Preoperative Oral Midazolam to Postoperative Pain Relief in Sleep Disturbance or Anxiety Patients With Colorectal Cancer (POMPPR)

Effects of Preoperative Oral Mmidazolam on Postoperative Pain in Sleep Disturbance or Anxiety Patients Undergoing Laparoscopic Colorectal Cancer Resection- A Prospective, Randomized, Double-blind, Placebo-controlled Clinical Study

Previous studies have indicated a high incidence of sleep disturbances and anxiety symptoms in individuals with colorectal cancers prior to undergoing surgery, leading to worsened postoperative pain, slower recovery, and higher risk of chronic pain. The enhancement of sleep quality is intricately linked to reducing stress. Preoperative drugs that combine hypnosis and anti-anxiety have not been studied in colorectal cancer patients. Midazolam oral solution is safe and effective for short-term hypnotic and anti-anxiety effects in clinical preoperative settings. In the current randomized controlled clinical trial, 280 patients experiencing sleep disturbance or anxiety prior to colorectal cancer surgery will receive midazolam solution to assess its potential efficacy in reducing postoperative pain, expediting recovery, and decreasing the likelihood of chronic pain. Additionally, the study aims to explore the potential connections between midazolam administration and reductions in stress and inflammation.

Study Overview

• Status: Recruiting
• Conditions: Pain, Postoperative; Anxiety; Sleep Disturbance; Preoperative; Midazolam
• Intervention / Treatment: Drug: Midazolam oral solution; Other: Placebo

Detailed Description

Preoperative sleep disturbance and anxiety worsen postoperative pain for patients undergoing surgeries. Research indicates that a significant proportion of patients, ranging from 8.8% to 79.1%, experience disturbances in sleep or anxiety prior to surgery. These preoperative issues have been shown to have lasting and intricate effects on postoperative pain, fatigue, and depression. Therefore, it is imperative for clinical doctors to promptly identify preoperative sleep disturbances and anxiety in order to offer appropriate support to patients.

Colorectal cancer is the fifth leading cause of death in China, with nearly 40% of patients experiencing insomnia before surgery, consistent with our previous studies. A case-control study demonstrated a protective association between improved sleep quality and relief of postoperative pain in colorectal cancers. Furthermore, individuals undergoing laparoscopic colorectal surgery showed a higher likelihood of experiencing visceral pain compared to somatic pain. Acute visceral pain has the potential to progress into chronic visceral pain, resulting in behavioral manifestations such as anxiety, fear, and depression, which may persist and exacerbate into enduring chronic pain, ultimately impacting the individual's quality of life. Currently, studies have shown that disturbed preoperative sleep has become a significant predictor of both acute and chronic postoperative pain. Therefore, finding effective interventions to promote preoperative sleep is a continuing consideration for clinicians.

Pharmacological intervention is the primary approach for preoperative sleep disturbances or anxiety. Finding appropriate drug is a challenge that needs to be solved in the clinical practice. There is currently a lack of evidence-based medical guidelines regarding pharmacologic interventions for preoperative sleep disturbances and anxiety. Research has indicated that zolpidem can enhance sleep quality in patients prior to surgery, decrease the need for analgesics during the procedure, and alleviate postoperative pain. Nevertheless, there is a demand for agents that possess both short-term hypnotic and anxiolytic properties, whereas zolpidem solely exhibits hypnotic effects. Midazolam, a short-acting benzodiazepine, is often used before anesthesia for its short-term hypnotic and anxiolytic effects. Studies have found that midazolam oral solution is safe and effective for short-term use in clinical pre-surgical settings. There are no studies on using oral midazolam solution to improve sleep and reduce anxiety in colorectal cancer patients before surgery. Our previous research found that a dose of 7.2mg can effectively induce sleep with minimal side effects in 50% patients before surgery.

In summary, the present study intends to carry out a prospective,randomized,double-blind,placebo-controlled clinical study to investigate the hypothesis that preoperative oral midazolam solution could reduce acute postoperative pain, promote early recovery, and reduce the risk of chronic pain in patients with poor sleep or anxiety before colorectal cancer surgery. It is postulated that the potential benefits of preoperative oral midazolam solution may be attributed to decreased stress levels, and lowered inflammation markers.

• Study Type: Interventional
• Enrollment (Estimated): 280
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: SanQing Jin, MD; Phone Number: 0086-13719366863; Email: jinsq@mail.sysu.edu.cn
• Study Contact Backup: Name: Yan Zhou, MD; Phone Number: 0086-13632404420; Email: zhouyan8@mail3.sysu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510655
      • Recruiting
      • The Sixth Affiliated Hospital, Sun Yat-sen University
      • Contact: SanQing Jin, MD; Phone Number: 0086-13719366863; Email: jinsq@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 1. Signed of informed consent voluntarily; 2. Native Chinese speaker; 3. Age 18-60 years old, male or female; 4. BMI 18-30 kg/m2; 5. American Society of Anesthesiologists (ASA) grade 1 or 2, New York Heart Association (NYHA) gradeⅠor Ⅱ; 6. Non-emergency laparoscopic colorectal cancer resection; 7. General anesthesia with tracheal intubation; 8. Sleep disturbance (the Insomnia Severity Index,ISI≥15 ) or Anxiety (Generalized Anxiety Disorder scale-7,GAD-7≥10 ) from admission to surgery.

Exclusion Criteria:

• 1. Contraindications for Midazolam Oral Solution (According to the Instruction for Midazolam Oral Solution); 2. High risk of Obstructive Sleep Apnea Symptoms (Total score of STOP-Bang scale ≥3 points); 3. Suspected dementia (Total score of Mini-Mental State Examination (MMSE) according to years of education: 0 year≤19 points; 1~6 years≤22 points; above of 6 years≤26 points); 4. Severe depressive symptom within two weeks (Total score of Patient Health Questionnaire-9 (PHQ-9)≥15); 5. History of Neurological and Psychiatric diseases (According to the electronic medical record system); 6. History of Chronic Obstructive Pulmonary Disease (According to the electronic medical record system); 7. History of Heart Failure (According to the electronic medical record system); 8. Intestinal obstruction(The electronic medical record system records those who currently have any type of intestinal obstruction); 9. Liver and renal insufficiency; 10. Have taken opioids or drugs that act on the central nervous system within one week; 11. Take CYP3A4 isoenzyme inhibitors or inducers within one week (According to the Instruction for Midazolam Oral Solution); 12. Consume any alcoholic beverage within 24 hours; 13. Substance abusers (including alcohol, drugs or addictive substances); 14. Pregnant or lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control Group; Placebo is a solution of midazolam oral solution that looks, tastes, and appears the same as the intervention drug, similar to the experimental group increment method.	Other: Placebo; Each individual administers placebo solution nightly from enrollment to the surgry.
Experimental: Midazolam oral solution Group; The intervention drug is midazolam oral solution at a dose of 7-10mg. The starting dosage is 7mg, with subsequent individual increases of 1mg up to a maximum dose of 10mg if patients do not achieve sleep within 30 minutes of administration. The individual dose wil be consistently maintained at the corresponding level every night until the surgery.	Drug: Midazolam oral solution; Each individual administers the midazolam oral solution nightly from enrollment to the surgry.; Other Names: Midazolam oral solution, YICHANG HUMANWELL PHARMACEUTICAL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of moderate to severe pain on the first postoperative day	NRS: Numerical Rating Scale, NRS pain score 0-3 for mild, 4-6 for moderate, 7-10 for severe; Moderate to severe pain: Mean NRS pain score ≥4; Mean NRS pain score: Mean pain is defined as the mean of NRS scores of the severest, lightest, average, and present pain within 24 hours using the Brief Pain Inventory Short version (BPIsf).	on the first postoperative day for Acute Postoperative Pain

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean NRS pain score	NRS: Numerical Rating Scale, NRS pain score 0-3 for mild, 4-6 for moderate, 7-10 for severe; Mean NRS pain score: Mean pain is defined as the mean of NRS scores of the severest, lightest, average, and present pain within 24 hours using the Brief Pain Inventory Short version (BPIsf).	on the first postoperative day for Acute Postoperative Pain
Mean NRS pain score	NRS: Numerical Rating Scale, NRS pain score 0-3 for mild, 4-6 for moderate, 7-10 for severe; Mean NRS pain score: Mean pain is defined as the mean of NRS scores of the severest, lightest, average, and present pain within 24 hours using the Brief Pain Inventory Short version (BPIsf).	on the second postoperative day for Acute Postoperative Pain
Mean NRS pain score	NRS: Numerical Rating Scale, NRS pain score 0-3 for mild, 4-6 for moderate, 7-10 for severe; Mean NRS pain score: Mean pain is defined as the mean of NRS scores of the severest, lightest, average, and present pain within 24 hours using the Brief Pain Inventory Short version (BPIsf).	on the third postoperative day for Acute Postoperative Pain
Incidence of moderate to severe pain	NRS: Numerical Rating Scale, NRS pain score 0-3 for mild, 4-6 for moderate, 7-10 for severe; Moderate to severe pain: Mean NRS pain score ≥4; Mean NRS pain score: Mean pain is defined as the mean of NRS scores of the severest, lightest, average, and present pain within 24 hours using the Brief Pain Inventory Short version (BPIsf).	on the second postoperative day for Acute Postoperative Pain
Incidence of moderate to severe pain	NRS: Numerical Rating Scale, NRS pain score 0-3 for mild, 4-6 for moderate, 7-10 for severe; Moderate to severe pain: Mean NRS pain score ≥4; Mean NRS pain score: Mean pain is defined as the mean of NRS scores of the severest, lightest, average, and present pain within 24 hours using the Brief Pain Inventory Short version (BPIsf).	on the third postoperative day for Acute Postoperative Pain
The number of times analgesics being added	The number of additional postoperative analgesics, by Patient-Controlled Analgesia or prescribed by doctors	on the first postoperative day for Acute Postoperative Pain
The number of times analgesics being added	The number of additional postoperative analgesics, by Patient-Controlled Analgesia or prescribed by doctors	on the second postoperative day for Acute Postoperative Pain
The number of times analgesics being added	The number of additional postoperative analgesics, by Patient-Controlled Analgesia or prescribed by doctors	on the third postoperative day for Acute Postoperative Pain
Total scores of the questionnaire of 15-item Quality of Recovery scale	QoR-15: 15-item Quality of Recovery scale; QoR-15 is a patient-reported measure, and is used to assess global recovery quality after surgery physiologically and psychologically. QoR-15 contents 15 items, which item is constructed by an 11-point numerical rating scale (for positive items, 0="none of the time"to 10="all of the time"; for negative items the scoring are reversed). The total scores are ranging from 0(extremely poor QoR) to 150 (excellent QoR).	on the first postoperative day
Total scores of the questionnaire of 15-item Quality of Recovery scale	QoR-15: 15-item Quality of Recovery scale; QoR-15 is a patient-reported measure, and is used to assess global recovery quality after surgery physiologically and psychologically. QoR-15 contents 15 items, which item is constructed by an 11-point numerical rating scale (for positive items, 0="none of the time"to 10="all of the time"; for negative items the scoring are reversed). The total scores are ranging from 0(extremely poor QoR) to 150 (excellent QoR).	on the second postoperative day
Total scores of the questionnaire of 15-item Quality of Recovery scale	QoR-15: 15-item Quality of Recovery scale; QoR-15 is a patient-reported measure, and is used to assess global recovery quality after surgery physiologically and psychologically. QoR-15 contents 15 items, which item is constructed by an 11-point numerical rating scale (for positive items, 0="none of the time"to 10="all of the time"; for negative items the scoring are reversed). The total scores are ranging from 0(extremely poor QoR) to 150 (excellent QoR).	on the third postoperative day
Requirement for propofol when induction of general anesthesia	Propofol is titrated for the purpose of achieving general anesthesia prior to colorectal cancer resection. Upon reaching the titration endpoint, indicated by an OAAS sedation score of 0, the dosage of propofol administered (in mg/kg) is documented. OAAS：Observer's Assessment Alertness/Sedation scale	on the day of colorectal cancer resection and general anesthesia
Incidence of post-anesthesia care unit (PACU) stays longer than 1 hour	Following the surgical procedure, the patient is relocated to the Post-Anesthesia Care Unit (PACU). Patients may be transferred to the general ward once their postoperative resuscitation meets established standards. Incidence of PACU stays longer than 1 hour is recorded.	on the day of colorectal cancer resection and general anesthesia
The amount of additional analgesics in PACU	The quantity of supplementary analgesic medications administered in PACU	on the day of colorectal cancer resection and general anesthesia
Incidence of fever in the first 72 hours after surgery	The incidence of axillary temperatures above 38℃ within 72 hours post-surgery is recorded.	In the third postoperative day
Length of hospital stay after surgery	Length of hospital stay after surgery：hospital stay time (days) from operation completion to actual hospital discharge	Days from operation completion to actual hospital discharge (expected 7 days after surgery)
The financial burden in the hospital after surgery	Medical costs from operation completion to actual hospital discharge	Days from operation completion to actual hospital discharge (expected 7 days after surgery)
Incidence of unplanned reoperations within 30 Days after Surgery	Incidence of unplanned reoperations within 30 Days after Surgery	within 30 days after surgery
Incidence of unplanned admissions within 30 Days after Surgery	Incidence of unplanned admissions within 30 Days after Surgery	within 30 days after surgery
Total score of The Brief Pain Inventory at the 30th day after surgery	The Brief Pain Inventory: to survey postoperative chronic pain after surgery	at the 30th day after surgery for chronic Postoperative Pain
Total score of The Brief Pain Inventory at the 90th day after surgery	The Brief Pain Inventory: to survey postoperative chronic pain after surgery	at the 90th day after surgery for chronic Postoperative Pain
Total score of SF-36 at the 30th day after surgery	SF-36: The short form (SF)-36 is an instrument to survey postoperative health status.	at the 30th day after surgery for postoperative health status
Total score of SF-36 at the 90th day after surgery	SF-36: The short form (SF)-36 is an instrument to survey postoperative health status.	at the 90th day after surgery for postoperative health status
Number of patients still taking pain medication on day 30 after surgery	Number of patients still taking pain medication on day 30 after surgery	on the 30th day after surgery
Number of patients still taking pain medication on day 90 after surgery	Number of patients still taking pain medication on day 90 after surgery	on the 90th day after surgery
Incidence of post-traumatic stress disorder (PTSD) at 30 days post-surgery	The prevalence of post-traumatic stress disorder as measured by the PC-PTSD scale at 30 days following surgical procedures. PC- PTSD：Primary Care Post traumatic Stress Disorder	on the 30th day after surgery
Incidence of post-traumatic stress disorder (PTSD) at 90 days post-surgery	The prevalence of post-traumatic stress disorder as measured by the PC-PTSD scale at 90 days following surgical procedures. PC- PTSD：Primary Care Post traumatic Stress Disorder	on the 90th day after surgery
The ratio of neutrophils to lymphocytes in peripheral blood on the first day after surgery	The ratio of neutrophils to lymphocytes in peripheral blood on the first day after surgery	on the first day after surgery
The ratio of neutrophils to lymphocytes in peripheral blood on the third day after surgery	The ratio of neutrophils to lymphocytes in peripheral blood on the third day after surgery	on the third day after surgery
The ratio of platelets to lymphocytes in peripheral blood on the first day after surgery	The ratio of platelets to lymphocytes in peripheral blood on the first day after surgery	on the first day after surgery
The ratio of platelets to lymphocytes in peripheral blood on the third day after surgery	The ratio of platelets to lymphocytes in peripheral blood on the third day after surgery	on the third day after surgery
C-reactive protein levels in peripheral blood on the first day after surgery	C-reactive protein levels in peripheral blood on the first day after surgery	on the first day after surgery
C-reactive protein levels in peripheral blood on the third day after surgery	C-reactive protein levels in peripheral blood on the third day after surgery	on the third day after surgery
Opioid consumption in milligrams of intravenous morphine equivalents within three days after surgery	Opioid consumption in milligrams of intravenous morphine equivalents within three days after surgery	within three days after surgery
Opioid consumption in milligrams of intravenous or oral morphine equivalents within 30 days after surgery	Opioid consumption in milligrams of intravenous or oral morphine equivalents within 30 days after surgery	within 30 days after surgery
Opioid consumption in milligrams of intravenous or oral morphine equivalents within 90 days after surgery	Opioid consumption in milligrams of intravenous or oral morphine equivalents within 90 days after surgery	within 90 days after surgery
Incidence of nausea (requiring treatment) and vomiting within three days after surgery	Incidence of nausea (requiring treatment) and vomiting within three days after surgery	within three days after surgery
Incidence of patients mobilising on the first day after surgery	Incidence of patients mobilising on the first day after surgery	on the first day after surgery
time until first flatus after surgery in days	time until first flatus after surgery in days	time until first flatus after surgery in days (generally, within the three days after surgery )
Incidence of complications related to surgery within 30 days after surgery	Incidence of complications related to surgery within 30 days after surgery [ complication grade according to Clavien-Dindo（No complications，Grade I-II，Grade IIIa + IIIb，Grade IV，Grade V）]	within 30 days after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Salivary cortisol	preoperative Salivary cortisol	Days from admission to the day of surgery (expected 5 days before surgery)
Cytokine group	Peripheral blood being collected before surgery	on the surgery day (before general anesthesia and surgery)
Endocannabinoids	Peripheral blood being collected before surgery	on the surgery day (before general anesthesia and surgery)

Collaborators and Investigators

• Sponsor: Sixth Affiliated Hospital, Sun Yat-sen University
• Investigators: Principal Investigator: Sanqing Jin, MD, The Sixth Affiliated Hospital, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): July 24, 2024
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: May 2, 2024
• First Submitted That Met QC Criteria: May 7, 2024
• First Posted (Actual): May 9, 2024

Study Record Updates

• Last Update Posted (Actual): April 6, 2025
• Last Update Submitted That Met QC Criteria: April 3, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: colorectal cancer; anxiety; postoperative pain; preoperative; sleep disturbance; oral midazolam
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Postoperative Complications; Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Sleep Wake Disorders; Pain, Postoperative; Anxiety Disorders; Colorectal Neoplasms; Dyssomnias; Parasomnias; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anesthetics; Central Nervous System Depressants; Neurotransmitter Agents; Adjuvants, Anesthesia; Hypnotics and Sedatives; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; GABA Modulators; GABA Agents; Midazolam; Pharmaceutical Solutions
• Other Study ID Numbers: 2024ZSLYEC-351

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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