last Update Submitted That Met QC Criteria: December 28, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: Remifentanil; Acetazolamide; Opioid hyperalgesia
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Nervous System Diseases; Substance-Related Disorders; Neurologic Manifestations; Sensation Disorders; Narcotic-Related Disorders; Somatosensory Disorders; Opioid-Related Disorders; Hyperalgesia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Carbonic Anhydrase Inhibitors; Natriuretic Agents; Diuretics; Anticonvulsants; Acetazolamide
• Other Study ID Numbers: 803/16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO