Does the Preoperative Midazolam Dose Affect Postoperative Pain?

Does the Preoperative Midazolam Dose Affect Postoperative Pain? - a Multicentric Randomized Controlled Trial in Ambulatory Surgery

To investigate whether midazolam has any effect on postoperative pain in outpatient surgery, the investigators will assess the impact of different midazolam doses on pain scores 24h, 7 days and 3 months after ambulatory surgery.

The investigators hypothesize that patients being administered higher midazolam doses will refer more pain.

Study Overview

• Status: Unknown
• Conditions: Pain, Postoperative
• Intervention / Treatment: Other: Normal saline; Procedure: Spinal anesthesia; Procedure: Surgery; Drug: Postoperative analgesia; Drug: Rescue analgesia; Drug: Wound infiltration; Drug: Analgesia at home; Drug: Midazolam Injectable Solution

Detailed Description

Systemic midazolam prescribed perioperatively might have impact on pain, with studies suggesting antinociceptive and hyperalgesic effects. Anxiety might be a confounder in this association. In order to investigate the effect of midazolam on postoperative pain, a clinical trial will be conducted in Portuguese ambulatory surgery units. A convenience sample with consecutive design will include patients admitted for open inguinal hernia repair, varicose vein stripping, knee arthroscopy or hallux valgus surgery under spinal anesthesia. Patients will be randomized into 3 premedication groups, and this randomization will be stratified for each centre and each type of surgery. Postoperative pain will be blindly assessed by telephone interviews at 24h, 7 days, and 3 months.

The investigators will use multiple regression models to explore the interaction of midazolam dose with preoperative anxiety, gender and chronic benzodiazepine use, as they hypothesize there might be a differential effect of midazolam on postoperative pain amongst these subgroups.

• Study Type: Interventional
• Enrollment (Anticipated): 168
• Phase: Phase 4

Contacts and Locations

Study Locations

• Portugal
  • Santa Maria Da Feira, Portugal
    • Centro Hospitalar Entre Douro e Vouga, EPE
  • Vila Nova De Gaia, Portugal
    • Centro Hospitalar Vila Nova de Gaia / Espinho, EPE

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• adult patients submitted to open inguinal hernia repair, varicose vein stripping, knee arthroscopy or hallux valgus surgery in Portuguese ambulatory surgery units

Exclusion Criteria:

• psychiatric disorders
• alcoholism
• illiteracy or poor understanding of Portuguese language
• history of chronic pain under opioids
• recurrent surgery
• contraindication for midazolam or deep sedation
• contraindication for spinal anesthesia

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: PC1; 5mL normal saline intravenous, single-administration, as pre-medication	Other: Normal saline; intravenous; Procedure: Spinal anesthesia; 8mg of heavy bupivacaine 0.5% injected in the subarachnoid space, during lateral decubitus; Procedure: Surgery; Open inguinal hernia repair, varicose vein stripping, knee arthroscopy or hallux valgus surgery; Drug: Postoperative analgesia; IV acetaminophen 1g + IV ketorolac 30mg; Drug: Rescue analgesia; Tramadol 2mg/Kg IV in 100mL of normal saline, if pain NRS>3.; Drug: Wound infiltration; Wound infiltration with 10mL of ropivacaine 0.75%, in open inguinal hernia repair; Drug: Analgesia at home; Oral acetaminophen 1g 6/6h + ibuprofen 400mg 8/8h (+ rescue analgesia with tramadol 50mg 6/6h)
Experimental: PC2; midazolam 0.02mg/Kg in 5mL normal saline, intravenous, single-administration, as pre-medication	Other: Normal saline; intravenous; Procedure: Spinal anesthesia; 8mg of heavy bupivacaine 0.5% injected in the subarachnoid space, during lateral decubitus; Procedure: Surgery; Open inguinal hernia repair, varicose vein stripping, knee arthroscopy or hallux valgus surgery; Drug: Postoperative analgesia; IV acetaminophen 1g + IV ketorolac 30mg; Drug: Rescue analgesia; Tramadol 2mg/Kg IV in 100mL of normal saline, if pain NRS>3.; Drug: Wound infiltration; Wound infiltration with 10mL of ropivacaine 0.75%, in open inguinal hernia repair; Drug: Analgesia at home; Oral acetaminophen 1g 6/6h + ibuprofen 400mg 8/8h (+ rescue analgesia with tramadol 50mg 6/6h); Drug: Midazolam Injectable Solution; intravenous; Other Names: Dormicum
Experimental: PC3; midazolam 0.06mg/Kg in 5mL normal saline, intravenous, single-administration, as pre-medication	Other: Normal saline; intravenous; Procedure: Spinal anesthesia; 8mg of heavy bupivacaine 0.5% injected in the subarachnoid space, during lateral decubitus; Procedure: Surgery; Open inguinal hernia repair, varicose vein stripping, knee arthroscopy or hallux valgus surgery; Drug: Postoperative analgesia; IV acetaminophen 1g + IV ketorolac 30mg; Drug: Rescue analgesia; Tramadol 2mg/Kg IV in 100mL of normal saline, if pain NRS>3.; Drug: Wound infiltration; Wound infiltration with 10mL of ropivacaine 0.75%, in open inguinal hernia repair; Drug: Analgesia at home; Oral acetaminophen 1g 6/6h + ibuprofen 400mg 8/8h (+ rescue analgesia with tramadol 50mg 6/6h); Drug: Midazolam Injectable Solution; intravenous; Other Names: Dormicum

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative pain	Assessed by the Brief Pain Inventory severity score (24h recall time): mean of 4 items assessing pain at the moment of the interview, on average, at its least and at its worst during the last 24h	Day 1 after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative pain	Assessed by the Brief Pain Inventory severity score (24h recall time): mean of 4 items assessing pain at the moment of the interview, on average, at its least and at its worst during the last 24h. Features of neuropathic pain as assessed by DN4 patient-reported symptoms	Day 7 after surgery
Postoperative pain	Assessed by the Brief Pain Inventory severity score (24h recall time): mean of 4 items assessing pain at the moment of the interview, on average, at its least and at its worst during the last 24h. Features of neuropathic pain as assessed by DN4 patient-reported symptoms	Month 3 after surgery
Pain interference in daily life	Assessed by the Brief Pain Inventory interference score (24h recall time): interference of pain in general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life.	Day 1 after surgery
Pain interference in daily life	Assessed by the Brief Pain Inventory interference score (24h recall time): interference of pain in general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life.	Day 7 after surgery
Pain interference in daily life	Assessed by the Brief Pain Inventory interference score (24h recall time): interference of pain in general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life.	Month 3 after surgery
Analgesic consumption	Total analgesic drugs taken in a time period (first day after surgery)	Day 1 after surgery
Analgesic consumption	Total analgesic drugs taken in a time period (first week after surgery)	Day 7 after surgery
Patient satisfaction	NRS 0-10	Day 7 after surgery
Patient satisfaction	NRS 0-10	Month 3 after surgery
Adverse events	Number of patients with adverse events like bleeding, nausea, uncontrolled pain	Day 7 after surgery
Global surgery recovery index	Global surgery recovery index (0-100%)	Month 3 after surgery

Collaborators and Investigators

• Sponsor: Universidade do Porto
• Collaborators: Centro Hospitalar de Entre o Douro e Vouga; Centro Hospitalar de Vila Nova de Gaia/Espinho

Publications and helpful links

General Publications

• Kain ZN, Sevarino F, Pincus S, Alexander GM, Wang SM, Ayoub C, Kosarussavadi B. Attenuation of the preoperative stress response with midazolam: effects on postoperative outcomes. Anesthesiology. 2000 Jul;93(1):141-7. doi: 10.1097/00000542-200007000-00024.
• Mantegazza P, Parenti M, Tammiso R, Vita P, Zambotti F, Zonta N. Modification of the antinociceptive effect of morphine by centrally administered diazepam and midazolam. Br J Pharmacol. 1982 Apr;75(4):569-72. doi: 10.1111/j.1476-5381.1982.tb09175.x.
• Tatsuo MA, Salgado JV, Yokoro CM, Duarte ID, Francischi JN. Midazolam-induced hyperalgesia in rats: modulation via GABA(A) receptors at supraspinal level. Eur J Pharmacol. 1999 Apr 1;370(1):9-15. doi: 10.1016/s0014-2999(99)00096-5.
• Frolich MA, Zhang K, Ness TJ. Effect of sedation on pain perception. Anesthesiology. 2013 Mar;118(3):611-21. doi: 10.1097/ALN.0b013e318281592d.
• Day MA, Rich MA, Thorn BE, Berbaum ML, Mangieri EA. A placebo-controlled trial of midazolam as an adjunct to morphine patient-controlled analgesia after spinal surgery. J Clin Anesth. 2014 Jun;26(4):300-8. doi: 10.1016/j.jclinane.2013.12.011. Epub 2014 Jun 2.
• Okulicz-Kozaryn I, Kaminska E, Luczak J, Szczawinska K, Kotlinska-Lemieszek A, Baczyk E, Mikolajczak P. The effects of midazolam and morphine on analgesic and sedative activity of ketamine in rats. J Basic Clin Physiol Pharmacol. 2000;11(2):109-25. doi: 10.1515/jbcpp.2000.11.2.109.
• Hasani A, Maloku H, Sallahu F, Gashi V, Ozgen SU. Preemptive analgesia with midazolam and diclofenac for hernia repair pain. Hernia. 2011 Jun;15(3):267-72. doi: 10.1007/s10029-010-0772-y. Epub 2010 Dec 28.

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2019
• Primary Completion (Anticipated): May 1, 2020
• Study Completion (Anticipated): August 1, 2020

Study Registration Dates

• First Submitted: April 22, 2018
• First Submitted That Met QC Criteria: May 11, 2018
• First Posted (Actual): May 23, 2018

Study Record Updates

• Last Update Posted (Actual): May 23, 2018
• Last Update Submitted That Met QC Criteria: May 11, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: midazolam; ambulatory surgery
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: Midazolam RCT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this article might be shared with other researchers after deidentification.
• IPD Sharing Time Frame: Beginning 6 months following article publication.
• IPD Sharing Access Criteria: Proposals should be directed to caroline.dahlem@gmail.com. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• 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