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To explore and compare antihyperalgesic effects of Dexmedetomidine,Nalmefene,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.
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. Dexmedetomidine is an 2-adrenergic agonist that has been shown to synergize with opioids. Dexmedetomidine inhibits NMDAR excitability by reducing the phosphorylation of N-methyl-D-aspartate receptor 2B subunit phosphorylation of spinal dorsal horn induced by remifentanil, thereby achieving the goal of reducing OIH. Nalmefene is a pure opioid receptor antagonist that antagonizes the Mu receptor, alleviating the central sensitization of NMDA, thereby reducing OIH. At the same time reported in the literature, opioid receptor has a bimode：On the one hand can be mediated by Gs protein-mediated pain, respiratory depression, nausea and vomiting, etc ; on the other hand can be coupled with Gi / Go protein mediated analgesic effect. Low-dose nalmefene (<1.0ug / kg) and other opioid receptor antagonists can antagonize the role of Gs protein-coupled opioid receptors, blocking the pathway of opioid excitatory effects, thereby reducing the incidence of adverse reactions.The following study is carried out to evaluate whether dexmedetomidine combined with nalmefene can be safely and effectively applied to prevent postoperative hyperalgesia induced by remifentanil in patients undergoing Laparoscopic gynecological surgery.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Normal Saline | Placebo Comparator | Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with remifentanil |
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| Sufentanil | Sham Comparator | Normal saline is intravenously admistrated before anesthesia induction and intraoperative pain management was with sufentanil |
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| Dexmedetomidine | Active Comparator | Dexmedetomidine is intravenously administrated at a dose of 0.5ug/kg 10min before anesthesia induction and intraoperative pain management was with remifentanil |
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| Nalmefene | Active Comparator | Nalmefene is intravenously administrated at a dose of 0.2ug/kg before anesthesia induction and intraoperative pain management was with remifentanil |
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| Dexmedetomidine-Nalmefene | Active Comparator | A dose of 0.1ug/kg nalmefene and a dose of 0.25ug/kg dexmedetomidine for 10 minutes before anesthesia induction and intraoperative pain management was with remifentanil |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Normal saline | Drug | Normal saline is intravenously administrated before anesthesia induction |
|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Wang Guolin, MD | Tianjin Medical University General Hospital | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Tianjin Medical University General Hospital | Tianjin | Tianjin Municipality | 300052 | China |
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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.
From February 2017 to September 2017, patients were recruited and estimated for eligibility
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| ID | Title | Description |
|---|---|---|
| FG000 | Normal Saline | Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with remifentanil Normal saline: Normal saline is intravenously administrated before anesthesia induction Remifentanil: Remifentanil is intravenously administrated |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Feb 15, 2017 | Nov 28, 2020 |
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Double Blind
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| Remifentanil | Drug | Remifentanil is intravenously administrated |
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| Sufentanil | Drug | Sufentanil is intravenously administrated |
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| Dexmedetomidine injection | Drug | Dexmedetomidine is intravenously administrated before anesthesia induction |
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| Nalmefene | Drug | Nalmefene is intravenously administrated before anesthesia induction |
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| 1hours,3hours，6hours，12hours，24hours after surgery |
| Pain Score (Numerical Rating Scale) | The pain score at rest was evaluated by pain 11-point numerical rating scale : 0 = no pain, 10 = greatest imaginable pain. | 1hours,3hours，6hours，12hours，24hours after surgery |
| Time of First Postoperative Analgesic Requirement | First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl. | postoperative 1 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 post-anaesthesia care unit . 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 | 1hours,3hours，6hours，12hours，24hours after surgery |
| Occurrence of Side Effects | Occurrence of side effects: nausea, vomiting, dizziness, headache, shivering, pruritus，hypotention/hypertention，bradycardia/tachycardia | 24 hours |
| Sufentanil |
Normal saline is intravenously admistrated before anesthesia induction and intraoperative pain management was with sufentanil Normal saline: Normal saline is intravenously administrated before anesthesia induction Sufentanil: Sufentanil is intravenously administrated |
| FG002 | Dexmedetomidine | Dexmedetomidine is intravenously administrated at a dose of 0.4ug/kg 10min before anesthesia induction until 30min prior to the end of surgery and intraoperative pain management was with remifentanil Remifentanil: Remifentanil is intravenously administrated Dexmedetomidine: Dexmedetomidine is intravenously administrated before anesthesia induction |
| FG003 | Nalmefene | Nalmefene is intravenously administrated at a dose of 0.3ug/kg before anesthesia induction and intraoperative pain management was with remifentanil Remifentanil: Remifentanil is intravenously administrated Nalmefene: Nalmefene is intravenously administrated before anesthesia induction |
| FG004 | Dexmedetomidine-Nalmefene | A dose of 0.3ug/kg nalmefene and a dose of 0.4ug/kg dexmedetomidine for 10 minutes before anesthesia induction until 30min prior to the end of surgery and intraoperative pain management was with remifentanil Remifentanil: Remifentanil is intravenously administrated Dexmedetomidine: Dexmedetomidine is intravenously administrated before anesthesia induction Nalmefene: Nalmefene is intravenously administrated before anesthesia induction |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Normal Saline | Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with remifentanil Normal saline: Normal saline is intravenously administrated before anesthesia induction Remifentanil: Remifentanil is intravenously administrated |
| BG001 | Sufentanil | Normal saline is intravenously admistrated before anesthesia induction and intraoperative pain management was with sufentanil Normal saline: Normal saline is intravenously administrated before anesthesia induction Sufentanil: Sufentanil is intravenously administrated |
| BG002 | Dexmedetomidine | Dexmedetomidine is intravenously administrated at a dose of 0.5ug/kg 10min before anesthesia induction and intraoperative pain management was with remifentanil Remifentanil: Remifentanil is intravenously administrated Dexmedetomidine: Dexmedetomidine is intravenously administrated before anesthesia induction |
| BG003 | Nalmefene | Nalmefene is intravenously administrated at a dose of 0.2ug/kg before anesthesia induction and intraoperative pain management was with remifentanil Remifentanil: Remifentanil is intravenously administrated Nalmefene: Nalmefene is intravenously administrated before anesthesia induction |
| BG004 | Dexmedetomidine-Nalmefene | A dose of 0.2ug/kg nalmefene and a dose of 0.5ug/kg dexmedetomidine for 10 minutes before anesthesia induction and intraoperative pain management was with remifentanil Remifentanil: Remifentanil is intravenously administrated Dexmedetomidine: Dexmedetomidine is intravenously administrated before anesthesia induction Nalmefene: Nalmefene is intravenously administrated before anesthesia induction |
| BG005 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| ||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| |||||||||||
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
| ||||||||||
| Region of Enrollment | Number | participants |
| |||||||||||
| Weight | Mean | Standard Deviation | Kg |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | Posted | Mean | Standard Deviation | g | 24 hours after surgery |
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| 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. | Not Posted | Dec 2021 | 1hours,3hours，6hours，12hours，24hours after surgery | Participants | ||||||||||||||||||||||||||||||||||||||||||
| Secondary | Pain Score (Numerical Rating Scale) | The pain score at rest was evaluated by pain 11-point numerical rating scale : 0 = no pain, 10 = greatest imaginable pain. | Not Posted | Dec 2021 | 1hours,3hours，6hours，12hours，24hours after surgery | Participants | ||||||||||||||||||||||||||||||||||||||||||
| Secondary | Time of First Postoperative Analgesic Requirement | First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl. | Not Posted | postoperative 1 hours | Participants | |||||||||||||||||||||||||||||||||||||||||||
| 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 post-anaesthesia care unit . 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 | Not Posted | 1hours,3hours，6hours，12hours，24hours after surgery | Participants | |||||||||||||||||||||||||||||||||||||||||||
| Secondary | Occurrence of Side Effects | Occurrence of side effects: nausea, vomiting, dizziness, headache, shivering, pruritus，hypotention/hypertention，bradycardia/tachycardia | Not Posted | 24 hours | Participants |
Incidence of adverse effects was evaluated during 24h after surgery
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Normal Saline | Normal saline is intravenously administrated before anesthesia induction and intraoperative pain management was with remifentanil Normal saline: Normal saline is intravenously administrated before anesthesia induction Remifentanil: Remifentanil is intravenously administrated | 0 | 27 | 0 | 27 | 0 | 27 |
| EG001 | Sufentanil | Normal saline is intravenously admistrated before anesthesia induction and intraoperative pain management was with sufentanil Normal saline: Normal saline is intravenously administrated before anesthesia induction Sufentanil: Sufentanil is intravenously administrated | 0 | 27 | 0 | 27 | 0 | 27 |
| EG002 | Dexmedetomidine | Dexmedetomidine is intravenously administrated at a dose of 0.4ug/kg 10min before anesthesia induction until 30min prior to the end of surgery and intraoperative pain management was with remifentanil Remifentanil: Remifentanil is intravenously administrated Dexmedetomidine: Dexmedetomidine is intravenously administrated before anesthesia induction | 0 | 27 | 0 | 27 | 0 | 27 |
| EG003 | Nalmefene | Nalmefene is intravenously administrated at a dose of 0.3ug/kg before anesthesia induction and intraoperative pain management was with remifentanil Remifentanil: Remifentanil is intravenously administrated Nalmefene: Nalmefene is intravenously administrated before anesthesia induction | 0 | 27 | 0 | 27 | 0 | 27 |
| EG004 | Dexmedetomidine-Nalmefene | A dose of 0.3ug/kg nalmefene and a dose of 0.4ug/kg dexmedetomidine for 10 minutes before anesthesia induction until 30min prior to the end of surgery and intraoperative pain management was with remifentanil Remifentanil: Remifentanil is intravenously administrated Dexmedetomidine: Dexmedetomidine is intravenously administrated before anesthesia induction Nalmefene: Nalmefene is intravenously administrated before anesthesia induction | 0 | 27 | 0 | 27 | 0 | 27 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Guolin Wang | Tianjin Medical University General Hospita | 13002211205 | 1464322162@qq.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 15, 2017 | Nov 28, 2020 | SAP_001.pdf |
| ID | Term |
|---|---|
| D010146 | Pain |
| D010149 | Pain, Postoperative |
| ID | Term |
|---|---|
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D011183 | Postoperative Complications |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D000077330 | Saline Solution |
| D012965 | Sodium Chloride |
| D000077208 | Remifentanil |
| D007267 | Injections |
| D017409 | Sufentanil |
| D020927 | Dexmedetomidine |
| C038981 | nalmefene |
| ID | Term |
|---|---|
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
| D011422 | Propionates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
| D010880 | Piperidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D004333 | Drug Administration Routes |
| D004358 | Drug Therapy |
| D013812 | Therapeutics |
| D005283 | Fentanyl |
| D007093 | Imidazoles |
| D001393 | Azoles |
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