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.
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
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
280
Each individual administers the midazolam oral solution nightly from enrollment to the surgry.
Each individual administers placebo solution nightly from enrollment to the surgry.
the Sixth Affiliated Hospital, Sun Yat-sen University
Guangzhou, Guangdong, China
RECRUITINGIncidence 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).
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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).
Time frame: 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).
Time frame: 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).
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: within 30 days after surgery
Incidence of unplanned admissions within 30 Days after Surgery
Incidence of unplanned admissions within 30 Days after Surgery
Time frame: 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
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: on the first day after surgery
time until first flatus after surgery in days
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 )
Incidence of complications related to surgery within 30 days after surgery
Incidence of complications related to surgery within 30 days after surgery \[ complication grade according to Clavien-Dindo（No complications，Grade I-II，Grade IIIa + IIIb，Grade IV，Grade V）\]
Time frame: within 30 days after surgery
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.