ERAS Protocols and Multimodal Pain Management in Surgery

*Gustavo Rodriguez, Emma Whiting and Juliet Lee*

#### **Abstract**

Pain is inherent to trauma and surgery, either by direct tissue trauma or by the activation of a surgical stress response characterized by endocrine, metabolic, and immunologic responses. Most pain from trauma and surgery is nociceptive in nature, but patients may also experience inflammatory and neuropathic pain. Therefore, it is necessary to consider the clinical context, patient factors, the type of trauma injury and surgery, the extent and degree of tissue involvement, and the severity of the response when deciding on pain management choices. In the past, surgery was approached mostly in an open fashion and led to a greater stress response and pain. Over the last 30 years, the minimally invasive approach with laparoscopic and robotic surgery has improved the experience of patients with regard to peri-operative pain. In addition, the advent of enhanced recovery protocols have sought to minimize this surgical stress response through targeting of pain control and pain management regimens. This chapter will focus on enhanced recovery after surgery protocols and multimodal pain regimens and will consider trauma and cancer patients as examples of surgical patients who benefit from this type of approach.

**Keywords:** enhanced recovery after surgery, multimodal pain management, post-operative pain, surgical stress response, trauma, cancer

#### **1. Introduction**

Trauma is sometimes described as the transfer of external energy to the human body, causing tissue disruption. Therefore, surgery can be considered controlled and orderly penetrating trauma in which the act of an incision, dissection, and retraction also imposes tissue changes. Both trauma and surgery can lead to similar stress responses including endocrine, metabolic, and immunologic or inflammatory responses.

The endocrine response to surgery includes activation of the hypothalamus, pituitary gland and the sympathetic nervous system [1]. Multiple endocrine effects such as secretion of cortisol from the adrenal cortex and vasopressin from the pituitary gland lead to metabolic changes. These culminate in an overall systemic effect characterized by increased catabolism, water resorption, and mobilization of stored energy within fat, glucagon within the liver, and skeletal and visceral protein. The activation of thyroid hormone increases glucose absorption from the gastrointestinal tract and stimulates the central and peripheral nervous systems.

The immunologic stress response involves the elaboration of cytokines where neutrophils, fibroblasts, and endothelial cells are activated. These proteins play a role in the inflammatory response to surgery and tissue trauma and promote systemic changes. The most prominent cytokines released in the post-operative period are interleukin-1, interleukin-6, and tumor necrosis factor-α. As a result, the secretion from the pituitary gland is augmented through secretion of adrenocorticotropic hormone and increasing the release of cortisol. In turn, this additional stimulation of cortisol amplifies the endocrine and metabolic responses to trauma and surgery [2].

Pain is an expected part of trauma and surgery and the wound itself elicits inflammatory and metabolic responses [3]. Direct stimulation of the hypothalamic–pituitary–adrenal axis is transmitted through small myelinated A-delta fibers and unmyelinated C fibers [4]. These nociceptive signals are then transmitted via sympathetic pathways at the level of the spinal cord. As a result, pro-inflammatory cytokines are secreted via the spinal cord as well as systemically [5]. Also, the pain stimulus itself has been demonstrated to elaborate endocrine, metabolic, and inflammatory responses [6].

From a clinical perspective, acute pain after trauma and surgery is a reminder of the local tissue injury and that pain is a protective mechanism to move away from a painful stimulus or to limit behaviors that would cause further tissue damage. Patients experience pain in both a physical and cognitive manner. Whether the physical pain is nociceptive, inflammatory or pathologic, insults from an external source or internally from a disease process lead to a systemic response. The affective and cognitive aspect includes the way patients experience pain and the cortical processing that occurs when pain is experienced.

In order to treat acute pain resulting from trauma and surgery, strategies should address the physical and cognitive aspects of how patients experience pain. Surgical and anesthetic techniques that mute the body's endocrine, metabolic or immunologic responses may serve to reduce pain responses.

#### **2. ERAS protocols**

Enhanced Recovery After Surgery (ERAS) is a multimodal perioperative protocol focused on evidence-based interventions to improve patient outcomes and recovery. ERAS was developed from the foundational work of Professor Henrik Kehlet of the University of Copenhagen in the 1990s where he discussed the pathophysiology behind the "surgical stress response" and designed a multimodal perioperative approach that differed from existing traditional consensus guidelines [7]. Building off Kehlet's early work, Professor Ken Fearon of the University of Edinburgh and Professor Olle Ljungqvist of the Karolinska Institutet founded the ERAS Study Group in 2001. The ERAS Study Group later became the ERAS Society, a non-profit organization whose mission is "to develop perioperative care and to improve recovery through research education, audit and implementation of evidence-based practice" [8]. ERAS protocols are based on more than 20 principal interventions throughout the pre-, intra-, and post-operative periods that aim to minimize surgical trauma and adverse outcomes, preserve appropriate physiologic function, as well as enhance the rate of recovery. ERAS guidelines exist for a variety of surgical subspecialties and even specific surgical interventions. ERAS compliance has been repeatedly demonstrated to reduce length of admission and complication rates [9] as well as be financially beneficial [10, 11].

#### **2.1 Pre-operative interventions for pain in ERAS**

In the pre-operative period, a variety of interventions are used to optimize a patient's readiness for surgery. These interventions are targeted to address modifiable risk factors and stabilize pre-operative physiology. The components of ERAS in the pre-operative period include preadmission counseling, pre-operative medical optimization, pre-rehabilitation, pre-operative nutrition and carbohydrate loading, thromboprophylaxis, and antibiotic prophylaxis.

An important initial part of pain management in ERAS is appropriate preadmission counseling. Pre-operative counseling is designed to ready the patient for surgery and provide the patient with needed information and realistic expectations regarding the peri-operative period. Ideally, this pre-operative education will include a discussion of post-operative pain. Although there is little up to date research into benefits of pre-operative education, general consensus guidelines support the use of pre-operative counseling in the case of all non-emergent surgeries. Egbert et al. [12] demonstrated a statistically significant reduction in post-operative narcotic use in patients who received pre-operative education of pain including relaxation techniques and discussion of pharmacologic methods to control pain. This was despite noting no difference in subjective grading of pain severity in this group compared to patients who did not received education or counseling. Additional benefits of pre-operative pain discussions include reduced fear and anxiety and reduced distress due to pain [13, 14].

#### **2.2 Intra-operative interventions for pain in ERAS**

At the time of surgery, ERAS protocol items are targeted to maintaining physiologic function and minimizing surgical trauma. These interventions are designed to attenuate the surgical stress response and prevent adverse outcomes as a result. The components of ERAS in the intra-operative period include preventing intra-operative hypothermia, anesthetic management, opioid-sparing pain control, minimallyinvasive surgery techniques, avoidance of prophylactic NG tubes and drains, nausea management, and peri-operative fluid management.

#### *2.2.1 Surgical technique*

Historically, procedures were performed in an open manner, where incisions allowed wide exposure of the involved structures. Newer developments in surgical technique such as minimally invasive surgery (MIS) require smaller surgical incisions and are designed to inflict less pain and trauma on the body. MIS encompasses both laparoscopic and robotic-assisted surgery techniques. Laparoscopy involves the use of a camera, also known as a laparoscope, and other elongated forms of surgical tools which are inserted through port sites at various locations on the abdomen or thorax. This allows surgeons to visualize structures and perform an operation entirely through multiple small surgical incisions. Robotic-assisted surgery is a newer approach where a surgeon controls laparoscopic tools from a console. This system uses instruments with an additional point of articulation as compared to laparoscopic instruments, which may allow for more precise, fine motor movements in the confined space of the abdomen, pelvis or thorax. The increased articulation of the robotic arms may further minimize tissue injury by decreasing the torque on the abdominal and chest wall and compensate for surgeon and patient characteristics that affect the ergonomics during the surgical intervention.

Open versus laparoscopic techniques have been extensively studied across a wide range of surgical procedures. In our review of the ERAS protocols for gastrectomy, bariatric surgery, and colorectal surgery, all protocols recommend the use of minimally-invasive surgery techniques whenever possible, appropriate, and within the expertise of the operating surgeon [15–17]. There is some variation in the grade of recommendation with colorectal and bariatric surgery giving a strong recommendation for MIS technique and gastrectomy recommendation varying based upon procedure and level of disease progression. In nine meta-analyses comparing open versus laparoscopic techniques in either distal gastrectomy [18–23] or total gastrectomy [24–26], the laparoscopic approach was consistently shown in all studies to have lower volume of blood loss. Laparoscopic surgery was associated with longer operating times and shorter hospital stays in 6 out of the 9 meta-analyses. In the studies that demonstrated shorter hospital stays with the minimally invasive approach, the hospital stay was 4–5 days less on average. A laparoscopic approach to gastric bypass was associated with shorter length of stay (LOS), earlier recovery, reduced rate of hernia and infection [27–30]. In multiple controlled trials in colorectal surgery, laparoscopic technique was associated with improved recovery, reduced length of stay, reduced blood loss, and complications [31–37]. Research comparing outcomes between laparoscopic and robotic-assisted surgery for colonic and rectal resection did not demonstrate significant differences in primary outcome measurements aside from reduced conversion rate associated with robotic technique and reduced operating time associated with laparoscopic method. Robotic-assisted surgery was associated with significantly increased cost despite not conferring major additional advantages [38, 39].

The LAFA-study, a nine-center randomized controlled trial (RCT) completed in 2011, compared outcomes including post-operative hospital stay, morbidity, reoperation rate, readmission rate, in-hospital mortality, quality of life, patient satisfaction, and in-hospital costs amongst open or laparoscopic and fast track multimodal management or standard care in the treatment of colon cancer [40]. The primary outcome of total post-operative hospital stay was dependent on the predefined discharge criteria which included adequate pain control with paracetamol and/or nonsteroidal anti-inflammatory drugs (NSAID), ability to tolerate solid foods, lack of nausea, passage of flatus or stool, mobilization, and acceptance of discharge. The laparoscopic/ fast track group had a median total post-operative hospital stay of 5 days as compared to 7 days in the open/fast track group, 6 days in the laparoscopic/standard group, and 7 days in the open/standard group (p < 0.001) [40]. Those in the laparoscopic/fast track group were meeting the defined discharge criteria earlier than the other categories implying that these fast-track and MIS interventions allowed for adequate pain control earlier in the post-operative course as compared to open and non-multimodal standard of care protocols.

#### *2.2.2 Opioid-sparing pain control and anesthetic management*

Pain control begins during the intra-operative period and continues into the post-operative period. Intra-operative pain control involves appropriate anesthetic management, the use of local anesthetics around incisions, and the use of additional pain-relieving adjunctive interventions. ERAS protocol suggests the use of multimodal opioid-sparing pain control regimens.

#### *2.2.3 Avoidance of prophylactic nasogastric (NG) tubes and drains*

In the pre-ERAS era, the use of drains and NG tubes were common despite lack of research support for these practices. In fact, the Cochrane review by Verma et al. [41] demonstrated that patients without NG tubes had an earlier return of bowel function and decreased complications. ERAS protocols suggest the avoidance of prophylactic NG tubes or drains given no clear benefit from their use in multiple studies and multiple types of surgery [41–45] as well as potential harms including pain and discomfort from the tube or drain, delayed nutrition, and decreased ambulation.

#### **2.3 Post-operative interventions for pain in ERAS**

Following surgery, ERAS guidelines focus on preventing complications and helping with the speed of recovery. The components of ERAS in the post-operative period include post-operative pain control, pain and nausea management, early oral nutrition, early ambulation, early catheter removal, prevention of post-operative ileus, and appropriate discharge criteria. In the post-operative period, it is an expectation that the patient will have some degree of pain because pain is an unavoidable sequelae of surgery. The goal of pain control in ERAS is not complete elimination of pain. Instead, the objective is dynamic pain relief, where pain is controlled to the point of allowing normal function in terms of both physiology and mobility.

#### *2.3.1 Nausea and prevention of post-operative ileus*

Post-operative nausea, vomiting, and ileus can be significant causes of patient pain and discomfort. Best practice recommendations for post-operative nausea and vomiting include the use of serotonin antagonists along with avoidance of opioid analgesics given their likelihood to cause GI side effects including nausea, constipation, and ileus. Other antiemetic medications commonly used include dopamine receptor antagonists, benzamides, and antihistamine medications. Other interventions targeted to minimize the risk of post-operative ileus include the use of central neural blocks. The rationale behind these neural blocks is two-fold as a method of pain control and acting as a sympathetic nerve block allowing for increased gastrointestinal motility and reduced rate of post-operative ileus [7].

#### *2.3.2 Early oral nutrition*

Historically, surgeons employed prolonged fasting periods after surgery with a gradual return to normal eating habits. Research has shown early nutrition to be associated with reduced rates of infections and decreased duration of hospital stay [46, 47], and demonstrated improvements in immune functioning [48, 49]. During the inflammatory reaction to trauma and surgical stress, hyperglycemia is common due to increased hepatic glucose production and decreased peripheral uptake [3]. This is compounded by relative insulin resistance. When cells do not have glucose readily available for metabolic needs, the body will enter into pathways that promote gluconeogenesis and leads to catabolism of skeletal and visceral protein. Because pain pathways and the immunologic stress response are linked, interventions that addresses insulin resistance would also mitigate pain responses and vice versa.

#### *2.3.3 Early ambulation*

Some interventions in ERAS that are designed to improve the rate of recovery may result in increased pain for the patient. ERAS protocols encourage prompt mobilization as early as the day of the operative procedure. Activity targets are dependent on pre-operative functioning and tolerance of physical activity requires adequate pain control. Although evidence of the positive benefits of early mobilization are limited, post-operative bed rest is associated with increased risk of thromboembolism and pulmonary complications. The surgical stress response causes both micro and macroscopic endothelial injury and post-operative immobilization increases venous stasis placing patients at significantly increased risk of thromboembolism regardless of the presence or lack of coagulopathy [7, 50, 51]. Bed rest and maintaining a supine position encourages positional-hypoxemia which may be improved with sitting positioning (>30° from horizontal) that allows for improved oxygenation, functional residual capacity, and decreased work of breathing [52]. Additionally, immobilization contributes to general catabolism and muscle wasting. An understanding of the pathophysiologic processes supports the continued use of this intervention despite its potential to cause patient discomfort.

#### **3. Multimodal pain management**

A central tenet of ERAS protocols is the use of multimodal pain management techniques. These techniques can be broken down into multiple subcategories including non-pharmacologic therapy, non-opioid pharmacotherapy, opioid pharmacotherapy, and regional anesthesia techniques. Multimodal pain management takes into consideration the multiple potential points of intervention for pain, targeting both ascending input to the brain and descending pain regulation pathways [53]. Using interventions at multiple points along the pain pathways helps to maximize pain control while minimizing unwanted effects or reliance on one specific strategy. The multimodal approach allows for plans tailored to the needs of the patient that can adapt and change with circumstances, pain control, patient preference, and symptoms.

#### **3.1 Non-pharmacologic pain management**

Non-pharmacologic pain management interventions can be used as adjunct therapies to traditional pain management techniques. These interventions can involve cognitive or physical strategies to reduce pain and discomfort. Common cognitive strategies include therapy (cognitive behavioral therapy, psychotherapy, music and art therapy), mindfulness and relaxation techniques, hypnosis, meditation, and virtual reality. Physical strategies include positioning, topical heat or cold application, acupuncture, massage, transcutaneous electrical nerve stimulation, and therapeutic ultrasound [53]. Many of these modalities are low cost interventions that confer minimal risk with potential benefit though quality of evidence of improved efficacy is variable.

#### **3.2 Non-opioid pharmacotherapy**

Various non-opioid medications exist and are commonly employed agents in standard pain control regimens. These include, but are not limited to anti-inflammatory

#### *ERAS Protocols and Multimodal Pain Management in Surgery DOI: http://dx.doi.org/10.5772/intechopen.111899*

drugs, local and regional anesthetics, gabapentinoids, symptom-driven adjuvant therapy, serotonin-norepinephrine reuptake inhibitors (SNRI), N-methyl-D-aspartate (NMDA) antagonists, and 2-agonists.

#### *3.2.1 Acetaminophen and NSAIDs*

Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of mild to moderate pain control in outpatient and inpatient settings. They can also be effectively employed in multimodal pain management approaches for more severe pain in the peri-operative period. Acetaminophen functions both as an analgesic and an antipyretic though its exact mechanism of action is unknown. NSAIDs inhibit cyclooxygenase and work as an analgesic, antipyretic, and antiinflammatory. General best practice recommendations include the use of these medications unless contraindicated. They can be used on an as needed basis or scheduled around the clock. These medications are preferably administered orally, but intravenous (IV) options are available in the setting of poor GI absorption or inability to tolerate oral intake.

#### *3.2.2 Symptom-driven adjuvant therapies*

Symptom-driven adjuvant therapies should be employed to target the specific symptoms that a patient is experiencing in the peri-operative period that are causing distress. This may include medications for symptoms including, but not limited to incisional pain, musculoskeletal pain, nausea and vomiting, and anxiety. Medications to consider in this category include lidocaine patches, skeletal muscle relaxants, and anti-nausea and antiemetic therapy.

#### *3.2.3 Neuropathic pain*

Most post-surgical pain fits into the category of nociceptive pain, where the pain results from damage to tissue and structures outside of the nervous system. Although to a smaller proportion, some degree of post-surgical pain may be of neuropathic origin. Initial management may include failed attempts with medications such as acetaminophen or NSAIDs, but neuropathic pain may be more responsive to a variety of alternative medications such as the antiepileptic and SNRI medication classes. Medications such as gabapentinoids and 2-agonists target reducing descending pain input through action on the presynaptic neuron.

#### **3.3 Opioid-pharmacotherapy**

Opioid medications are synthetic analogues of opiates and act on both ascending and descending pain pathways via action on opioid receptors, primarily - and -receptors. Opioid medications are incredibly effective methods of pain control, but come with significant risks including respiratory and central nervous system depression, and abuse potential. Other less severe effects include opioid-associated ileus, nausea and vomiting, and urinary retention. These side effects are non-desirable in a post-operative patient with recent abdominal surgery where the goal is to preserve normal physiologic functioning. Therefore, there is significant reason to avoid these medications when possible.

#### **3.4 Local and regional anesthesia techniques**

The use of local and regional anesthesia is a common practice that functions well in the multimodal pain management approach and can limit the need for other medications including opioids. Incisional lidocaine and the use of single injection nerve blocks are useful adjuncts that can be employed for short-term pain relief. Other methods include placement of a catheter in a particular region or nerve distribution and analgesic medication is continuously administered. This is generally used when analgesia will be required for greater than 12 hours. Some of the more common regional anesthesia blocks used in abdominal surgeries and trauma include epidural, paravertebral, and transverse abdominis plane (TAP). All of these options provide some relief of abdominal wall pain. The physiologic basis of the use of local and regional anesthetics is centered on the evidence that neural blockade attenuates the hormonal and inflammatory response [54] to surgery.

#### **4. Pain management in trauma patients**

Trauma is one of the leading causes of mortality in younger populations [55], but it can affect patients of all ages alike. Unsurprisingly, the most common complaint from trauma patients is pain. The management of this acute pain has been shown to be critical in improving patient outcomes after trauma; poor pain management is associated with longer hospital stays, delays in return to work, decreased quality of life, and increased risk of developing debilitating conditions like post-traumatic stress disorder (PTSD) and chronic pain [55–57]. Traditionally, opiates were one of the main pharmacologic agents used to treat pain caused by traumatic injuries. In recent years, trauma surgeons and emergency medicine physicians have shifted towards a multimodal approach to pain management by including non-opiate pharmacologic agents and regional anesthetics as part of the arsenal of treatments to alleviate acute pain. This shift in paradigm arises in the context of a worsening opioid epidemic in which trauma patients have higher rates of pre-injury opioid use, estimated to be as high as four times that of the average population [58]. The higher prevalence of pre-injury opioid use makes managing acute pain in trauma patients more challenging with patients developing some degree of tolerance to narcotics and putting them at increased risk of withdrawal. Consequently, the higher dose of narcotics required to manage their pain puts them at increased risk of developing dangerous adverse effects including oversedation, urinary retention, nausea, ileus, constipation, and respiratory depression. Considering trauma patients are often critically ill with multiple traumatic injuries, these effects can be deleterious.

#### **4.1 Pharmacologic options**

Patients who suffer significant traumatic injuries can present with a wide range of physiologic derangements in response to the acute stress from trauma, which can be far greater than that caused by elective surgery [58–60]. Special attention must be given to a patient's mental, hemodynamic and respiratory status when choosing an appropriate medication for pain relief in order to minimize further physiologic derangements [61]. Additionally, pharmacologic options for pain relief are further limited by route of administration. Oral medications are typically not first-line in the

#### *ERAS Protocols and Multimodal Pain Management in Surgery DOI: http://dx.doi.org/10.5772/intechopen.111899*

resuscitative period for several reasons including decreased absorption, inability to tolerate enteral intake due to mental status changes or injury to the digestive tract. Intravenously administered drugs are preferred given their rapid onset and more predictable effects. As patients recover from their acute injuries and their physiologic status approximates normalcy, additional pharmacologic and nonpharmacologic options become available.

#### *4.1.1 Opioid analgesics*

Although one of the main goals of multimodal analgesia is to optimize pain management while reducing the use of narcotic pain medications, opioids are still the cornerstone of pain management in trauma and critically ill patients given their familiarity, efficacy and known pharmacokinetics. Fentanyl is typically the opioid of choice in the acute resuscitative period, given its minimal effects on hemodynamics, rapid onset and short half-life. However, its short-acting effects means frequent dosing is required for adequate pain relief. Once in the intensive care unit (ICU), continuous infusions of systemic opioids are typically employed for pain management. However, inadequate titration of these medications can cause systemic drug accumulation and result in decreased cognition, ileus, and respiratory depression. A viable option for awake patients is IV narcotics such as hydromorphone or morphine delivered through a patient-controlled analgesic pump. Clinicians should also be aware of the paradoxical syndrome of Opioid-induced hyperesthesia (OIH). Although poorly understood, this syndrome has been observed in patients with chronic opioid use and is characterized by worsening pain with increasing doses of opioids. Furthermore, use of opioid analgesics induces tolerance and exposes patients to possible addiction. Use of other pharmacologic agents for pain relief overall can decrease these adverse effects while improving pain management.

#### *4.1.2 Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs)*

Although acetaminophen and NSAIDs may not provide adequate analgesia for severe pain alone, the use of these agents as part of multimodal therapies can be beneficial in pain management. Acetaminophen has been shown to reduce the use of opioids and sedatives in critically ill patients in doses up to 4,000 mg per day. Its availability in oral, rectal and IV formulations make it a viable option as part of a multimodal pain management in most patients.

The efficacy of NSAIDs like ketorolac, celecoxib and ibuprofen in critically ill patients has not been well studied. Their use is often overlooked due to their dosedependent side effects including gastritis, renal impairment and platelet dysfunction. Specifically in patients with rib fractures, the use of ketorolac has been shown to reduce the risk of pneumonia and ICU length of stays significantly, and use of IV ibuprofen reduces the use of opioids and overall hospital length of stay [62, 63]. Traditionally, some clinicians have been reluctant to prescribe NSAIDs in patients with fractures due to concerns regarding their effects on bone healing. A recent review of the evidence demonstrated that the data supporting the avoidance of NSAIDs in patients with fractures is conflicting and insufficient to formulate clinical recommendations [64–66]. Given their known benefits in relieving pain from musculoskeletal injuriesinjuries, some guidelines actually recommend the routine use of NSAIDs as part of multimodal pain management in patients with non-operative and operative fractures [67].

#### *4.1.3 Anticonvulsants*

Gabapentin and pregabalin are two commonly used anticonvulsants in some multimodal pain regimens. The mechanism of their analgesic effects is not entirely understood, but these medications have been effective in treatment of neuropathic pain [68]. Their effects on analgesia related to traumatic injuries is thought to be secondary to their suppression of nociceptive neuronal firing [58]. Their side effect profile which includes dizziness, somnolence, ataxia, convulsions, and visual disturbances, as well as their lack of IV formulations may limit their use in trauma patients. Some studies have shown benefits to using anticonvulsants in patients with phantom limb pain, post-thoracotomy pain, and burns [58, 69, 70]. Furthermore, use of these medications may help prevent transition of acute pain into chronic pain due to their dampening effect on neuronal pathways responsible for the hyperesthesia secondary to nociceptive stimuli [68].

#### *4.1.4 Ketamine*

The use of ketamine in the management of acute pain has been studied extensively in recent years. An NMDA receptor antagonist, ketamine has become one of the preferred agents for analgesia in trauma patients for multiple reasons. Its limited effects on hemodynamics, short half-life, quick onset of action, and limited CNS depression have identified it as a favored option in the acute resuscitative period after traumatic injuries [71, 72]. Unlike opioids, ketamine has no effect on the respiratory system and is especially useful in trauma patients who are at high risk of complications from respiratory depression due to multi-system injuries. Studies have shown it to be an effective agent in the treatment of acute pain and reduces the use of opioids in the pre-hospital and emergency room settings [73]. Use of analgesic-dose IV ketamine has been seen to reduce the need for narcotics in the postoperative period as well [74]. Furthermore, its use in traumatic brain injuries has become a preferred agent because of its neuroprotective effects [75].

#### *4.1.5 Other adjuncts*

The use of dexmedetomidine has shown promise in the perioperative period for trauma patients, with some studies showing decreased opioid use associated with administration of dexmedetomidine in patients undergoing intra-abdominal surgeries. The addition of dexmedetomidine as part of multimodal pain management is limited by its effects on hemodynamics including bradycardia and hypotension [76]. For this reason, dexmedetomidine is considered a better option for analgesia and sedation during the post-resuscitative phase [77]. Other adjuncts to pain management have been used in some perioperative settings, including IV lidocaine, though studies on its use in trauma populations has been limited [78].

#### **4.2 Non-pharmacologic options**

Use of regional analgesia, including peripheral nerve blocks (PNBs), fascial plane blocks and neuraxial blocks, has shown significant promise in the improvement of pain in patients with multiple injuries [79]. When appropriate, implementation of regional analgesia has been shown to decrease requirements for opioid and non-opioid analgesic in trauma patients requiring laparotomies

*ERAS Protocols and Multimodal Pain Management in Surgery DOI: http://dx.doi.org/10.5772/intechopen.111899*

[80]. Neuraxial blocks have demonstrated a reduction in the postoperative risk of venous thromboembolism and cardiopulmonary complications [81]. The effects of regional analgesia have been best described in cases of thoracic trauma and orthopedic injuries. Specifically, paravertebral blocks in patients with rib fractures have shown significant improvements in pulmonary function, pain control and decreased length of stay. Similar effects have been seen in elderly patients after hip fracture, and in addition, these patients experienced less delirium [82]. Because of these benefits of regional analgesia, early implementation of these modalities should be considered with consultation of an acute pain management service to provide satisfactory pain control in trauma patients.

#### **5. Pain management in cancer patients**

One of the most common symptoms for patients with cancer is pain, which can be secondary to the cancer itself or related to the treatment [83]. In the era of the opioid epidemic, there has been a drive to move away from opiate-centered pain management because cancer survivors have a higher risk of opioid misuse due to exposure to opioids during their treatment [84]. The American College of Physicians (ACP), National Comprehensive Cancer Networks (NCCN), the National Cancer Institute (NCI), and the American Society of Clinical Oncology (ASCO) have developed guidelines for the management of cancer-related pain with the overarching concept of using a combination of pharmacologic and nonpharmacologic modalities for pain management. By employing a multimodal approach to pain management clinicians can enhance pain relief and limit side effects from the treatment of pain. This becomes especially important in patients who are already suffering significant side effects from undergoing cancer treatment.

#### **5.1 The WHO analgesic ladder**

In an effort to improve cancer-related pain management, the World Health Organization (WHO) developed an "analgesic ladder," a guideline for clinicians to use in their efforts to treat their patients' pain [85]. Originally established in 1986, the analgesic ladder has been modified over the years to include other non-cancer related painful conditions, acute and chronic. The guideline consists of a step-wise approach to pain management starting with non-opioid medications, including NSAIDs and acetaminophen along with other adjuvants, followed by the introduction of weak and then potent opioids. A progressive plan based on pain levels adjusts dosing to balance pain relief with the associated negative side effects these medications may cause. Importantly, this stepwise management is based on the continuous assessment of a patient's level of pain in order to effectively develop individualized, patient-centered treatment plans that can be modified as a patient progresses through the course of the disease.

The first step includes basic non-opioid medications like acetylsalicylic acid (ASA), paracetamol, ibuprofen, indomethacin, and other alternatives. The second step includes "weak" opioids for mild to moderate pain, which include codeine, dihydrocodeine, and tramadol. The third step introduces "potent" opioids, or opioids used for moderate to severe pain. These include morphine, methadone, oxycodone, and buprenorphine. Adjuvant medications are added throughout these steps to manage unwanted side effects, enhance pain relief or for the treatment of concomitant

problems like anxiety, insomnia and depression. These medications include antiemetics to treat nausea, laxatives to treat constipation, corticosteroids for the treatment of nerve compression or bone metastases, and psychotropic medications to treat anxiety, depression or other associated conditions. A distinction is also made for neuropathic pain, for which use of tricyclic antidepressants (TCAs) and antiepileptic drugs are recommended [86].

#### **5.2 Nonpharmacologic alternatives to pain management**

Initially the analgesic ladder consisted of three steps, each introducing only pharmacologic options for pain management. In recent years, however, the WHO has added a fourth step to include invasive and minimally invasive procedures as a way of managing pain that persists despite optimal pharmacologic therapy. These include epidural and intrathecal analgesia, neurosurgical procedures, neuromodulation strategies, peripheral nerve stimulation, nerve blocks, ablative procedures, and palliative radiotherapy. These techniques have been shown to be effective in the treatment of some cancer-related pain [86–90]. Additionally, integrative medicine therapies like hypnosis, acupuncture and music therapy have also been shown to play a role in the reduction of pain [91].

#### **6. Conclusions**

Surgery and traumatic injuries are on a spectrum of energy transfer to the body leading to tissue disruption. As a result of the tissue disruption, multiple responses occur which elaborate a cascade of reactions that cause and augment the pain response. In the management of pain in the peri-operative period, multimodal pain management has evolved as the preferred strategy to control pain and to mitigate the surgical stress response. The ERAS protocols and guidelines for pain control in the injured patient and cancer patient might be summarized in the word "PAIN" itself, now used as a mnemonic. In order, pain control starts with "P" for prevention through use of local anesthesia prior to incision and/or dissection that reduces the endocrine and inflammatory response. Next, patients should be offered "A" for anti-inflammatory agents, followed by "I" for intervention consisting of neural blocks such as epidural or spinal interventions as well as blocking the distribution of named nerve. Finally, "N" for narcotics should be considered for moderate and severe pain and after the previous methods have been attempted so that we move away from opioids as a singular choice. This approach may help to address some of the issues with the opioid crisis.

#### **Conflict of interest**

The authors declare no conflict of interest.

*ERAS Protocols and Multimodal Pain Management in Surgery DOI: http://dx.doi.org/10.5772/intechopen.111899*

#### **Author details**

Gustavo Rodriguez1 , Emma Whiting2 and Juliet Lee1 \*

1 Department of Surgery, George Washington University School of Medicine and Health Sciences, DC, USA

2 George Washington University School of Medicine and Health Sciences, DC, USA

\*Address all correspondence to: jclee@mfa.gwu.edu

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Desborough JP, Hall GM. Endocrine response to surgery. In: Kaufman L, editor. Anaesthesia Review. Vol. 10. Edinburgh: Churchill Livingtone; 1993. pp. 131-148

[2] Desborough JP. The stress response to trauma and surgery. British Journal of Anaesthesia. 2000;**85**(1):109-117

[3] Carli F. Physiologic considerations of enhanced recovery after surgery (ERAS) programs: Implications of the stress response. Canadian Journal of Anaesthesia. 2015;**62**(2):110-119. DOI: 10.1007/s12630-014-0264-0 Epub 2014 Dec 12

[4] Kehlet H. Surgical stress: The role of pain and analgesia. British Journal of Anaesthesia. 1989;**63**:189-195

[5] Wolf G, Livshits D, Beilin B, Yirmiya R, Shavit Y. Interleukin-1 signaling is required for induction and maintenances of postoperative incisional pain: Genetic and pharmacologic studies in mice. Brain, Behavior, and Immunity. 2008;**22**:1072-1077

[6] Griesen J, Juhl CB, Grofte T, Vilstrup H, Jensen TS, Schmitz O. Acute pain induces insulin resistance in humans. Anesthesiology. 2001;**95**(3):578-584

[7] Kehlet H. Multimodal approach to control postoperative pathophysiology and rehabilitation. British Journal of Anaesthesia. 1997;**78**(5):606-617

[8] ERAS® Society. History [Internet]. 2023. Available from: https://erassociety. org/about/history/ [Accessed: April 30, 2023]

[9] Ljungqvist O. ERAS--enhanced recovery after surgery: Moving evidence-based perioperative

care to practice. JPEN. Journal of Parenteral and Enteral Nutrition. 2014;**38**(5):559-566

[10] Noba L, Rodgers S, Doi L, Chandler C, Hariharan D, Yip V. Costs and clinical benefits of enhanced recovery after surgery (ERAS) in pancreaticoduodenectomy: An updated systematic review and meta-analysis. Journal of Cancer Research and Clinical Oncology. Advance Online Publication. 2023;**11**:1-22. DOI: 10.1007/ s00432-022-04508-x

[11] Noba L, Rodgers S, Chandle C, Balfour A, Hariharan D, Yip VS. Enhanced recovery after surgery (ERAS) reduces hospital costs and improve clinical outcomes in liver surgery: A systematic review and meta-analysis. Journal of Gastrointestinal Surgery. 2020;**24**(4):918-932

[12] Egbert LD, Battit GE, Welch CE, Bartlett MK. Reduction of postoperative pain by encouragement and instruction of patients - a study of doctor-patient rapport. NEJM. 1964;**270**:825-827

[13] Hathaway D. Effect of preoperative instruction on postoperative outcomes: A meta-analysis. Nursing Research. 1986;**35**(5):269-275

[14] Mogan J, Wells N, Robertson E. Effects of preoperative teaching on postoperative pain: A replication and expansion. International Journal of Nursing Studies. 1985;**22**(3):267-280

[15] Stenberg E, dos Reis Falcao LF, O'Kane M, Liem R, Pournaras DJ, Salminen P, et al. Guidelines for perioperative Care in Bariatric Surgery: Enhanced recovery after surgery (ERAS) society. Recommendations:

A 2021 update. World Journal of Surgery. 2022;**46**:729-751

[16] Gustafsson UO, Scott MJ, Hubner M, Nygren J, Demartines N, Francis N, et al. Guidelines for perioperative Care in Elective Colorectal Surgery: Enhanced recovery after surgery (ERAS®) society recommendations: 2018. World Journal of Surgery. 2019;**43**:659-695

[17] Mortensen K, Nilsson M, Slim K, Schäfer M, Mariette C, Braga M, et al. Consensus guidelines for enhanced recovery after gastrectomy. The British Journal of Surgery. 2014;**101**:1209-1229

[18] Ding J, Liao GQ, Liu HL, Liu S, Tang J. Meta-analysis of laparoscopyassisted distal gastrectomy with D2 lymph node dissection for gastric cancer. Journal of Surgical Oncology. 2012;**105**(3):297-303

[19] Memon MA, Khan S, Yunus RM, Barr R, Memon B. Meta-analysis of laparoscopic and open distal gastrectomy for gastric carcinoma. Surgical Endoscopy. 2008;**22**(8):1781-1789

[20] Ohtani H, Tamamori Y, Noguchi K, Azuma T, Fujimoto S, Oba H, et al. A meta-analysis of randomized controlled trials that compared laparoscopy-assisted and open distal gastrectomy for early gastric cancer. Journal of Gastrointestinal Surgery. 2010;**14**(6):958-964

[21] Viñuela EF, Gonen M, Brennan MF, Coit DG, Strong VE. Laparoscopic versus open distal gastrectomy for gastric cancer: A meta-analysis of randomized controlled trials and high-quality nonrandomized studies. Annals of Surgery. 2012;**255**(3):446-456

[22] Yakoub D, Athanasiou T, Tekkis P, Hanna GB. Laparoscopic assisted distal gastrectomy for early gastric cancer:

Is it an alternative to the open approach? Surgical Oncology. 2009;**18**(4):322-333

[23] Zeng YK, Yang ZL, Peng JS, Lin HS, Cai L. Laparoscopy-assisted versus open distal gastrectomy for early gastric cancer: Evidence from randomized and nonrandomized clinical trials. Annals of Surgery. 2012;**256**(1):39-52

[24] Bracale U, Rovani M, Bracale M, Pignata G, Corcione F, Pecchia L. Totally laparoscopic gastrectomy for gastric cancer: Meta-analysis of short-term outcomes. Minimally Invasive Therapy & Allied Technologies. MITAT. 2012;**21**(3):150-160

[25] Martínez-Ramos D, Miralles-Tena JM, Cuesta MA, Escrig-Sos J, Van der Peet D, Hoashi JS, et al. Laparoscopy versus open surgery for advanced and resectable gastric cancer: A meta-analysis. Revista espanola de enfermedades digestivas. 2011;**103**(3):133-141

[26] Huang YL, Lin HG, Yang JW, Jiang FQ, Zhang T, Yang HM, et al. Laparoscopy-assisted versus open gastrectomy with D2 lymph node dissection for advanced gastric cancer: A meta-analysis. International Journal of Clinical and Experimental Medicine. 2014;**7**(6):1490-1499

[27] Luján JA, Frutos MD, Hernández Q, Liron R, Cuenca JR, Valero G, et al. Laparoscopic versus open gastric bypass in the treatment of morbid obesity: A randomized prospective study. Annals of Surgery. 2004;**239**(4):433-437

[28] Nguyen NT, Goldman C, Rosenquist CJ, Arango A, Cole CJ, Lee SJ, et al. Laparoscopic versus open gastric bypass: A randomized study of outcomes, quality of life, and costs. Annals of Surgery. 2001;**234**(3):279-291

[29] Westling A, Gustavsson S. Laparoscopic vs open roux-en-Y gastric bypass: A prospective, randomized trial. Obesity Surgery. 2001;**11**(3):284-292

[30] Buchwald H, Estok R, Fahrbach K, Banel D, Sledge I. Trends in mortality in bariatric surgery: A systematic review and meta-analysis. Surgery. 2007;**142**(4):621-635

[31] Bonjer HJ, Deijen CL, Abis GA, Cuesta MA, van der Pas MH, de Lange-de Klerk ES, Lacy AM, Bemelman WA, Andersson J, Angenete E, Rosenberg J, Fuerst A, Haglind E, COLOR II Study Group. A randomized trial of laparoscopic versus open surgery for rectal cancer. NEJM 2015; 372(14): 1324-1332

[32] Green BL, Marshall HC, Collinson F, Quirke P, Guillou P, Jayne DG, et al. Long-term follow-up of the Medical Research Council CLASICC trial of conventional versus laparoscopically assisted resection in colorectal cancer. The British Journal of Surgery. 2013;**100**(1):75-82

[33] Guillou PJ, Quirke P, Thorpe H, Walker J, Jayne DG, Smith AM, et al. Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): Multicentre, randomised controlled trial. Lancet. 2005;**365**(9472):1718-1726

[34] Jeong SY, Park JW, Nam BH, Kim S, Kang SB, Lim SB, et al. Open versus laparoscopic surgery for mid-rectal or low-rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): Survival outcomes of an open-label, noninferiority, randomised controlled trial. The Lancet. Oncology. 2014;**15**(7):767-774

[35] Kang SB, Park JW, Jeong SY, Nam BH, Choi HS, Kim DW, et al. Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): Short-term outcomes of an open-label randomised controlled trial. The Lancet. Oncology. 2010;**11**(7):637-645

[36] Lacy AM, Delgado S, Castells A, Prins HA, Arroyo V, Ibarzabal A, et al. The long-term results of a randomized clinical trial of laparoscopy-assisted versus open surgery for colon cancer. Annals of surgery. 2008;**248**(1):1-7

[37] Weeks JC, Nelson H, Gelber S, Sargent D, Schroeder G. Clinical outcomes of surgical therapy (COST) study group. Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: A randomized trial. Journal of the American Medical Association. 2002;**287**(3):321-328

[38] Phan K, Kahlaee HR, Kim SH, Toh JW. Laparoscopic vs. robotic rectal cancer surgery and the effect on conversion rates: A meta-analysis of randomized controlled trials and propensity-score-matched studies. Techniques in Coloproctology. 2019;**23**:221-230

[39] Huang YJ, Kang YN, Huang YM, Wu AT, Wang W, Wei PL. Effects of laparoscopic vs robotic-assisted mesorectal excision for rectal cancer: An update systematic review and metaanalysis of randomized controlled trials. Asian Journal of Surgery. 2019;**42**(6):657-666

[40] Vlug MS, Jan W, Hollmann M, Ubbink DT, Cense H, Engel AF, et al. Laparoscopy in combination with fast track multimodal management is the best perioperative strategy in patients undergoing colonic surgery: A randomized clinical trial (LAFA-study). Annals of Surgery. 2011;**254**(6):868-875

*ERAS Protocols and Multimodal Pain Management in Surgery DOI: http://dx.doi.org/10.5772/intechopen.111899*

[41] Verma R, Nelson RL. Prophylactic nasogastric decompression after abdominal surgery. Cochrane database of systematic reviews. 2007;**3**:CD004929

[42] Rao W, Zhang X, Zhang J, Yan R, Hu Z, Wang Q. The role of nasogastric tube in decompression after elective colon and rectum surgery: A metaanalysis. International journal of colorectal disease. 2011;**26**:423-429

[43] Tanguy M, Seguin P, Mallédant Y. Bench-to-bedside review: Routine postoperative use of the nasogastric tube – Utility or futility? Critical Care. 2007;**11**(1):1-7

[44] Ichida H, Imamura H, Yoshimoto J, Sugo H, Ishizaki Y, Kawasaki S. Randomized controlled trial for evaluation of the routine use of nasogastric tube decompression after elective liver surgery. Journal of Gastrointestinal Surgery. 2016;**20**:1324-1330

[45] Peter SDS, Valusek PA, Little DC, Snyder CL, Holcomb GW III, Ostlie DJ. Does routine nasogastric tube placement after an operation for perforated appendicitis make a difference? Journal of Surgical Research. 2007;**143**(1):66-69

[46] Moore FA, Feliciano DV, Andrassy RJ, McArdle AH, Booth FV, Morgenstein-Wagner TB, et al. Early enteral feeding, compared with parenteral, reduces postoperative septic complications. The results of a meta-analysis. Annals of surgery. 1992;**216**(2):172-183

[47] Carr CS, Ling KD, Boulos P, Singer M. Randomised trial of safety and efficacy of immediate postoperative enteral feeding in patients undergoing gastrointestinal resection. BMJ. 1996;**312**(7035):869-871

[48] Alexander JW. Immunoenhancement via Enteral Nutrition. Archives of Surgery. 1993;**128**(11):1242-1245

[49] Daly JM, Weintraub FN, Shou J, Rosato EF, Lucia M. Enteral nutrition during multimodality therapy in upper gastrointestinal cancer patients. Annals of surgery. 1995;**221**(4):327-338

[50] Convertino VA. Cardiovascular consequences of bed rest: Effect on maximal oxygen uptake. Medicine and Science in Sports and Exercise. 1997;**29**(2):191-196

[51] Kehlet H, Wilmore DW. Multimodal strategies to improve surgical outcome. American Journal of Surgery. 2002;**183**(6):630-641

[52] Mezidi M, Guérin C. Effects of patient positioning on respiratory mechanics in mechanically ventilated ICU patients. Annals of Translational Medicine. 2018;**6**(19):384-392

[53] Best Practice Guidelines for Acute Pain Management in Trauma Patients. American College of Surgeons Trauma Quality Programs. 2020. Available from: https://www.facs.org/media/exob3dwk/ acute\_pain\_guidelines.pdf [Accessed: April 30, 2023]

[54] Uchida I, Asoh T, Shirasaka C, Tsuji H. Effect of epidural analgesia on postoperative insulin resistance as evaluated by insulin clamp technique. The British Journal of Surgery. 1988;**75**:557-562

[55] World Health Organization. 2021. Injuries and Violence. https://www. who.int/news-room/fact-sheets/detail/ injuries-and-violence

[56] Visser E, Gosens T, Den Oudsten BL, De Vries J. The course, prediction, and treatment of acute

and posttraumatic stress in trauma patients: A systematic review. Journal of Trauma and Acute Care Surgery. 2017 Jun;**82**(6):1158-1183

[57] Puntillo KA, Naidu R. Chronic pain disorders after critical illness and ICUacquired opioid dependence: Two clinical conundra. Current Opinion in Critical Care. 2016;**22**(5):506-512

[58] Cohen SP, Christo PJ, Moroz L. Pain management in trauma patients. American Journal of Physical Medicine & Rehabilitation. 2004;**83**(2):142-161

[59] Pandya U, O'Mara MS, Wilson W, Opalek J, Lieber M. Impact of preexisting opioid use on injury mechanism, type, and outcome. The Journal of Surgical Research. 2015 Sep;**198**(1):7-12

[60] Seekamp A, Jochum M, Ziegler M, van Griensven M, Martin M, Regel G. Cytokines and adhesion molecules in elective and accidental trauma- related ischemia/reperfusion. The Journal of Trauma. 1998;**44**(5):874-882

[61] Johnson KB, Egan TD, Kern SE, McJames SW, Cluff ML, Pace NL. Influence of hemorrhagic shock followed by crystalloid resuscitation on propofol: A pharmacokinetic and pharmacodynamic analysis. Anesthesiology. 2004;**101**(3):647-659

[62] Yang Y, Young JB, Schermer CR, Utter GH. Use of ketorolac is associated with decreased pneumonia following rib fractures. American Journal of Surgery. 2014;**207**(4):566-572

[63] Bayouth L, Safcsak K, Cheatham ML, Smith CP, Birrer KL, Promes JT. Early intravenous ibuprofen decreases narcotic requirement and length of stay after traumatic rib fracture. The American Surgeon. 2013;**79**(11):1207-1212

[64] Borgeat A, Ofner C, Saporito A, Farshad M, Aguirre J. The effect of nonsteroidal anti- inflammatory drugs on bone healing in humans: A qualitative, systematic review. Journal of Clinical Anesthesia. 2018;**49**:92-100

[65] Dodwell ER, Latorre JG, Parisini E, Zwettler E, Chandra D, Mulpuri K, et al. NSAID exposure and risk of nonunion: A meta-analysis of case-control and cohort studies. Calcified Tissue International. 2010;**87**:193-202

[66] Kurmis AP, Kurmis TP, O'Brien JX, Dalen T. The effect of nonsteroidal antiinflammatory drug administration on acute phase fracture-healing: A review. The Journal of Bone and Joint Surgery. American Volume. 2012;**94**:815-823

[67] Hsu JR, Mir H, Wally MK, Seymour RB. Orthopaedic trauma association musculoskeletal pain task force. Clinical practice guidelines for pain Management in Acute Musculoskeletal Injury. Journal of Orthopaedic Trauma. 2019;**33**(5):e158-e182

[68] Tremont-Lukats IW, Megeff C, Backonja MM. Anticonvulsants for neuropathic pain syndromes: Mechanisms of action and place in therapy. Drugs. 2000;**60**:1029-1052

[69] Bone M, Critchley P, Buggy DJ. Gabapentin in postamputation phantom limb pain: A randomized, double-blind, placebo-controlled, cross-over study. Regional Anesthesia and Pain Medicine. 2002;**27**(5):481-486

[70] Sihoe AD, Lee TW, Wan IY, Thung KH, Yim AP. The use of gabapentin for post-operative and post-traumatic pain in thoracic surgery patients. European Journal of Cardio-Thoracic Surgery. 2006;**29**(5):795-799

[71] Karlow N, Schlaepfer CH, Stoll CR, Doering M, Carpenter CR, Colditz GA,

#### *ERAS Protocols and Multimodal Pain Management in Surgery DOI: http://dx.doi.org/10.5772/intechopen.111899*

et al. A systematic review and metaanalysis of ketamine as an alternative to opioids for acute pain in the emergency department. Academic Emergency Medicine. 2018;**25**(10):1086-1097

[72] Bowers KJ, McAllister KB, Ray M, Heitz C. Ketamine as an adjunct to opioids for acute pain management in the emergency department: A randomized controlled trial. Academic Emergency Medicine. 2017;**6**:676-685

[73] Motov S, Rosenbaum S, Vilke GM, Nakajima Y. Is there a role for intravenous subdissociative-dose ketamine administered as an adjunct to opioids or as a single agent for acute pain management in the emergency department? The Journal of Emergency Medicine. 2016;**51**(6):752-757

[74] Jouguelet-Lacoste J, La Colla L, Schilling D, Chelly JE. The use of intravenous infusion or single dose of lowdose ketamine for postoperative analgesia: A review of the current literature. Pain Medicine. 2015;**16**(2):383-403

[75] Chang LC, Raty SR, Ortiz J, Bailard NS, Mathew SJ. The emerging use of ketamine for anesthesia and sedation in traumatic brain injuries. CNS Neuroscience & Therapeutics. 2013;**19**(6):390-395

[76] Jessen Lundorf L, Korvenius Nedergaard H, Møller AM. Perioperative dexmedetomidine for acute pain after abdominal surgery in adults. Cochrane Database of Systematic Reviews. 2016;**18**(2):CD010358

[77] Karamchandani K, Klick JC, Linskey Dougherty M, Bonavia A, Allen SR, Carr ZJ. Pain management in trauma patients affected by the opioid epidemic: A narrative review. Journal of Trauma and Acute Care Surgery. 2019;**87**(2):430-439

[78] Weibel S, Jelting Y, Pace NL, Helf A, Eberhart LH, Hahnenkamp K, et al. Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery in adults. Cochrane Database of Systematic Reviews. 2018;**6**:CD009642

[79] Richman JM, Liu SS, Courpas G, Wong R, Rowlingson AJ, McGready J, et al. Does continuous peripheral nerve block provide superior pain control to opioids? A meta-analysis. Anesthesia & Analgesia. 2006;**102**(1):248-257

[80] Chelly JE, Ghisi D, Fanelli A. Continuous peripheral nerve blocks in acute pain management. British Journal of Anaesthesia. 2010;**105**(Suppl 1):i86-i96

[81] Nishimori M, Low JH, Zheng H, Ballantyne JC. Epidural pain relief versus systemic opioid-based pain relief for abdominal aortic surgery. Cochrane Database of Systematic Reviews. 2012;**7**:CD005059

[82] Mouzopoulos G, Vasiliadis G, Lasanianos N, Nikolaras G, Morakis E, Kaminaris M. Fascia iliaca block prophylaxis for hip fracture patients at risk for delirium: A randomized placebo-controlled study. Journal of Orthopaedics and Traumatology. 2009;**10**:127-133

[83] Sheinfeld Gorin S, Krebs P, Badr H, Janke EA, Jim HS, Spring B, et al. Metaanalysis of psychosocial interventions to reduce pain in patients with cancer. Journal of Clinical Oncology. 2012;**30**:539-547

[84] Salz T, Lavery JA, Lipitz-Snyderman AN, Boudreau DM, Moryl N, Gillespie EF, et al. Trends in opioid use among older survivors of colorectal, lung, and breast cancers. Journal of Clinical Oncology. 2019;**37**:1001-1011

[85] World Health Organization. Cancer Pain Relief: With a Guide to Opioid Availability. 2nd ed. Geneva, Switzerland: World Health Organization; 1996

[86] Di Napoli R, Esposito G, Cascella M. Intrathecal catheter. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022

[87] Cascella M, Muzio MR, Viscardi D, Cuomo A. Features and role of minimally invasive palliative procedures for pain Management in Malignant Pelvic Diseases: A review. The American Journal of Hospice & Palliative Care. 2017;**34**(6):524-531

[88] Kanpolat Y. Percutaneous destructive pain procedures on the upper spinal cord and brain stem in cancer pain: CT-guided techniques, indications and results. Advances and Technical Standards in Neurosurgery. 2007;**32**:147-173

[89] Cahana A, Mavrocordatos P, Geurts JW, Groen GJ. Do minimally invasive procedures have a place in the treatment of chronic low back pain? Expert Review of Neurotherapeutics. 2004;**4**(3):479-490

[90] Zhang H. Cancer pain managementnew therapies. Current Oncology Reports. 2022;**24**(2):223-226

[91] Deng G. Integrative medicine therapies for pain Management in Cancer Patients. Cancer Journal. 2019;**25**(5):343-348

### **Chapter 5**
