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

Not Applicable

Completed

Conditions: Pain
Anesthesia

Interventions: Drug: Normal Saline
Drug: Butorphanol
Drug: Flurbiprofen axetil
Drug: Remifentanil
Drug: Sufentanil

Registration Number: NCT02043366

Lead Sponsor: Tianjin Medical University General Hospital

Brief Summary: 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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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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 180

Inclusion Criteria

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

Exclusion Criteria

Subject has a diagnosis of renal or liver failure.
Subject has a diagnosis of Insulin dependent diabetes.
Subject is allergy and contraindication to butorphanol or NSAIDs.
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.
Subject has any contraindication for the use of patient-controlled analgesia (PCA).
Subject is pregnant or breast-feeding.
Subject is obese (body mass index >30kg/m^2).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sufentanil	Normal Saline	Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with sufentanil
Normal Saline	Remifentanil	Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with remifentanil
Normal Saline	Normal Saline	Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with remifentanil
Butorphanol	Remifentanil	Butorphanol is intravenously administrated at a dose of 20μg/ kg before anesthesia induction and intraoperative pain management was with remifentanil
Butorphanol	Butorphanol	Butorphanol is intravenously administrated at a dose of 20μg/ kg before anesthesia induction and intraoperative pain management was with remifentanil
Flurbiprofen axetilⅠ	Flurbiprofen axetil	Flurbiprofen axetil is intravenously administrated at a dose of 1.0mg/ kg before anesthesia induction and intraoperative pain management was with remifentanil
Flurbiprofen axetilⅠ	Remifentanil	Flurbiprofen axetil is intravenously administrated at a dose of 1.0mg/ kg before anesthesia induction and intraoperative pain management was with remifentanil
Flurbiprofen axetilⅡ	Remifentanil	Flurbiprofen axetil is intravenously administrated at a dose of 1.0mg/ kg before the skin closure and intraoperative pain management was with remifentanil
Butorphanol-Flurbiprofen axetil	Remifentanil	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
Flurbiprofen axetilⅡ	Flurbiprofen axetil	Flurbiprofen axetil is intravenously administrated at a dose of 1.0mg/ kg before the skin closure and intraoperative pain management was with remifentanil
Butorphanol-Flurbiprofen axetil	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
Sufentanil	Sufentanil	Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with sufentanil
Butorphanol-Flurbiprofen axetil	Butorphanol	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

Primary Outcome Measures

Name	Time	Method
Mechanical Hyperalgesia Threshold on the Dominant Inner Forearm	24 hours after surgery	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

Secondary Outcome Measures

Name	Time	Method
Normalized Area of Hyperalgesia Around the Incision	24 hours after surgery	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.
Occurrence of Side Effects	24 hours	Occurrence of side effects: nausea, vomiting, dizziness, headache, shivering, pruritus
Cumulative Sufentanyl Consumption	24 hours	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
Total Dose of First Postoperative Analgesic Requirement	1 hour after surgery	First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl.
Pain Score (NRS)	3h, 6h, 12h, and 24h after surgery	The pain score at rest was evaluated by pain 11-point numerical rating scale (NRS): 0 = no pain, 10 = greatest imaginable pain.
Time of First Postoperative Analgesic Requirement	1 hour post surgery	First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl.