Effect of Dexmedetomidine Combined With Low-dose Nalmefene on Preventing Remifentanil-induced Postoperative Hyperalgesia

• Sponsor: Tianjin Medical University General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT03096730
• Collaborator: (none)
• Enrollment: 150
• Location: 1
• Arms: 5
• Actual Duration (Months): 10.7
• Patients Per Site Per Month: 14

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Pain; Anesthesia	Drug: Normal saline; Drug: Remifentanil; Drug: Sufentanil; Drug: Dexmedetomidine injection; Drug: Nalmefene	N/A

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. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Investigator, Outcomes Assessor)
• Masking Description: Double Blind
• Primary Purpose: Prevention
• Official Title: The Effect of Dexmedetomidine Combined With Low-dose Nalmefene on Preventing Remifentanil-induced Postoperative Hyperalgesia in Patients Undergoing Gynecological Surgery
• Actual Study Start Date: Feb 6, 2017
• Actual Primary Completion Date: Dec 20, 2017
• Actual Study Completion Date: Dec 30, 2017

Arms and Interventions

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; Other Names: 0. 9% Sodium Chloride Injection ; Drug: Remifentanil; Remifentanil is intravenously administrated; Other Names: Remifentanil Hydrochloride for Injection
Sham Comparator: Sufentanil Normal saline is intravenously admistrated before anesthesia induction and intraoperative pain management was with sufentanil	Drug: Normal saline; Normal saline is intravenously administrated before anesthesia induction; Other Names: 0. 9% Sodium Chloride Injection ; Drug: Sufentanil; Sufentanil is intravenously administrated; Other Names: Sufentanil injection
Active Comparator: Dexmedetomidine Dexmedetomidine is intravenously administrated at a dose of 0.5ug/kg 10min before anesthesia induction and intraoperative pain management was with remifentanil	Drug: Remifentanil; Remifentanil is intravenously administrated; Other Names: Remifentanil Hydrochloride for Injection ; Drug: Dexmedetomidine injection; Dexmedetomidine is intravenously administrated before anesthesia induction; Other Names: Dexmedetomidine
Active Comparator: Nalmefene Nalmefene is intravenously administrated at a dose of 0.2ug/kg before anesthesia induction and intraoperative pain management was with remifentanil	Drug: Remifentanil; Remifentanil is intravenously administrated; Other Names: Remifentanil Hydrochloride for Injection ; Drug: Nalmefene; Nalmefene is intravenously administrated before anesthesia induction
Active Comparator: Dexmedetomidine-Nalmefene 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	Drug: Remifentanil; Remifentanil is intravenously administrated; Other Names: Remifentanil Hydrochloride for Injection ; Drug: Dexmedetomidine injection; Dexmedetomidine is intravenously administrated before anesthesia induction; Other Names: Dexmedetomidine ; Drug: Nalmefene; Nalmefene is intravenously administrated before anesthesia induction

Outcome Measures

Primary Outcome Measures

1. 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

1. Normalized Area of Hyperalgesia Around the Incision [1hours,3hours，6hours，12hours，24hours 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.

2. Pain Score (Numerical Rating Scale) [1hours,3hours，6hours，12hours，24hours after surgery]

   The pain score at rest was evaluated by pain 11-point numerical rating scale : 0 = no pain, 10 = greatest imaginable pain.

3. Time of First Postoperative Analgesic Requirement [postoperative 1 hours]

   First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl.

4. Cumulative Sufentanyl Consumption [1hours,3hours，6hours，12hours，24hours after surgery]

   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

5. Occurrence of Side Effects [24 hours]

   Occurrence of side effects: nausea, vomiting, dizziness, headache, shivering, pruritus，hypotention/hypertention，bradycardia/tachycardia

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 65 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients are scheduled to undergo Gynecological surgery under a short general anesthesia of 1-3 hours.

2. American Society of Anesthesiologists physical status is I-II.

3. Written informed consent was obtained from all the subjects.

Exclusion Criteria:

1. Subject has a diagnosis of Coronary heart disease, bronchial asthma, cardiac, lung, hepatic and renal insufficiency.

2. Subject has a diagnosis of Severe high blood pressure , diabetes, obesity (BMI>30).

3. 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 h before surgery.

4. .Subject has Pregnancy, psychiatric disease.

5. Subject has any contraindication for the use of patient-controlled analgesia (PCA).

6. Inability to understand the Study Information Sheet and provide a written consent to take part in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tianjin Medical University General Hospital	Tianjin	Tianjin	China	300052

Sponsors and Collaborators

• Tianjin Medical University General Hospital

Investigators

• Study Director: Wang Guolin, MD, Tianjin Medical University General Hospital

Study Documents (Full-Text)

• Study Protocol - Feb 15, 2017
• Statistical Analysis Plan - Feb 15, 2017

More Information

Publications

None provided.

• Responsible Party: Guolin Wang, Professor, Tianjin Medical University General Hospital
• ClinicalTrials.gov Identifier: NCT03096730
• Other Study ID Numbers: GWang003
• First Posted: Mar 30, 2017
• Last Update Posted: Aug 3, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Guolin Wang, Professor, Tianjin Medical University General Hospital: Remifentanil; Opioid-induced hyperalgesia; Postoperative pain; pain intensity
• Additional relevant MeSH terms: Hyperalgesia; Sufentanil; Dexmedetomidine; Remifentanil; Dsuvia; Nalmefene

Study Results

Participant Flow

Recruitment Details	From February 2017 to September 2017, patients were recruited and estimated for eligibility
Pre-assignment Detail	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.

Arm/Group Title	Normal Saline	Sufentanil	Dexmedetomidine	Nalmefene	Dexmedetomidine-Nalmefene
Arm/Group Description	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	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	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	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	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
Period Title: Overall Study
STARTED	30	30	30	30	30
COMPLETED	27	27	27	27	27
NOT COMPLETED	3	3	3	3	3

Baseline Characteristics

Arm/Group Title	Normal Saline	Sufentanil	Dexmedetomidine	Nalmefene	Dexmedetomidine-Nalmefene	Total
Arm/Group Description	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	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	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	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	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	Total of all reporting groups
Overall Participants	27	27	27	27	27	135
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.0 (5.0)	46.0 (8.0)	45.0 (12)	47.0 (10)	46.0 (9)	46.2 (8.8)
Sex: Female, Male (Count of Participants)
Female	27 100%	27 100%	27 100%	27 100%	27 100%	135 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
China	27 100%	27 100%	27 100%	27 100%	27 100%	135 100%
Weight (Kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg]	60 (7)	57 (8)	59 (7)	58 (5)	60 (8)	59 (7)

Outcome Measures

1. Primary Outcome

Title	Mechanical Hyperalgesia Threshold on the Dominant Inner Forearm
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Normal Saline	Sufentanil	Dexmedetomidine	Nalmefene	Dexmedetomidine-Nalmefene
Arm/Group Description	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	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	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	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	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
Measure Participants	27	27	27	27	27
Mean (Standard Deviation) [g]	61.5 (6.0)	88.2 (23.40)	73.0 (3.2)	67.2 (3.3)	74.0 (9.3)

2. Secondary Outcome

Title	Normalized Area of Hyperalgesia Around the Incision
Description	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	1hours,3hours，6hours，12hours，24hours after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Pain Score (Numerical Rating Scale)
Description	The pain score at rest was evaluated by pain 11-point numerical rating scale : 0 = no pain, 10 = greatest imaginable pain.
Time Frame	1hours,3hours，6hours，12hours，24hours after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Time of First Postoperative Analgesic Requirement
Description	First postoperative pain (NRS≥5) is initially controlled by titration of sufentanyl.
Time Frame	postoperative 1 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Cumulative Sufentanyl Consumption
Description	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
Time Frame	1hours,3hours，6hours，12hours，24hours after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Occurrence of Side Effects
Description	Occurrence of side effects: nausea, vomiting, dizziness, headache, shivering, pruritus，hypotention/hypertention，bradycardia/tachycardia
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Incidence of adverse effects was evaluated during 24h after surgery
Arm/Group Title	Normal Saline		Sufentanil		Dexmedetomidine		Nalmefene		Dexmedetomidine-Nalmefene
Arm/Group Description	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		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		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		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		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
All Cause Mortality
	Normal Saline		Sufentanil		Dexmedetomidine		Nalmefene		Dexmedetomidine-Nalmefene
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/27 (0%)		0/27 (0%)		0/27 (0%)		0/27 (0%)
Serious Adverse Events
	Normal Saline		Sufentanil		Dexmedetomidine		Nalmefene		Dexmedetomidine-Nalmefene
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/27 (0%)		0/27 (0%)		0/27 (0%)		0/27 (0%)
Other (Not Including Serious) Adverse Events
	Normal Saline		Sufentanil		Dexmedetomidine		Nalmefene		Dexmedetomidine-Nalmefene
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/27 (0%)		0/27 (0%)		0/27 (0%)		0/27 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.