In 1994, Engelman and colleagues published the results of a fast-track recovery technique in patients undergoing coronary artery bypass surgery with modified anesthesia protocols, aiming to reduce the extubation time from 22.1 to 15.4 hours. This also led to a 21% shorter intensive care unit length of stay (LOS) and a 19% reduction on the hospital LOS, with comparable rates of morbidity and mortality.1 Other studies on rapid recovery programs (combined general and epidural anesthesia, early nutrition and mobilization, and reduced opioid use) reported shorter hospital stays after intestinal surgeries.2,3 On the basis of these results, a group of European surgeons developed the concept of multidisciplinary-multitask, patient-centered, and evidence-based perioperative protocols in 2001. This model broadened the spectrum of interventions from postoperative care to the entire perioperative period. The creators became known as the Enhanced Recovery After Surgery (ERAS) study group.4
The ERAS protocols seek to reduce the physiological response to the surgical insult. Twenty-four core elements are distributed along the patients’ pathway administered by different departments and professionals working in synergy between one element and the next.5 The protocols are under continuous audit and implement effective changes as new evidence comes to light to reduce LOS, complications, and readmissions.5 However, these short-term outcomes do not exactly reflect patients’ satisfaction and functional recovery after surgery.6 Lee et al7 considered postsurgical recovery as a complex multidimensional process that embraces a wide spectrum of physical, psychological, economical, and social domains with different implications.
Pain is one of the most distressing symptoms of the perioperative period and an ideal management strategy remains elusive. A United States national survey published in 2014 by Gan et al8 reported that 75% of patients experienced moderate to severe postoperative pain. Poorly controlled acute postoperative pain is reported as one of the main factors leading the transition to chronic postsurgical pain (CPSP), defined by the International Association for the Study of Pain as “pain beyond normal tissue healing which is assumed to be 3 months.”9–12 Chronic pain after surgery not only promotes chronic opioid use but also other analgesic medication, depending on the severity of pain.13 Elderly patients are confronted with long-term opioid and nonsteroidal anti-inflammatory drug (NSAID) usage associated with CPSP.
Opioids remain an important component of modern anesthesia and postoperative pain management.14 Multimodal anesthesia and analgesia based on opioid-free or opioid-sparing regimens (including regional anesthesia techniques) have demonstrated the ability to limit perioperative opioid consumption across several surgical specialties with diminished opioid exposure, availability of opioids, and the risk of prolonged use or misuse.15 Moreover, the various side effects (sedation, nausea and vomiting, respiratory depression, ileus, urinary retention, addictive potential) have a negative impact on LOS and patient satisfaction. Additionally, opioids are not always effective for postoperative pain management because their use at high doses can rapidly produce opioid-induced hyperalgesia (OIH) or tolerance.15
Although opioids have proven to be effective low-cost analgesics, their efficacy is more noticeable in rest pain than pain associated with the activity. Therefore, their role in functional recovery in patients with persistent postsurgical pain is questionable.16 Persistence of pain after surgery has additional deleterious effects, such as postoperative delirium, in some vulnerable groups of patients (elderly and oncological patients).17,18 However, the literature reports the prevalence of chronic use of opioid analgesics in patients that underwent surgery even in the absence of pain.19 Chronic opioid use is defined as “the need for filling 10 or more prescriptions for >120 days’ supply within a 1-year period.”20 There is evidence that the use of opioids during and after surgery to treat acute pain could increase the risk of long-term opioid use up to 44%.21 Moreover, conditions such as patient susceptibility and psychological or behavioral disorders may amplify the risk of chronic opioid use.20
In the last decade, a myriad of articles have discussed the implementation of ERAS protocols and opioid-sparing strategies during the perioperative period and quality of recovery in surgical patients. Nonetheless, the potential impact of ERAS programs implementation on prolonged use of opioids requires further investigation. However, sufficient body of evidence supports the association between ERAS pathways and a significant reduction in opioid consumption which potentially may have a positive impact on long-term opioid use, dependence, addiction, diversion, and misuse.22–28 On the other hand, medium and long-term impact of ERAS implementation is yet to be determined.22,29
We reviewed current scientific evidence on the role of ERAS implementations in reducing postoperative opioid consumption and their potential association with the risk reduction for long-term opioid use, physical opioid dependency, and opioid addiction.
An extensive review of the current literature to identify published full-length studies in PubMed and Embase was conducted using the following medical subject heading keywords: “postoperative pain,” “postoperative pain management,” “multimodal analgesia,” “ERAS,” “Enhanced Recovery,” “opioid-free analgesia,” or “opioid crisis.” Two authors screened and reviewed the articles independently for eligibility and the articles were selected if they were: (1) published in English language comparing ERAS and non-ERAS setting, (2) addressing pain management in ERAS setting, (3) systematic reviews and meta-analysis based on prospective and retrospective studies of ERAS short-term outcomes, (4) published between January 1, 2002, and June 30, 2019. The publications were excluded if they were: reviews of nonprimary objectives research abstract publications, specific to definite pain, case reports, focused on the evaluation of a specific opioid brand, a series of case reports, or not written in English. A final review of all databases was conducted on July 30, 2019.
RESULTS AND DISCUSSION
The Opioid Crisis in the USA
The 2014 National Survey on Drug Use and Health reported that >10 million people were using prescribed opioids for nonmedical reasons.30 Of these: 21% to 29% of patients misused the opioids prescribed for chronic pain, 8% to 12% developed an opioid use disorder, and 4% to 6% who misused prescription opioids transitioned to heroin.31 In addition, the vast majority of the 52,000 cases of reported overdoses in 2015 were a result of opioids and millions of Americans were struggling with opioid addiction or opioid abuse.30 Other figures displayed the growing significance of the public health crisis in the 30% increase in opioid overdoses from July 2016 through September 2017 in 52 areas in 45 states (54% in large cities of 16 states).32 In 2017, the consequences of these irrefutable statistics led to the Department of Health and Human Services declaration of the Opioid Epidemic within the United States and the proposition of a Master Plan to face this serious problem. This plan was based on five priority actions, of which “better practices for pain management” were established as the fifth specific strategy to fight the opioid crisis. Since then, opioid-sparing or opioid-free multimodal schemes for pain management during the perioperative period have solidified their importance in the ERAS models.15,33–36 So far, the abuse or misuse of opioids as a significant public health problem appear restricted to only the United States. Other countries with more stringent laws regulating the use of opioids have not yet reported the abuse of these drugs as a prominent health issue. Nevertheless, researchers from Denmark, Norway, and Sweden have recently discovered that prescriptions for oxycodone have significantly increased in all 3 countries during the last decade after liberating the regulatory measures of opioid prescriptions in patients with noncancer pain.37 In all likelihood, other factors besides a lack of stringent regulations may exist within different cultures of pain approach and opioid prescriptions outside of the United States.
Multimodal Opioid-free Analgesia (OFA) Within ERAS Pathways
The use of procedure-specific multimodal perioperative pain management within ERAS protocols offers a rational basis for optimal postoperative analgesia, fewer adverse effects, and enhanced patient satisfaction.
Multimodal analgesia (MMA), proposed by the ERAS Society, consists of a combination of pharmacological agents and nonpharmacological techniques acting on different pathways of the nociceptive mechanism (transduction, transmission, modulation, and perception).3,15,33,36Table 1 summarizes the meta-analyses conducted on postoperative pain for the ERAS setting that met our eligibility criteria.22,38,39
An effective OFA strategy depends on the synergistic effect of the simultaneous use of multiple pharmacological agents (NSAIDs, acetaminophen, gabapentinoids, dexmedetomidine, and ketamine), locoregional anesthesia techniques, and alternative therapies.15,33,40–44 Extensive evidence suggests that MMA regimens, implemented for postoperative pain management per ERAS protocols, are associated with a decrease in opioid dosing and subsequent side effects during the first 72 hours after surgery when compared with non-ERAS methodologies.15,33,35,40–42 However, opioid patient controlled analgesia (PCA) remains widely used as rescue medication, despite associated opioid-induced tolerance, and OIH or hyperpathia.45,46
ERAS pathways for pain management consist of multiple preoperative, intraoperative, and postoperative interventions interacting to provide an adequate level of analgesia and patient comfort while reducing or avoiding opioid consumption.33,39,47 The appropriate preoperative management of prevalent nociceptive conditions such as neuropathic pain and certain psychosocial factors may also positively impact the severity and duration of postoperative pain, and in some cases, result in the progression to chronic pain.11,12
ERAS Interventions in the Preoperative Period
The existence of preoperative neuropathic pain is more prevalent in certain surgical pathologies such as spinal surgery. The presence of preoperative or acute postoperative neuropathic pain is also a significant risk factor for higher postoperative pain scores and opioid consumption.48,49 Therefore, adequate diagnosis and treatment of this condition may help to improve postoperative pain scores and reduce disability.50,51
Preoperative chronic pain be associated with psychological conditions such as pain catastrophizing, anxiety, and depression, all of which may increase the intensity of postoperative pain.51 Preoperative evaluation of these factors, use of validated methods (Pain Catastrophizing Scale [PCS], Hospital Anxiety and Depression Scale [HADS]) helps to identify patients at risk, and/or stratify those already with any of the aforementioned psychological conditions. Pain catastrophizing behavior has been defined as a negative cognitive-affective state leading to the belief that actual or anticipated pain will inexorably result in the worst possible pain.51 This condition is believed to be a multidimensional construct comprising rumination, exaggeration, and pessimism of pain sensations and may also coexist with anxiety (fear, worry, apprehension) and depression (sadness, hopelessness).52 Early diagnosis and preoperative psychological intervention by mental health professionals have demonstrated an ability to reduce the severity of postsurgical pain and improve the quality of recovery.53 Unlike previously reported results, Dunn et al,54 in a recent prospective observational study, found that patients with higher catastrophizing scores (PCS≥30) were more prone to have maximum postoperative pain scores; however, the level of anxiety and depression did not correlate with postoperative opioid use.
Preoperative care may include the use of pharmacological analgesic agents and nonpharmacological methods seeking to minimize pain before surgery; however, the effectiveness of the administration of antinociceptive drugs before surgery remains controversial.35,41,55 Doleman et al43 published a meta-analysis concluding that preoperative acetaminophen administration reduced pain scores and opioid consumption, although the effect was limited to the initial 2 postoperative hours. Dexamethasone has also been used as preoperative medication showing a moderate reduction in postoperative pain. However, its use remains controversial due to potential side effects (disturbed sleep and fatigue, increased risk of infection, postoperative blood glucose elevation).56,57 Recently, an additional meta-analysis concluded that dexamethasone reduces postoperative pain as well as opioid consumption for up to 48 hours.44 Despite this, the efficacy of preoperative administration of gabapentinoids (gabapentin and pregabalin) to mitigate postoperative pain and lower opioid consumption remains unclear. Some meta-analyses report positive short-term outcomes within the first 24 hours after surgery but unfortunately, they also note a significant incidence of deleterious effects.58,59 A recent meta-analysis concluded that preoperative gabapentin or pregabalin administration was associated with reduced opioid consumption in the postanesthesia care unit, but only gabapentin decreased postoperative pain at 24 hours following breast cancer surgery.60 On the other hand, several meta-analyses reported no consistent evidence of gabapentin effectiveness in reducing postoperative pain and opioid use with associated side effects.61,62
Multimodal Opioid-Sparing Techniques in the Intraoperative Period
ERAS pathways that include opioid-free or opioid-sparing anesthesia techniques reduce the risk of OIH by limiting intraoperative opioid administration.20,24,47,63 The multimodal approach to achieve opioid-free postoperative analgesia starts in the intraoperative period with the use of nonopioid pharmacological agents such as acetaminophen, NSAIDs, alpha-2 agonists (dexmedetomidine, clonidine), N-methyl-D-aspartate antagonists (ketamine, Mg2+), glucocorticoids, and locoregional anesthesia (neuraxial and peripheral blocks).33,39,40 Intraoperative use of dexmedetomidine is effective for opioid-sparing analgesia during the first 24 hours after surgery. However, the side effects of dexmedetomidine such as hemodynamic instability, bradycardia, and somnolence have limited its postoperative use.64,65
Multimodal Strategies of OFA in the Postoperative Period
MMA based on OFA has emerged as a standard technique part of ERAS pathways, demonstrating its efficacy in controlling perioperative pain and minimizing total opioid exposure in various surgical procedures without affecting postsurgical pain scores. OFA also represents an important tool to limit opioid prescriptions after discharge as well as their excessive availability and health risks associated with prolonged use.33,39,47,66
The postoperative use of nonopioid medications on scheduled doses proved to be more effective in preventing or minimizing opioid-based PCA during the immediate postoperative period; however, their mid-term and long-term postoperative effectiveness has uncertain results.43,67–69 The addition of NSAIDs may improve pain control but has been associated with surgical complications such as a high risk of anastomotic leakage in gastrointestinal surgeries. Therefore, routine inclusion of selective or nonselective NSAIDs in pain management strategies should be determined considering the type of surgery.70–72 In addition, postoperative gabapentinoids used in many MMA protocols under ERAS guidelines provided inconsistent evidence on opioid-sparing and postoperative pain control.34,60–62
Noncompetitive N-methyl-D-aspartate antagonists, such as ketamine and magnesium avoid central sensitization to pain, and their use has been linked to a reduction in OIH and opioid tolerance up to 24 hours after surgery. It is suggested that low doses of ketamine (0.15 to 0.5 mg/kg) could be used as an adjunct for intraoperative MMA and during the postoperative period in patients at high risk for hyperalgesia, hyperpathia, or opioid tolerance.34,73,74
Neuraxial anesthesia techniques are part of the interventions for pain management with a growing tendency to use epidural anesthesia and regional blocks in a continuous mode.40,75,76 Locoregional techniques decreased rescue opioid-PCA use to treat breakthrough pain after surgery up to 3 days.77 A single-shot technique of nerve or periarticular infiltration with long-acting local anesthetic agents, such as liposomal bupivacaine, offered similar positive results.78
Continuous Thoracic Epidural Analgesia (CTEA)
CTEA with local anesthetics (bupivacaine, ropivacaine) is likely the core of neuraxial analgesia in ERAS protocols providing effective postoperative analgesia in open abdominal surgery with uncertain evidence in laparoscopic procedures.38,79 The combination of CTEA with peripheral blocks (transversus abdominis plane block) has been successfully used for postoperative pain management in patients undergoing rectal stump surgery80,81 and hepatectomies.82
Continuous High Thoracic Epidural
Continuous high thoracic epidural and paravertebral blocks are an integral part of ERAS protocols for thoracic surgery (open thoracotomy, video-assisted thoracotomy) improving the management of postoperative pain.83,84
Combining pectoral blocks and paravertebral block with systemic MMA has been effective in providing adequate postoperative analgesia and was included in recent ERAS guidelines for mastectomy and breast reconstruction.85,86 The use of intravenous ketorolac and local infiltration with liposomal bupivacaine and hydrochloride bupivacaine in patients undergoing lump mastectomy and breast reconstruction was linked to a reduced postoperative opioid requirement.87
Preoperative and postoperative nonpharmacological interventions such as physical therapy (transcutaneous electrical nerve stimulation, acupuncture, massage), and cognitive-behavioral therapy (relaxation, mindfulness) have shown favorable results reducing the severity of postoperative pain and have been included in the recommendations of the Guidelines From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists, music therapy, and reiki.40
The Transition From Acute to CPSP
The transition of acute postoperative pain to CPSP is a complex process and not completely understood, encompassing biological, psychosocial, and environmental factors.9,88 Recent publications estimate the incidence of persistent postsurgical pain to be 10% to 50% of surgical patients in the United States.20,88 Current ERAS protocols have been less effective for patients undergoing surgical procedures associated with direct nerve injury and postoperative neuropathic and/or inflammatory pain.9–12,89 Patients presenting with long-term severe pain after surgery are at risk of developing chronic opioid use as well as substance use disorder. Therefore, OFA strategies should continue to reduce this transition from acute pain to chronic pain syndromes that may lead to physical dependence or addiction9–11,20,88,90 (Table 2).
The aforementioned short-term outcomes could be triggered by patient-related factors in addition to surgical pain. Sufficient evidence has demonstrated that chronic opioid use before surgery plays an important role in persistent opioid use after surgery.91 According to some studies, 64% to 77% of chronic opioid users before surgery continue their long-term use postoperatively.92,93 Other relevant patient-related factors are: (1) younger females, although some authors have reported that males older than 50 years were associated with increased risk of persistent CPSP and chronic opioid use, (2) lower family income status, (3) specific comorbidities (diabetes, heart failure, pulmonary disease), (4) preoperative use of some drugs (benzodiazepines, angiotensin-converting enzyme inhibitors, selective serotonin reuptake inhibitors), (5) preoperative tobacco use, (6) preoperative substance and alcohol abuse and (7) preoperative pain syndromes.11,12,20,90,94
The greater weight of evidence suggests that CPSP can be minimized or prevented by aggressive analgesic perioperative multimodal approaches despite contradictory data.11,12
Role of ERAS Pathways on Postsurgical Opioid Prescription Patterns
Persistence of postsurgical pain after discharge is often accompanied by the renewal of opioid prescriptions that unintentionally lead to prolonged use.94 The results of a recent survey focused on identifying a correlation between postoperative prescription habits and long-term opioid use showed that patients often transition from a short-term opioid treatment for an acute pain condition such as surgery or trauma to long-term use (27.0%, 95% confidence interval, 18.5-35.5).95 Long-term opioid therapy is defined as the use of prescribed opioids beyond the acute recovery phase of a pain condition, usually for >90 consecutive days.94 The regulation of prescribed opioids for postoperative pain management is paramount considering that the majority of narcotic overdoses are connected to patients undergoing opioid treatment and their acquaintances.96 Opioid tolerance develops earlier than other adverse events such as gastrointestinal transit and respiratory depression.97 This physiological response poses a particular challenge to clinicians because the opioid requirement to maintain the analgesic effectiveness increases alongside the risk of addiction and/or overdose.98 Although prolonged exposure is associated with physical dependence or addiction, some physicians use these terms indistinctly.98,99 Physical dependence results from repeated exposure to opioids and is clinically expressed by a withdrawal syndrome when medication is discontinued (chills, dysphoria, irritability, agitation, piloerection, insomnia, cramps, diarrhea, nausea, vomiting, seizures). The severity of the withdrawal symptoms is associated with the potency of the opioid medication being used and the duration of treatment.100 Opioid addiction is less frequent, with a prevalence of <1% to 26%, and requires a longer period of exposure (usually months) to develop.100,101 Some of the addicted patients (15% to 26%) develop addiction-aberrant behaviors and only 4% to 6% transition to heroin use.100,102,103
ERAS protocols show conflicting results concerning discharge opioid prescriptions. Brandal et al104 analyzed prescriptions in colorectal surgery patients upon discharge and, despite a reduction in pain scores, opioid prescription did not change after ERAS implementation due to physician-prescribing behavior. Conversely, Gray et al,105 reported that 99% of gynecologic cancer patients were still prescribed opioids at discharge but the average number of pills was significantly reduced in ERAS patients. Rojas et al87 supported the latter and even stated that their ERAS protocols annulled the need for postoperative opioid prescriptions after breast lumpectomies up to 6 months after discharge. Nevertheless, a recent retrospective cohort study published by Smith et al106 revealed that ERAS implementation reduced opioid doses prescribed at discharge in opioid-naive patients undergoing gynecologic cancer surgery whereas chronic opioid users not only received higher doses of opioids upon discharge but also required more additional prescriptions within 30 days after discharge (29.4% vs. 7.6% P<0.001). Another retrospective study conducted by Hillman et al107 showed that 971 patients (45.8%) undergoing gynecologic surgery under the ERAS program did not use opioids before discharge. Hill et al108 had previously reported a 72% reduction in postoperative opioid consumption with the implementation of ERAS for gynecologic surgery. A prospective cohort study carried out by Ali et al in patients undergoing spinal and peripheral nerve surgery recently reported that patients in the ERAS group not only used fewer intravenous opioids during the acute postoperative period when compared with the non-ERAS group (0.5% vs. 54.1%, P<0.001), but also at 1 month after surgery (38.8% vs. 52.7%, P=0.041).109
The lack of knowledge and strategies for tapering opioids postoperatively is also a contributing factor for unplanned, long-term opioid therapy.40 A wider understanding of adverse pharmacological and behavioral effects of opioids that lie beneath their antinociceptive capabilities may promote beneficial changes in clinical and prescription practices.
Our perspective review identified a clear trend of ERAS protocols limiting intraoperative and postoperative opioid use by replacing them with different medications and nonpharmacological therapies. Patient and family counseling on perioperative opioid use, anxiety, and pain catastrophizing are important steps. Perioperative use of opioid-free anesthesia and analgesia regimens implemented as a significant component of ERAS protocols have proven to reduce or replace opioid use.
The multidisciplinary structure of ERAS integrates the work of health care providers on promoting the advantages of OFA techniques in postoperative pain management, and educates patients and family members on the importance of safe use and weaning after discharge. Including transitional pain services to ERAS may improve the acute and long-term management of pain by providing guidelines to prevent CPSP and support weaning from opioid medication. Patient-centered protocols like ERAS and perioperative surgical home have the potential to design more specific treatment plans for patients at risk for chronic opioid use and to modify prescription practices after discharge. However, there is no definitive evidence supporting the impact of ERAS programs on chronic opioid use. To date, more randomized control trials designed to quantify the impact of ERAS programs on opioid use at 6 to 12 months after hospital discharge must be completed. These studies should also focus on the long-term functional recovery of patients undergoing surgery under ERAS settings and provide a substrate for systematic reviews and meta-analyses.
The authors acknowledge Andrew Costa, BS, Department of Anesthesiology, The Ohio State University, College of Arts and Sciences, Wexner Medical Center, Columbus, OH (premedical program) for his contribution during the final editing process.
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