Pain, Anesthesia
Conditions
Keywords
Remifentanil, Opioid-induced hyperalgesia, Postoperative pain, Pain Intensity
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. .
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.
Interventions
DRUGNormal Saline
Normal Saline is intravenously administrated before anesthesia induction
DRUGButorphanol
Butorphanol is intravenously administrated
Flurbiprofen axetil is intravenously administrated
DRUGRemifentanil
Remifentanil is intravenously administrated
DRUGSufentanil
Sufentanil is intravenously administrated
Sponsors
Tianjin Medical University General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 60 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Time of First Postoperative Analgesic Requirement | 1 hour post surgery | First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl. |
| Occurrence of Side Effects | 24 hours | Occurrence of side effects: nausea, vomiting, dizziness, headache, shivering, pruritus |
| 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. |
| 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 |
| 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. |
| Total Dose of First Postoperative Analgesic Requirement | 1 hour after surgery | First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl. |
Countries
China
Participant flow
Recruitment details
From February 2014 to June 2015, patients were recruited and estimated for eligibility
Pre-assignment details
Exclusion criteria: coronary heart disease, bronchial asthma, cardiac, lung, hepatic and renal insufficiency, severe hypertension, diabetes mellitus, psychiatric disease, obesity, a history of chronic pain, a history of alcohol or opioid abuse, pregnancy, allergy and contraindication to study drugs, a history of gastrointestinal disease
Participants by arm
| Arm | Count |
|---|---|
| Normal Saline Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with remifentanil
Normal Saline | 28 |
| Flurbiprofen AxetilⅠ Flurbiprofen axetil is intravenously administrated at a dose of 1.0mg/ kg before anesthesia induction and intraoperative pain management was with remifentanil
Flurbiprofen axetil: Flurbiprofen axetil is intravenously administrated | 28 |
| 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
Flurbiprofen axetil: Flurbiprofen axetil is intravenously administrated | 28 |
| Butorphanol Butorphanol is intravenously administrated at a dose of 20μg/ kg before anesthesia induction and intraoperative pain management was with remifentanil. | 28 |
| 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. | 28 |
| Sufentanil Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with sufentanil. | 28 |
| Total | 168 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 2 | 2 | 2 | 2 | 2 |
Baseline characteristics
| Characteristic | Normal Saline | Flurbiprofen AxetilⅠ | Flurbiprofen AxetilⅡ | Butorphanol | Butorphanol-Flurbiprofen Axetil | Sufentanil | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 44.2 years STANDARD_DEVIATION 11 | 45.3 years STANDARD_DEVIATION 9.7 | 47.9 years STANDARD_DEVIATION 10 | 46.5 years STANDARD_DEVIATION 9.7 | 45.1 years STANDARD_DEVIATION 7.9 | 43.5 years STANDARD_DEVIATION 10.8 | 45.5 years STANDARD_DEVIATION 9.8 |
| Region of Enrollment China | 28 participants | 28 participants | 28 participants | 28 participants | 28 participants | 28 participants | 168 participants |
| Sex: Female, Male Female | 28 Participants | 28 Participants | 28 Participants | 28 Participants | 28 Participants | 28 Participants | 168 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 28 | 0 / 28 | 0 / 28 | 0 / 28 | 0 / 28 | 0 / 28 |
| serious Total, serious adverse events | 0 / 28 | 0 / 28 | 0 / 28 | 0 / 28 | 0 / 28 | 0 / 28 |
Outcome results
Primary
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
Time frame: 24 hours after surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Saline | Mechanical Hyperalgesia Threshold on the Dominant Inner Forearm | 60.57 g | Standard Deviation 22.55 |
| Flurbiprofen AxetilⅠ | Mechanical Hyperalgesia Threshold on the Dominant Inner Forearm | 78.29 g | Standard Deviation 24.76 |
| Flurbiprofen AxetilⅡ | Mechanical Hyperalgesia Threshold on the Dominant Inner Forearm | 68.50 g | Standard Deviation 21.98 |
| Butorphanol | Mechanical Hyperalgesia Threshold on the Dominant Inner Forearm | 79.7 g | Standard Deviation 20.93 |
| Butorphanol-Flurbiprofen Axetil | Mechanical Hyperalgesia Threshold on the Dominant Inner Forearm | 81.64 g | Standard Deviation 20.4 |
| Sufentanil | Mechanical Hyperalgesia Threshold on the Dominant Inner Forearm | 89.5 g | Standard Deviation 23.4 |
Secondary
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
Time frame: 24 hours
Secondary
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.
Time frame: 24 hours after surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Saline | Normalized Area of Hyperalgesia Around the Incision | 60.46 cm^2 | Standard Deviation 9.98 |
| Flurbiprofen AxetilⅠ | Normalized Area of Hyperalgesia Around the Incision | 53.64 cm^2 | Standard Deviation 8.63 |
| Flurbiprofen AxetilⅡ | Normalized Area of Hyperalgesia Around the Incision | 56.57 cm^2 | Standard Deviation 8.98 |
| Butorphanol | Normalized Area of Hyperalgesia Around the Incision | 54.00 cm^2 | Standard Deviation 9.3 |
| Butorphanol-Flurbiprofen Axetil | Normalized Area of Hyperalgesia Around the Incision | 52.5 cm^2 | Standard Deviation 9.15 |
| Sufentanil | Normalized Area of Hyperalgesia Around the Incision | 49.89 cm^2 | Standard Deviation 8.57 |
Secondary
Occurrence of Side Effects
Occurrence of side effects: nausea, vomiting, dizziness, headache, shivering, pruritus
Time frame: 24 hours
Secondary
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.
Time frame: 3h, 6h, 12h, and 24h after surgery
Secondary
Time of First Postoperative Analgesic Requirement
First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl.
Time frame: 1 hour post surgery
Secondary
Total Dose of First Postoperative Analgesic Requirement
First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl.
Time frame: 1 hour after surgery