Clinical trial NCT06407518: Preoperative Oral Midazolam to Postoperative Pain Relief in Sleep Disturbance or Anxiety Patients With Colorectal Cancer
Official 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Preoperative
Sleep Disturbance
Anxiety
Midazolam
Pain, Postoperative
Keywords: preoperative
oral midazolam
sleep disturbance
anxiety
postoperative pain
colorectal cancer
Lead sponsor: Sixth Affiliated Hospital, Sun Yat-sen University
Sponsor class: OTHER
First posted: 2024-05-09
Enrollment: 280
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of moderate to severe pain on the first postoperative day
timeFrame: on the first postoperative day for Acute Postoperative Pain
Secondary outcomes:
measure: Mean NRS pain score
timeFrame: on the first postoperative day for Acute Postoperative Pain
measure: Mean NRS pain score
timeFrame: on the second postoperative day for Acute Postoperative Pain
measure: Mean NRS pain score
timeFrame: on the third postoperative day for Acute Postoperative Pain
measure: Incidence of moderate to severe pain
timeFrame: on the second postoperative day for Acute Postoperative Pain
measure: Incidence of moderate to severe pain
timeFrame: on the third postoperative day for Acute Postoperative Pain
measure: The number of times analgesics being added
timeFrame: on the first postoperative day for Acute Postoperative Pain
measure: The number of times analgesics being added
timeFrame: on the second postoperative day for Acute Postoperative Pain
measure: The number of times analgesics being added
timeFrame: on the third postoperative day for Acute Postoperative Pain
measure: Total scores of the questionnaire of 15-item Quality of Recovery scale
timeFrame: on the first postoperative day
measure: Total scores of the questionnaire of 15-item Quality of Recovery scale
timeFrame: on the second postoperative day
measure: Total scores of the questionnaire of 15-item Quality of Recovery scale
timeFrame: on the third postoperative day
measure: Requirement for propofol when induction of general anesthesia
timeFrame: on the day of colorectal cancer resection and general anesthesia
measure: Incidence of post-anesthesia care unit (PACU) stays longer than 1 hour
timeFrame: on the day of colorectal cancer resection and general anesthesia
measure: The amount of additional analgesics in PACU
timeFrame: on the day of colorectal cancer resection and general anesthesia
measure: Incidence of fever in the first 72 hours after surgery
timeFrame: In the third postoperative day
measure: Length of hospital stay after surgery
timeFrame: Days from operation completion to actual hospital discharge (expected 7 days after surgery)
measure: The financial burden in the hospital after surgery
timeFrame: Days from operation completion to actual hospital discharge (expected 7 days after surgery)
measure: Incidence of unplanned reoperations within 30 Days after Surgery
timeFrame: within 30 days after surgery
measure: Incidence of unplanned admissions within 30 Days after Surgery
timeFrame: within 30 days after surgery
measure: Total score of The Brief Pain Inventory at the 30th day after surgery
timeFrame: at the 30th day after surgery for chronic Postoperative Pain
measure: Total score of The Brief Pain Inventory at the 90th day after surgery
timeFrame: at the 90th day after surgery for chronic Postoperative Pain
measure: Total score of SF-36 at the 30th day after surgery
timeFrame: at the 30th day after surgery for postoperative health status
measure: Total score of SF-36 at the 90th day after surgery
timeFrame: at the 90th day after surgery for postoperative health status
measure: Number of patients still taking pain medication on day 30 after surgery
timeFrame: on the 30th day after surgery
measure: Number of patients still taking pain medication on day 90 after surgery
timeFrame: on the 90th day after surgery
measure: Incidence of post-traumatic stress disorder (PTSD) at 30 days post-surgery
timeFrame: on the 30th day after surgery
measure: Incidence of post-traumatic stress disorder (PTSD) at 90 days post-surgery
timeFrame: on the 90th day after surgery
measure: The ratio of neutrophils to lymphocytes in peripheral blood on the first day after surgery
timeFrame: on the first day after surgery
measure: The ratio of neutrophils to lymphocytes in peripheral blood on the third day after surgery
timeFrame: on the third day after surgery
measure: The ratio of platelets to lymphocytes in peripheral blood on the first day after surgery
timeFrame: on the first day after surgery
measure: The ratio of platelets to lymphocytes in peripheral blood on the third day after surgery
timeFrame: on the third day after surgery
measure: C-reactive protein levels in peripheral blood on the first day after surgery
timeFrame: on the first day after surgery
measure: C-reactive protein levels in peripheral blood on the third day after surgery
timeFrame: on the third day after surgery
measure: Opioid consumption in milligrams of intravenous morphine equivalents within three days after surgery
timeFrame: within three days after surgery
measure: Opioid consumption in milligrams of intravenous or oral morphine equivalents within 30 days after surgery
timeFrame: within 30 days after surgery
measure: Opioid consumption in milligrams of intravenous or oral morphine equivalents within 90 days after surgery
timeFrame: within 90 days after surgery
measure: Incidence of nausea (requiring treatment) and vomiting within three days after surgery
timeFrame: within three days after surgery
measure: Incidence of patients mobilising on the first day after surgery
timeFrame: on the first day after surgery
measure: time until first flatus after surgery in days
timeFrame: time until first flatus after surgery in days (generally, within the three days after surgery )
measure: Incidence of complications related to surgery within 30 days after surgery
timeFrame: within 30 days after surgery
Other outcomes:
measure: Salivary cortisol
timeFrame: Days from admission to the day of surgery (expected 5 days before surgery)
measure: Cytokine group
timeFrame: on the surgery day (before general anesthesia and surgery)
measure: Endocannabinoids
timeFrame: on the surgery day (before general anesthesia and surgery)
Locations:
city: Guangzhou
country: China
facility: the Sixth Affiliated Hospital, Sun Yat-sen University
state: Guangdong
Study officials:
affiliation: The Sixth Affiliated Hospital, Sun Yat-sen University
name: sanqing Jin, MD
role: PRINCIPAL_INVESTIGATOR
References: