Opioid analgesics for sedation-based gastrointestinal endoscopy

Abstract

Gastrointestinal endoscopy is a common examination for digestive system. The stimulation of endoscope often causes cough, nausea and vomiting, increased heart rate and blood pressure, arrhythmia, and even cardiovascular and cerebrovascular accidents, thus makes people fear of this procedure. Sedation or anesthesia can effectively improve the safety, comfort and quality of gastrointestinal endoscopy. A small dose of opioids is a good adjuvant to sedatives. In this narrative review, we summarized the main roles of opioid analgesics in gastrointestinal endoscopy, including reducing visceral pain, throat irritation and the dose of sedatives. Moreover, the frequently used and novel opioids are reviewed. Classic fentanyl, sufentanil and dezocine are preferable by anesthesiologists. Newly approved oliceridine is promising to render ideal analgesic effects for gastrointestinal endoscopy. Clinical studies on oliceridine in endoscopic procedures are urgently needed.

Key Words: Opioids; Gastrointestinal endoscopy; Fentanyl; Sufentanil; Dezocine; Oliceridine

Core Tip: Safety, comfort and quality of gastrointestinal endoscopy are the concerns for both patients and doctors. Low-dose synthetic opioids play an important role in this procedure. In China, fentanyl, sufentanil and dezocine are the top three choices. Oliceridine should be paid more attention when performing related studies.

INTRODUCTION

Digestive system is a huge part of the body. It is reported that the burden of digestive diseases made up over 33% of the total[1]. The International Agency for Research on Cancer released the latest data that the global number of esophagus, stomach and colorectum cancer diagnoses reached over 3 million in 2022[2]. Moreover, the number of deaths caused by these cancers has been increasing[3,4]. Nonmalignant diseases of digestive track, such as gastroesophageal reflux and peptic ulcer, also keep growing[5,6]. Early detection, diagnosis and treatment is of great importance and necessity. Gastrointestinal endoscopy is recognized as an effective tool.

Most patients are nervous, anxious and fearful of digestive endoscopy. Cough, nausea and vomiting, increased heart rate, increased blood pressure, arrhythmia, and other serious complications such as angina pectoris, myocardial infarction, stroke or cardiac arrest may occur during this procedure. A small number of patients cannot tolerate and cooperate with the digestive endoscopy, which makes it difficult for endoscopists to diagnose and treat the related diseases. The purpose of sedation/anesthesia for endoscopic diagnosis and treatment is to eliminate or reduce the anxiety and discomfort of patients, so as to improve the patient's tolerance and satisfaction with the endoscopic procedure, minimize the risk of injury and accident during the endoscopic procedure, and provide the best diagnosis and treatment conditions for operators[7].

With the development of painless technics and comfort medicine, sedation-based gastrointestinal endoscopy has become priority for the most patients. The painless status is attributed to procedural sedation and analgesia. In this review, we aimed to focus on the opioid analgesics for gastrointestinal endoscopy.

THE ROLE OF OPIOID ANALGESICS IN GASTROINTESTINAL ENDOSCOPY

Reducing visceral pain

visceral pain is mainly caused by internal organ disorders, often induced by mechanical traction, spasm, ischemia, inflammation and other stimuli. Visceral pain is a unique manifestation of pain, which is characterized by: (1) Mixed nature, diffuse pain, and difficult to locate[8]; (2) The mechanism of visceral pain is poorly understood, and visceral pain is more difficult to control than somatic pain[9]; and (3) Visceral pain can cause nausea and vomiting, night sweats, abnormal autonomic reflexes and emotional changes[10]. During gastrointestinal endoscopy, mechanical traction is common and inevitable. Although visceral and somatic pain can be treated differently, visceral analgesia is still inseparable from opioids, and the choice of opioids is also inseparable from the guidance of opioid receptors. The receptor theory is still the best clinical basis for opioid use.

There are three primary types of opioid receptors, namely mu (μ), Kappa (κ), and Delta (δ). The μ receptor is closely related to somatic pain, and the κ receptor is mainly responsible for the regulation of visceral pain[11]. The analgesic effect of μ receptor agonists is mainly in the central nervous system, and it can induce respiratory depression, nausea and vomiting, smooth muscle spasm, pruritus and tolerable adverse reactions[12]. The main effect of κ receptor agonists is peripheral, and its advantage is that it has no effect on smooth muscle and gastrointestinal activity, and there are no adverse reactions such as skin itching and body tolerance[13]. However, excessive use of κ receptor agonist can produce central adverse effects such as dizziness, nausea and vomiting, and excessive sedation[13].

Reducing throat irritation

When inserting endoscope through the throat, mechanical stimulation activates the sympathetic-adrenergic system and the renin-angiotensin system, causes activation and reflex of the sympathetic or parasympathetic nervous system, and leads to a sharp increase in blood pressure and tachycardia or bradycardia. Local analgesia and opioids (especially μ receptor agonists) are effective in inhibiting this adverse event[14,15].

Reducing the dose of sedatives

The single use of sedatives with common dose for gastrointestinal endoscopy is not sufficient to inhibit the stimulation intensity of the endoscopic operation[16]. Thus, single sedatives often lead to excessive dosage, which delays the recovery of patients and increases the side effects of sedatives. Guidelines recommend the combination of sedatives and opioids[17,18].

APPLICATION OF OPIOIDS IN GASTROINTESTINAL ENDOSCOPY

Fentanyl

Fentanyl is a synthetic opioid with high selectivity for μ receptors. The potency is 50-100 times that of morphine, which makes fentanyl a favorable anesthetic and analgesic. A recent study using receptor-binding simulation demonstrated that the binding points with μ receptor of fentanyl and morphine[19]. Morphine mainly binds to transmembrane regions 3 and 5, while fentanyl primarily interacts with transmembrane regions 6 and 7 (vital regions for activation of μ receptors). This difference may explain the higher potency and selectivity of fentanyl toward the receptor. Fentanyl is primarily devitalized by the P450 3A3/4 (CYP3A3/4) enzyme, whose activity is significantly depressed in liver diseases[20]. In addition, the metabolism of fentanyl for hypoalbuminemia is inactivated due to the heavily protein bound property of fentanyl. However, liver diseases seem not significantly impact the pharmacokinetics of fentanyl[21].

Fentanyl is commonly used as an adjunct to sedatives during gastrointestinal endoscopic procedures. It takes effects rapidly and generally lasts for less than 2 hours[22]. Common side reactions of fentanyl include nausea, vomiting, constipation, sedation and confusion, whereas serious ones may include respiratory and circulatory suppression, illusion and serotonin syndrome[22]. The Chinese guideline recommended that loading dose of fentanyl for endoscopic sedation is 30-50 μg in adults[23]. The American Association of Gastroenterology recommended an initial dose of 50-100 μg[24].

Sufentanil

Sufentanil, a potent opioid with approximately fifty times the analgesic effect of fentanyl, is widely used in clinical practice for a variety of medical procedures requiring analgesia. The targeted opioid receptor and metabolism are similar to that of fentanyl[21]. The use of sufentanil can not only effectively relieve the pain of patients during endoscopy, but also reduce the dose of other anesthetic drugs, thereby reducing the incidence of adverse reactions such as respiratory depression, nausea and vomiting[25,26]. The current studies showed that sufentanil was safe when used for painless gastrointestinal endoscopy, especially when anesthesia was performed in older patients[25,27]. This makes sufentanil an ideal option in painless endoscopy. When combined with sedatives, Chinese experts suggest giving 3-5 μg sufentanil[23], whereas American anesthesiologists usually use 5-10 μg[28].

Dezocine

Dezocine is a μ receptor partial agonist and κ receptor antagonist, and can inhibit the reabsorption of norepinephrine and serotonin by binding to their transporters[29,30]. The analgesic effect of dezocine is longer than that of fentanyl, but the inhibitory effect on the respiratory system is not significant[31]. In gastrointestinal endoscopy procedures, a meta-analysis involving 677 patients showed that dezocine was superior than fentanyl when combined with propofol in terms of the reduction in propofol dose, awakening time and incidence of hypopnea[32]. Specifically, the advantages included less propofol dose, less respiratory inhibition and faster recovery. The common dose of dezocine reported in studies are 0.05 mg/kg and 5 mg[33-35].

Alfentanil

Alfentanil was synthesized in the United Kingdom in 1976. It mainly acts on μ-opioid receptors and is a short-acting analgesic with an analgesic intensity 15 times that of morphine. Its metabolism is mainly performed by the hepatic cytochrome CYP3A3/4 enzyme. The metabolites have no opioid-like activity, and the urinary excretion of the prototype is less than 1%. After discontinuation of alfentanil infusion, the plasma concentration of alfentanil in human body decreased rapidly, and the second peak of plasma concentration was not observed[36]. The plasma concentration time curve decreased exponentially after discontinuation of alfentanil infusion, suggesting that the elimination process of alfentanil conformed to the first-order elimination kinetics. The onset of alfentanil is four times faster than that of fentanyl, and the action time is one third of that of fentanyl. The order of analgesic potency relative to morphine is as follows: Sufentanil (1000 ×) > remifentanil (300 ×) > fentanyl (100 ×) > alfentanil (15 ×) > morphine (1 ×) > pethidine (0.1 ×)[37]. Thus, the dose of alfentanil is approximately 7 times that of fentanyl.

The application of alfentanil in painless gastrointestinal endoscopy is related to satisfactory analgesia, less dosage of intravenous anesthetic drugs, faster recovery, and fewer adverse reactions after surgery. Clinical observations have found that compared with fentanyl, alfentanil combined with propofol could reduce the incidence of respiratory depression and had advantages in rapid onset and recovery[38,39]. For special patients such as morbid obese patients, propofol combined with alfentanil or ketamine can provide adequate sedation and analgesia, but the consumption of propofol is higher when combined with ketamine, so the combination of propofol and alfentanil is more recommended[40].

Nalbuphine

Nalbuphine is an opioid receptor agonist that was synthesized in 1965 to overcome the adverse reactions caused by pure opioid receptor agonists. In 1971, it was first used in clinical practice abroad, and it has been on the market in Western countries since 1978. However, nalbuphine was put into clinical use in China in 2016. It is a new type of κ receptor agonist and μ receptor partial antagonist[41]. A key characteristic of nalbuphine is that it causes slight respiratory depression, and this effect has a capping effect[41]. Another advantage of nalbuphine using during gastrointestinal endoscopy is its superior alleviation of visceral pain[42]. However, the incidence of nalbuphine-induced nausea was reported significantly higher than that of sufentanil[43]. This may partly explain its limited application in gastrointestinal endoscopy.

Oliceridine

Opioid receptors are G protein-coupled receptors and function primarily through the G protein pathway and β-inhibitory proteins[44]. G protein mainly mediates analgesia, while β-repressor protein is associated with side effects such as respiratory depression and gastrointestinal reactions, and can attenuate analgesia[45,46]. Oliceridine is a novel opioid screened by high-throughput chemical library and is the first approved biased μ receptor agonist, which means it activates G protein, but its activity on β-inhibitory protein is low, so the incidence of side effects is lower than that of the classical opioids[47]. Nausea, vomiting, dizziness, headache, constipation, pruritus, and hypoxia are common side effects (≥ 10%) in APOLLO-1 and APOLLO-2 studies, and the incidence of side effects was significantly lower with oliceridine than with morphine[48,49]. Considering these properties, experts have thought that oliceridine is promising to be applied in gastrointestinal endoscopy procedures[50,51]. Unfortunately, no related clinical studies have been published.

WHICH ONE IS THE PREFERENCE FOR ANESTHESIOLOGISTS

In China, a national survey on the practice and regional disparity of procedural sedation for gastrointestinal endoscopy was performed between October and December 2017[52]. This study analyzed the responses of department leaders and endoscopic anesthesiologists from 2758 hospitals. The results indicated that fentanyl (36.3% for gastroscopies and 31.9% for colonoscopies) was the most popular analgesic, followed by sufentanil (29.0% for gastroscopies and 30.8% for colonoscopies) and dezocine (20.5% for gastroscopies and 20.8% for colonoscopies).

CONCLUSION

Medication of opioids is an important part of painless gastrointestinal endoscopy, especially the synthetic ones. Classic opioids such as fentanyl, sufentanil and dezocine are still the foundation stone, whereas oliceridine is believed to an ideal analgesic for gastrointestinal endoscopy. Further clinical studies should verify the dose, effectiveness and safety of oliceridine in endoscopic procedures.