December 8, 2023

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Progress in clinical application of opioid-free anesthesia

Progress in clinical application of opioid-free anesthesia



Progress in clinical application of opioid-free anesthesia.  In recent years, as the understanding of opioids has been deepened and the development of enhanced recovery after surgery (ERAS) has been accelerated, clinical anesthesia is rarely used, and even more and more operations are performed without opioids for anesthesia.

A new method of anesthesia accompanied by it-opioid-free anesthesia (OFA) is receiving great attention and welcome. This article reviews the progress of OFA’s clinical application to provide reference for perioperative management.

Progress in clinical application of opioid-free anesthesia
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1 The concept and development of OFA

As a powerful analgesic, opioids have the characteristics of inhibiting sympathetic reactions and stabilizing hemodynamics in anesthesia. Its anti-injury effect is the core of traditional balanced anesthesia. However, the side effects and drug abuse caused by opioids have caused widespread concern. During the perioperative period, opioids produce side effects such as nausea and vomiting, sedation, respiratory depression, constipation, drowsiness, delirium, increased postoperative pain and morphine dosage, immunosuppression, pain hypersensitivity, and chronic postoperative pain. Increase hospital stay and delay recovery. Therefore, ERAS proposes a multimodal analgesic treatment strategy, which aims to reduce the use of opioids and related side effects and promote recovery.


As the core of multi-modal analgesia, opioid frugal technology that uses less or no opioids on the premise of effective analgesia is advocated. No opioid postoperative analgesia has been recommended for more than ten years. Based on the same opioid frugality principle, how to reduce the intraoperative opioid dosage? In clinical practice, some methods or strategies to reduce opioids have gradually attracted attention, and OFA has emerged. OFA is a multimodal anesthetic method related to hypnotics, NMDA receptor antagonists, local anesthetics, anti-inflammatory drugs and α2 agonists. The earliest OFA focused on bariatric surgery that is prone to respiratory complications, and then OFA was used in awake neurosurgery and a variety of major and minor operations.


At present, OFA does not have a unified definition. Although opioids are not used in anesthesia, it does not mean that there is no analgesia. On the contrary, as part of multimodal analgesia, non-opioid analgesic interventions and medications should be routinely included in each patient’s perioperative pain management plan. Therefore, Elkasabany and Mariano define OFA as a perioperative treatment strategy from admission to discharge of the patient, that is, use non-opioid mode for anesthesia and analgesia as much as possible, and reserve opioids for severe acuteness that cannot be relieved by other methods.

Analgesia of pain. Forget believes that OFA can be defined as a comprehensive application of different opioid-saving techniques to achieve intraoperative opioid-free anesthesia. Mulier distinguishes OFA from opioid-free analgesia, and believes that OFA means that opioids are not used before and during surgery until the patient wakes up. No opioid analgesia means that patients who are anesthetized with OFA or only short-acting opioids (opioids cannot be detected in the body after surgery), do not use opioids for analgesia after surgery. The simple definition of OFA is a method in which opioid anesthesia is not administered from any route (systemic, central, body cavity, or tissue infiltration) during surgery.


From the above concepts, it can be seen that the absence of opioids in OFA is not analgesia-free, but based on the concept of multi-modal anesthesia, through related drugs and/or methods to provide a high-quality general anesthesia without opioids. OFA, as an anesthesia method, was used in plastic surgery and bariatric surgery in the early stage, and has been used in many operations (such as gynecological surgery, general surgery, spinal joint surgery, minimally invasive surgery or open major surgery, and even CPB lower coronary artery Bypass grafting). Enten et al. also reported that multi-mode opioid-free general anesthesia is safe and feasible for cesarean section surgery.

OFA is developing gradually and has a rapid development trend. It has developed from a single case report and forward-looking systematic research and development, from anesthesia for normal people to surgical anesthesia for special patients (such as super obesity, heart disease, atrophic myotonia, cerebral palsy, etc.) expand. The European Conference on Anesthesia in Copenhagen in 2018 held a debate on the support and opposition of OFA, which is intended to arouse anesthesia colleagues’ thinking about opioid anesthesia and OFA. OFA has been implemented in many places in the world and some have been routinely applied.



2 OFA’s advantages, indications and contraindications

Multi-mode anesthesia without opioids under general anesthesia can reliably control cardiovascular and inflammatory responses caused by surgical stimulation. OFA is clinically safe and feasible. Some case reports and studies have shown that the anesthesia is stable, awake and rapid, and pain is less.


2.1 The advantages of OFA

OFA can reduce opioid-related side effects and significantly reduce postoperative nausea and vomiting (PONV). In bariatric surgery patients with triple combination of dexamethasone, ondansetron and droperidol to prevent vomiting, compared with opioid balanced anesthesia, the absolute risk of PONV in patients with intravenous OFA was reduced by 17.3%, and the degree of PONV was reduced.

OFA improves postoperative analgesia and reduces postoperative opioid demand, which in turn can reduce postoperative pain hypersensitivity and persistent pain, reduce cognitive dysfunction and immunosuppression, and may help reduce tumor recurrence and metastasis. However, studies have shown that opioids are associated with increased tumor recurrence rates in cancer patients after surgery. Although the exact role of opioids in tumor recurrence is still controversial, OFA reduces the use of opioids in postoperative pain control, which may be beneficial to cancer patients.


2.2   OFA indications and contraindications

Indications: Intraoperative opioids in high-risk patients with high risk of postoperative respiratory safety (such as obesity, obstructive sleep apnea syndrome, day surgery, etc.), PONV high-risk groups, and postoperative pain sensitive patients, etc. It can also be used for chronic obstructive pulmonary disease, complex regional pain syndrome, acute and chronic opioid addiction, and cancer surgery. OFA is safe and effective for bariatric surgery.

Contraindications: trauma surgery, hypovolemia, severe atrioventricular block, patients with fragile autonomic nervous system, etc.



3 OFA drug selection and methods

Related drugs for OFA include NMDA antagonists (ketamine, lidocaine, magnesium sulfate), sodium channel blockers (local anesthetics), anti-inflammatory drugs (non-steroidal anti-inflammatory drugs, dexamethasone, local anesthetics) ) And α2 agonists (clonidine, dexmedetomidine). Comprehensive utilization of these non-opioids and adjuvant drugs produces anesthesia, anti-sympathetic and analgesic effects.


3.1 Drug selection

α2 agonist: It is the main drug of OFA. In particular, dexmedetomidine has a unique analgesic effect on the spinal cord and spinal cord. Dexmedetomidine has an opioid frugal effect, which can reduce the intraoperative opioid dosage by more than 50%. Dexmedetomidine alone can provide appropriate analgesia during laparoscopic surgery. Compared with clonidine, dexmedetomidine causes less hypotension, has less effect on breathing, and has a strong bronchiectasis effect, which can prevent chills and does not prolong the recovery time. 20 µg dexmedetomidine can replace 2 mg midazolam for preoperative anti-anxiety.


Ketamine: has an important position in OFA. It can inhibit NMDA receptors and has analgesic effect in small doses. Whether it is a single intravenous injection or continuous administration, it not only reduces the amount of opioids, but also stabilizes hemodynamics and improves postoperative pain management.

Magnesium sulfate: It exerts analgesic effect by regulating calcium ions entering the cell and a non-competitive NMDA receptor antagonist. It can inhibit neuropathic pain, reduce postoperative opioid demand, and reduce postoperative pain scores. After the load is 30-50 mg/kg, pump 10 mg·kg−1·h−1. Pay attention to its synergy with anesthetics and muscle relaxants.


Acetaminophen: It is a non-opioid analgesic with strong antipyretic effect and weak anti-inflammatory effect. Intravenous administration takes effect faster and stronger than oral administration. The administration of acetaminophen after hip and knee surgery can reduce the amount of opioids by 46% on the first day. Pay attention to liver toxicity, intravenous injection of 15 mg/kg every 6 hours, the maximum amount does not exceed 4 g per day.


Non-steroidal anti-inflammatory drugs: Ketorolac is the most commonly used non-steroidal anti-inflammatory drug in OFA. It has a significant analgesic effect and can reduce the side effects of opioids, especially effective in treating uterine contractions. The opioid thrifty effect of ketorolac is associated with reducing cancer recurrence after breast cancer surgery.


Dexamethasone: Dexamethasone (such as 8 mg) recommended for the prevention of PONV can save the amount of morphine, reduce fatigue and PONV, and promote recovery. A single administration of dexamethasone 0.1 mg/kg before surgery can not only prevent PONV, but also has a certain analgesic effect.

Lidocaine: Intravenous lidocaine can be used to control intraoperative pain and reduce postoperative pain scores. The analgesic effect of lidocaine can last several months after surgery. It may be related to the continuous concentration of lidocaine in the cerebrospinal fluid. The exact mechanism of lidocaine is still unclear, and it may be related to inhibition of voltage-gated sodium channels, stabilization of cell membranes, reduction of central sensitization, inhibition of NMDA receptors, and reduction of inflammatory markers. Lidocaine used in abdominal surgery can reduce postoperative intestinal obstruction and PONV, and the effect is similar to that of epidural local anesthetics. Lidocaine also has a neuroprotective effect and can prevent postoperative cognitive dysfunction. Intravenous lidocaine and dexamethasone are recommended for major surgery, especially major abdominal surgery.


Other drugs: The inhibitory neurotransmitter γ-aminobutyric acid derivatives (gabapentin and pregabalin) are effective for neuropathic pain. Although opioid receptor agonist antagonists (such as dezocine and buprenorphine) have a lower upper limit of analgesia than pure opioid agonists, they are less addictive and respiratory depression, and are beneficial for the treatment of opioid addiction. Both preclinical and clinical studies have shown that Dezocine can reduce the dependence on morphine and improve the patient experience. The short-acting beta-blocker esmolol has an anti-nociceptive effect and contributes to multimodal analgesia.


3.2   OFA specific medication plan

Different opioid-free combinations have been successfully used for intraoperative anesthesia and postoperative analgesia. Based on the multi-mode concept, the combined application of related drugs with anesthetic and analgesic effects to complete the OFA, the specific medication plan should be adjusted according to the patient’s condition, the size of the operation, and whether the complex area is blocked or not. According to whether inhalation anesthesia is used, it is divided into total intravenous OFA and intravenous combined OFA. Based on the difference of intraoperative maintenance drugs, it is further subdivided as follows:


Total intravenous OFA: ① Dexmedetomidine + propofol. Ziemann-Gimmel et al. reported a total intravenous OFA program for bariatric surgery. Preoperative intravenous injection of midazolam 2~4 mg, intravenous injection of dexmedetomidine load 0.5 µg/kg (over 10 min), propofol 1.0~2.5 mg/kg and muscle relaxant intubation after entering the room; The anesthesia maintenance infusion is dexmedetomidine 0.1~0.3 µg·kg−1·h−1 and propofol 75~150 µg·kg−1·min−1. Ketamine 0.5 mg/kg before cutting the skin. Acetaminophen 1 g was intravenously injected 20 min after induction of anesthesia, and ketorolac 30 mg was intravenously injected 20 min before recovery. ② Dexmedetomidine + lidocaine + ketamine. Mulier reports on practical OFA protocols that have been used in a variety of surgeries. 15 min before induction of anesthesia, a loading dose of dexmedetomidine 0.25 µg/kg was infused, lidocaine 1 mg/kg, dexmedetomidine 0.1 µg/kg, and propofol were injected intravenously during anesthesia induction. Ketamine 50 mg was infused before skin incision, dexmedetomidine 0.1 µg·kg−1·h−1, lidocaine 1 mg·kg−1·h−1, ketamine 0.1 mg·kg−1· for maintenance of anesthesia h−1. Before waking up, long-acting local anesthetics are infiltrated and given non-steroidal anti-inflammatory drugs and acetaminophen.


Intravenous inhalation compound OFA:

① Dexmedetomidine + lidocaine compound low-dose inhalation anesthetic.

Boysen et al. reported that the OFA method was continuous intravenous injection of lidocaine 0.03 mg·kg−1·min−1 and dexmedetomidine 0.5 µg·kg−1·h−1, combined with inhalation of 0.5 MAC isoflurane. For surgery within 2 hours, lidocaine and dexmedetomidine are given 1 load. For operations over 2 hours, no load is required. Supplement with acetaminophen, ketamine, ibuprofen or ketorolac to complete OFA.

② Dexmedetomidine + lidocaine + ketamine compound low-dose inhalation anesthetic.

Estebe et al. reported 311 cases of major abdominal surgery performed OFA between 2015 and 2018. After opening the vein, dexmedetomidine was continuously infused with 1.0~1.4 μg·kg−1·h−1. Anesthesia was induced by intravenous injection of lidocaine 1.0~1.5 mg/kg, ketamine 0.10~0.15 mg/kg, dexamethasone 0.1 mg/kg, propofol and muscle relaxants, and intubation.

Anesthesia was maintained by continuous infusion of lidocaine 1 mg·kg−1·h−1 and ketamine 0.1 mg·kg−1·h−1. In severe bradycardia, dexmedetomidine is reduced to 0.8~1.0 µg·kg−1·h−1, and inhalation anesthesia maintains a low MAC (approximately 0.8 MAC). Dexmedetomidine and ketamine were discontinued 30-50 minutes before the end of the operation, and lidocaine continued until the PACU was discharged.

Acetaminophen and Nefopam combined with ketoprofen enhance analgesia. The OFA is safe and effective for major abdominal surgery, can better control intraoperative cardiovascular and inflammatory reactions, and has a low postoperative pain score. The OFA public research program initiated by Beloeil et al. is similar to this method.

Anesthesia was induced by intravenous injection of propofol 1.5~2.0 mg/kg, lidocaine 1.5 mg/kg, ketamine 0.5 mg/kg, dexamethasone 8 mg, dexmedetomidine 0.4~1.4 µg/kg and muscle relaxants , Intubation. For maintenance of anesthesia, inhaled desflurane, intravenous lidocaine 1.5 mg·kg−1·h−1, ketamine 0.25 mg·kg−1·h−1, and dexmedetomidine 0.4~1.4 µg·kg−1· h−1.


3.3  OFA combined with regional block or local anesthesia

General anesthesia combined with effective regional block of OFA has proven to be safe and reliable. Perfect regional block or local anesthesia can effectively block the influx of noxious stimuli. In OFA, combined local anesthetics, regional anesthesia (nerve block and fascial block) and intraspinal anesthesia can improve perioperative pain management. Adding non-opioid adjuvants (such as dexamethasone) to local anesthetics can prolong the action time of local anesthetics. Especially ultrasound-guided regional block can reduce the complications of nerve block and improve the success rate.


Using local anesthesia instead of opioids provides good analgesia, helps reduce or even avoid the use of opioids, and thus turns into OFA. Tripathy et al. reported that paravertebral block and thoracic nerve block combined with dexmedetomidine and sevoflurane are safe for modified radical mastectomy and axillary lymph node dissection under OFA.

Recently, Chanowski et al. reported a case of coronary artery bypass grafting under the OFA ultra-fast channel CPB with erector spinal muscle plane block: ultrasound-guided bilateral injection of 0.5% ropivacaine at the level of the erector spinal muscle of the 7 thoracic vertebrae 20 ml juxtaposed tube, induction of anesthesia, intravenous injection of midazolam 4 mg, ketamine 50 mg, propofol 3 mg/kg (divided) and rocuronium 100 mg, intravenous esmolol 50 before intubation mg, inhaled sevoflurane to maintain anesthesia, dexmedetomidine 0.5 µg·kg−1·h−1, magnesium sulfate 1 g, and ketamine 50 mg were given before skin incision, and patient-controlled sedation was performed through the erector spinal plane catheter after the operation pain. This multi-mode opioid-free method provides stable anesthesia and quick recovery.

Chakravarthy also suggested that regional anesthesia for cardiothoracic surgery is a trend towards OFA. Sternal or thoracic surgery analgesia can be performed by paravertebral block, serratus anterior plane block, erector spinal block or thoracic nerve block. Local anesthesia of the surgical incision, intercostal nerve block, and injection of local anesthetics between the pleura or around the drainage tube can alleviate the pain of the drainage tube. These methods are combined with non-steroidal anti-inflammatory drugs to achieve OFA.


OFA compound regional block is more and more used in spinal joint surgery. Chin and Lewis reported that OFA combined with erector spinal muscle plane block was successfully performed in a case of cerebral palsy after scoliosis correction surgery. Kline and Clin used OFA combined with modified lumbar erector spinae (deep and superficial dual injection) block to perform multiple laminectomy. The anesthesia effect is ideal and there is no obvious postoperative pain.



4 OFA’s controversy and future

Although OFA is safe and feasible, and clinical experience continues to increase, its more benefits and long-term impact on patients still need to be further observed. Its indications and contraindications are not yet fully clarified, especially what kind of surgery and/or OFA is suitable for More evidence is needed to support which patients are more beneficial.

Therefore, there is a certain controversy in clinical routine application, and some scholars believe that OFA is not enough to formally recommend. Lirk and Rathmell believe that it is too early to adopt OFA, but even so dissidents also support the minimization of perioperative opioid use, and advocate that we should do our best to promote multi-modal analgesia, and then see if there is enough evidence to support OFA moves forward. OFA is a new type of anesthesia. Questioning the practice of anesthesia is helpful for the rational use of opioids during the perioperative period.


Many OFA unsolved problems are exactly the direction that OFA needs to work on in the future:

First, we urgently need reliable tools to evaluate intraoperative noxious stimuli, so as to objectively evaluate the analgesic efficacy and advantages of OFA;

Second, the indications of OFA need to be further clarified, that is, what kind of patients or what kind of operation is more suitable for OFA ?

Third, the optimal drug combination and compatibility of OFA is still unclear. How do these drugs adapt to different surgeries and/or different patients?

Fourth, the short-term and long-term advantages and disadvantages of OFA for surgical patients need more observation. Fifth, what is the difference between low-dose opioid anesthesia and OFA on the prognosis of patients?

As OFA research continues to deepen, we look forward to more high-quality, large-sample, and rigorously designed research results that will point out the direction for future OFA research.


In summary, as the application of OFA continues to increase, it will promote us to better practice the concept of multi-modal anesthesia and analgesia, and to use opioids rationally. In the future, with the popularization and development of ultrasound-guided visual nerve block technology, precise injection, adequate analgesia, and effective blocking of noxious stimuli will help the development of OFA.



(source:internet, reference only)

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