Review Article
Opioid-Sparing in Multimodal Analgesia for Perioperative Pain Management
Volume 32,Issue 1,Pages 3-9
Shih-Yuan Liu1 , Chih-Shung Wong2.3

1School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan

2Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan

3Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan

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Optimal perioperative management is one of the key matters in the evidence-based enhanced recovery after surgery protocol with the improvement of clinical outcomes and life quality. Perioperative multimodal analgesia (MMA) is known to provide better postoperative pain management and reduce the risk of chronic postsurgical pain and opioid use disorder. The opioid epidemic was reported in the US, which is more than a national public health problem. To deal with the crisis, in 2018, the National Institutes of Health initiated a new program called Helping to End Addiction Long-term (HEAL) in the US. The key of HEAL program is to treat perioperative pain in the acute phase by using more than one analgesic with diverse mechanisms of action via different routes and achieves better pain management with less opioid dose. MMA is proven to treat acute pain effectively, ease the pain, use fewer opioids, and recover quickly from surgery.


enhanced recovery after surgery (ERAS), helping to end addiction long-term (HEAL), multimodal
analgesia (MMA), naldebain, opioid-sparing effect


Starting in the 1990s, physicians were encouraged to control pain as the introduction of the “fifth vital sign”; the use of opioids for the treatment of non-cancer pain was liberated [1-3]. Because of the outstanding effi cacy of opioids in pain relief, the use of opioid analgesics in pain control increased substantially [2,4]. However, opioid-related overdose, as well as side effects, also increased. Oxycodone and methadone prescriptions were nearly quadrupled between 1997 and 2002 and reached a peak in 2011 [1,3,5]. In 2010s, unintentional drug overdose has become the second leading cause of accidental death in the US. Studies have indicated a strong association between drug-poisoning mortality with the amount of opioid consumption [1,3,5]. A review of multiple studies found various ways for patients to obtain prescription drugs, and 20% of the studies were from a single physician, and 2% of them were from multiple doctors, while only 5% of them were purchased from drug dealers. The consensus on iatrogenic opioid overdose was initiated; physicians in the US had started to decrease opioid analgesics since 2011 [1,5]. However, in the US, opioids still gave rise to 1 death approximately every 35 minutes in 2017 [2,5]. Similarly, the consumption of opioid analgesics has substantially increased over the last 20 years worldwide, which means three things: (1) the severity of opioid abuse which can cause an opioid epidemic, (2) the need for an alternative protocol with less or even no opioid to treat acute postoperative pain which can save patients from opioid dependence and abuse, and (3) the need to propagate the pain management to avoid the spreading of an opioid epidemic.

Enhanced Recovery After Surgery and Intraoperative Pain Monitoring

Enhanced recovery after surgery (ERAS), also referred to as “fast-track protocols,” is a multimodal, multidisciplinary approach to improving the care of surgical patients with evidence-based protocols [5,6]. It was first proposed by Henrik Kehlet in 1994 and significantly shortened hospital stay [5]. Colorectal resection surgery was first implemented, and the concept has been expanded to a variety of surgical procedures, including breast reconstruction, cardiothoracic surgery, pancreaticoduodenectomy, cystectomy, lung resection, abdominal hysterectomy, gastric resection, bariatric surgery, liver resection, major gynecology surgery, revision hip and knee arthroplasty, urologic surgery, and head and neck cancer surgery [6,7]. The ERAS society published evidence-based guidelines for various surgical procedures for subspecialties and specific procedures [5,6]. ERAS emphasizes the quality of recovery. Outcomes of ERAS protocols are significant, including satisfactory postoperative pain relief by using fewer opioids, chronic postsurgical pain (CPSP) relief, fewer complications, morbidity, hospital readmissions, and costs [5-7]. ERAS is composed of several components, among which perioperative multimodal analgesia (MMA) plays a key role [7,8].

On the other hand, inadequate postoperative analgesia can delay recovery after surgery and cause postoperative delirium. To control the depth of analgesia, hemodynamic changes are usually used to guide intraoperative opioid analgesic administration [9-11]. Currently, objective techniques are available for the depth of analgesia, surgical pleth index, and analgesia nociception index [12]. They are derived from the analysis of heart rate variability. Observational studies have demonstrated that analgesia monitoring guided analgesics administration during operation provides better postoperative pain relief with less fentanyl consumption in the postanesthesia care unit; opioid consumption could be tailored and reduced to achieve the opioid-sparing pain control [9,10].



In the era of the opioid epidemic, MMA protocol has emerged to achieve effective analgesia with minimal opioid use to reduce the risk of opioid abuse and opioid-related side effects [6,13]. It is an essential component of ERAS [5-7]. MMA achieves postoperative pain control by combing different medications and routes of administration, including systemic, regional, and neuraxial techniques [13]. MMA not only covers the intraoperative and postoperative period but also incorporates preemptive analgesia, which is administering analgesics before the painful stimulus, like surgical incision. Preemptive analgesia has been shown to reduce pain and inflammation at the very beginning. There are different neurotransmitters involved in inflammation and pain transduction in which different analgesics can take part. By applying them simultaneously via various routes, MMA protocol aims to block pain transduction at many levels, from peripheral to central [5,6]. Analgesics include nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, local analgesics, opioid, ketamine, gabapentin, and melatonin. According to different features and effects, these agents can be administered via systemic routes (oral, intravenous, intramuscular), epidurally, and even for peripheral nerve block [5,6,13,14]. By reducing pain sensation and pain sensitivity, MMA protocol has been proved to achieve well manage acute postsurgical pain and reduce the risk of CPSP. CPSP is a major late complication after surgery and is typically derived from poor acute pain control which induces neuronal and molecular sensitization in the peripheral and central nervous systems to both noxious and non-noxious stimuli [1,5,6,15].


NSAIDs reduce pain by inhibiting cyclooxygenase (COX) which takes part in producing prostaglandins and inflammatory mediators [5,13,16-18]. Since NSAIDs exert the effect at the very beginning of the pain transduction pathway, NSAIDs have analgesic, anti-inflammatory, and antipyretic effects. Nonselective NSAIDs inhibit both COX-1 and COX-2, while selective COX-2 inhibitors have little effect on COX1; thus COX-2 inhibitors have weaker gastrointestinal side effects, especially peptic ulcer [16-18]. However, COX-2 inhibitors do increase the risk of cardiovascular side effects, such as myocardial infarction [16,18,19]. NSAIDs are the first choice for pain management [16,18,20]. Meta-analyses of randomized trials presented that the combination of NSAIDs with patient-controlled analgesia morphine can decrease morphine consumption by 15%–55% in the first 24 hours postoperative and also decrease pain intensity compared to morphine alone [20]. NSAIDs, because of opioid-sparing effect, also significantly reduced the incidence of postoperative nausea/vomiting by 6.8% and sedation by 2.7% [19].


The exact mechanism of acetaminophen is not fully understood. It not only has an antinociceptive effect and some COX inhibition but also seems to act on the opioid receptors as well [5,13]. A systematic review concluded that adding acetaminophen to systemic opioids for perioperative pain management can decrease morphine consumption, which supported its opioid-sparing synergic analgesic effect [20]. With its weak side effects, acetaminophen is widely used and commonly involved in MMA therapy and ERAS protocol [5,13,21-23].

Local Anesthetics

Local anesthetics block the sodium channels at peripheral nerves, prevent depolarization and propagation of action potential, and block pain transduction. Lidocaine and bupivacaine are the most commonly used agents [5,13,24,25]. A pilot randomized controlled study had demonstrated intravenous lidocaine provided similar analgesia to intravenous morphine for severe pain in the emergency department (87% vs. 88%) [26,27]. They can be administered intravenously as nerve blocks to reduce inflammation and provide pain relief [22,23]. A randomized controlled trial demonstrated lidocaine as an opioid-sparing analgesic in MMA with fewer side effects and lesser morphine. When applied in nerve blocks, the dosages of opioids and side effects can be further reduced to a minimum with good pain control [22,23,28,29]. In our hospital, we applied lidocaine and opioids for ultrasound-guided peripheral nerve block and showed good pain control with less opioid consumption [23,29].


An opioid is undoubted, an important medication in pain management [2,30]. Its powerful analgesic effects can be clearly seen in the World Health Organization Pain Ladder although the ladder was mainly for cancer pain [15]. Opioids target modulation pathways to reduce nociceptive and neuropathic pain. By binding to μ-, κ-, and δ-opioid receptors, opioids raise pain threshold and change pain perception. Morphine and fentanyl are the most commonly used opioid medications in clinical pain management.

They are full μ-opioid receptor agonists and provide satisfactory analgesic effects. However, it comes with side effects, such as nausea and vomiting, itching, and respiratory depression. Furthermore, when opioids are used in the long term, constipation, opioid dependence, opioid abuse, and opioid crisis will be developed. Thus, the prescription of classical opioids, such as morphine and fentanyl, must be more careful to reduce the risk of dependence [4]. The opioid epidemic issue has come into notice; a case-control cohort study showed an ultra-restrictive opioid prescription protocol implementation on patients after gynecologic and abdominal surgery demonstrated a significant decrease in opioid prescription without changes in pain scores, complications, or medication refill requests [4]. The study demonstrated that as long as we handle opioids carefully, opioids can definitely provide good pain relief with fewer associated side effects, and the opioid epidemic crisis can further be limited. A new opioid medication, dinalbuphine sebacate (DS), an extended-release prodrug of nalbuphine, was introduced to Taiwan in 2017 with its unique affinity to opioid receptors, [31,32]. It acts as a partial agonist at the κ-opioid receptor and a weak antagonist at the µ-opioid receptor [33]. Compared to morphine, DS is slightly less potent but comes with less dependence, less sedation, and less respiratory depression [29,31,33,34]. Thus, DS is not on the control dug list in Taiwan. Intramuscular injection of DS provides an effective nalbuphine analgesic blood level for approximately 7 days [23]; it offers not only preemptive analgesia but also continuously provides postoperative pain control for another 5–6 days when injected 12–24 hours before surgery. It has been commonly used in many hospitals in Taiwan now [23,29,32]. In our previous study, we compared the length of surgery, anesthetics used during operation, and the postoperative visual analog scale pain score between the MMA protocol with preoperative DS and post-operative morphine on patients undergoing laparoscopic cholecystectomy. Results showed no statistically significant difference. Furthermore, in combination with ultrasound-guided transversus abdominis plane block with lidocaine for immediate pain control for about 12 hours to cover DS to achieve the analgesic blood concentration, we injected DS right before the surgical incision on a morbid obesity bariatric surgery also provided a satisfactory pain control [29]. In this MMA protocol, ketamine and dexamethasone were also given for preemptive analgesia and postoperative nausea and vomiting (PONV) prevention, respectively [35-38]. Acetaminophen and ketorolac were given immediately after the surgery; the patient recovered well with little pain and no more opioid prescription after discharge [29]. It was clearly seen that DS is a potential opioid medication with a long duration of action and no risk of dependence and may be included in more MMA protocols for various surgery [29,32].

N-Methyl-D-Aspartate Receptor Antagonist: Ketamine

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is also commonly used in MMA protocol. It acts on both the central and peripheral nervous systems. One randomized controlled study demonstrated that intraoperative ketamine reduced pain in 48 hours after surgery and reduced opioid consumption after spinal fusion surgery in patients with opioid dependence [39-41]. Opioid-sparing effect of ketamine on pain relief and reduction of opioid consumption lasted for 6 months and also inhibited CPSP [41]. Though not fully understood, one of the theories of opioid-induced hyperalgesia (OIH) is the overactivation and stimulation of the NMDA receptors [42]. This mechanism explains the reason why low-dose ketamine could enhance opioid sensitivity and show effectiveness in treating OIH [42,43]. As to its role in MMA, according to a randomized controlled trial, perioperative low-dose ketamine produced a significant analgesic effect within 5 minutes and lasted for 2 hours [40]. Several studies reported that ketamine can reduce postoperative opioid consumption in various types of surgery [24,37,39,44].Thus, we included low-dose ketamine at the beginning of surgery in our anesthesia practice. For example, we combined pre-incisional low dose ketamine with DS, lidocaine, acetaminophen, and ketorolac as an MMA protocol in rotator cuff surgery, laparoscopic bariatric surgery, and laparoscopic cholecystectomy in our anesthesia practice and perioperative pain management, as expected, with less opioid consumption and good quality of postoperative pain control, and no chronic pain was observed [29,32,35,39].


As a second-generation anticonvulsant, gabapentin blocks presynaptic calcium channel subunit α2δ, reduces intracellular calcium flow, and subsequently inhibits the release of glutamate. A systematic review and meta-analysis concluded that gabapentin, as an adjuvant in MMA, reduced morphine requirement and postoperative pain, with less opioid-associated PONV and pruritus in the first 24 hours [45]. Moreover, gabapentin could reduce preoperative anxiety and increase patients’ satisfaction, which was independent of the type of surgery [45,46].


Although the exact mechanisms remain unknown, melatonin is found related to pain control [47,48]. It has been well used in fibromyalgia, migraines, irritable bowel syndrome, chronic back pain, and rheumatoid arthritis [49,50]. More than just a common medication for chronic pain, melatonin can also be used for acute pain management. In a randomized-controlled study, melatonin was given the night before and 1 hour before prostatectomy, and patients reported less pain, used less intraoperative fentanyl, and had better postoperative sleep [51].

The precise mechanisms underlying the analgesic effects of melatonin are not known although several possibilities have been suggested, which include the involvement of β-endorphins, γ-aminobutyric acid receptors, opioid l-receptors, and nitric oxidearginine pathway. Melatonin increases the release of β-endorphin from the pituitary gland, and it has been observed that naloxone, which blocks β-endorphin binding to opioid receptors, may antagonize the melatonin-induced nociceptive effects. Melatonin may also mediate its analgesic activity by interacting with opioidergic, benzodiazepinergic, muscarinic, nicotinic, serotonergic, and α1 and α2-adrenergic receptors located in the central nervous system and also in the dorsal horn of the spinal cord. Furthermore, inasmuch as melatonin-induced long-term analgesia may be antagonized by naloxone, and opioid receptors are likely involved in melatonin action.


Opioids have been a mainstay in postoperative analgesia for decades for the outstanding analgesic effect and cheap price. However, opioid-related adverse effects such as PONV and respiratory depression are common. Most of all, over prescription of opioids led to opioid abuse and gave rise to the opioid epidemic crisis in the US. To combat this epidemic, MMA emerged. MMA protocols have shown synergic effect of each analgesic by combining opioid and non opioid medication through different routes. It provides satisfactory pain relief and significantly reduces opioid consumption. Moreover, the new uncontrolled opioid medication, DS (naldebain), was introduced to Taiwan with its unique mechanism of action from classic opioids with a low risk of opioid dependence. Naldebain has been included in many MMA protocols in practice in our hospital and may be widely used in the future. By covering the whole perioperative period, MMA provides better quality of postoperative recovery of patients and reduces hospital stay, which meets the main idea of opioid-sparing ERAS and prevents CPSP.


This is a short text to acknowledge the contributions of specific colleagues, institutions, or agencies that aided the efforts of the authors.

Author Contributions

SY Liu writes the manuscript and Dr. CS Wong guides, discusses, and reviews the manuscript writing.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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