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NCT Number: NCT06407518

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

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.

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Key information

Conditions

Preoperative Anxiety Anxiety Disorders Colonic Diseases Colorectal Neoplasms Digestive System Diseases Digestive System Neoplasms Gastrointestinal Diseases Gastrointestinal Neoplasms Intestinal Diseases Intestinal Neoplasms Mental Disorders Midazolam Neoplasms Neoplasms by Site Nervous System Diseases Neurologic Manifestations Pain Pain, Postoperative Parasomnias Pathologic Processes Pathological Conditions, Signs and Symptoms Postoperative Complications Rectal Diseases Signs and Symptoms Sleep Disturbance Sleep Wake Disorders

Age range

18 year–60 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

the Sixth Affiliated Hospital, Sun Yat-sen University

Guangzhou, Guangdong, 510655, China

Location status: Recruiting

Location contact

SanQing Jin, MD

CONTACT

[email protected]

0086-13719366863

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Midazolam oral solution

Drug

Each individual administers the midazolam oral solution nightly from enrollment to the surgry.

Other names: Midazolam oral solution, YICHANG HUMANWELL PHARMACEUTICAL

Placebo

Other

Each individual administers placebo solution nightly from enrollment to the surgry.

Primary outcomes

  1. Incidence of moderate to severe pain on the first postoperative day

    Time frame: on the first postoperative day for Acute Postoperative 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).

Secondary outcomes

  1. Mean NRS pain score

    Time frame: on the first postoperative day for Acute Postoperative Pain

    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).

  2. Mean NRS pain score

    Time frame: on the second postoperative day for Acute Postoperative Pain

    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).

  3. Mean NRS pain score

    Time frame: on the third postoperative day for Acute Postoperative Pain

    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).

  4. Incidence of moderate to severe pain

    Time frame: on the second postoperative day for Acute Postoperative 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).

  5. Incidence of moderate to severe pain

    Time frame: on the third postoperative day for Acute Postoperative 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).

  6. The number of times analgesics being added

    Time frame: on the first postoperative day for Acute Postoperative Pain

    The number of additional postoperative analgesics, by Patient-Controlled Analgesia or prescribed by doctors

  7. The number of times analgesics being added

    Time frame: on the second postoperative day for Acute Postoperative Pain

    The number of additional postoperative analgesics, by Patient-Controlled Analgesia or prescribed by doctors

  8. The number of times analgesics being added

    Time frame: on the third postoperative day for Acute Postoperative Pain

    The number of additional postoperative analgesics, by Patient-Controlled Analgesia or prescribed by doctors

  9. Total scores of the questionnaire of 15-item Quality of Recovery scale

    Time frame: on the first postoperative day

    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).

  10. Total scores of the questionnaire of 15-item Quality of Recovery scale

    Time frame: on the second postoperative day

    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).

  11. Total scores of the questionnaire of 15-item Quality of Recovery scale

    Time frame: on the third postoperative day

    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).

  12. Requirement for propofol when induction of general anesthesia

    Time frame: on the day of colorectal cancer resection and 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

  13. Incidence of post-anesthesia care unit (PACU) stays longer than 1 hour

    Time frame: on the day of colorectal cancer resection and general anesthesia

    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.

  14. The amount of additional analgesics in PACU

    Time frame: on the day of colorectal cancer resection and general anesthesia

    The quantity of supplementary analgesic medications administered in PACU

  15. Incidence of fever in the first 72 hours after surgery

    Time frame: In the third postoperative day

    The incidence of axillary temperatures above 38℃ within 72 hours post-surgery is recorded.

  16. Length of hospital stay after surgery

    Time frame: Days from operation completion to actual hospital discharge (expected 7 days after surgery)

    Length of hospital stay after surgery：hospital stay time (days) from operation completion to actual hospital discharge

  17. The financial burden in the hospital after surgery

    Time frame: Days from operation completion to actual hospital discharge (expected 7 days after surgery)

    Medical costs from operation completion to actual hospital discharge

  18. Incidence of unplanned reoperations within 30 Days after Surgery

    Time frame: within 30 days after surgery

    Incidence of unplanned reoperations within 30 Days after Surgery

  19. Incidence of unplanned admissions within 30 Days after Surgery

    Time frame: within 30 days after surgery

    Incidence of unplanned admissions within 30 Days after Surgery

  20. Total score of The Brief Pain Inventory at the 30th day after surgery

    Time frame: at the 30th day after surgery for chronic Postoperative Pain

    The Brief Pain Inventory: to survey postoperative chronic pain after surgery

  21. Total score of The Brief Pain Inventory at the 90th day after surgery

    Time frame: at the 90th day after surgery for chronic Postoperative Pain

    The Brief Pain Inventory: to survey postoperative chronic pain after surgery

  22. Total score of SF-36 at the 30th day after surgery

    Time frame: at the 30th day after surgery for postoperative health status

    SF-36: The short form (SF)-36 is an instrument to survey postoperative health status.

  23. Total score of SF-36 at the 90th day after surgery

    Time frame: at the 90th day after surgery for postoperative health status

    SF-36: The short form (SF)-36 is an instrument to survey postoperative health status.

  24. Number of patients still taking pain medication on day 30 after surgery

    Time frame: on the 30th day after surgery

    Number of patients still taking pain medication on day 30 after surgery

  25. Number of patients still taking pain medication on day 90 after surgery

    Time frame: on the 90th day after surgery

    Number of patients still taking pain medication on day 90 after surgery

  26. Incidence of post-traumatic stress disorder (PTSD) at 30 days post-surgery

    Time frame: on the 30th day after 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

  27. Incidence of post-traumatic stress disorder (PTSD) at 90 days post-surgery

    Time frame: on the 90th day after 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

  28. The ratio of neutrophils to lymphocytes in peripheral blood on the first day after surgery

    Time frame: on the first day after surgery

    The ratio of neutrophils to lymphocytes in peripheral blood on the first day after surgery

  29. The ratio of neutrophils to lymphocytes in peripheral blood on the third day after surgery

    Time frame: on the third day after surgery

    The ratio of neutrophils to lymphocytes in peripheral blood on the third day after surgery

  30. The ratio of platelets to lymphocytes in peripheral blood on the first day after surgery

    Time frame: on the first day after surgery

    The ratio of platelets to lymphocytes in peripheral blood on the first day after surgery

  31. The ratio of platelets to lymphocytes in peripheral blood on the third day after surgery

    Time frame: on the third day after surgery

    The ratio of platelets to lymphocytes in peripheral blood on the third day after surgery

  32. C-reactive protein levels in peripheral blood on the first day after surgery

    Time frame: on the first day after surgery

    C-reactive protein levels in peripheral blood on the first day after surgery

  33. C-reactive protein levels in peripheral blood on the third day after surgery

    Time frame: on the third day after surgery

    C-reactive protein levels in peripheral blood on the third day after surgery

  34. Opioid consumption in milligrams of intravenous morphine equivalents within three days after surgery

    Time frame: within three days after surgery

    Opioid consumption in milligrams of intravenous morphine equivalents within three days after surgery

  35. Opioid consumption in milligrams of intravenous or oral morphine equivalents within 30 days after surgery

    Time frame: within 30 days after surgery

    Opioid consumption in milligrams of intravenous or oral morphine equivalents within 30 days after surgery

  36. Opioid consumption in milligrams of intravenous or oral morphine equivalents within 90 days after surgery

    Time frame: within 90 days after surgery

    Opioid consumption in milligrams of intravenous or oral morphine equivalents within 90 days after surgery

  37. Incidence of nausea (requiring treatment) and vomiting within three days after surgery

    Time frame: within three days after surgery

    Incidence of nausea (requiring treatment) and vomiting within three days after surgery

  38. Incidence of patients mobilising on the first day after surgery

    Time frame: on the first day after surgery

    Incidence of patients mobilising on the first day after surgery

  39. time until first flatus after surgery in days

    Time frame: time until first flatus after surgery in days (generally, within the three days after surgery )

    time until first flatus after surgery in days

  40. Incidence of complications related to surgery within 30 days after surgery

    Time frame: 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）]

Other outcomes

  1. Salivary cortisol

    Time frame: Days from admission to the day of surgery (expected 5 days before surgery)

    preoperative Salivary cortisol

  2. Cytokine group

    Time frame: on the surgery day (before general anesthesia and surgery)

    Peripheral blood being collected before surgery

  3. Endocannabinoids

    Time frame: on the surgery day (before general anesthesia and surgery)

    Peripheral blood being collected before surgery

Study contacts

Contact information is provided by the study sponsor or research team.

Sanqing Jin, MD

CONTACT

[email protected]

0086-13719366863

Yan Zhou, MD

CONTACT

[email protected]

0086-13632404420

Sponsors and collaborators

Lead sponsor

Sixth Affiliated Hospital, Sun Yat-sen University

Other

Registry information

Official study title

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

Acronym: POMPPR

Important dates

Study start
2024
Primary completion
2025
Study completion
2025
First posted
May 9, 2024
Registry last updated
Apr 6, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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