Effect of Butorphanol Combined With Flurbiprofen Axetil on Preventing Hyperalgesia Induced by Remifentanil in Patients

Effect of Butorphanol Combined With Flurbiprofen Axetil on Preventing Postoperative Hyperalgesia Induced by Remifentanil in Patients Undergoing Lower Abdomimal Surgery

Purpose:

To explore and compare antihyperalgesic effects of butorphanol, flurbiprofen axetil, and a combination of both received before anesthesia induction.

To evaluate and examine the incidence of adverse effects with the purpose of selecting the optimum dose.

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Study Overview

• Status: Completed
• Conditions: Pain; Anesthesia
• Intervention / Treatment: Drug: Normal Saline; Drug: Remifentanil; Drug: Butorphanol; Drug: Flurbiprofen axetil; Drug: Sufentanil

Detailed Description

There are a dramatically increasing number of evidences that administration of the potent, ultra-short-acting opioid remifentanil seems to cause opioid-induced hyperalgesia (OIH) more frequently and predictably compared with the others, likely due to its rapid onset and offset. Therefore, prophylaxis of remifentanil induced hyperalgesia is indispensable to postoperative comfort and satisfaction.

There is no denying the fact that OIH is related to central glutaminergic system and N-methyl-d-aspartate (NMDA) receptor-activation induced central sensitization. Prostaglandins can promote glutamate release from both astrocytes and spinal cord dorsal horns with subsequent activation of the NMDA receptors, and flurbiprofen axetil, as non-steroidal anti-inflammatory drugs (NSAIDs), not only functionally antagonizes the NMDA receptor activation via inhibition of prostaglandins, but also is a targeted drug which gathers at the site of inflammation, thus greatly enhances the analgesic effect. While butorphanol has both spinal analgesic and sedative functions because of predominantly central κ-receptor agonist activation, other advantages of butorphanol include few side effects, very low addiction potential, and low toxicity on account of a partial agonist-antagonist activity to μ-receptor. Moreover, antihyperalgesic activity of κ opioids at the site of inflammation has been reported in various acute pain models. The following study is carried out to evaluate whether butorphanol combined with flurbiprofen axetil can be safely and effectively applied to preventing postoperative hyperalgesia induced by remifentanil in patients undergoing lower abdominal surgery.

• Study Type: Interventional
• Enrollment (Actual): 180
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300052
      • Tianjin Medical University General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subject is scheduled to undergo lower abdominal surgery under a short general anesthesia of less than 2 hours
2. Subject's American Society of Anesthesiologists physical status is I-II.
3. The subject's parent/legally authorized guardian has given written informed consent to participate.

Exclusion Criteria:

1. Subject has a diagnosis of renal or liver failure.
2. Subject has a diagnosis of Insulin dependent diabetes.
3. Subject is allergy and contraindication to butorphanol or NSAIDs.
4. Subject has a history of chronic pain, a history of alcohol or opioid abuse, pre-existing therapy with opioids, intake of any analgesic drug within 48 hours before surgery.
5. Subject has any contraindication for the use of patient-controlled analgesia (PCA).
6. Subject is pregnant or breast-feeding.
7. Subject is obese (body mass index >30kg/m^2).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Normal Saline; Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with remifentanil	Drug: Normal Saline; Normal Saline is intravenously administrated before anesthesia induction; Drug: Remifentanil; Remifentanil is intravenously administrated
Active Comparator: Butorphanol; Butorphanol is intravenously administrated at a dose of 20μg/ kg before anesthesia induction and intraoperative pain management was with remifentanil	Drug: Remifentanil; Remifentanil is intravenously administrated; Drug: Butorphanol; Butorphanol is intravenously administrated
Active Comparator: Flurbiprofen axetilⅠ; Flurbiprofen axetil is intravenously administrated at a dose of 1.0mg/ kg before anesthesia induction and intraoperative pain management was with remifentanil	Drug: Remifentanil; Remifentanil is intravenously administrated; Drug: Flurbiprofen axetil; Flurbiprofen axetil is intravenously administrated
Active Comparator: Flurbiprofen axetilⅡ; Flurbiprofen axetil is intravenously administrated at a dose of 1.0mg/ kg before the skin closure and intraoperative pain management was with remifentanil	Drug: Remifentanil; Remifentanil is intravenously administrated; Drug: Flurbiprofen axetil; Flurbiprofen axetil is intravenously administrated
Active Comparator: Butorphanol-Flurbiprofen axetil; A dose of 10μg/ kg butorphanol and a dose of 0.5mg/ kg flurbiprofen axetil are intravenously administrated before anesthesia induction and intraoperative pain management was with remifentanil	Drug: Remifentanil; Remifentanil is intravenously administrated; Drug: Butorphanol; Butorphanol is intravenously administrated; Drug: Flurbiprofen axetil; Flurbiprofen axetil is intravenously administrated
Sham Comparator: Sufentanil; Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with sufentanil	Drug: Normal Saline; Normal Saline is intravenously administrated before anesthesia induction; Drug: Sufentanil; Sufentanil is intravenously administrated

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mechanical Hyperalgesia Threshold on the Dominant Inner Forearm	The mechanical hyperalgesia threshold was defined as the lowest force (g) necessary to bend a Von Frey filament, which was perceived to be painful by the patient and measured by Von Frey filament at 24 hours postoperatively	24 hours after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Dose of First Postoperative Analgesic Requirement	First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl.	1 hour after surgery
Pain Score (NRS)	The pain score at rest was evaluated by pain 11-point numerical rating scale (NRS): 0 = no pain, 10 = greatest imaginable pain.	3h, 6h, 12h, and 24h after surgery
Time of First Postoperative Analgesic Requirement	First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl.	1 hour post surgery
Occurrence of Side Effects	Occurrence of side effects: nausea, vomiting, dizziness, headache, shivering, pruritus	24 hours
Cumulative Sufentanyl Consumption	Each patient was administered analgesics using a PCA pump containing sufentanil (100μg) in normal saline at a total volume of 100 ml after leaving PACU. This device was set to deliver a basal infusion of 2 ml/h and bolus doses of 0.5 ml with a 15-min lockout period. Sufentanyl cumulative consumption is recorded 24 hours postoperatively	24 hours
Normalized Area of Hyperalgesia Around the Incision	The skin around the incision is stimulated in steps of 5 mm at intervals of 1 s starting outside of the hyperalgesic area in the direction of the incision. The distance from the incision to the first point where a 'painful', 'sore' or 'sharper' feeling occurred is measured and noted. This measurement is repeated at predefined radial lines around the incision. To eliminate the variable length of incision, this length is subtracted from the longer diameter leaving four radial distances from the end and from the middle of the incision. The normalized area of hyperalgesia is calculated by summing up the areas of the remaining four triangles measured by and Von Frey filament.	24 hours after surgery

Collaborators and Investigators

• Sponsor: Tianjin Medical University General Hospital

Publications and helpful links

General Publications

• Zhang L, Shu R, Zhao Q, Li Y, Yu Y, Wang G. Preoperative butorphanol and flurbiprofen axetil therapy attenuates remifentanil-induced hyperalgesia after laparoscopic gynaecological surgery: a randomized double-blind controlled trial. Br J Anaesth. 2016 Oct;117(4):504-511. doi: 10.1093/bja/aew248. Epub 2016 Oct 17.

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: January 15, 2014
• First Submitted That Met QC Criteria: January 21, 2014
• First Posted (Estimate): January 23, 2014

Study Record Updates

• Last Update Posted (Estimate): January 8, 2016
• Last Update Submitted That Met QC Criteria: December 8, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: Remifentanil; Postoperative pain; Opioid-induced hyperalgesia; Pain Intensity
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Sensation Disorders; Somatosensory Disorders; Hyperalgesia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Narcotic Antagonists; Respiratory System Agents; Antitussive Agents; Remifentanil; Sufentanil; Flurbiprofen; Flurbiprofen axetil; Butorphanol
• Other Study ID Numbers: GWang001