Objective: Identification of pain as the fifth vital sign has resulted in over-prescription and overuse of opioids in the United States (US), with addiction reaching epidemic proportions. In Europe, and more recently in the US, a shift has occurred with the global adoption of multimodal analgesia (MMA), which seeks to minimize perioperative opioid use. Improved functional outcomes and reduced healthcare utilization costs have been demonstrated with MMA, but wide-scale use of opioids in pain management protocols continues. As a next step in the pain management evolution, opioid-free analgesia (OFA) MMA strategies have emerged as feasible in many surgical settings.

Methods: A MEDLINE search for articles published within the last 10 years was performed using the terms “opioid” and “acute pain” or “post(-)operative pain”. Articles were limited to clinical studies and meta-analyses focusing on comparisons between opioid-intensive and opioid‑free/opioid-sparing strategies published in English.

Results: In this review, elimination or substantial reduction in opioid use with OFA strategies for perioperative acute pain are discussed, with an emphasis on improved pain control and patient satisfaction. Improved functional outcomes and patient recovery as well as reduced healthcare utilization costs also are discussed, along with challenges facing implementation of such strategies.

Conclusions: Effective MMA strategies have paved the way for OFA approaches to postoperative pain management, with goals to reduce opioid prescriptions, improve patient recovery, and reduce overall healthcare resource utilization and costs. However, institution-wide deployment and adoption of OFA still is in early stages and will require personalization and better management of patient expectations.

Over-prescription of opioids has resulted in an opioid epidemic in the United States (US), with one death every 36 minutes considered attributable to opioids1 . In 2015, 63.1% of deaths related to drug overdose in the US involved an opioid 2 . In 2016, the US Department of Health and Human Services reported that 116 people die each day from opioid-related drug overdose 3 . To address this issue, the recent Call to Action by the Office of the US Surgeon General highlighted an urgent need for change in current pain management strategies, with particular emphasis on reducing the prescription of opioids throughout the continuum of care 4 .

Although opioids have long been the mainstay of pain management strategies in the US, their use has failed to result in incremental improvements in patients’ experience of pain over the past decade. Low patient satisfaction is a common consequence of pain management strategies that rely heavily on opioids, primarily attributable to opioid-related adverse drug events (ORADEs), which can significantly lower patient quality of life and increase health-related costs 5 . ORADEs may have both short- and long-term consequences, including disruptions in normal gastrointestinal function (postoperative nausea and vomiting, postoperative ileus, constipation), respiratory depression, and mental confusion5 . Opioid use also is associated with an increased risk of hyperalgesia, tolerance, and addiction 6 .

Opioid use impacts a wide range of patient populations undergoing treatment for acute as well as chronic conditions. While opioid use and pain management have been studied in detail for chronic conditions, opioid exposure due to prescriptions for acute pain remains an under‑recognized risk for developing chronic addiction 7 . A survey in 2013 reported that 84% of patients experience postsurgical pain after hospital discharge8 , a 2017 survey found that doctors in the US treat acute pain with opioids in 97% of cases 9. Thus, acute care settings represent a major source of opioid prescriptions; they contribute significantly to chronic opioid use and addiction, particularly in opioid-naïve patients. Examples of such acute care settings include patient emergency department (ED) visits and hospitalizations for surgical procedures requiring intraoperative use and perioperative prescription of pain medication 10,11 . Further, patients prescribed opioids prior to surgical interventions have evident increases in postoperative opioid use 12 . Recent data show that tolerance to opioids in such patients can develop in as little as a few hours, resulting in suboptimal analgesic effects and the need to increase drug doses 13 .

Leveraging an understanding of the complex humoral and neuronal response associated with surgery and pain, multimodal analgesic regimens were introduced in Europe nearly two decades ago to improve analgesia. Multimodal management protocols involve the simultaneous use of drugs with different modes of action, leading to additive or synergistic pain relief by exerting effects at different points along nociceptive pathways. Such approaches also prevent the development of adverse drug reactions associated with the use of larger doses of a single agent, specifically opioids 14 . Broadly, multimodal pain management protocols often involve the use of multiple pre-, intra- and postoperative analgesics. Currently available analgesics such as acetaminophen, gabapentin, ketamine, and nonsteroidal anti-inflammatory drugs (NSAIDs), as well as the increased adoption of regional anesthesia techniques, have the potential to reduce or eliminate opioid use during the perioperative period.

To date, several multimodal pain management strategies have been implemented, including the use of neuraxial and peripheral nerve blocks and regional anesthesia, combinations of nonopioid medications, and, as necessary, the combination of nonopioid and opioid analgesics 15 . The use of such MMA strategies have been shown to enhance patient recovery by reducing the occurrence of ORADEs and decreasing the length of stay in hospital recovery rooms, thereby reducing the burden on healthcare resources and improving patient quality of life16 . In the perioperative setting, most enhanced recovery after surgery (ERAS) protocols emphasize the use of such strategies 17 . The following section details several recent studies and protocols utilizing MMA opioid-sparing regimens.

Opioid-Sparing Pain Management Utilizing Multimodal Analgesia Protocols:

Several studies have been conducted on the use of multi-modal opioid-sparing pain management regimens for acute surgical care Table 1 . Such approaches can be used across age groups and surgery types, aiming to reduce the need for intraoperative and postoperative opioids, thereby improving patient satisfaction and recovery.

Table 1

Multimodal Approach	Opioid Monotherapy	Type of Surgery	Effect on Opioid Consumption/Prescription	Reference
Opioid Sparing
IV acetaminophen (1000 mg every 6 hours) plus opioids	Fentanyl, morphine, hydromorphone, meperidine, or oxycodone	Hysterectomy	26% reduction in opioid use over the total perioperative period (p = 0.001)	Herring et al., 2014 18
IV acetaminophen plus MSO4 (PCA)	MSO4 PCA	LaparoscopicRoux-en-Y gastric bypass	25% reduction in narcotic demand 24 hours postoperatively (p < 0.05)	Saurabh et al., 2015 19
IV acetaminophen (1000 mg every 6 hours) postoperatively plus opioids	Only opioids	Laparoscopic sleeve gastrectomy/ laparoscopic Roux-en-Y gastric bypass	Mean reduction of 27.7 mg morphine equivalents (p < 0.001)	Song et al., 2014 20
IV paracetamol (1000 mg) OR IV dexketoprofen (50 mg) plus PCA morphine	PCA with morphine	Lumbar disk surgery	Cumulative morphine consumption increased in all groups (p > 0.05)	Tunali et al., 2013 21
Dexmedetomidine infusion + intraoperative opioids	Intraoperative opioids alone	Open and laparoscopic gynecologic surgery	15 mg vs 21 mg morphine equivalents in PACU (p = 0.0003)	McQueen-Shadfar et al., 2011 22
Ketamine + PCA	Standard intraoperative anesthesia + PCA	Open ventral hernia repair	11.6 mg vs 47.6 mg MSO4 equivalents (p < 0.001)	Warren et al., 2017 23
Opioid Free
Gabapentin, 300 mg(10 total doses) OR active/inactive placebo	Previously prescribed opioids	Thoracotomy, video-assisted thoracoscopic surgery, primary or revision total hip replacement, primary or revision total knee replacement, unilateral or bilateral mastectomy, breast lumpectomy (with or without sentinel node biopsy or axillary node dissection), hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, and shoulder arthroscopy	24% increase in the rate of postoperative opioid cessation (p = 0.05)	Hah et al., 201724
Parecoxib/valdecoxib + supplemental analgesia	Placebo + supplemental analgesia	Major noncardiac surgery	31% decrease in postoperative opioid consumption vs placebo (p < 0.0001)	Langford et al., 2009 25
Ketorolac, clonidine, lidocaine, ketamine, magnesium sulfate, andmethylprednisolone	Sevoflurane and fentanyl	Gastric bypass surgery	5.2 mg/h morphine PCA vs 7.8 mg/h morphine PCA in the PACU	Feld et al., 2003 26
IV lidocaine + epidural analgesia	Saline + epidural analgesia	Complex spine surgery	55 mg vs 74 mg morphine equivalents (p = 0.011)	Farag et al., 2013 27

IV, intravenous; MSO, morphine sulfate; PACU, post-anesthesia care unit; PCA, patient-controlled analgesia

In addition, meta-analyses related to their use have also been conducted. A meta-analysis of 52 randomized trials evaluating the effect of multimodal analgesic options such as acetaminophen, NSAIDs, and selective COX-2 inhibitors in combination with morphine patient controlled analgesia (PCA) on opioid use in adults also reported a 15%‑55% decrease in median 24-hour morphine consumption versus controls 28. Similarly, a recent meta‑analysis of 31 randomized controlled trials evaluating the effect of NSAIDs and/or paracetamol used in combination with systemic opioids for pediatric perioperative pain management reported significant reductions in postoperative opioid use and superior pain relief in the multimodal analgesia group, with reductions in opioid use ranging from about 24% to 32% 29 . A meta-analysis of eight studies evaluating the effect of perioperative magnesium sulfate administration on intraoperative fentanyl consumption reported a reduction of 53.57 µg in fentanyl use in the magnesium sulfate group (p < 0.001) 30 .

A few case examples of opioid-sparing multimodal protocols pertaining to colorectal surgery are presented in Table 2 .

Table 2

Age (years)	Sex	Diagnosis	Procedure	Preoperative Medications	Perioperative Medications	Postoperative Medications	Discharge Medications	Discharge day (POD)
78	M	Transverse colon adenocarcinoma	Laparoscopic extended right hemicolectomy	None	Fentanyl 100 µg (once) Bupivacaine 40 ccAcetaminophen 1000 mg (once)	Ketorolac 15 mg IV q6h (5 doses) Acetaminophen 1000 mg IV q6h (3 doses)	Gabapentin 300 mg PO TID	3 days
69	M	Abnormal appendiceal orifice and abnormal cecum on CT	Laparoscopic right hemicolectomy	None	Fentanyl 100 µg (once) Acetaminophen 1000 mg (once) Bupivacaine 40 cc	Acetaminophen 1000 mg IV q6h (2 doses) Ketorolac 15 mg IV q6h (2 doses)	Tramadol 50 mg TID	2
27	F	Recurrent neo-terminal ileal Crohn disease	Laparoscopic Redo-ileocolic resection	Celecoxib 200 mg PO (once) Gabapentin 600 mg PO (once)	Fentanyl 100 µg (once) Bupivacaine 20 cc	Acetaminophen 1000 mg IV q6h (4 doses) Ketorolac 30 mg IV q6h (5 doses) Methocarbamol 500 mg PO (once) Tramadol 50 mg q4h (3 doses)	Tramadol 50 mg q6h	2
33	F	Familial adenomatous polyposis	Laparoscopic total proctocolectomy, ileoanal J-pouch to diverting ileostomy, transanal TME	Celecoxib 200 mg PO (once) Gabapentin 600 mg PO (once)	Fentanyl 100 µg (once) Acetaminophen 1000 mg (once)	Acetaminophen 1000 mg IV q6h (5 doses) Gabapentin 300 mg PO TID (6 doses) Ketorolac 30 mg IV q6h (7 doses) Tramadol 50 mg q4h (4 doses)	None	2
c

c, cubic centimeters; CT, computed tomography; IV, intravenous; PO, orally; POD, postoperative day; q4h, every 4 hours; q6h, every 6 hours; TID, three times a day; TME, total mesorectal excision.

In these patients, regional anesthetics such as bupivacaine along with ketorolac or intravenous (IV) acetaminophen were used perioperatively. Ketorolac, IV acetaminophen, methocarbamol/gabapentin, and tramadol used postoperatively in these example protocols allowed the prescription of relatively low doses of analgesics at dischargeFigure 1 .

CT, computed tomography; IV, intravenously; PO, orally.

Opioid-Sparing versus Opioid-Intensive Regimens: Patient Satisfaction and Cost Savings:

Patient Satisfaction and Quality of Life:

In comparison with opioid monotherapy, the use of a multimodal approach has been shown to provide several benefits for patients receiving intraoperative and perioperative pain medications. The most important among these are improved patient satisfaction and cost savings. Several studies have shown that patient satisfaction improves with the use of opioid-sparing multimodal pain management compared with standard opioid-based regimens. A pooled analysis of five methodologically similar, double-blind, randomized clinical trials evaluating patient satisfaction after surgery found that the use of perioperative regimens that included IV acetaminophen resulted in significantly higher rates of patient satisfaction than standard opioid-based regimens—32.3% of patients reported satisfaction ratings of “excellent” in the IV acetaminophen group versus 15.9% in the group receiving the standard opioid-based regimen 31 . In a prospective, randomized controlled trial that evaluated quality of recovery in patients undergoing surgery for breast cancer, patients reported significantly better pain scores and equal levels of comfort when multimodal opioid free anesthesia was used (ketamine, lidocaine, and clonidine) versus an opioid-based regimen 32 . A retrospective study of inpatients undergoing colorectal surgery reported a negative correlation between increased opioid doses and pain scores or levels of patient satisfaction. This study, which assessed 943 adult patients who underwent nonemergent colorectal surgery, reported an inverse association between opioid dose and pain-related patient satisfaction scores (p < 0.001) 33 . Similarly, a retrospective cohort study conducted on survey responses received from 2107 adult ED patients failed to find an association between opioid prescriptions, increasing morphine equivalents, and patient satisfaction scores 34 .

C ost-Related Outcomes:

In addition to outcomes related to patient satisfaction and recovery, multimodal pain management approaches provide benefits in terms of healthcare resource utilization and associated costs Figure 2 , with factors such as reduced occurrence of adverse events (AEs) and improved patient recovery and function being important contributors. Specifically, ORADEs such as postoperative ileus and respiratory depression contribute to increased costs, morbidity, and mortality, extended length of hospital stay, and higher rates of hospital re-admissions 35,36 .

Maiese 2017 37 and Apfel 2015 38 compared costs between MMA regimens that included IV APAP and MMA regimens without IV APAP or opioid based monotherapy. Xie 2013 39 included patients who received opioid prescriptions in ED or inpatient settings. Comorbidities such as arthritis, lower back pain, and other back/neck disorders were common at baseline. Duncan 2009 40 compared costs for patients undergoing lower-extremity joint replacement receiving the Mayo Clinic TJRA multimodal protocol versus those receiving standard-of-care pain management. Gold 201641 compared costs over a period of 12 months for patients who were prescribed LAOs after joint replacement surgery versus those who were not. p < 0.001 when IV APAP/MMA is compared to controls for all pain management regimens.

ED, emergency department; IV APAP, intravenous acetaminophen; LAO, long-acting opioid; MMA, multimodal analgesia; TJRA, total joint regional anesthesia.

A recent study assessing the incidence of postoperative ileus in patients undergoing gastric surgery reported that those who received higher morphine equivalent doses (MED; median MED 285 mg versus 95 mg, p < 0.0001) were twice as likely to develop ileus. The study also reported that patients who received opioids and developed ileus had re-admission rates 2.3%-5.3% higher than those who did not 42 . Similarly, an analysis of the MarketScan databases including patients prescribed opioids during ED or inpatient visits revealed that patients prescribed opioids incurred significantly higher overall healthcare resource utilization costs than those who were not prescribed opioids ($49,766 versus $19,875) 39 .

A retrospective analysis of postoperative pain management data from more than 140,000 patients undergoing hip or knee surgery showed significant reductions in total hospitalization costs in the group receiving IV acetaminophen-based multimodal analgesia versus the group receiving IV opioid monotherapy (p < 0.0001)37 . These findings were consistent with the results of a matched-pairs analysis of adult in-patients undergoing elective total hip arthroplasty or total knee arthroplasty, which showed that reductions in hospital costs may be due to a reduced length of hospital stay and a decreased occurrence of AEs 38 . Similarly, results from a comparison of a prospective cohort with retrospective historical controls in patients undergoing open abdominal hysterectomy showed that the length of hospital stay for patients receiving multimodal analgesia, including gabapentin, ketorolac, and IV acetaminophen, was significantly reduced compared with those receiving postoperative morphine alone (1.6 days versus 3.3 days; p < 0.001) 43 . In a retrospective cohort study of more than 225,000 obstetrics and gynecology patients undergoing surgery, a significant reduction in hospitalization costs and opioid use was observed among patients receiving multimodal IV acetaminophen-based analgesia compared with those receiving IV opioid analgesia alone (p = 0.0006; p < 0.0001). However, the difference in length of hospital stay between the two groups was not significantly different 44 . A study of patients who underwent joint replacement surgery also demonstrated long-term cost savings in patients who did not receive long-acting opioids (LAOs) versus those who did. The authors reported that postsurgical costs for up to 12 months differed significantly between the two groups, with the non‑LAO group accruing median costs of $8,400 versus $11,900 in the LAO group (p < 0.0001) 41 .

Evolving from Opioid-Sparing to Opioid-Free Pain Management:

While multi-modal opioid sparing approaches are now widely recommended, recognized, and used as part of ERAS protocols, opioid-free anesthesia appears to be feasible and may offer additional benefits for some patients and caregivers. A recent retrospective analysis of patients receiving analgesics for different types of surgery reported that patients and surgeons were equally satisfied with opioid-sparing and opioid free analgesia regimens. Of greater clinical importance, this analysis revealed that patient opioid use in both the post-anesthesia care unit (PACU) and the surgical postoperative unit doubled when an opioid-based/opioid-sparing regimen was used versus an opioid-free regimen (p < 0.007). Additionally, the authors reported that 73% of patients receiving opioid-free analgesia required no postoperative use of opioids versus approximately 35%-55% of patients in the other two groups 45 .

In this section, we summarize studies that have employed different types of opioid-free pain management protocols and comparisons with standard opioid-based regimens. As part of the search strategy, the MEDLINE database was searched using the terms “opioid” and “acute pain” or “postoperative pain.” English language articles published within the last 10 years focusing on comparisons between opioid-free pain management strategies and standard opioid-based strategies were retrieved. The abstracts of these articles were reviewed for relevance. Relevant clinical trials, retrospective analyses, and meta-analyses have been included below. Specifically, articles pertaining to opioid-free analgesia and patient outcomes (AE occurrence and recovery, patient satisfaction, and hospital discharge times) are discussed.

Several prospective studies have shown advantages of opioid-free pain management across different surgery types and patient populations. A randomized, controlled trial that included 80 patients undergoing laparoscopic cholecystectomy showed that opioid-free IV analgesia (dexmedetomidine, lidocaine, and propofol infusions) was significantly superior to standard opioid-based analgesia (remifentanil and propofol infusions) in terms of postoperative fentanyl use delivered via a PCA pump (at 2 hours post-surgery; p = 0.04), rescue analgesic need (p = 0.034), and pain scores measured on a 11-point numerical rating scale (NRS; p = 0.028) 46 . In another study, patients undergoing bariatric surgery were randomized to one of two anesthetic regimens, an opioid dependent one (OA; sufentanil) and an OFA group (dexmedetomidine, ketamine, lidocaine). Postoperative analgesia included paracetamol and morphine (delivered via a PCA pump). The OFA regimen was found to be significantly superior to the OA regimen in terms of AEs such as PONV, hypertension and bleeding, opioid consumption in the PACU and quality of recovery on the day after surgery (measured by the QoR40 scale) 47 . Similar differences were observed in another trial which included patients undergoing bariatric surgery at high risk for PONV. Patients were randomized to an opioid free TIVA regimen of propofol, ketamine, and dexmedetomidine or to a classic opioid containing regimen of fentanyl, sevoflurane and morphine/hydromorphone. In both groups, postoperative pain was treated with acetaminophen and ketorolac and breakthrough pain was treated with oxycodone or hydromorphone. The absolute risk of developing PONV was reduced by 17.3% in the opioid free group compared to the group receiving the classical opioid based regimen48 .

In a cohort of 48 breast cancer patients undergoing modified radical mastectomy, an opioid free anesthetic regimen (including lidocaine, bupivacaine and dexmedetomidine along with propofol induction and isoflurane maintenance) was compared with a standard opioid based anesthetic regimen (including injectable morphine and vecuronium along with propofol induction and isoflurane maintenance). The incidence of PONV, length of stay in the PACU, postoperative analgesic requirements, pain scores on a VAS scale and QoL scores on the Euro QoL-5D questionnaire were compared between groups. The opioid free regimen was associated with better outcomes on all parameters, along with significantly better patient satisfaction and hospital discharge times 49 .

Similarly, studies on pediatric patients have also demonstrated significant benefits of opioid free anesthetic regimens. In a randomized study conducted on children undergoing distal hand surgery, the use of an opioid free regimen including peripheral nerve blocks was compared to an IV-opioid based anesthetic regimen. The incidence of PONV, time to oral intake and time to meet discharge criteria were all reduced in the opioid free group 50 . Another trial conducted on 101 pediatric patients undergoing tonsillectomy compared outcomes between a fentanyl-based anesthetic regimen and a dexmedetomidine based one. Outcomes including rescue medication use (morphine sulfate), and incidence of PONV were assessed between groups. While the incidence of PONV and the proportion of patients requiring morphine rescue was lower in the group of patients receiving opioid free anesthesia, the length of stay in the PACU was significantly longer, in contrast to what was reported in previous studies 51 .

Apart from being assessed in prospective studies, opioid free approaches to surgical pain management have also been shown to be beneficial in cases of patients presenting with complications or in patients in whom the use of an opioid-based regimen was shown to be infeasible. For example, morbidly obese patients prone to respiratory depression 52,53 patients with a high risk of opioid induced PONV 54 post-partum patients 55 or those with opioid‑induced delirium 56 have been shown to benefit from such approaches. Additionally, the use of opioid free regimens also has specifically benefited patients with comorbidities such as diabetes, hypertension, and obesity, by preventing the occurrence of ORADEs (particularly respiratory depression) in high-risk patients 57,58.

Challenges in Implementing Opioid Free Multimodal Pain Management:

Despite the potential advantages of opioid free multimodal pain management strategies, there exist numerous challenges that prevent their widespread use. Patient expectations pertaining to pain relief, the requirement for an interdisciplinary approach to pain management, and short-term versus long-term cost and value estimations represent some of the major hurdles. Patient expectations with respect to pain levels often dictate the intensity/type of pain management regimen used and contribute to overall patient satisfaction. Thus, goals for acute pain management should not aim for zero pain, but rather focus on achieving a manageable level of pain. A survey of 522 ED patients concluded that many patients expect complete analgesia, and patient expectations with respect to pain relief do not vary based on the initial intensity of the pain they experienced 59

Postoperative addiction to opioids also is linked to several patient- and caregiver-related factors. Patient anxiety regarding impending pain and a heightened perception of pain can make it more difficult for an opioid free technique to be successful. Challenges in the management of patient dependence and withdrawal symptoms, and in the identification of appropriate personalized care on the part of caregivers also are important determinants for opioid addiction 60 . A recent analysis of perspectives of patients discharged from an urban ED after receiving pain medication revealed that approximately one of four (24.1%) patients were unaware that opioids could be addictive and approximately two of three patients (64.4%) did not discuss their personal experience with pain medication with their caregivers. Conversely, the analysis also identified that certain patients feared addiction to opioids and therefore risked inadequate pain control 61 .

In addition, the implementation of multimodal analgesic approaches is not always straightforward and often involves collaboration between different stakeholders, viz., surgeons, anesthesia providers, patients and their families. Discussions between patients and caregivers on expectations and long-term consequences of different analgesic approaches can help tailor the pain management regimen to the patients’ needs, and frequent communication between physicians and patients forms the cornerstone of effective patient-centered pain management 62 . Moreover, unanticipated patient-specific AEs and drug interactions may arise from the use of multiple analgesics (as recommended by multimodal pain management protocols) and hence, individualization of such regimens is required 63 . Thus, the implementation of opioid-free multimodal pain management strategies requires more planning and personalization and may be more time consuming at the outset. However, the positive long-term benefits of such an approach in terms of overall healthcare resource utilization, total time spent, and costs are currently under-recognized, and institution‑wide measures are required to tackle this issue. Recent examples of such measures include the presence of a dedicated acute pain service team comprising physicians and nurses across disciplines that enables rigorous surveillance of patient pain levels 64 .

Another major issue in implementing opioid-free multimodal pain management protocols is the perception value and cost estimation due to higher drug acquisition costs of multimodal pain medications when compared to opioids. Whereas lower direct costs (including drug acquisition costs, hospitalization costs, and costs related to AE management when accounted for together) are associated with multimodal approaches, drug acquisition costs alone may be lower for opioid‑based analgesia 65 .

As the biology of pain is further elucidated, new challenges will be presented. Recent research has shown that sensitivity to pain medication is dependent on and the result of the genetic constitution of the patient. The use of pharmacogenomics to predict patient response to individual analgesics and to optimize opioid-free analgesic regimens is therefore likely to emerge as an important area of investigation and clinical practice.