1. Starkweather, Angela PhD, ACNP-BC, CNRN, FAAN
  2. Perry, Mallory BSN, RN


The potential for accelerated recovery and postoperative rehabilitation by reducing the perioperative stress response was a concept put forth by Kehlet in the 1990s.1,2 Initial implementation of a multimodal enhanced recovery program in Denmark for patients undergoing colorectal surgery significantly reduced postoperative hospital stay from 8 to 12 days to 2 to 3 days and substantially decreased hospital costs.3 After this initial demonstration, a collaboration was formed between 5 centers in northern Europe, including Kehlet's team in Denmark, the Netherlands, Norway, Sweden, and England, to implement and evaluate standardized perioperative protocols.

Article Content

Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to:


1. Explain the development of enhanced recovery programs.


2. List the components of an enhanced recovery program.


3. Contrast the strategies used for perioperative pain management in different enhanced recovery protocols.


4. Compare outcomes from enhanced recovery implementation among different surgical patient populations.


Multimodal pain management is an important aspect of an Enhanced Recovery After Surgery (ERAS) program. This article reviews the development, implementation, and evaluation of enhanced recovery protocols, with specific focus on the perioperative and postoperative pain management strategies commonly incorporated in such programs. This article also addresses the need for greater multidisciplinary coordination so that enhanced recovery protocols can have a sustained impact on patient outcomes.


Conceptualization of ERAS Programs

The potential for accelerated recovery and postoperative rehabilitation by reducing the perioperative stress response was a concept put forth by Kehlet in the 1990s.1,2 Initial implementation of a multimodal enhanced recovery program in Denmark for patients undergoing colorectal surgery significantly reduced postoperative hospital stay from 8 to 12 days to 2 to 3 days and substantially decreased hospital costs.3 After this initial demonstration, a collaboration was formed between 5 centers in northern Europe, including Kehlet's team in Denmark, the Netherlands, Norway, Sweden, and England, to implement and evaluate standardized perioperative protocols.4 In 2009, the Department of Health in England established the Enhanced Recovery Program across 8 elective surgical procedures in 4 specialties: colorectal surgery, orthopedics, gynecology, and urology. Improvements in patient satisfaction and reduction in length of stay were documented.5 In 2010, the ERAS Society was established in Kista, Sweden.


Since then, ERAS programs have evolved to encompass a wide range of surgical procedures. Guidelines have been published by the ERAS Society for perioperative care of patients undergoing surgery for major head and neck cancer, bladder cancer, liver, rectal/pelvic diseases, colonic pathology, pancreaticoduodenectomy, gastrectomy, and bariatric and gynecologic-oncology surgery.6


The main goals of an ERAS program are to return the patients to their presurgical level of functioning as soon as possible, while reducing complications and costs. The ERAS approach is similar to clinical care pathways that have been used by nurses for decades. However, involvement of the entire health care team is embedded in the process of development and implementation.


By reducing variability in perioperative care and establishing milestones for recovery and rehabilitation, outliers can be identified earlier, so that appropriate provision of care and resources can be administered to improve patient outcomes. Implementation of ERAS has led to improved patient-reported outcomes, reduced complications, length of hospital stay, and costs.7 In fact, a recent study reported a significant positive association between the number of ERAS components that were adhered to and greater reduction in hospital length of stay and costs.8


Pain management is a critical component of an ERAS program. A major focus is on reducing the surgical stress response and the untoward side effects of traditional pre- or perioperative procedures, such as nasogastric decompression, excessive administration of IV fluids, and extended use of urinary catheters. The main target of an ERAS protocol is the surgical stress response, which is represented by hormonal and metabolic challenges that can result in altered endocrine-immune responses that influence organ function and development of complications.


Surgical Stress Response

The stress response because of surgery is characterized by increased secretion of pituitary hormones and activation of the sympathetic nervous system.9 Target organs are affected by increased secretion of pituitary hormones, resulting in increased catabolism to mobilize substrates for energy, and retention of salt and water to maintain fluid volume and cardiovascular homeostasis (Figure 1).

Figure 1 - Click to enlarge in new windowFigure 1. Surgical stress response. Proinflammatory cytokines activated at the surgical site initiate the inflammatory cascade, whereas primary afferent signals trigger the release of catecholamines from the adrenals. Increased secretion of hormones from the hypothalamus, primarily corticotropin-releasing hormone, stimulates secretion of anterior pituitary hormones ACTH and GH, which have significant metabolic consequences. Both cortisol and GH promote a catabolic phase characterized by increased oxygen consumption, glycolysis, and gluconeogenesis through the breakdown of muscle protein. (Image courtesy of Murgatroyd C, Spenger D. CC-BY 3.0 license.)

Hypothalamic activation of the sympathetic nervous system results in increased secretion of corticotropin-releasing hormone, which stimulates release of adrenocorticotropic hormone (ACTH) from the pituitary. Increased ACTH, in turn, stimulates release of cortisol from the adrenal cortex and catecholamines from the adrenal medulla, resulting in release of norepinephrine from presynaptic nerve terminals.10 Increased sympathetic activity results in cardiovascular responses of tachycardia and hypertension. Arginine vasopressin is secreted from the posterior pituitary and increases the reabsorption of water in the nephrons. Insulin release from the pancreas is diminished along with increased release of glucagon as more glucose is released from the liver, thereby causing a state of hyperglycemia.


In the state of surgical stress, carbohydrate, fat, and protein metabolism is altered.9,10 Specifically, cortisol decreases glucose use by most cells of the body and promotes lipolysis, thereby increasing the production of gluconeogenic precursors from the breakdown of triglyceride into glycerol and fatty acids. It increases the enzymes required to convert amino acids into glucose in the liver and causes mobilization of amino acids mainly from skeletal muscle. In turn, more amino acids become available in the plasma for gluconeogenesis in the liver in order to form glucose. This results in increased glycogen storage in the liver cells. Similar to cortisol, growth hormone (GH) release also increases blood glucose by stimulating glycogenolysis and through its anti-insulin effects. Cortisol inhibits the differentiation of monocytes into macrophages, can interfere with T-cell signaling and production of histamine, thereby decreasing immune cell migration and function.


Reduction of the surgical stress response is achieved by reducing fasting time of liquids to 2 hours before induction of anesthesia, and 6 hours for solids,11 avoiding hypothermia, fluid overload, postoperative pain, nausea, and vomiting and maintaining normoglycemia.12 In addition, early postoperative diet and early, scheduled mobilization are essential for returning the patient to baseline levels of function.


Components of ERAS Protocols

There are many general components of relevance across surgical procedures that should be considered when developing an ERAS program13,14 (Figure 2). These include preadmission information, presurgical counseling and medical optimization (including preoperative nutrition) correction of anemia, bowel preps, smoking cessation, reduction of alcohol consumption, physical activity, preoperative fasting, no/select premedication, anesthetic protocol, maintenance of normothermia, antibiotic and thromboembolic prophylaxis, early oral diet, prevention of postoperative nausea and vomiting, prevention of postoperative ileus, no/select surgical drain and sealants, postoperative analgesia, mobilization and exercise, discharge instructions, postdischarge support, and audits. Glycemic control, fluid balance (prevention of salt and water overload), early discontinuation of catheters, and stimulation of gut motility may also be relevant based on the type of surgery and surgical population.14

Figure 2 - Click to enlarge in new windowFigure 2. Components of an enhanced recovery program.

The development of an ERAS program requires a multidisciplinary and systems-level approach to make it successful because it involves a wide range of disciplines.15 Engagement of the surgeons, anesthesiologists, nurses, dieticians, and physical therapists is crucial for development and implementation and sustainability. Information about the evidence guiding an ERAS program should be given to patients and families to improve their engagement in the process. Focus on preparing the patient for the surgery entails providing presurgical consultations with the surgeon, anesthesiologist, nurses, and other health care team members, which can help alleviate anxiety and improve pain outcomes.16


In addition, the institutional systems must also be on board for successful implementation of an ERAS program. This entails supporting systems for communicating, tracking, and documenting the components of the ERAS program throughout the preoperative to postoperative periods. Institutional resources for monitoring implementation and evaluation, including patient-centered outcomes, should be established. The audit process plays an imperative role in measuring outcomes, identifying barriers to implementation, and assessing areas for improvement.14,15


The importance of providing adequate analgesia has been recognized in ERAS protocols because postoperative pain is one of the most significant reasons for delayed transfer or discharge.17 Pain management strategies during the pre-, intra- and postoperative periods involve multimodal pharmacologic interventions.


Preoperative Medications

Increased preoperative anxiety has been associated with poor postoperative outcomes including increased pain, analgesic requirements, and nausea.18,19 A review of 17 randomized controlled trials (RCTs) demonstrated that anxiolytic premedication in day surgery (benzodiazepines, opioids, or [beta]-blockers), as compared with placebo, was safe.20 However, there was significant heterogeneity in the sample populations and procedures, and the efficacy of preanesthetic anxiolytics was not evaluated.


More recently, an RCT that enrolled 1062 adults undergoing elective surgery under general anesthesia was conducted to evaluate the use of lorazepam (2.5-mg tablet) compared with no predication or placebo on patient satisfaction, time to extubation, and cognitive recovery.21 The premedication with lorazepam did not improve global ratings of patient satisfaction compared with the no premedication or placebo, even among patients with increased anxiety. Time to extubation was significantly longer (P < 0.001) and the rate of early cognitive recovery was lower (P < 0.001) in the lorazepam premedication group than in the no-premedication and placebo groups. Sedation with morphine or midazolam administration in healthy young adults was associated with increased pharyngeal and/or laryngeal dysfunction and discoordinated breathing and swallowing.22 The impairment in airway protection could increase the risk of pulmonary aspiration, particularly among older adults. Given the risks and lack of improvement in patient-centered outcomes, preoperative sedative hypnotics are not recommended.23 Instead, the focus should be on preventing anxiety by providing adequate presurgical psychological preparation and information that will help the patient and family to effectively manage their anxiety.


The effects of preemptive analgesics have been extensively studied. In a systematic review that included 80 RCTs of preemptive versus postincisional analgesia, there was no convincing evidence to support the use of preemptive analgesics [including nonsteroidal anti-inflammatory drugs (NSAIDs), IV opioids, N-methyl-D aspartic acid (NMDA) receptor antagonists, epidural anesthesia, and local infiltration].24


More recently, a meta-analysis compared preemptive analgesics with postoperative administration on pain intensity, requirement for additional analgesics, and time to first requirement by classifying 66 RCTs according to the type of analgesic administered.25 Local infiltration and NSAIDs decreased analgesic requirements and increased the time to first requirement, whereas epidural analgesia improved all 3 outcomes. In contrast, preemptive systemic opioids and NMDA receptor antagonists had the least impact. Based on these findings, it is common for ERAS protocols to include multimodal preemptive pharmacotherapy with NSAIDs, gabapentin, and acetaminophen.26-28


Strategies for Intraoperative Analgesia

ERAS protocols for intraoperative pain management rely heavily on the use of short-acting agents, regional anesthesia techniques, and epidural analgesics to shorten time to extubation, reduce complications including agitation, delirium, and cognitive impairment, and reduce hospital length of stay. A major emphasis is on using multimodal pharmacotherapy with emphasis on opioid-sparing modalities. Short-acting induction anesthesia, with agents such as propofol or dexmedetomidine, and opioids such as sufentanil and remifentanil are often included in ERAS.7 Likewise, short-acting muscle relaxants are suggested when they are indicated. Regional techniques, particularly epidural anesthesia, are important.29 Depending on the type of surgery and extent of tissue damage, a thoracic epidural catheter is recommended whenever possible to provide analgesia with a local anesthetic that does not include opioids, such as a transverse abdominis plane block. The benefits of epidural anesthesia have been demonstrated, especially in restoration of bowel function, reduction of postoperative insulin resistance, and shortened hospital stay.30 Injection of local anesthetics into the surgical wound may also be employed and has been shown to reduce opioid requirements.31-33


Multimodal analgesia is commonly employed in the intraoperative period, and may include the use of ketamine or lidocaine. Low-dose ketamine (0.3 mg/kg) has been shown to reduce the rise in C-reactive protein after emergency cesarean section in women with spinal anesthesia.34


Minimal-dose IV S-ketamine (a 0.015 mg/kg/h infusion after a saline bolus) showed equivalent reduction in postoperative opioid consumption and less delirium compared with low-dose S-ketamine (0.25 mg/kg bolus and 0.125 mg/kg/h infusion for 48 hours) and placebo in patients undergoing elective major abdominal surgery.35


After extubation, IV ketamine (0.5 mg/kg) and paracetamol 1 g resulted in an overall reduction in pain scores, decreased postoperative analgesic requirements and lower agitation score compared with IV paracetamol 1 g and tramadol 0.7 mg/kg for patients undergoing renal surgery.36


Ketamine may also be added for wound infiltration37,38 or with local anesthetic39 to provide pain relief.


IV lidocaine infusion has also been shown to have analgesic, anti-inflammatory, and antihyperalgesic properties. A systematic review of 8 trials comparing IV lidocaine with placebo in patients undergoing abdominal surgery showed a decrease in postoperative pain, duration of ileus, and length of hospital stay.40 An RCT comparing continuous infusion of lidocaine and thoracic epidural anesthesia in patients undergoing laparoscopic colorectal resection demonstrated no difference in return of gastrointestinal function and length of hospital stay.41 However, a more recent RCT in patients undergoing laparoscopic gastrectomy showed a reduction in postoperative fentanyl consumption and pain with preoperative and intraoperative injection of lidocaine by patient-controlled analgesia.42


Corticosteroids are commonly administered intraoperatively to reduce postoperative nausea, vomiting, and pain. In a recent RCT involving elective Roux-en-Y-gastric bypass patients, the effect of corticosteroid administration on postoperative nausea and vomiting was evaluated.43 Patients were randomly assigned to either 8-mg betamethasone orally (n = 50) or parentally (n = 25) or as controls (n = 25), in a double-blind design. There were no significant differences between groups on demographics or risk factors for nausea, and all patients had the same anesthetic technique. Between groups, neither peak values nor total amount of nausea differed and the number of supplemental injections was the same for all groups. Although this was a small-scale study, the results bring into question whether corticosteroids provide benefit in reducing postoperative symptoms. Because of effects on hyperglycemia and impaired wound healing, corticosteroids are not recommended in diabetic patients.


Postoperative Pain Management

Multimodal postoperative pain management is heavily emphasized in ERAS protocols. For minor or minimally invasive surgeries, oral analgesics may be adequate to provide sufficient pain relief.23 Epidural analgesia and local wound infiltration may be used for postoperative pain management for major surgeries. For abdominal surgery, the evidence is high that epidural analgesics should continue for 48 hours and, after a successful stop test, replaced by oral multimodal analgesia.7 If needed, functioning epidural catheters may be used for a longer duration. Epidural analgesia has been shown to reduce sympathetic stimulation (cortisol and epinephrine levels) and opioid consumption. Epidural analgesia has also been shown to increase levels of insulin, and may have a beneficial effect on immunological responses.44-46 The immunological benefits may be particularly relevant for surgeries in patients with cancer.47


Multimodal postoperative pain management may include both pharmacologic and non-pharmacologic therapies. Although opioids have long been a primary method of postoperative pain management, the use of opioids is limited by dose-related side effects, which have led to increased emphasis on multimodal analgesic regimens that reduce opioid demand. Using this approach, opioids are viewed as rescue analgesia when nonopioid analgesics are not enough to provide adequate pain relief. Therefore, a majority of ERAS protocols include routine administration of acetaminophen and NSAIDs, unless there are contraindications.7


Opioids can be administered intravenously via a patient-controlled analgesia pump or scheduled around the clock in the initial postoperative period. Using an opioid in conjunction with a nonopioid has been proven to be effective in the treatment of postoperative pain management and may enhance opioid analgesia.48 Nonopioids are not isolated to NSAIDs and acetaminophen, but may also include [alpha]-2 adrenoreceptor agonists (clonidine, dexmedetomidine), gabapentinoid anticonvulsants (gabapentin, pregabalin), NMDA-receptor antagonists (ketamine, dextromethorphan, memantine, magnesium), capsaicin, lidocaine, and dexamethasone.49,50


Although nonpharmacologic therapies are not typically addressed in ERAS protocols, some strategies have been found to provide significant postoperative pain relief including guided imagery, relaxation methods, music therapy, hypnosis, and intraoperative suggestions.51 Some studies using these approaches have demonstrated decreased opioid consumption and reduced symptom burden, but not all patients respond similarly.52 However, with the lack of adverse effects associated with their use, clinicians may incorporate these modalities as part of a multimodal program. More research is needed to identify the most effective nonpharmacologic modalities for augmenting analgesia. Currently, the inclusion of cognitive-behavioral modalities for postoperative pain management is only a weak recommendation with moderate-quality evidence because of the lack of comparative effectiveness trials to identify therapies that are most effective.51 However, clinicians are encouraged to discuss the use of cognitive-behavioral strategies with the patient and family as part of an overall perioperative pain management plan.


Other physical modalities that may be used include acupuncture, transcutaneous nerve stimulation (TENS), and cold therapy. Several studies have found decreased opioid consumption, postoperative nausea and vomiting, and urinary retention among patients receiving acupuncture as part of a multimodal postoperative pain management program. However, because of low-quality evidence, questions about its efficacy remain.52 Similarly, studies on cold therapy are difficult to summarize because of the wide range in regimens used between studies. Of these modalities, only TENS has shown a significant reduction in postoperative analgesic use when integrated as an adjunct to other postoperative pain treatments.51 Therefore, clinicians are encouraged to consider the use of TENS as an adjunct (weak recommendation, moderate-quality evidence).51


The differences in specific TENS regimens across studies does not allow for a recommendation on how it should be administered; it seems that TENS placed near the surgical site or at acupoints away from the incision provides similar results. Because of the lack of high-quality evidence on the use of acupuncture, massage, or cold therapy for postoperative pain, there are no recommendations provided on these modalities.


Along with adequate postoperative pain management, early scheduled postoperative mobilization is a priority in ERAS protocols. Pain is often one of the most significant barriers to early mobilization, along with urinary catheters and IV lines. However, early postoperative ambulation has been associated with less pain and adverse events over the course of hospitalization.53 Again, the use of multimodal therapies with pharmacologic and nonpharmacologic approaches can benefit early mobilization. Emphasis is on preparing the patient for early mobilization, providing instruction on correct techniques and use of nonpharmacologic modalities such as breathing, and premobilization analgesic administration.


A Multidisciplinary Journey

The implementation of an enhanced recovery program entails collaboration across disciplines, with each clinician adding his or her discipline-specific knowledge to reduce the surgical stress response and standardize surgical care throughout each phase.


Although uptake of ERAS programs has been slower in the United States than in Europe, Gillissen et al54 have shown that a concerted effort in implementing a multimodal perioperative care program is possible. In their pre-/post-noncontrolled study, 33 hospitals in Denmark participated in the implementation of an enhanced recovery program for elective colonic surgery. Participating hospitals reduced the length of stay by a median of 3 days, and evaluation of the program revealed higher adherence to the enhanced recovery program during the preoperative and intraoperative phases as compared with the postoperative phase. The elements of the enhanced recovery program that made the most impact included the cessation of IV fluids and mobilization on postoperative day 1, and administration of laxatives postoperatively.


As a follow-up to this landmark study, the authors evaluated the sustainability of the enhanced recovery program 3 to 5 years later among 10 of the hospitals that demonstrated successful implementation.55 Overall, the median length of stay increased slightly from 5.25 to 6 days but was not statistically significant. Adherence to postoperative elements showed the most variability, particularly in cessation of IV fluids in the first postoperative day, mobilization for more than 3 hours, and resumption of solid foods. Despite a slight decrease in protocol adherence and variance between hospitals, the authors concluded that the enhanced recovery program was sustained reasonably well in the 10 selected hospitals.55


The opportunity to capitalize on the enhanced recovery framework for perioperative pain management is noteworthy. Although guidelines are available for implementation,51 the translation into practice is often difficult to coordinate. The process encapsulated by the enhanced recovery framework can make this possible by garnering engagement by key stakeholders in administration and bedside clinicians who are making the decisions in patient care. Additional research on postoperative pain management is especially critical, particularly in the area of standardized weaning protocols for postoperative analgesics.



Multimodal perioperative pain management is a significant element of an enhanced recovery program. The enhanced recovery framework engages efforts across disciplines to reduce the surgical stress response, reduce adverse events, and improve patient outcomes after surgery. A heavy emphasis during the intraoperative period focuses on multimodal therapy with opioid-sparing techniques. Postoperative pain management includes scheduled use of nonopioid analgesics, adjunctive medications, and nonpharmacologic strategies. Studies on the implementation of enhanced recovery programs have shown the benefits in improving patient-centered outcomes, reducing complications, hospital length of stay, and costs.




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Enhanced recovery; Fast-track; Perioperative pain management