Preface

*Non est vivere, sed valere vita est Marcus Valerius Martialis Epigrammaton Liber VI, Carmen 70, 15*

In recent decades, notable advances have been carried out in pain medicine due to enhanced knowledge of the pathophysiology of acute and chronic pain, the newest pharmacological options, the significant role of nonpharmacological strategies, and the development of minimally invasive approaches. In particular, individualized, dynamic, and multicomponent paths (multimodal therapy) represent a real revolution in this field of medicine.

Nevertheless, to date, pain relief often remains an unmet need. For instance, up to 80% of postsurgical patients experience pain, which is described as severe in 10–20% of cases. Furthermore, primary and secondary chronic painful conditions are often managed by focusing only on pain intensity instead of considering the multiple aspects related to disease and disability. This poses a great challenge because pain as a symptom and pain as a disease are leading causes of suffering and disability. Furthermore, undertreated pain leads to serious problems such as increased opioid prescription and use, which can result in opioid addiction.

This book analyzes several important aspects of pain treatment, from acute pain in surgical settings to chronic pain in cancer and other diseases, from opioids research to interventional procedures, and from optimization of conventional strategies to innovative therapeutic approaches. Coverage of these topics augmented with attractive iconography and up-to-date references. This volume is an important source for specialized pain therapists, owing to the comprehensive coverage of the topics and the scientific value of each chapter. Furthermore, for nonspecialized physicians, it is a very useful guide for managing different types of pain.

I would like to express thanks to all the internationally recognized experts in the treatment of pain who collaborated in producing this volume. Finally, I am especially grateful to Mr. Luka Cvjetkovic, author service manager at IntechOpen publishing. This book offered me the opportunity to collaborate with a qualified professional and it is my sincere belief that this significant partnership will be further strengthened in the years to come.

**II**

**Section 3**

Cancer Pain

*by Xue-Bin Yan*

**Section 4**

**Section 5**

Health

Breakthrough Cancer Pain

*by Laura Tyler Perryman*

Cancer Pain **87**

**Chapter 7 89**

**Chapter 8 121**

Non-Pharmacological Approaches **135**

**Chapter 9 137**

**Chapter 10 149**

Opioid Research **187**

**Chapter 11 189**

Food-Derived Opioids: Production and the Effects of Opioids on Human

*by Arūnas Ščiupokas, Liuda Brogienė and Dalia Skorupskienė*

Wireless Neuromodulation: From Bench to Bedside

*by Gillian Lauder, Nicholas West and Greg Siren*

*by Sevda Arısoy, Işık Çoban and Özlem Üstün-Aytekin*

*myoActivation*: A Structured Process for Chronic Pain Resolution

**Marco Cascella** Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori – IRCCS – Fondazione 'G. Pascale', Naples, Italy

**1**

Section 1

Acute Pain

Section 1 Acute Pain

**3**

**Chapter 1**

*Marco Cascella*

Introductory Chapter: The

Rationale for a Multimodal

Approach to Pain Treatment

**1. Common issues in acute and chronic pain management**

**1.1 The unmet need of postoperative pain relief**

The symptom pain is a perception affected by complex interconnections of biological, psychological, and social factors. Analgesic monotherapy can often provide pain relief in clinical conditions featuring non-severe pain. In other circumstances, such as those characterized by intractable cancer pain, or concerning acute/ chronic non-cancer neuropathic pain, the intensity and quality of the pain require individualized multidrug approaches, with different analgesics and adjuvants used in combination according to clinical practice guidelines published by international and regional professional associations [1]. Moreover, because pharmacological strategies may not be able to successfully treat all patients with acute or chronic pain, nonpharmacological strategies should be included in the analgesic program, supporting and strengthening drug therapy [2]. Again, especially, chronic pain represents a dynamic experience, profoundly changeable in a spatial-temporal manner; thus, standardized and fixed protocols are not universally applicable for pain therapy. From these premises, the individualized, dynamic, and multicomponent pathway is summarized by the concept of the multimodal approach to pain management and represents a real revolution in this field of medicine. This optimization strategy can allow managing the pain by treating this symptom in its variegated clinical expressions through multiple interventions. According to the concept of multimodal therapy, the objective of pain relief is possible by targeting different sites of the nociceptive pathway [3] and by managing the galaxy of pain-related conditions through pharmacologic and nonpharmacologic modalities [4]. However, several considerations should be addressed in order to better understand its rational application for both acute (e.g., postoperative) and chronic pain management.

According to the Lancet's data, more than 230 million people undergo surgery each year worldwide and this huge number tends to increase year over year [5]. Postoperative pain is a typical example of acute pain and, probably, it represents the classic example of unmet need in surgery as up to 80% of postsurgical patients experience pain which in 10–20% of cases is described as severe [6]. This topic is of paramount importance, as inadequately controlled pain impairs quality of life (QoL) and functional recovery, increases the risk of postsurgical complications, and lengthens the time of hospitalization. Increased morbidity and prolonged opioid use during and after hospitalization are serious problems which call for effective preventive interventions. Furthermore, treating chronic pain induced by ineffective

#### **Chapter 1**

## Introductory Chapter: The Rationale for a Multimodal Approach to Pain Treatment

*Marco Cascella*

#### **1. Common issues in acute and chronic pain management**

The symptom pain is a perception affected by complex interconnections of biological, psychological, and social factors. Analgesic monotherapy can often provide pain relief in clinical conditions featuring non-severe pain. In other circumstances, such as those characterized by intractable cancer pain, or concerning acute/ chronic non-cancer neuropathic pain, the intensity and quality of the pain require individualized multidrug approaches, with different analgesics and adjuvants used in combination according to clinical practice guidelines published by international and regional professional associations [1]. Moreover, because pharmacological strategies may not be able to successfully treat all patients with acute or chronic pain, nonpharmacological strategies should be included in the analgesic program, supporting and strengthening drug therapy [2]. Again, especially, chronic pain represents a dynamic experience, profoundly changeable in a spatial-temporal manner; thus, standardized and fixed protocols are not universally applicable for pain therapy. From these premises, the individualized, dynamic, and multicomponent pathway is summarized by the concept of the multimodal approach to pain management and represents a real revolution in this field of medicine. This optimization strategy can allow managing the pain by treating this symptom in its variegated clinical expressions through multiple interventions. According to the concept of multimodal therapy, the objective of pain relief is possible by targeting different sites of the nociceptive pathway [3] and by managing the galaxy of pain-related conditions through pharmacologic and nonpharmacologic modalities [4]. However, several considerations should be addressed in order to better understand its rational application for both acute (e.g., postoperative) and chronic pain management.

#### **1.1 The unmet need of postoperative pain relief**

According to the Lancet's data, more than 230 million people undergo surgery each year worldwide and this huge number tends to increase year over year [5]. Postoperative pain is a typical example of acute pain and, probably, it represents the classic example of unmet need in surgery as up to 80% of postsurgical patients experience pain which in 10–20% of cases is described as severe [6]. This topic is of paramount importance, as inadequately controlled pain impairs quality of life (QoL) and functional recovery, increases the risk of postsurgical complications, and lengthens the time of hospitalization. Increased morbidity and prolonged opioid use during and after hospitalization are serious problems which call for effective preventive interventions. Furthermore, treating chronic pain induced by ineffective

acute pain management increases the cost of care, enormously [7]. From these data, it is clear that the commonly used strategies to address postoperative pain are very often inadequate.

#### **1.2 The issue of pain chronitization**

Undertreated acute postoperative pain is the main cause determining the development of postsurgical chronic pain (PSCP), which is difficult to treat and often invalidating in form. The pain chronitization is the final stage of a complex pathogenetic cascade. Summarizing, these mechanisms involve the activation of peripheral and central sensitization pathways. Data from a wide number of preclinical investigations demonstrated that activation and sensitization of peripheral nociceptors, spinal dorsal horn neurons, and central nervous system (CNS) brain areas may occur [8]. The role of specific peripheral mechanisms contributing to pain after surgical incision and manipulation has been investigated as well. The literature on the topic encompasses an incredible number of studies on nociceptors, molecular mechanisms, fiber sensitization processes, inflammatory cytokines, and so on [9–13]. While according to a classical point of view, the CNS involvement is strictly related to the mechanisms of chronic pain; however, it may result in difficulty to identify the borderline between acute and chronic pain. There are many good reasons to believe that many gaps such as the role of the environment (i.e., epigenetic) and genetics are not still well explained. Again, no clear criteria for diagnosing central sensitization have been recognized. The chronicity of pain is the effect of changes in pain processing through transcription and transduction processes. Preclinical studies suggested that alterations in the mRNA expression occur within the first 42–48 hours after surgery [14]. These sensitization processes seem to be quite rapid, at least in the experimental field. Thus, postoperative pain is a convoluted process engaging both the peripheral nervous system (PNS) and the CNS and, in turn, the exact distinction between acute and chronic postoperative pain is not always easy to establish.

#### **1.3 Toward an early and combined strategy**

Rather than dissecting the precise pathophysiology of acute and chronic pain, our knowledge on the matter must be translated in the most effective way to limit acute pain and to prevent mechanisms of sensitization. For these aims, all our "analgesic arsenal" must be defused as soon as possible, and before that surgery may trigger the first fuse. For instance, it has been demonstrated that tailored preoperative educational programs reduced postoperative opioid requirement and shortened the length of stay [15]. Furthermore, several self-management programs focused on patient's education and training may reduce risk factors (e.g., lifestylerelated), enhance protective factors, and, finally, prevent pain chronitization [16]. As a consequence, individualized programs for perioperative pain management can be performed by acting simultaneously on different targets or implementing different strategies according to the timing.

#### **1.4 The opioid crisis**

Ineffective management of perioperative pain and poorly controlled postoperative pain may induce development of PSCP, increased opioid prescription and use, until opioid addiction. Because the opioids epidemic in the United States and Canada is a dramatic phenomenon which has been responsible for up to 70,000 drug overdose deaths, in 2017 [17], the time has come to look at more effective

**5**

**2.1 Surgical settings**

*Introductory Chapter: The Rationale for a Multimodal Approach to Pain Treatment*

solutions and less harmful approaches capable of inducing optimal pain relief combined with lessening opioid use, opioid prescriptions, and reduced opioid-related complications. Controlled investigations and evidence-based analysis demonstrated that multimodal approaches to postoperative pain improved analgesia and lowered opioid consumption is several clinical settings such as those underwent orthopedic

These problems, linked to a lack of efficacy and to a criticality due to the use of opioids, do not only concern the postoperative pain chapter but also involve the management of chronic pain in its two sides of the coin, chronic cancer pain and chronic non-cancer pain. To understand the numerical terms of the matter, chronic pain is among the most common reasons for seeking medical care because it is reported by up 50% of patients seen in primary care [20]. Of note, chronic pain with neuropathic features, which often represents a hard task for clinicians, seems to be more common in the general population than earlier reported [21]. Because in cancer patients, pain has a multifactorial etiology and is quite a dynamic process, its management should be conducted through a careful combination of pharmacological agents with nonpharmacological strategies. This dynamical approach should be based on pain intensity and the complexity of symptoms, pain pathophysiology,

**2. Features of the multimodal approaches to pain management**

The concept of "multimodal" analgesia was introduced by Kehlet and Dahl, in 1993 [22]. This approach is based on the use of two or more distinct methods or drugs to treat pain rather than using opioids, or other strategies, alone. The rationale is that by combining medications and techniques with different mechanisms and sites of action, better pain relief can be achieved, with reduced side effects [23]. Different combinations of analgesic medications, adjuvants, and procedures can act on different sites and pathways in an additive or synergistic fashion. Clinicians may choose among a wide range of options included in several categories: pharmacologic, physical medicine, education and behavioral approaches, interventional, and surgical modalities. In the surgical setting, anesthesiologists may combine regional anesthetics, and/or nonopioid analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX2) inhibitors, NMDA-receptor antagonists, and antiepileptic, and antidepressant medications with or without conventional opioids. On the other hand, chronic cancer and non-cancer pain chronic cancer treatment often requires the involvement of a multidisciplinary team which combines resources based on the patient's needs, obtaining an individually tailored program.

Multimodal approaches to pain management can be included among more complex systematic processes adopted for managing the whole perioperative course. The Enhanced Recovery After Surgery (ERAS) pathway, for instance, is a multidisciplinary model of care born with the aim of guaranteeing optimal recovery and an early and safe return to daily activities after surgery. The pathway is a patient-tailored process provided by a team of surgeons, anesthesiologists, nurses, nutritionists, and physical therapists. In this scenario, the perioperative pain management is a keystone of the whole pathway [24]. Indeed, reduced need for opioids

*DOI: http://dx.doi.org/10.5772/intechopen.85864*

[18] or colorectal surgery [19].

and presence of comorbidities.

**1.5 Chronic pain**

*Introductory Chapter: The Rationale for a Multimodal Approach to Pain Treatment DOI: http://dx.doi.org/10.5772/intechopen.85864*

solutions and less harmful approaches capable of inducing optimal pain relief combined with lessening opioid use, opioid prescriptions, and reduced opioid-related complications. Controlled investigations and evidence-based analysis demonstrated that multimodal approaches to postoperative pain improved analgesia and lowered opioid consumption is several clinical settings such as those underwent orthopedic [18] or colorectal surgery [19].

#### **1.5 Chronic pain**

*From Conventional to Innovative Approaches for Pain Treatment*

often inadequate.

**1.2 The issue of pain chronitization**

pain is not always easy to establish.

ent strategies according to the timing.

**1.4 The opioid crisis**

**1.3 Toward an early and combined strategy**

acute pain management increases the cost of care, enormously [7]. From these data, it is clear that the commonly used strategies to address postoperative pain are very

Undertreated acute postoperative pain is the main cause determining the development of postsurgical chronic pain (PSCP), which is difficult to treat and often invalidating in form. The pain chronitization is the final stage of a complex pathogenetic cascade. Summarizing, these mechanisms involve the activation of peripheral and central sensitization pathways. Data from a wide number of preclinical investigations demonstrated that activation and sensitization of peripheral nociceptors, spinal dorsal horn neurons, and central nervous system (CNS) brain areas may occur [8]. The role of specific peripheral mechanisms contributing to pain after surgical incision and manipulation has been investigated as well. The literature on the topic encompasses an incredible number of studies on nociceptors, molecular mechanisms, fiber sensitization processes, inflammatory cytokines, and so on [9–13]. While according to a classical point of view, the CNS involvement is strictly related to the mechanisms of chronic pain; however, it may result in difficulty to identify the borderline between acute and chronic pain. There are many good reasons to believe that many gaps such as the role of the environment (i.e., epigenetic) and genetics are not still well explained. Again, no clear criteria for diagnosing central sensitization have been recognized. The chronicity of pain is the effect of changes in pain processing through transcription and transduction processes. Preclinical studies suggested that alterations in the mRNA expression occur within the first 42–48 hours after surgery [14]. These sensitization processes seem to be quite rapid, at least in the experimental field. Thus, postoperative pain is a convoluted process engaging both the peripheral nervous system (PNS) and the CNS and, in turn, the exact distinction between acute and chronic postoperative

Rather than dissecting the precise pathophysiology of acute and chronic pain, our knowledge on the matter must be translated in the most effective way to limit acute pain and to prevent mechanisms of sensitization. For these aims, all our "analgesic arsenal" must be defused as soon as possible, and before that surgery may trigger the first fuse. For instance, it has been demonstrated that tailored preoperative educational programs reduced postoperative opioid requirement and shortened the length of stay [15]. Furthermore, several self-management programs focused on patient's education and training may reduce risk factors (e.g., lifestylerelated), enhance protective factors, and, finally, prevent pain chronitization [16]. As a consequence, individualized programs for perioperative pain management can be performed by acting simultaneously on different targets or implementing differ-

Ineffective management of perioperative pain and poorly controlled postopera-

tive pain may induce development of PSCP, increased opioid prescription and use, until opioid addiction. Because the opioids epidemic in the United States and Canada is a dramatic phenomenon which has been responsible for up to 70,000 drug overdose deaths, in 2017 [17], the time has come to look at more effective

**4**

These problems, linked to a lack of efficacy and to a criticality due to the use of opioids, do not only concern the postoperative pain chapter but also involve the management of chronic pain in its two sides of the coin, chronic cancer pain and chronic non-cancer pain. To understand the numerical terms of the matter, chronic pain is among the most common reasons for seeking medical care because it is reported by up 50% of patients seen in primary care [20]. Of note, chronic pain with neuropathic features, which often represents a hard task for clinicians, seems to be more common in the general population than earlier reported [21]. Because in cancer patients, pain has a multifactorial etiology and is quite a dynamic process, its management should be conducted through a careful combination of pharmacological agents with nonpharmacological strategies. This dynamical approach should be based on pain intensity and the complexity of symptoms, pain pathophysiology, and presence of comorbidities.

#### **2. Features of the multimodal approaches to pain management**

The concept of "multimodal" analgesia was introduced by Kehlet and Dahl, in 1993 [22]. This approach is based on the use of two or more distinct methods or drugs to treat pain rather than using opioids, or other strategies, alone. The rationale is that by combining medications and techniques with different mechanisms and sites of action, better pain relief can be achieved, with reduced side effects [23]. Different combinations of analgesic medications, adjuvants, and procedures can act on different sites and pathways in an additive or synergistic fashion. Clinicians may choose among a wide range of options included in several categories: pharmacologic, physical medicine, education and behavioral approaches, interventional, and surgical modalities. In the surgical setting, anesthesiologists may combine regional anesthetics, and/or nonopioid analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX2) inhibitors, NMDA-receptor antagonists, and antiepileptic, and antidepressant medications with or without conventional opioids. On the other hand, chronic cancer and non-cancer pain chronic cancer treatment often requires the involvement of a multidisciplinary team which combines resources based on the patient's needs, obtaining an individually tailored program.

#### **2.1 Surgical settings**

Multimodal approaches to pain management can be included among more complex systematic processes adopted for managing the whole perioperative course. The Enhanced Recovery After Surgery (ERAS) pathway, for instance, is a multidisciplinary model of care born with the aim of guaranteeing optimal recovery and an early and safe return to daily activities after surgery. The pathway is a patient-tailored process provided by a team of surgeons, anesthesiologists, nurses, nutritionists, and physical therapists. In this scenario, the perioperative pain management is a keystone of the whole pathway [24]. Indeed, reduced need for opioids through regional anesthetic block used in addition to general anesthesia during surgery, or other minimally invasive approaches, may be effective for both pain relief and enhanced recovery target [25]. Apart from the ERAS strategy, another recent approach to perioperative pain management is the so-called opioid-free anesthesia (OFA) [26]. This term refers to a fascinating option for anesthesia administration that maximizes the patient's comfort (including pain relief) while eliminating the unwanted side effects of opioids. Through this model, no intraoperative systemic, neuraxial, or intracavitary opioid is administered during the anesthetic course. The rationale of the OFA model is the avoidance of the opioid-induced hyperalgesia phenomenon, a paradoxical effect in which opioid therapy enhances or aggravates preexisting pain [27], the reduced occurrence of postoperative delirium, and postoperative cognitive dysfunction in elderly [28, 29] and in high-risk patients [30]. Furthermore, the OFA technique seems to be appropriate for minimizing respiratory depression in patients that have impaired respiratory function (e.g., due to sleep apnea, or obesity), for reducing postoperative nausea and vomiting, and for treating patients who have chronic pain conditions, or are on chronic opioid therapy, or opioid addiction [31, 32]. Although the effect of opioids on cancer recurrence or progression remains an open issue [33], the OFA approach can be considered as a protective strategy against cancer progression [34]. In the surgical setting, it is possible to obtain a multimodal strategy without completely avoiding opioids. Low-dose opioids can be combined with one or more additional pain management methods (e.g., peripheral nerve blocks and neuraxial analgesia) and/ or medications such as acetaminophen, steroids, gabapentin/pregabalin, NSAIDs, dexmedetomidine, intravenous lidocaine, COX-2 inhibitors, or ketamine. Recently, Cozowicz et al. [35] demonstrated that this approach was correlated with a reduction in opioid use, postoperative complications, and less resource utilization. Again, multimodal analgesia may reduce the occurrence of PSCP, even when expressed as postsurgery pain syndrome [36], although the link between perioperative analgesic modes and the postoperative chronitization of pain should be better investigated [37]. The challenge of the OFA or the opioid-sparing regimens remains the choice of medication pathway in terms of number, the timing of use, and doses useful in different patient subgroups. While the use of a single drug (e.g., intravenous acetaminophen or methylprednisolone) was not associated with decreased opioids consumption [38], complex regimens featuring numerous medications may only increase drug-related side effects without improving outcomes.

#### **2.2 Chronic cancer pain: beyond the analgesic ladder**

In 1986, the World Health Organization (WHO) developed the classic threestep ladder model based on the use of analgesics for pain management in accordance with pain intensity in a linear movement directed toward the high or low steps of the ladder [39]. Subsequently, it was proposed a further step concerning interventional methods such as neurosurgical procedures (e.g., neuromodulation, nerve blocks, brain stimulators, and nerve lysis) robustly recommended for managing persistent pain even following the use of strong opioids. This revised four-step path can be adopted in a bidirectional way on the basis of the type of pain and its intensity [40]. Other attempts to modify the ladder strategy have also been proposed. According to the neuromatrix theory, chronic pain represents a multidimensional experience induced by the activation of a neural network ("neurosignature patterns") extensively distributed in the CNS [41]. From these premises, Leung hypothetically revised the original analgesic WHO ladder into a new analgesic path illustrated as a platform [42]. In this model, pain management followed a three-dimensional perspective including different areas of expertise

**7**

*Introductory Chapter: The Rationale for a Multimodal Approach to Pain Treatment*

that, in a multimodal fashion, can be combined with classical analgesics, on the basis of the pain condition. Despite its novelty, Leung's system seems to be lacking in completeness because it does not consider the dynamic perspective. The Cuomo et al. [43] "trolley analgesic model" is focused on individualized tailored therapies with dynamic multimodal approaches which are modulated according to the pain intensity, the physiopathology of pain, the multiplicity of symptoms, the presence of comorbidities, and psychological status and the patient's social context. The pharmacological agents and the nonpharmacological methods are included in different drawers of the trolley. It is possible to draw on one, or more, drawers of the trolley, and to choose within the contents of each drawer the most useful therapeutic method. According to the patient's needs, therapists can close or open different

Chronic non-cancer pain conditions such as low back pain (LBP), osteoarthritis, headache, and neuropathic pain represent a significant problem in terms of psychosocial and socioeconomic consequences [44]. Due to the complexity of clinical features and multiple underlying mechanisms, this issue requires a multimodal approach. Since the 1980s, Kohles et al. [45] proposed a combined (multimodal) strategy focused on medical, behavioral, physical, and educational programs. Through this approach, defined as "functional restoration," the restoring of physical and psychological performances was obtained by the involvement of a multidisciplinary team composed of clinicians from a variety of medical disciplines (e.g., pain therapists, neurologists, orthopedics, rheumatologists), psychologists and psychiatrists, nurses, physical, and occupational therapists [46]. More recently, a task force of the German International Association for the Study of Pain (IASP) chapter has defined the principles of this approach, in terms of resources and operating methods [47]. Currently, the multimodal path has been widely recognized as winning strategy for addressing several chronic non-cancer pain conditions such as LBP, headache, and fibromyalgia although several obstacles still limit its routinely

Multimodal approaches through the combined use of multiple modalities in analgesic protocols have the potential to offer a significant improvement in pain management for different acute, or chronic, clinical settings. Concerning perioperative pain management, included or not among ERAS or OFA pathways, multimodal modes can allow reducing opioid use, opioid prescriptions, and common opioid-related side effects, improving, in turn, outcomes. It seems that multimodal pain management may be able to prevent the development of chronic postsurgical pain conditions. Moreover, different attempts to better frame chronic pain in its many components, and for an effective treatment through a holistic approach, are being made to address the matter. Thus, the combined use of multiple modalities in analgesic protocols is worldwide encouraged. However, further research is needed to evaluate optimal multimodal regimens in terms of medications, doses, and timing (including the duration) of the administration, as well as to offer data useful for evidence-based practice. Finally, because lack of training (e.g., for invasive techniques or new techniques in regional anesthesia) and poor sources are huge obstacles for a routine application of multimodal approaches, identification of key

barriers for their implementation seems to be a research priority.

*DOI: http://dx.doi.org/10.5772/intechopen.85864*

drawers, in a dynamic fashion.

clinical application [48].

**3. Conclusion**

**2.3 Chronic non-cancer pain: toward a winning strategy**

*Introductory Chapter: The Rationale for a Multimodal Approach to Pain Treatment DOI: http://dx.doi.org/10.5772/intechopen.85864*

that, in a multimodal fashion, can be combined with classical analgesics, on the basis of the pain condition. Despite its novelty, Leung's system seems to be lacking in completeness because it does not consider the dynamic perspective. The Cuomo et al. [43] "trolley analgesic model" is focused on individualized tailored therapies with dynamic multimodal approaches which are modulated according to the pain intensity, the physiopathology of pain, the multiplicity of symptoms, the presence of comorbidities, and psychological status and the patient's social context. The pharmacological agents and the nonpharmacological methods are included in different drawers of the trolley. It is possible to draw on one, or more, drawers of the trolley, and to choose within the contents of each drawer the most useful therapeutic method. According to the patient's needs, therapists can close or open different drawers, in a dynamic fashion.

#### **2.3 Chronic non-cancer pain: toward a winning strategy**

Chronic non-cancer pain conditions such as low back pain (LBP), osteoarthritis, headache, and neuropathic pain represent a significant problem in terms of psychosocial and socioeconomic consequences [44]. Due to the complexity of clinical features and multiple underlying mechanisms, this issue requires a multimodal approach. Since the 1980s, Kohles et al. [45] proposed a combined (multimodal) strategy focused on medical, behavioral, physical, and educational programs. Through this approach, defined as "functional restoration," the restoring of physical and psychological performances was obtained by the involvement of a multidisciplinary team composed of clinicians from a variety of medical disciplines (e.g., pain therapists, neurologists, orthopedics, rheumatologists), psychologists and psychiatrists, nurses, physical, and occupational therapists [46]. More recently, a task force of the German International Association for the Study of Pain (IASP) chapter has defined the principles of this approach, in terms of resources and operating methods [47]. Currently, the multimodal path has been widely recognized as winning strategy for addressing several chronic non-cancer pain conditions such as LBP, headache, and fibromyalgia although several obstacles still limit its routinely clinical application [48].

#### **3. Conclusion**

*From Conventional to Innovative Approaches for Pain Treatment*

increase drug-related side effects without improving outcomes.

In 1986, the World Health Organization (WHO) developed the classic threestep ladder model based on the use of analgesics for pain management in accordance with pain intensity in a linear movement directed toward the high or low steps of the ladder [39]. Subsequently, it was proposed a further step concerning interventional methods such as neurosurgical procedures (e.g., neuromodulation, nerve blocks, brain stimulators, and nerve lysis) robustly recommended for managing persistent pain even following the use of strong opioids. This revised four-step path can be adopted in a bidirectional way on the basis of the type of pain and its intensity [40]. Other attempts to modify the ladder strategy have also been proposed. According to the neuromatrix theory, chronic pain represents a multidimensional experience induced by the activation of a neural network ("neurosignature patterns") extensively distributed in the CNS [41]. From these premises, Leung hypothetically revised the original analgesic WHO ladder into a new analgesic path illustrated as a platform [42]. In this model, pain management followed a three-dimensional perspective including different areas of expertise

**2.2 Chronic cancer pain: beyond the analgesic ladder**

through regional anesthetic block used in addition to general anesthesia during surgery, or other minimally invasive approaches, may be effective for both pain relief and enhanced recovery target [25]. Apart from the ERAS strategy, another recent approach to perioperative pain management is the so-called opioid-free anesthesia (OFA) [26]. This term refers to a fascinating option for anesthesia administration that maximizes the patient's comfort (including pain relief) while eliminating the unwanted side effects of opioids. Through this model, no intraoperative systemic, neuraxial, or intracavitary opioid is administered during the anesthetic course. The rationale of the OFA model is the avoidance of the opioid-induced hyperalgesia phenomenon, a paradoxical effect in which opioid therapy enhances or aggravates preexisting pain [27], the reduced occurrence of postoperative delirium, and postoperative cognitive dysfunction in elderly [28, 29] and in high-risk patients [30]. Furthermore, the OFA technique seems to be appropriate for minimizing respiratory depression in patients that have impaired respiratory function (e.g., due to sleep apnea, or obesity), for reducing postoperative nausea and vomiting, and for treating patients who have chronic pain conditions, or are on chronic opioid therapy, or opioid addiction [31, 32]. Although the effect of opioids on cancer recurrence or progression remains an open issue [33], the OFA approach can be considered as a protective strategy against cancer progression [34]. In the surgical setting, it is possible to obtain a multimodal strategy without completely avoiding opioids. Low-dose opioids can be combined with one or more additional pain management methods (e.g., peripheral nerve blocks and neuraxial analgesia) and/ or medications such as acetaminophen, steroids, gabapentin/pregabalin, NSAIDs, dexmedetomidine, intravenous lidocaine, COX-2 inhibitors, or ketamine. Recently, Cozowicz et al. [35] demonstrated that this approach was correlated with a reduction in opioid use, postoperative complications, and less resource utilization. Again, multimodal analgesia may reduce the occurrence of PSCP, even when expressed as postsurgery pain syndrome [36], although the link between perioperative analgesic modes and the postoperative chronitization of pain should be better investigated [37]. The challenge of the OFA or the opioid-sparing regimens remains the choice of medication pathway in terms of number, the timing of use, and doses useful in different patient subgroups. While the use of a single drug (e.g., intravenous acetaminophen or methylprednisolone) was not associated with decreased opioids consumption [38], complex regimens featuring numerous medications may only

**6**

Multimodal approaches through the combined use of multiple modalities in analgesic protocols have the potential to offer a significant improvement in pain management for different acute, or chronic, clinical settings. Concerning perioperative pain management, included or not among ERAS or OFA pathways, multimodal modes can allow reducing opioid use, opioid prescriptions, and common opioid-related side effects, improving, in turn, outcomes. It seems that multimodal pain management may be able to prevent the development of chronic postsurgical pain conditions. Moreover, different attempts to better frame chronic pain in its many components, and for an effective treatment through a holistic approach, are being made to address the matter. Thus, the combined use of multiple modalities in analgesic protocols is worldwide encouraged. However, further research is needed to evaluate optimal multimodal regimens in terms of medications, doses, and timing (including the duration) of the administration, as well as to offer data useful for evidence-based practice. Finally, because lack of training (e.g., for invasive techniques or new techniques in regional anesthesia) and poor sources are huge obstacles for a routine application of multimodal approaches, identification of key barriers for their implementation seems to be a research priority.

*From Conventional to Innovative Approaches for Pain Treatment*

#### **Author details**

Marco Cascella Department of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS—Fondazione G. Pascale, Naples, Italy

\*Address all correspondence to: m.cascella@istitutotumori.na.it

© 2019 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.

**9**

*Introductory Chapter: The Rationale for a Multimodal Approach to Pain Treatment*

look. Journal of Cellular Physiology.

[10] Pasquinucci L, Turnaturi R, Montenegro L, Caraci F, Chiechio S, Parenti C. Simultaneous targeting of MOR/DOR: A useful strategy for inflammatory pain modulation. European Journal of Pharmacology.

[11] Tsuda M. Modulation of pain and itch by spinal glia. Neuroscience

[12] Zhang L, Terrando N, Xu ZZ, Bang S, Jordt SE, Maixner W, et al. Distinct analgesic actions of DHA and DHA-derived specialized pro-resolving mediators on post-operative pain after bone fracture in mice. Frontiers in Pharmacology. 2018;**9**:412. DOI: 10.3389/fphar.2018.00412. eCollection

[13] Lueptow LM, Fakira AK, Bobeck EN. The contribution of the descending pain modulatory pathway in opioid tolerance. Frontiers in Neuroscience. 2018;**12**:886. DOI: 10.3389/fnins.2018.

[14] Spofford CM, Brennan TJ. Gene expression in skin, muscle, and dorsal root ganglion after plantar incision in the rat. Anesthesiology.

[15] Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM, Bickler S, Brennan T, et al. Management of postoperative pain: A clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. The Journal of Pain.

Bulletin. 2018;**34**(1):178-185

2018;**233**(4):2824-2838

2019;**847**:97-102

2018

00886

2012;**117**(1):161-172

2016;**17**(2):131-157

*DOI: http://dx.doi.org/10.5772/intechopen.85864*

[1] Cruccu G, Truini A. A review of neuropathic pain: From guidelines to clinical practice. Pain and therapy.

**References**

2017;**6**(Suppl 1):35-42

[2] Cascella M, Thompson NS, Muzio MR, Forte CA, Cuomo A. The underestimated role of psychological and rehabilitation approaches for management of cancer pain. A brief commentary. Recenti Progressi in Medicina. 2016;**107**(8):418-421

[3] Manworren RC. Multimodal pain management and the future of a

[4] Bonakdar RA. Integrative pain management. The Medical Clinics of North America. 2017;**101**(5):987-1004

[5] Weiser TG, Regenbogen SE,

2008;**372**(9633):139-144

[7] Gan TJ. Poorly controlled postoperative pain: Prevalence, consequences, and prevention. Journal of Pain Research. 2017;**10**:2287-2298

PR9.0000000000000588

[9] Pace MC, Passavanti MB, De Nardis L, Bosco F, Sansone P, Pota V, et al. Nociceptor plasticity: A closer

[8] Pogatzki-Zahn EM, Segelcke D, Schug SA. Postoperative pain-from mechanisms to treatment. Pain Reports. 2017;**2**(2):e588. DOI: 10.1097/

Thompson KD, Haynes AB, Lipsitz SR, Berry WR, et al. An estimation of the global volume of surgery: A modeling strategy based on available data. Lancet.

[6] Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: Results from a national survey suggest postoperative pain continues to be undermanaged. Anesthesia and Analgesia. 2003;**97**:534-540

personalized medicine approach to pain. AORN Journal. 2015;**101**(3):308-314

*Introductory Chapter: The Rationale for a Multimodal Approach to Pain Treatment DOI: http://dx.doi.org/10.5772/intechopen.85864*

#### **References**

*From Conventional to Innovative Approaches for Pain Treatment*

© 2019 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,

Department of Anesthesia and Pain Medicine, Istituto Nazionale Tumori,

\*Address all correspondence to: m.cascella@istitutotumori.na.it

**8**

**Author details**

Marco Cascella

provided the original work is properly cited.

IRCCS—Fondazione G. Pascale, Naples, Italy

[1] Cruccu G, Truini A. A review of neuropathic pain: From guidelines to clinical practice. Pain and therapy. 2017;**6**(Suppl 1):35-42

[2] Cascella M, Thompson NS, Muzio MR, Forte CA, Cuomo A. The underestimated role of psychological and rehabilitation approaches for management of cancer pain. A brief commentary. Recenti Progressi in Medicina. 2016;**107**(8):418-421

[3] Manworren RC. Multimodal pain management and the future of a personalized medicine approach to pain. AORN Journal. 2015;**101**(3):308-314

[4] Bonakdar RA. Integrative pain management. The Medical Clinics of North America. 2017;**101**(5):987-1004

[5] Weiser TG, Regenbogen SE, Thompson KD, Haynes AB, Lipsitz SR, Berry WR, et al. An estimation of the global volume of surgery: A modeling strategy based on available data. Lancet. 2008;**372**(9633):139-144

[6] Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: Results from a national survey suggest postoperative pain continues to be undermanaged. Anesthesia and Analgesia. 2003;**97**:534-540

[7] Gan TJ. Poorly controlled postoperative pain: Prevalence, consequences, and prevention. Journal of Pain Research. 2017;**10**:2287-2298

[8] Pogatzki-Zahn EM, Segelcke D, Schug SA. Postoperative pain-from mechanisms to treatment. Pain Reports. 2017;**2**(2):e588. DOI: 10.1097/ PR9.0000000000000588

[9] Pace MC, Passavanti MB, De Nardis L, Bosco F, Sansone P, Pota V, et al. Nociceptor plasticity: A closer

look. Journal of Cellular Physiology. 2018;**233**(4):2824-2838

[10] Pasquinucci L, Turnaturi R, Montenegro L, Caraci F, Chiechio S, Parenti C. Simultaneous targeting of MOR/DOR: A useful strategy for inflammatory pain modulation. European Journal of Pharmacology. 2019;**847**:97-102

[11] Tsuda M. Modulation of pain and itch by spinal glia. Neuroscience Bulletin. 2018;**34**(1):178-185

[12] Zhang L, Terrando N, Xu ZZ, Bang S, Jordt SE, Maixner W, et al. Distinct analgesic actions of DHA and DHA-derived specialized pro-resolving mediators on post-operative pain after bone fracture in mice. Frontiers in Pharmacology. 2018;**9**:412. DOI: 10.3389/fphar.2018.00412. eCollection 2018

[13] Lueptow LM, Fakira AK, Bobeck EN. The contribution of the descending pain modulatory pathway in opioid tolerance. Frontiers in Neuroscience. 2018;**12**:886. DOI: 10.3389/fnins.2018. 00886

[14] Spofford CM, Brennan TJ. Gene expression in skin, muscle, and dorsal root ganglion after plantar incision in the rat. Anesthesiology. 2012;**117**(1):161-172

[15] Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM, Bickler S, Brennan T, et al. Management of postoperative pain: A clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. The Journal of Pain. 2016;**17**(2):131-157

[16] Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011

[17] National Institute on Drug Abuse. Overdose Death Rates. Available at: https://www.drugabuse.gov/relatedtopics/trends-statistics/overdose-deathrates [Accessed: 28-01-2019]

[18] Halawi MJ, Grant SA, Bolognesi MP. Multimodal analgesia for total joint arthroplasty. Orthopedics. 2015;**38**(7):e616-e625

[19] Wick EC, MC2 G, Wu CL. Postoperative multimodal analgesia pain management with nonopioid analgesics and techniques: A review. JAMA Surgery. 2017;**152**(7):691-697

[20] Elliott AM, Smith BH, Penny KI, Smith WC, Chambers WA. The epidemiology of chronic pain in the community. Lancet. 1999;**354**(9186):1248

[21] Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. The Journal of Pain. 2006;**7**(4):281-289

[22] Kehlet H, Dahl JB. The value of "multimodal" or "balanced analgesia" in postoperative pain treatment. Anesthesia and Analgesia. 1993;**77**(5):1048-1056

[23] Clarke H, Poon M, Weinrib A, Katznelson R, Wentlandt K, Katz J. Preventive analgesia and novel strategies for the prevention of chronic postsurgical pain. Drugs. 2015;**75**(4):339-351

[24] Simpson JC, Bao X, Agarwala A. Pain management in enhanced recovery after surgery (ERAS) protocols. Clinics in Colon and Rectal Surgery. 2019;**32**(2):121-128

[25] Beverly A, Kaye AD, Ljungqvist O, Urman RD. Essential elements of multimodal analgesia in enhanced recovery after surgery (ERAS) guidelines. Anesthesiology Clinics. 2017;**35**(2):e115-e143

[26] Harkouk H, Fletcher D, Beloeil H. Opioid free anaesthesia: Myth or reality? Anaesthesia Critical Care & Pain Medicine. 2019;**38**(2):111-112. DOI: 10.1016/j.accpm.2019.01.005

[27] Tompkins DA, Campbell CM. Opioid-induced hyperalgesia: Clinically relevant or extraneous research phenomenon? Current Pain and Headache Reports. 2011;**15**(2):129-136

[28] Cascella M, Bimonte S. The role of general anesthetics and the mechanisms of hippocampal and extra-hippocampal dysfunctions in the genesis of postoperative cognitive dysfunction. Neural Regeneration Research. 2017;**12**(11):1780-1785

[29] Cascella M, Muzio MR, Bimonte S, Cuomo A, Jakobsson JG. Postoperative delirium and postoperative cognitive dysfunction: Updates in pathophysiology, potential translational approaches to clinical practice and further research perspectives. Minerva Anestesiologica. 2018;**84**(2):246-260

[30] Cascella M, Di Napoli R, Carbone D, Cuomo GF, Bimonte S, Muzio MR. Chemotherapy-related cognitive impairment: Mechanisms, clinical features and research perspectives. Recenti Progressi in Medicina. 2018;**109**(11):523-530

[31] Miceli L, Bednarova R, Vetrugno L, Cascella M, Cuomo A. Is the limit of 60mg of oral morphine equivalent daily dose still actual for the access to rapid onset opioids therapy? Current Problems in Cancer. 2018;**42**(3):367-368

[32] Miceli L, Bednarova R, Rizzardo A, Cuomo A, Riccardi I, Vetrugno L, et al. Opioids prescriptions in pain therapy

**11**

*Introductory Chapter: The Rationale for a Multimodal Approach to Pain Treatment*

database analysis. Anesthesiology.

[39] Ventafridda V, Saita L, Ripamonti C, De Conno F. WHO guidelines for the use of analgesics in cancer pain. International Journal of Tissue

[40] Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Twenty-four years of experience. Canadian Family

2018;**129**(1):77-88

Reactions. 1985;**7**(1):93-96

Physician. 2010;**56**(6):514-517

[41] Melzack R. Evolution of the

2005;**5**(2):85-94

2012;**4**(3):254-258

S178910. eCollection 2019

patients with chronic pain.

1990;**15**(12):1321-1324

2016;**100**:43-53

[44] Cheatle MD. Biopsychosocial approach to assessing and managing

Medical Clinics of North America.

[45] Kohles S, Barnes D, Gatchel RJ, Mayer TG. Improved physical

performance outcomes after functional restoration treatment in patients with chronic low-back pain. Early versus recent training results. Spine.

[46] Cascella M, Cuomo A, Viscardi D. Pain management team and palliative care setting. In: Cascella M, Cuomo A, Viscardi D, editors. Features and Management of the Pelvic Cancer Pain.

neuromatrix theory of pain. The Prithvi Raj Lecture: Presented at the Third World Congress of World Institute of Pain, Barcelona 2004. Pain Practice.

[42] Leung L. From ladder to platform: A new concept for pain management. Journal of Primary Health Care.

[43] Cuomo A, Bimonte S, Forte CA, Botti G, Cascella M. Multimodal approaches and tailored therapies for pain management: The trolley analgesic model. Journal of Pain Research. 2019;**12**:711-714. DOI: 10.2147/JPR.

*DOI: http://dx.doi.org/10.5772/intechopen.85864*

and risk of addiction: A one-year survey in Italy. Analysis of national opioids database. Annali dell'Istituto Superiore

[33] Bimonte S, Barbieri A, Cascella M, Rea D, Palma G, Del Vecchio V, et al. The effects of naloxone on human breast cancer progression: In vitro and in vivo studies on MDA.MB231 cells. OncoTargets and Therapy. 2018;**11**: 185-191. DOI: 10.2147/OTT.S145780.

[34] Clarke H, Soneji N, Ko DT, Yun L, Wijeysundera DN. Rates and risk factors for prolonged opioid use after major surgery: Population based cohort study. BMJ. 2014;**348**:g1251. DOI: 10.1136/bmj.

[35] Cozowicz C, Poeran J, Zubizarreta N, Liu J, Weinstein SM, Pichler L, et al. Non-opioid analgesic modes of pain management are associated with reduced postoperative complications and resource utilisation: A retrospective study of obstructive sleep apnoea patients undergoing elective joint arthroplasty. British Journal of Anaesthesia. 2019;**122**(1):131-140

[36] Cascella M, Cuomo A, Viscardi D. Pain syndromes associated with cancer therapy. In: Cascella M, Cuomo A, Viscardi D, editors. Features and Management of the Pelvic Cancer Pain. Springer: Verlag; 2016. pp. 25-62. DOI:

10.1007/978-3-319-33587-2\_3

of chronic postsurgical pain and reducing postoperative opioid use. Journal of Opioid Management.

2018;**14**(6):453-461

[37] Jian W, Rejaei D, Shihab A, Alston TA, Wang J. The role of multimodal analgesia in preventing the development

[38] Wasserman I, Poeran J, Zubizarreta N, Babby J, Serban S, Goldberg AT, et al. Impact of intravenous acetaminophen on perioperative opioid utilization and outcomes in open colectomies: A claims

di Sanità. 2018;**54**(4):370-374

eCollection 2018

g1251

*Introductory Chapter: The Rationale for a Multimodal Approach to Pain Treatment DOI: http://dx.doi.org/10.5772/intechopen.85864*

and risk of addiction: A one-year survey in Italy. Analysis of national opioids database. Annali dell'Istituto Superiore di Sanità. 2018;**54**(4):370-374

*From Conventional to Innovative Approaches for Pain Treatment*

[25] Beverly A, Kaye AD, Ljungqvist O, Urman RD. Essential elements of multimodal analgesia in enhanced recovery after surgery (ERAS) guidelines. Anesthesiology Clinics.

[26] Harkouk H, Fletcher D, Beloeil H. Opioid free anaesthesia: Myth or reality? Anaesthesia Critical Care & Pain Medicine. 2019;**38**(2):111-112. DOI:

10.1016/j.accpm.2019.01.005

[27] Tompkins DA, Campbell CM. Opioid-induced hyperalgesia: Clinically

[28] Cascella M, Bimonte S. The role of general anesthetics and the mechanisms of hippocampal and extra-hippocampal

[29] Cascella M, Muzio MR, Bimonte S, Cuomo A, Jakobsson JG. Postoperative

[30] Cascella M, Di Napoli R, Carbone D, Cuomo GF, Bimonte S, Muzio MR. Chemotherapy-related cognitive impairment: Mechanisms, clinical features and research perspectives. Recenti Progressi in Medicina.

[31] Miceli L, Bednarova R, Vetrugno L, Cascella M, Cuomo A. Is the limit of 60mg of oral morphine equivalent daily dose still actual for the access to rapid onset opioids therapy? Current Problems in Cancer. 2018;**42**(3):367-368

[32] Miceli L, Bednarova R, Rizzardo A, Cuomo A, Riccardi I, Vetrugno L, et al. Opioids prescriptions in pain therapy

relevant or extraneous research phenomenon? Current Pain and Headache Reports. 2011;**15**(2):129-136

dysfunctions in the genesis of postoperative cognitive dysfunction. Neural Regeneration Research.

2017;**12**(11):1780-1785

2018;**109**(11):523-530

delirium and postoperative cognitive dysfunction: Updates in pathophysiology, potential translational approaches to clinical practice and further research perspectives. Minerva Anestesiologica. 2018;**84**(2):246-260

2017;**35**(2):e115-e143

[16] Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011

[17] National Institute on Drug Abuse. Overdose Death Rates. Available at: https://www.drugabuse.gov/relatedtopics/trends-statistics/overdose-death-

[18] Halawi MJ, Grant SA, Bolognesi MP. Multimodal analgesia for total joint arthroplasty. Orthopedics.

Postoperative multimodal analgesia pain management with nonopioid analgesics and techniques: A review. JAMA Surgery. 2017;**152**(7):691-697

[20] Elliott AM, Smith BH, Penny KI,

[21] Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general

population survey. The Journal of Pain.

[22] Kehlet H, Dahl JB. The value of "multimodal" or "balanced analgesia" in postoperative pain treatment. Anesthesia and Analgesia.

[23] Clarke H, Poon M, Weinrib A, Katznelson R, Wentlandt K, Katz J. Preventive analgesia and novel strategies for the prevention of chronic postsurgical pain. Drugs. 2015;**75**(4):339-351

[24] Simpson JC, Bao X, Agarwala A. Pain management in enhanced recovery after surgery (ERAS) protocols. Clinics in Colon and Rectal

Surgery. 2019;**32**(2):121-128

Smith WC, Chambers WA. The epidemiology of chronic pain in the community. Lancet.

1999;**354**(9186):1248

2006;**7**(4):281-289

1993;**77**(5):1048-1056

rates [Accessed: 28-01-2019]

[19] Wick EC, MC2 G, Wu CL.

2015;**38**(7):e616-e625

**10**

[33] Bimonte S, Barbieri A, Cascella M, Rea D, Palma G, Del Vecchio V, et al. The effects of naloxone on human breast cancer progression: In vitro and in vivo studies on MDA.MB231 cells. OncoTargets and Therapy. 2018;**11**: 185-191. DOI: 10.2147/OTT.S145780. eCollection 2018

[34] Clarke H, Soneji N, Ko DT, Yun L, Wijeysundera DN. Rates and risk factors for prolonged opioid use after major surgery: Population based cohort study. BMJ. 2014;**348**:g1251. DOI: 10.1136/bmj. g1251

[35] Cozowicz C, Poeran J, Zubizarreta N, Liu J, Weinstein SM, Pichler L, et al. Non-opioid analgesic modes of pain management are associated with reduced postoperative complications and resource utilisation: A retrospective study of obstructive sleep apnoea patients undergoing elective joint arthroplasty. British Journal of Anaesthesia. 2019;**122**(1):131-140

[36] Cascella M, Cuomo A, Viscardi D. Pain syndromes associated with cancer therapy. In: Cascella M, Cuomo A, Viscardi D, editors. Features and Management of the Pelvic Cancer Pain. Springer: Verlag; 2016. pp. 25-62. DOI: 10.1007/978-3-319-33587-2\_3

[37] Jian W, Rejaei D, Shihab A, Alston TA, Wang J. The role of multimodal analgesia in preventing the development of chronic postsurgical pain and reducing postoperative opioid use. Journal of Opioid Management. 2018;**14**(6):453-461

[38] Wasserman I, Poeran J, Zubizarreta N, Babby J, Serban S, Goldberg AT, et al. Impact of intravenous acetaminophen on perioperative opioid utilization and outcomes in open colectomies: A claims

database analysis. Anesthesiology. 2018;**129**(1):77-88

[39] Ventafridda V, Saita L, Ripamonti C, De Conno F. WHO guidelines for the use of analgesics in cancer pain. International Journal of Tissue Reactions. 1985;**7**(1):93-96

[40] Vargas-Schaffer G. Is the WHO analgesic ladder still valid? Twenty-four years of experience. Canadian Family Physician. 2010;**56**(6):514-517

[41] Melzack R. Evolution of the neuromatrix theory of pain. The Prithvi Raj Lecture: Presented at the Third World Congress of World Institute of Pain, Barcelona 2004. Pain Practice. 2005;**5**(2):85-94

[42] Leung L. From ladder to platform: A new concept for pain management. Journal of Primary Health Care. 2012;**4**(3):254-258

[43] Cuomo A, Bimonte S, Forte CA, Botti G, Cascella M. Multimodal approaches and tailored therapies for pain management: The trolley analgesic model. Journal of Pain Research. 2019;**12**:711-714. DOI: 10.2147/JPR. S178910. eCollection 2019

[44] Cheatle MD. Biopsychosocial approach to assessing and managing patients with chronic pain. Medical Clinics of North America. 2016;**100**:43-53

[45] Kohles S, Barnes D, Gatchel RJ, Mayer TG. Improved physical performance outcomes after functional restoration treatment in patients with chronic low-back pain. Early versus recent training results. Spine. 1990;**15**(12):1321-1324

[46] Cascella M, Cuomo A, Viscardi D. Pain management team and palliative care setting. In: Cascella M, Cuomo A, Viscardi D, editors. Features and Management of the Pelvic Cancer Pain. Springer: Verlag; 2016. pp. 151-157. DOI: 10.1007/978-3-319-33587-2\_11

[47] Arnold B, Brinkschmidt T, Casser HR, Gralow I, Irnich D, Klimczyk K, et al. Multimodal pain therapy: Principles and indications [in German]. Schmerz. 2009;**23**:112-120

[48] Kaiser U, Treede RD, Sabatowski R. Multimodal pain therapy in chronic noncancer pain-gold standard or need for further clarification? Pain. 2017;**158**(10):1853-1859

**13**

dental treatment [4].

**Chapter 2**

**Abstract**

*Sameer Shaikh*

Management of Odontogenic and

Pain in the orofacial region is by far the commonest reason for patients to seek treatment. Tooth and intraoral structures are often the main sources of orofacial pain. Odontogenic pain, also commonly known as tooth pain, originates from dental structures, pulpal or periodontal. Nonodontogenic oral pain can originate from intraoral structures such as gingiva and buccal mucosa. Arriving at a correct and definitive diagnosis is of paramount importance to institute an appropriate treatment. Obtaining a detailed history from the patient including the location, duration, frequency, periodicity, character, and quality of pain assists in differentiating odontogenic from nonodontogenic causes. Wide varieties of pharmacological agents, along with invasive and noninvasive procedures, are available to manage odontogenic and nonodontogenic pain. While managing orofacial pain, clinical and pharmacological judgment should encompass a systematic and objective assessment in compliance with the strongest evidence available. In this chapter, there will be a discussion of various choices and options available to manage a few of the orofacial pain complaints.

**Keywords:** orofacial pain, odontogenic pain, nonodontogenic oral pain, pain management, pulpitis, periapical periodontitis, traumatic periodontitis, cracked tooth syndrome, noninfectious and nonmalignant oral ulcers,

Odontogenic pain, a common malady globally and the most prevalent type of orofacial pain, originates from dental structures, pulpal or periodontal [1]. Differential diagnosis for odontogenic pain is outlined in **Table 1**. Oral pain of nonodontogenic origin can originate from the intraoral structures, such as buccal mucosa, gingival tissues, and alveolar bone. Some of the main causes for nonodontogenic pain of oral origin are shown in **Table 2**. The complexity of the orofacial region makes the management of odontogenic and nonodontogenic pain of oral origin a challenging task for the clinicians. For an effective diagnosis and treatment, the clinician should have a thorough knowledge of the various pain complaints pertaining to the orofacial region and the different options available for their optimal management [2, 3]. For managing odontogenic pain, The "3-D's" principle—diagnosis, dental treatment, and drugs—should be used. The first and foremost step is to determine the condition causing the pain and then to discover that what caused that condition. Removal of the cause usually leads to rapid recovery and should be done by an appropriate dental treatment. Medications should only be used to complement the

burning mouth syndrome, oral mucositis

**1. Introduction**

Nonodontogenic Oral Pain

#### **Chapter 2**

*From Conventional to Innovative Approaches for Pain Treatment*

Springer: Verlag; 2016. pp. 151-157. DOI:

[47] Arnold B, Brinkschmidt T, Casser HR, Gralow I, Irnich D, Klimczyk K, et al. Multimodal pain therapy: Principles and indications [in German].

[48] Kaiser U, Treede RD, Sabatowski R. Multimodal pain therapy in chronic noncancer pain-gold standard or need for further clarification? Pain.

10.1007/978-3-319-33587-2\_11

Schmerz. 2009;**23**:112-120

2017;**158**(10):1853-1859

**12**

## Management of Odontogenic and Nonodontogenic Oral Pain

*Sameer Shaikh*

#### **Abstract**

Pain in the orofacial region is by far the commonest reason for patients to seek treatment. Tooth and intraoral structures are often the main sources of orofacial pain. Odontogenic pain, also commonly known as tooth pain, originates from dental structures, pulpal or periodontal. Nonodontogenic oral pain can originate from intraoral structures such as gingiva and buccal mucosa. Arriving at a correct and definitive diagnosis is of paramount importance to institute an appropriate treatment. Obtaining a detailed history from the patient including the location, duration, frequency, periodicity, character, and quality of pain assists in differentiating odontogenic from nonodontogenic causes. Wide varieties of pharmacological agents, along with invasive and noninvasive procedures, are available to manage odontogenic and nonodontogenic pain. While managing orofacial pain, clinical and pharmacological judgment should encompass a systematic and objective assessment in compliance with the strongest evidence available. In this chapter, there will be a discussion of various choices and options available to manage a few of the orofacial pain complaints.

**Keywords:** orofacial pain, odontogenic pain, nonodontogenic oral pain, pain management, pulpitis, periapical periodontitis, traumatic periodontitis, cracked tooth syndrome, noninfectious and nonmalignant oral ulcers, burning mouth syndrome, oral mucositis

#### **1. Introduction**

Odontogenic pain, a common malady globally and the most prevalent type of orofacial pain, originates from dental structures, pulpal or periodontal [1]. Differential diagnosis for odontogenic pain is outlined in **Table 1**. Oral pain of nonodontogenic origin can originate from the intraoral structures, such as buccal mucosa, gingival tissues, and alveolar bone. Some of the main causes for nonodontogenic pain of oral origin are shown in **Table 2**. The complexity of the orofacial region makes the management of odontogenic and nonodontogenic pain of oral origin a challenging task for the clinicians. For an effective diagnosis and treatment, the clinician should have a thorough knowledge of the various pain complaints pertaining to the orofacial region and the different options available for their optimal management [2, 3].

For managing odontogenic pain, The "3-D's" principle—diagnosis, dental treatment, and drugs—should be used. The first and foremost step is to determine the condition causing the pain and then to discover that what caused that condition. Removal of the cause usually leads to rapid recovery and should be done by an appropriate dental treatment. Medications should only be used to complement the dental treatment [4].


#### **Table 1.**

*Differential diagnosis for odontogenic pain.*


#### **Table 2.**

*Causes of nonodontogenic pain of oral origin.*

For managing nonodontogenic pain particularly in complex cases, a multidisciplinary pain management approach should be adopted encompassing both nonpharmacological and pharmacological modalities [5].

#### **2. Odontogenic pain**

#### **2.1 Pulpal pain**

#### *2.1.1 Dentine hypersensitivity*

Dissolution of the dental enamel results in development of dental caries. If caries goes unchecked, it may involve the dentin and the pulp, resulting in pain. In the initial stages, caries penetrates and exposes the dentin leading to dentine hypersensitivity. The pain due to dentin exposure is of a sharp and shooting nature with a shorter duration and is classically stimulated by exposure to heat, cold, sweet drinks/food, and mechanical trauma such as tooth brushing. Apart from caries, there exist other predisposing factors for dentine hypersensitivity. These include anatomical defects, gingival recession, erosion, abrasion, and attrition. The diagnosis of dentine hypersensitivity is based upon detection of dentin exposure or tooth wear. Therapies for managing dentinal hypersensitivity are aimed at: sealing the exposed dentinal tubules (composite resin application), reducing dentinal neuron activity (application of desensitizing agents such as potassium nitrate and strontium chloride), and making the enamel and dentin more resistant to demineralization (application of fluoride-containing medicaments) [6, 7].

**15**

*Management of Odontogenic and Nonodontogenic Oral Pain*

The extension of caries to pulp leads to pulpal inflammation known as pulpitis. Other cause of pulpitis can be operative dental procedures. The chemicals, heat, and friction involved in such procedures may trigger pulpal inflammation. Pulpitis has two clinical forms: acute (reversible) and chronic (irreversible). Acute pulpitis represents mild inflammation and is characteristically associated with sharp and shooting pain of a shorter duration. On the other hand, inflammation in irreversible pulpitis is severe enough to undermine the pulp. It is characterized by spontaneous and dull pain that persists even after the removal of a stimulus such as cold or

Diagnosis of pulpitis is based mainly on clinical evaluation and pulp vitality tests. Radiographs can be helpful in cases where carious lesions are not clinically

The management strategies are determined based on the type of pulpitis and presence of infection involving the periapical area. In reversible pulpitis, pulp vitality can be maintained if the tooth is treated, usually by removing the caries, and then restored [10]. In irreversible pulpitis, management options include endodontic (root canal) therapy or tooth extraction. In root canal treatment, an opening is made in the tooth and the pulp is extirpated. The root canal system is thoroughly cleaned, shaped, and then obturated with gutta-percha points. Following root canal therapy, adequate healing is manifested clinically by resolution of symptoms and radiographically by bone filling in the radiolucent area at the root apex over a period of months. If symptoms persist or worsen, root canal therapy is usually repeated in

Cracked tooth syndrome occurs when a crack has occurred in the enamel or dentine and reaches the pulp chamber. The crack is usually not visible to the naked eye. Application of excessive force on a normal tooth or physiologic forces applied to a weakened tooth can lead to cracks. The diagnosis of cracked tooth is often tricky. Radiography is not helpful in detection of fractures, as cracks occur in a mesiodistal direction, parallel to that of the plane of the film. Simple test is to have patient bite on a cotton roll that evokes a sharp pain. Pain due to cracked tooth is sharp and shooting in nature, and is usually associated with biting and chewing. Hot and cold stimuli also evoke the pain. Restorable teeth should be treated endodontically, followed by a full-coverage restoration of tooth. However, tooth with large cracks may

*2.2.1 Periapical periodontitis (periapical abscess, granuloma, and cyst)*

Pulpitis, if untreated, is followed by death of the pulp. The necrotic pulp is infected and leads to spread of infection through the apical foramina into the periapical tissues. This in turn causes inflammation and destruction of the periradicular tissues known as periapical periodontitis. It includes acute/chronic nonsuppurative inflammation and suppurative inflammation. Periapical granuloma forms due to chronic inflammation without pus, while periapical abscess is the result of inflammation involving pus. The other likely cause of periapical periodontitis can be chemical irritation. This irritation can be due to the escape of antiseptics used for root canal sterilization through the root apex into the surrounding periapical area [11, 12].

*DOI: http://dx.doi.org/10.5772/intechopen.83837*

*2.1.2 Reversible and irreversible pulpitis*

case a root canal was missed [11, 12].

require extraction [7, 13].

**2.2 Periodontal pain**

*2.1.3 Cracked tooth or cracked cusp syndrome*

heat [6–8].

visible [8, 9].

#### *2.1.2 Reversible and irreversible pulpitis*

*From Conventional to Innovative Approaches for Pain Treatment*

Pulpal pain Dentine hypersensitivity

Periodontal pain Periapical periodontitis

Reversible pulpitis Irreversible pulpitis Cracked tooth syndrome

• Periapical abscess

Traumatic periodontitis Periodontal (lateral) abscess

• Periapical granuloma and cyst

Perio-endo, endo-perio, and combined lesions

**Origin Possible causes**

• Noninfectious and nonmalignant oral ulcers

• Acute necrotizing ulcerative gingivitis (ANUG)

nonpharmacological and pharmacological modalities [5].

tion (application of fluoride-containing medicaments) [6, 7].

For managing nonodontogenic pain particularly in complex cases, a multidisciplinary pain management approach should be adopted encompassing both

Dissolution of the dental enamel results in development of dental caries. If caries goes unchecked, it may involve the dentin and the pulp, resulting in pain. In the initial stages, caries penetrates and exposes the dentin leading to dentine hypersensitivity. The pain due to dentin exposure is of a sharp and shooting nature with a shorter duration and is classically stimulated by exposure to heat, cold, sweet drinks/food, and mechanical trauma such as tooth brushing. Apart from caries, there exist other predisposing factors for dentine hypersensitivity. These include anatomical defects, gingival recession, erosion, abrasion, and attrition. The diagnosis of dentine hypersensitivity is based upon detection of dentin exposure or tooth wear. Therapies for managing dentinal hypersensitivity are aimed at: sealing the exposed dentinal tubules (composite resin application), reducing dentinal neuron activity (application of desensitizing agents such as potassium nitrate and strontium chloride), and making the enamel and dentin more resistant to demineraliza-

• Acute alveolar osteitis (dry socket) • Burning mouth syndrome (BMS)

*Differential diagnosis for odontogenic pain.*

• Desquamative gingivitis (DG)

*Causes of nonodontogenic pain of oral origin.*

• Acute pericoronitis

• Oral mucositis (OM)

**2. Odontogenic pain**

*2.1.1 Dentine hypersensitivity*

**2.1 Pulpal pain**

**Table 2.**

**Table 1.**

**14**

The extension of caries to pulp leads to pulpal inflammation known as pulpitis. Other cause of pulpitis can be operative dental procedures. The chemicals, heat, and friction involved in such procedures may trigger pulpal inflammation. Pulpitis has two clinical forms: acute (reversible) and chronic (irreversible). Acute pulpitis represents mild inflammation and is characteristically associated with sharp and shooting pain of a shorter duration. On the other hand, inflammation in irreversible pulpitis is severe enough to undermine the pulp. It is characterized by spontaneous and dull pain that persists even after the removal of a stimulus such as cold or heat [6–8].

Diagnosis of pulpitis is based mainly on clinical evaluation and pulp vitality tests. Radiographs can be helpful in cases where carious lesions are not clinically visible [8, 9].

The management strategies are determined based on the type of pulpitis and presence of infection involving the periapical area. In reversible pulpitis, pulp vitality can be maintained if the tooth is treated, usually by removing the caries, and then restored [10]. In irreversible pulpitis, management options include endodontic (root canal) therapy or tooth extraction. In root canal treatment, an opening is made in the tooth and the pulp is extirpated. The root canal system is thoroughly cleaned, shaped, and then obturated with gutta-percha points. Following root canal therapy, adequate healing is manifested clinically by resolution of symptoms and radiographically by bone filling in the radiolucent area at the root apex over a period of months. If symptoms persist or worsen, root canal therapy is usually repeated in case a root canal was missed [11, 12].

#### *2.1.3 Cracked tooth or cracked cusp syndrome*

Cracked tooth syndrome occurs when a crack has occurred in the enamel or dentine and reaches the pulp chamber. The crack is usually not visible to the naked eye. Application of excessive force on a normal tooth or physiologic forces applied to a weakened tooth can lead to cracks. The diagnosis of cracked tooth is often tricky. Radiography is not helpful in detection of fractures, as cracks occur in a mesiodistal direction, parallel to that of the plane of the film. Simple test is to have patient bite on a cotton roll that evokes a sharp pain. Pain due to cracked tooth is sharp and shooting in nature, and is usually associated with biting and chewing. Hot and cold stimuli also evoke the pain. Restorable teeth should be treated endodontically, followed by a full-coverage restoration of tooth. However, tooth with large cracks may require extraction [7, 13].

#### **2.2 Periodontal pain**

#### *2.2.1 Periapical periodontitis (periapical abscess, granuloma, and cyst)*

Pulpitis, if untreated, is followed by death of the pulp. The necrotic pulp is infected and leads to spread of infection through the apical foramina into the periapical tissues. This in turn causes inflammation and destruction of the periradicular tissues known as periapical periodontitis. It includes acute/chronic nonsuppurative inflammation and suppurative inflammation. Periapical granuloma forms due to chronic inflammation without pus, while periapical abscess is the result of inflammation involving pus. The other likely cause of periapical periodontitis can be chemical irritation. This irritation can be due to the escape of antiseptics used for root canal sterilization through the root apex into the surrounding periapical area [11, 12].

Acute periapical abscesses characteristically present with severe pain in the area of the nonvital tooth particularly on percussion, inflammation, or complaint of pus drainage (with its associated foul taste). Pain also typically interferes with sleep. Treatment includes drainage through an opening in the tooth itself or through the soft tissue surrounding the jaw, if cellulitis has developed. If patients with abscess have systemic signs of infection (e.g., fever), an oral antimicrobial is prescribed (amoxicillin 500 mg every 8 hours; for patients allergic to penicillin, clindamycin 150 or 300 mg every 6 hours). On resolution of the abscess, the patient should undergo root canal therapy or extraction [8, 10, 11, 14].

Periapical granulomas or cysts usually follow acute pulpal infection that remains unresolved due to inadequate drainage. Tooth with periapical granulomas may present with a dull pain or may be asymptomatic. Radiographically, abscesses, granulomas, or cysts have the same features and microscopic examination should be done for distinction. Teeth with periapical granulomas are nonvital and needs root canal treatment or removal. Root canal treatment done competently leads to healing even if cystic phase has started. Persistence of periapical radiolucency after 6–12 months may be due to technical faults associated with root canal treatment. In such a case, apical curettage with apicoectomy may be indicated [6, 8, 14, 15].

#### *2.2.2 Traumatic periodontitis*

Traumatic periodontitis is a painful condition that arises because of injury to the periodontium. This injury is caused by the trauma from excessive occlusal forces. The occlusal trauma affecting periodontium can be primary, secondary, or combined. Tooth or teeth with normal periodontal support enduring increased occlusal loads may undergo primary occlusal trauma. The causes may include bruxism, overextended margins of restorations, excessive loading during orthodontic movements, and recent fitting of a new partial denture. Tooth or teeth with inadequate periodontal support if subjected to normal occlusal forces may undergo secondary occlusal trauma. Excessive occlusal force on a diseased periodontium may lead to combined occlusal trauma. The excessive occlusal forces are generally from parafunctional movements such as bruxism. The clinical features of traumatic periodontitis include pain on chewing/biting or percussion, progressive tooth mobility, and nonphysiological movement of tooth during function (fremitus). Additionally, there can be gingival inflammation with pocket formation in combined occlusal trauma.

Radiographic features include evidence of circumferential and furcal bone loss, in combination with widening of the periodontal ligament space.

The goal of management of traumatic periodontitis is the removal of excessive occlusal forces and brings the dentition in occlusal harmony. Primary occlusal trauma can be managed with analysis and correction of occlusion. One or more of the following steps can do occlusal adjustments: tooth movements, tooth removal, dental restorations, coronoplasty, etc. Progressive tooth mobility due to secondary occlusal trauma may be reduced by occlusal adjustment. Pain occurring due to hypermobility can be managed by splinting of teeth. The aim of splinting is to increase the resistance of dentition to the occlusal forces through stabilization. It involves joining of two or more teeth [16, 17]. Managing the periodontal inflammation is of primary importance in cases of combined occlusal trauma. Premature occlusal contacts usually contribute to the progression of periodontitis. This can be tackled by simple correction of the occlusion that may eradicate the premature occlusal contacts [16, 17].

#### *2.2.3 Periodontal (lateral) abscess*

A periodontal abscess arises because of acute infection of a periodontal pocket. Unlike a periapical abscess, periodontal abscess is associated with a vital tooth.

**17**

reactions, etc.

*Management of Odontogenic and Nonodontogenic Oral Pain*

Varieties of reasons are implicated in causation of periodontal abscess. Primarily incomplete calculus removal can be a causative factor. Occasionally, it may occur following root planing, as the trauma to pocket lining implants bacteria into the periodontal tissues. Other contributing factors can be food packing down between teeth with poor contact points or foreign body (e.g., fish bone) driven through the floor of a pocket. Poorly controlled diabetes mellitus can also be a predisposing

Periodontal abscess has a rapid onset. The gingival swelling and inflammatory edema prevent drainage through the pocket orifice. The initial gingival tenderness progresses to throbbing pain that is well localized. The affected tooth is tender to percussion or biting. There is tooth mobility with its elevation in the socket. Pus exudation may occur from the pocket; however, a deep abscess has a sinus tract that points on the alveolar mucosa. Fever and regional lymphadenopathy can be occasional clinical features. The vitality of the tooth, deep pocketing, and less severe tenderness helps to differentiate between a periodontal and

Periodontal abscess should be ideally drained through pocket or occasionally by an incision through the gingiva. If the abscess is too large and drainage cannot be done, subgingival scaling and root planing or deferring the surgical access until the major clinical signs have subsided. Before initiating the treatment of acute periodontal abscess, the evaluation of patient's medical history, dental history, and systemic conditions is crucial to determine the need for antibiotics. The indications for antimicrobial therapy in patients with acute abscess are fever, lymphadenopathy, evidence of spreading of infection (cellulitis), deep periodontal pocketing, and immunosuppression. Administration of antibiotics alone without the local drainage of the abscess is contraindicated. The drainage is mandatory in order to eliminate the etiologic factors. Extraction of the affected tooth can be considered as a last resort to treat the periodontal abscess, if there is poor response to therapy, horizontal tooth mobility exceeding 1 mm, pocketing exceeding 8 mm, and more than 40%

In perio-endo lesions, microorganisms from the periodontal pockets can reach the pulp through accessory canals, thereby leading to pulpal inflammation and necrosis. In endo-perio lesions, pulpal necrosis leads to involvement and destruction of the periodontal ligament and adjacent alveolar bone. Clinically endo-perio lesions present as deep periodontal probing depth extending to the apex of the tooth. In managing the lesions of pulpal or periodontal origin, making an accurate diagnosis as to the source of infection is a critical determinant of the treatment outcome. Sequence of the disease process can be an important factor in determining the exact nature of lesions: perio-endo and endo-perio lesions. Conventional root canal therapy (RCT) alone leads to a complete resolution of the periodontal defects arising from primary pulpal infection. However, pulpal infections resulting from primary periodontal infections require both endodontic and periodontal treatments

Oral ulcers are a broad entity that encompasses a variety of causes, such as infections (bacterial, viral, and fungal), neoplasia, immunological disturbances, drug

*DOI: http://dx.doi.org/10.5772/intechopen.83837*

factor for periodontal abscess formation.

alveolar bone resorption [6, 18, 19].

for achieving complete healing [18].

**3. Nonodontogenic pain of oral origin**

*2.2.4 Perio-endo, endo-perio, and combined lesions*

pulpal abscess.

#### *Management of Odontogenic and Nonodontogenic Oral Pain DOI: http://dx.doi.org/10.5772/intechopen.83837*

*From Conventional to Innovative Approaches for Pain Treatment*

undergo root canal therapy or extraction [8, 10, 11, 14].

apical curettage with apicoectomy may be indicated [6, 8, 14, 15].

in combination with widening of the periodontal ligament space.

*2.2.2 Traumatic periodontitis*

Acute periapical abscesses characteristically present with severe pain in the area of the nonvital tooth particularly on percussion, inflammation, or complaint of pus drainage (with its associated foul taste). Pain also typically interferes with sleep. Treatment includes drainage through an opening in the tooth itself or through the soft tissue surrounding the jaw, if cellulitis has developed. If patients with abscess have systemic signs of infection (e.g., fever), an oral antimicrobial is prescribed (amoxicillin 500 mg every 8 hours; for patients allergic to penicillin, clindamycin 150 or 300 mg every 6 hours). On resolution of the abscess, the patient should

Periapical granulomas or cysts usually follow acute pulpal infection that remains unresolved due to inadequate drainage. Tooth with periapical granulomas may present with a dull pain or may be asymptomatic. Radiographically, abscesses, granulomas, or cysts have the same features and microscopic examination should be done for distinction. Teeth with periapical granulomas are nonvital and needs root canal treatment or removal. Root canal treatment done competently leads to healing even if cystic phase has started. Persistence of periapical radiolucency after 6–12 months may be due to technical faults associated with root canal treatment. In such a case,

Traumatic periodontitis is a painful condition that arises because of injury to the periodontium. This injury is caused by the trauma from excessive occlusal forces. The occlusal trauma affecting periodontium can be primary, secondary, or combined. Tooth or teeth with normal periodontal support enduring increased occlusal loads may undergo primary occlusal trauma. The causes may include bruxism, overextended margins of restorations, excessive loading during orthodontic movements, and recent fitting of a new partial denture. Tooth or teeth with inadequate periodontal support if subjected to normal occlusal forces may undergo secondary occlusal trauma. Excessive occlusal force on a diseased periodontium may lead to combined occlusal trauma. The excessive occlusal forces are generally from parafunctional movements such as bruxism. The clinical features of traumatic periodontitis include pain on chewing/biting or percussion, progressive tooth mobility, and nonphysiological movement of tooth during function (fremitus). Additionally, there can be gingival inflammation with pocket formation in combined occlusal trauma.

Radiographic features include evidence of circumferential and furcal bone loss,

The goal of management of traumatic periodontitis is the removal of excessive occlusal forces and brings the dentition in occlusal harmony. Primary occlusal trauma can be managed with analysis and correction of occlusion. One or more of the following steps can do occlusal adjustments: tooth movements, tooth removal, dental restorations, coronoplasty, etc. Progressive tooth mobility due to secondary occlusal trauma may be reduced by occlusal adjustment. Pain occurring due to hypermobility can be managed by splinting of teeth. The aim of splinting is to increase the resistance of dentition to the occlusal forces through stabilization. It involves joining of two or more teeth [16, 17]. Managing the periodontal inflammation is of primary importance in cases of combined occlusal trauma. Premature occlusal contacts usually contribute to the progression of periodontitis. This can be tackled by simple correction of the occlusion that may eradicate the premature occlusal contacts [16, 17].

A periodontal abscess arises because of acute infection of a periodontal pocket. Unlike a periapical abscess, periodontal abscess is associated with a vital tooth.

**16**

*2.2.3 Periodontal (lateral) abscess*

Varieties of reasons are implicated in causation of periodontal abscess. Primarily incomplete calculus removal can be a causative factor. Occasionally, it may occur following root planing, as the trauma to pocket lining implants bacteria into the periodontal tissues. Other contributing factors can be food packing down between teeth with poor contact points or foreign body (e.g., fish bone) driven through the floor of a pocket. Poorly controlled diabetes mellitus can also be a predisposing factor for periodontal abscess formation.

Periodontal abscess has a rapid onset. The gingival swelling and inflammatory edema prevent drainage through the pocket orifice. The initial gingival tenderness progresses to throbbing pain that is well localized. The affected tooth is tender to percussion or biting. There is tooth mobility with its elevation in the socket. Pus exudation may occur from the pocket; however, a deep abscess has a sinus tract that points on the alveolar mucosa. Fever and regional lymphadenopathy can be occasional clinical features. The vitality of the tooth, deep pocketing, and less severe tenderness helps to differentiate between a periodontal and pulpal abscess.

Periodontal abscess should be ideally drained through pocket or occasionally by an incision through the gingiva. If the abscess is too large and drainage cannot be done, subgingival scaling and root planing or deferring the surgical access until the major clinical signs have subsided. Before initiating the treatment of acute periodontal abscess, the evaluation of patient's medical history, dental history, and systemic conditions is crucial to determine the need for antibiotics. The indications for antimicrobial therapy in patients with acute abscess are fever, lymphadenopathy, evidence of spreading of infection (cellulitis), deep periodontal pocketing, and immunosuppression. Administration of antibiotics alone without the local drainage of the abscess is contraindicated. The drainage is mandatory in order to eliminate the etiologic factors. Extraction of the affected tooth can be considered as a last resort to treat the periodontal abscess, if there is poor response to therapy, horizontal tooth mobility exceeding 1 mm, pocketing exceeding 8 mm, and more than 40% alveolar bone resorption [6, 18, 19].

#### *2.2.4 Perio-endo, endo-perio, and combined lesions*

In perio-endo lesions, microorganisms from the periodontal pockets can reach the pulp through accessory canals, thereby leading to pulpal inflammation and necrosis.

In endo-perio lesions, pulpal necrosis leads to involvement and destruction of the periodontal ligament and adjacent alveolar bone. Clinically endo-perio lesions present as deep periodontal probing depth extending to the apex of the tooth.

In managing the lesions of pulpal or periodontal origin, making an accurate diagnosis as to the source of infection is a critical determinant of the treatment outcome. Sequence of the disease process can be an important factor in determining the exact nature of lesions: perio-endo and endo-perio lesions. Conventional root canal therapy (RCT) alone leads to a complete resolution of the periodontal defects arising from primary pulpal infection. However, pulpal infections resulting from primary periodontal infections require both endodontic and periodontal treatments for achieving complete healing [18].

#### **3. Nonodontogenic pain of oral origin**

Oral ulcers are a broad entity that encompasses a variety of causes, such as infections (bacterial, viral, and fungal), neoplasia, immunological disturbances, drug reactions, etc.

#### **3.1 Noninfectious and nonmalignant oral ulcers**

A detailed clinical history and examination, and laboratory investigations including biopsy, culture, and immunochemistry tests are essential for ruling out the neoplastic, infectious, and immunological causes of oral ulcerations. The causative factors for noninfectious and nonmalignant oral ulcers usually include mechanical trauma (self-induced trauma such as on chewing and biting, aggressive tooth brushing, and iatrogenic causes particularly due to dental treatment) and chemicals (aspirin, acetylsalicylic acid, acid etchants, etc.)

Superficial ulcers usually lead to soreness; severe pain and discomfort are the features of deep ulcers.

On elimination of cause, acute forms of traumatic- and chemical-induced ulcers usually heal in 7–10 days. They develop chronicity if subjected to continuous trauma or irritation. The considerations in management of such type of ulcers are as follows:


Tetracycline (e.g., doxycycline), or tetracycline plus nicotinamide in rinse form may provide significant pain relief and reduce ulcer duration, particularly in aphthous ulcers. However, usage of tetracycline should be avoided in children below 12 years of age due to the risk of tooth staining. For oral rinsing, a tetracycline capsule (250 mg) is crushed and stirred in a little water and held in the mouth for 2–3 minutes, three times daily.

Tetracycline mouth rinses can also reduce the frequency of aphthous ulcers on regular usage for 3 days each week.

Salicylates based on their anti-inflammatory role can be helpful in reducing the discomfort of oral ulcers. Over the counter, preparation of choline salicylate in gel form is recommended for application to ulcers, 3–5 times daily [6, 20, 21].

**19**

*Management of Odontogenic and Nonodontogenic Oral Pain*

It is the inflammation of the flap of tissues (operculum) around an erupting tooth, and most commonly associated with impacted mandibular third molars. The chief complaints in this condition are severe pain that can radiate to surrounding areas and swelling of the pericoronal tissues. The hyperplastic-inflamed flap of tissue can become a hotbed for bacteria, as it readily holds food particles and debris. This scenario leads to bacterial infection with clinical manifestations of discharge of pus, trismus, fever, regional lymphadenopathy, and in some cases spread of the

If the pain and inflammation are limited to the tooth, local measures, such as debridement of food debris and plaque, irrigation with normal saline or hydrogen

Antimicrobial therapy is indicated for patients presenting with fever, trismus, and pus exudation. Metronidazole 400 mg three times a day for 5 days is to be prescribed in combination with phenoxymethylpenicillin 500 mg four times a day for 5 days. If it is envisaged that the tooth can be useful for chewing and patient also has the desire to retain the tooth, hyperplastic pericoronal tissue should be excised out through a minor oral surgery procedure known as operculectomy. This will allow better access to properly clean the area and prevent the accumulation of bacteria and food debris. In some unfortunate instances, the gum tissue may grow back and

Since impacted teeth frequently are unfavorably aligned and do not erupt completely, extraction of such tooth is commonly performed. This method eliminates

The risks and benefits of removal of impacted molars are mired in controversy, as extraction can lead to inferior alveolar nerve damage; retention can precipitate

This painful condition is a complication that may occur following dental extraction. It presents with a severe throbbing pain caused by bone exposure at the site of extraction. Following the extraction, a blood clot forms within the extraction socket to safeguard the bone. If a blood clot forms inadequately in the socket or it is dislodged, the bone and nerves are exposed, leading to pain. Smoking, excessive extraction trauma, difficult disimpactions of third molars, vasoconstrictor in local anesthetic, and oral contraceptives are some of the predisposing factors to alveolar osteitis. Alveolar osteitis can strike 3–5 days after an extraction and may persist for a week. The exposed bone is acutely tender to touch; hence, mechanical stimulation by tongue movement and food particles results in frequent acute pain. On clinical

examination, the socket appears empty with visible bony lamina dura.

Minimization of trauma related to the extraction procedure can be an important factor in prevention of dry socket. Since removal of the debris from the socket expedites healing, irrigation with warmed saline or chlorhexidine is suggestive. Use of intra-alveolar dressing materials such as bismuth iodoform paraffin paste and lidocaine gel on ribbon gauze can protect the socket from painful stimuli and collection of food debris. These dressing materials also impart a soothing sensation of warmth in the painful area. Usually after one or two dressings, significant pain relief is achieved. It is better to be on the lookout for signs of infection, such as pus in the socket, localized swelling, and lymphadenopathy. Antibiotics should be prescribed if these signs are there. It is crucial that

peroxide, and avoidance of occlusal trauma are recommended.

*DOI: http://dx.doi.org/10.5772/intechopen.83837*

infection to adjacent tissue spaces.

create the same problem.

any chance of recurrence of pericoronitis.

**3.3 Acute alveolar osteitis (dry socket)**

serious, even life-threatening infection [14, 22].

**3.2 Acute pericoronitis**

#### **3.2 Acute pericoronitis**

*From Conventional to Innovative Approaches for Pain Treatment*

chemicals (aspirin, acetylsalicylic acid, acid etchants, etc.)

gel, which can remain in place for several hours.

features of deep ulcers.

as follows:

A detailed clinical history and examination, and laboratory investigations including biopsy, culture, and immunochemistry tests are essential for ruling out the neoplastic, infectious, and immunological causes of oral ulcerations. The causative factors for noninfectious and nonmalignant oral ulcers usually include mechanical trauma (self-induced trauma such as on chewing and biting, aggressive tooth brushing, and iatrogenic causes particularly due to dental treatment) and

Superficial ulcers usually lead to soreness; severe pain and discomfort are the

On elimination of cause, acute forms of traumatic- and chemical-induced ulcers usually heal in 7–10 days. They develop chronicity if subjected to continuous trauma or irritation. The considerations in management of such type of ulcers are

1. Maintenance of oral hygiene. In the presence of an ulcer, tooth brushing particularly near to the ulcerative area can be detrimental. In such as case, an antiseptic mouthwash (e.g., 0.2% chlorhexidine solution) can be of considerable help. Chlorhexidine mouth rinse is recommended to be used three times daily after meals and held in the mouth for at least 1 minute. Oral rinsing with chlorhexidine has been found to lessen down the discomfort and duration of aphthous stomatitis.

2. Avoidance of irritation or injury to the area of ulceration. Covering agents, e.g., carboxymethylcellulose paste (Orabase®) and carmellose sodium can be helpful in safeguarding the ulcers from the effects of friction or injury. When correctly applied, these covering agents absorb moisture and form an adhesive

3. For management of pain, over-the-counter anesthetic agent (an example is Orobase® with 20% benzocaine). Topical application of weak potency corticosteroids (hydrocortisone hemisuccinate) and medium potency steroids (triamcinolone acetonide) also assist in reducing the associated pain and inflammation; however, they are unlikely to expedite the healing of ulcers. Hydrocortisone hemisuccinate 2.5 mg pellets allowed to be dissolved in the mouth close to ulcers, three times a day. Triamcinolone 0.1% in Orabase applied to ulcer three times daily. However, long-term and/or repeated topical application of such corticosteroids has a downside in the form of adrenal suppression. This concern can be addressed by using the topical corticosteroids at the lowest possible concentration and frequency. The problem of adrenal suppression is not evidenced with 0.05% fluocinonide in adhesive paste and betamethasone-17-valerate mouth rinse. Tetracycline (e.g., doxycycline), or tetracycline plus nicotinamide in rinse form may provide significant pain relief and reduce ulcer duration, particularly in aphthous ulcers. However, usage of tetracycline should be avoided in children below 12 years of age due to the risk of tooth staining. For oral rinsing, a tetracycline capsule (250 mg) is crushed and stirred in a little water and held in the mouth for

Tetracycline mouth rinses can also reduce the frequency of aphthous ulcers on

Salicylates based on their anti-inflammatory role can be helpful in reducing the discomfort of oral ulcers. Over the counter, preparation of choline salicylate in gel

form is recommended for application to ulcers, 3–5 times daily [6, 20, 21].

**3.1 Noninfectious and nonmalignant oral ulcers**

**18**

2–3 minutes, three times daily.

regular usage for 3 days each week.

It is the inflammation of the flap of tissues (operculum) around an erupting tooth, and most commonly associated with impacted mandibular third molars. The chief complaints in this condition are severe pain that can radiate to surrounding areas and swelling of the pericoronal tissues. The hyperplastic-inflamed flap of tissue can become a hotbed for bacteria, as it readily holds food particles and debris. This scenario leads to bacterial infection with clinical manifestations of discharge of pus, trismus, fever, regional lymphadenopathy, and in some cases spread of the infection to adjacent tissue spaces.

If the pain and inflammation are limited to the tooth, local measures, such as debridement of food debris and plaque, irrigation with normal saline or hydrogen peroxide, and avoidance of occlusal trauma are recommended.

Antimicrobial therapy is indicated for patients presenting with fever, trismus, and pus exudation. Metronidazole 400 mg three times a day for 5 days is to be prescribed in combination with phenoxymethylpenicillin 500 mg four times a day for 5 days.

If it is envisaged that the tooth can be useful for chewing and patient also has the desire to retain the tooth, hyperplastic pericoronal tissue should be excised out through a minor oral surgery procedure known as operculectomy. This will allow better access to properly clean the area and prevent the accumulation of bacteria and food debris. In some unfortunate instances, the gum tissue may grow back and create the same problem.

Since impacted teeth frequently are unfavorably aligned and do not erupt completely, extraction of such tooth is commonly performed. This method eliminates any chance of recurrence of pericoronitis.

The risks and benefits of removal of impacted molars are mired in controversy, as extraction can lead to inferior alveolar nerve damage; retention can precipitate serious, even life-threatening infection [14, 22].

#### **3.3 Acute alveolar osteitis (dry socket)**

This painful condition is a complication that may occur following dental extraction. It presents with a severe throbbing pain caused by bone exposure at the site of extraction. Following the extraction, a blood clot forms within the extraction socket to safeguard the bone. If a blood clot forms inadequately in the socket or it is dislodged, the bone and nerves are exposed, leading to pain. Smoking, excessive extraction trauma, difficult disimpactions of third molars, vasoconstrictor in local anesthetic, and oral contraceptives are some of the predisposing factors to alveolar osteitis. Alveolar osteitis can strike 3–5 days after an extraction and may persist for a week. The exposed bone is acutely tender to touch; hence, mechanical stimulation by tongue movement and food particles results in frequent acute pain. On clinical examination, the socket appears empty with visible bony lamina dura.

Minimization of trauma related to the extraction procedure can be an important factor in prevention of dry socket. Since removal of the debris from the socket expedites healing, irrigation with warmed saline or chlorhexidine is suggestive. Use of intra-alveolar dressing materials such as bismuth iodoform paraffin paste and lidocaine gel on ribbon gauze can protect the socket from painful stimuli and collection of food debris. These dressing materials also impart a soothing sensation of warmth in the painful area. Usually after one or two dressings, significant pain relief is achieved. It is better to be on the lookout for signs of infection, such as pus in the socket, localized swelling, and lymphadenopathy. Antibiotics should be prescribed if these signs are there. It is crucial that

the reason for infection is determined such as retained root or bony fragments. A radiograph can be helpful. Surgical extraction is indicated for removal of root tip or bone sequestrum [6, 13, 23].

#### **3.4 Burning mouth syndrome (BMS)**

Burning mouth syndrome (BMS) is a complex painful disorder that is characterized by warm, burning, or tingling sensation in the oral mucosa, tongue, or lips. The pain may be associated with a feeling of intermittent numbness. Other associated features may include metallic taste and dryness in the mouth. Interestingly, a variety of names has been associated with this condition such as oral dysesthesia, stomatodynia, glossodynia, stomatopyrosis, glossopyrosis, sore mouth, and sore tongue. BMS is a reasonably common chronic complaint to affect middle age or elderly patients, especially females. Diagnosis of BMS is challenging, because usually no clear-cut dental or medical cause is evident and laboratory findings does not reveal any abnormality.

BMS can be classified into two clinical variants, namely, primary and secondary BMS. If no underlying medical or dental problem becomes evident on investigations, the diagnosis is primary or idiopathic BMS. Probably, the damage to the nerves that control pain and taste leads to primary BMS. Secondary BMS is caused by local, systemic, or psychological factors. A few common causes of secondary BMS include, dry mouth, acid reflux, deficiency of iron or vitamin B, hormonal disturbances (such as from thyroid problem or diabetes), etc. Because burning mouth syndrome can be associated with a wide array of local, systemic, or psychological conditions, an ambitious diagnostic approach is warranted. This approach should be based on a detailed history, clinical examination, laboratory tests, and exclusion of all other possible oral and systemic problems.

If no organic cause can be found and diagnosis suggests psychological factors such as anxiety, stress, and depression, it is advisable to make the patient aware by explaining that depression and other emotional disturbances are just as much illnesses and cause as much suffering as physical diseases. Apart from psychogenic medications, cognitive behavioral therapy is indicated in BMS.

Depending on the causative factors, medications used for BMS include antidepressants, analgesics, antiepileptic, antifungal, antibacterial, sialagogues, antihistamines, anxiolytics, antipsychotics, and vitamin, mineral, and hormonal replacements.

The topical application of clonazepam (by sucking a tablet of 1 mg), three times a day for 14 days can reduce the burning symptoms. *Aloe vera* gel also helps to reduce the burning sensation and pain in the sore areas of the tongue. Symptoms of secondary BMS go away when the underlying medical condition, such as diabetes or acid reflux, is treated [24, 25].

Overall, successful management of BMS is dependent on a holistic diagnostic workup and collaborative management involving dental practitioners, psychologist, and physician.

#### **3.5 Specific anticancer treatment painful oral complications: oral mucositis (OM)**

This grossly painful disorder usually occurs as a complication of chemo- and radiotherapy. An allergic reaction to certain medications, dental materials, or infections may also lead to nonspecific mucositis. Oral mucosal injury is the hallmark of OM that occurs due to the interference of chemotherapy and/or radiation therapy with normal turnover of oral mucosal cells.

Chemotherapy-induced and/or radiation therapy-induced OM clinically manifests as the painful swelling, atrophy, and ulceration of the oral mucosa. *Candida*

**21**

used instead.

stimulated nerve endings [20].

*Management of Odontogenic and Nonodontogenic Oral Pain*

and streptococcal infections may also occur due to the disintegration of the oral mucosa.OM-affecting pharynx and other areas of alimentary canal can lead to complications, including dysphagia, electrolyte disturbances, systemic infection,

Oral mucosal injury tends to be acute in cases where chemotherapy is administered over a short span of time. Chemotherapy-induced mucosal damage usually develops within a week after the start of therapy and peaks within 2 weeks. Radiotherapy-induced mucositis has a slower onset since it is most often administered in small fractions given over weeks. Radiation-induced mucositis typically starts in 1–2 weeks of starting the radiotherapy at cumulative doses of about 15 Gy (gray, a unit of absorbed radiation). At doses greater than 30 Gy, OM attains full

Factors related to treatment and patient characteristic can influence the development of OM. Treatment factors that influence the severity and presence of mucositis include the class, dose, and administration frequency of systemic chemotherapeutic agents, radiation dose and field, and use of adjuvant chemotherapy and radiation. The majority of patients treated for head and neck cancers or those receiving high-dose chemotherapy develop severe OM. Usually the healing within lesions of OM is evidenced within 2–4 weeks after stoppage of either therapy. So much so, the OM is a painful and agonizing condition that it has a drastic impact on oral hygiene maintenance, nutritional intake, and quality of life. Current clinical management of OM is largely supportive and aimed at maintaining oral hygiene, pain relief, and nutritional support. A majority of patients with mucositis pain has difficulty in food intake through mouth and a nasogastric tube or gastrostomy tube helps to achieve nutrition. Diet modifications in the form of liquid and soft diet are suggested to facilitate the food intake during the cancer therapy [27]. Maintenance of oral hygiene has an important contribution in the prevention and management of OM; however, it remains a neglected habit. Moreover, a good oral care helps to prevent secondary infection and sepsis in the lesions of OM. Oral hygiene measure such as tooth brushing, flossing, rinsing with sterile water, and using mouth moisturizers helps control pain and bleeding and prevent infections of the oral soft tissue. However, at the same time, caution must be exercised that tooth brushing and flossing do not traumatize the oral mucosa. In case, a patient with OM is unable to tolerate the use of a tooth brush, oral sponges and foam brushes can be

Simple analgesia, e.g., paracetamol (1 g four times a day) in soluble form used as a mouth rinse will be adequate to control the mild-to-moderate pain of OM. For controlling severe pain, opioid analgesics (e.g., hydromorphone or morphine) can be used. Use of opioids is both logical and appropriate to alleviate the intolerable

When swallowing pills can be problematic in patients with severe OM, the use of parenteral administration of opioid analgesics is required. For seeking short-term relief in pain of OM, oral rinsing with 2% viscous lidocaine (topical anesthetic) in combination with diphenhydramine and magnesium aluminum hydroxide may allow the patient to eat and maintain oral hygiene. Mucosal-coating agents such as sucralfate, Gelclair®, and Caphosol® by adhering to oral mucosa form a protective coating. This coating aids in patient comfort by shielding the exposed and over-

Prevention of OM is also an important aspect to be considered and has involved

multiple medications. The updated clinical practice guidelines for the prevention and treatment of mucositis have suggested the use of chemo-preventative agents to prevent and/or reduce severity of OM. The most commonly prescribed preventative agents for OM are ice chips (given 30 minutes prior to chemotherapy)

pain of OM, and strong opioids can be helpful in this direction.

*DOI: http://dx.doi.org/10.5772/intechopen.83837*

malnutrition, and even death [20, 26].

severity and may last for weeks or even months.

*From Conventional to Innovative Approaches for Pain Treatment*

or bone sequestrum [6, 13, 23].

**3.4 Burning mouth syndrome (BMS)**

of all other possible oral and systemic problems.

acid reflux, is treated [24, 25].

and physician.

**mucositis (OM)**

with normal turnover of oral mucosal cells.

medications, cognitive behavioral therapy is indicated in BMS.

the reason for infection is determined such as retained root or bony fragments. A radiograph can be helpful. Surgical extraction is indicated for removal of root tip

Burning mouth syndrome (BMS) is a complex painful disorder that is characterized by warm, burning, or tingling sensation in the oral mucosa, tongue, or lips. The pain may be associated with a feeling of intermittent numbness. Other associated features may include metallic taste and dryness in the mouth. Interestingly, a variety of names has been associated with this condition such as oral dysesthesia, stomatodynia, glossodynia, stomatopyrosis, glossopyrosis, sore mouth, and sore tongue. BMS is a reasonably common chronic complaint to affect middle age or elderly patients, especially females. Diagnosis of BMS is challenging, because usually no clear-cut dental or medical cause is evident and laboratory findings does not reveal any abnormality.

BMS can be classified into two clinical variants, namely, primary and secondary BMS. If no underlying medical or dental problem becomes evident on investigations, the diagnosis is primary or idiopathic BMS. Probably, the damage to the nerves that control pain and taste leads to primary BMS. Secondary BMS is caused by local, systemic, or psychological factors. A few common causes of secondary BMS include, dry mouth, acid reflux, deficiency of iron or vitamin B, hormonal disturbances (such as from thyroid problem or diabetes), etc. Because burning mouth syndrome can be associated with a wide array of local, systemic, or psychological conditions, an ambitious diagnostic approach is warranted. This approach should be based on a detailed history, clinical examination, laboratory tests, and exclusion

If no organic cause can be found and diagnosis suggests psychological factors such as anxiety, stress, and depression, it is advisable to make the patient aware by explaining that depression and other emotional disturbances are just as much illnesses and cause as much suffering as physical diseases. Apart from psychogenic

Depending on the causative factors, medications used for BMS include antidepressants, analgesics, antiepileptic, antifungal, antibacterial, sialagogues, antihistamines, anxiolytics, antipsychotics, and vitamin, mineral, and hormonal replacements.

The topical application of clonazepam (by sucking a tablet of 1 mg), three times

Overall, successful management of BMS is dependent on a holistic diagnostic workup and collaborative management involving dental practitioners, psychologist,

This grossly painful disorder usually occurs as a complication of chemo- and radiotherapy. An allergic reaction to certain medications, dental materials, or infections may also lead to nonspecific mucositis. Oral mucosal injury is the hallmark of OM that occurs due to the interference of chemotherapy and/or radiation therapy

Chemotherapy-induced and/or radiation therapy-induced OM clinically manifests as the painful swelling, atrophy, and ulceration of the oral mucosa. *Candida*

a day for 14 days can reduce the burning symptoms. *Aloe vera* gel also helps to reduce the burning sensation and pain in the sore areas of the tongue. Symptoms of secondary BMS go away when the underlying medical condition, such as diabetes or

**3.5 Specific anticancer treatment painful oral complications: oral** 

**20**

and streptococcal infections may also occur due to the disintegration of the oral mucosa.OM-affecting pharynx and other areas of alimentary canal can lead to complications, including dysphagia, electrolyte disturbances, systemic infection, malnutrition, and even death [20, 26].

Oral mucosal injury tends to be acute in cases where chemotherapy is administered over a short span of time. Chemotherapy-induced mucosal damage usually develops within a week after the start of therapy and peaks within 2 weeks. Radiotherapy-induced mucositis has a slower onset since it is most often administered in small fractions given over weeks. Radiation-induced mucositis typically starts in 1–2 weeks of starting the radiotherapy at cumulative doses of about 15 Gy (gray, a unit of absorbed radiation). At doses greater than 30 Gy, OM attains full severity and may last for weeks or even months.

Factors related to treatment and patient characteristic can influence the development of OM. Treatment factors that influence the severity and presence of mucositis include the class, dose, and administration frequency of systemic chemotherapeutic agents, radiation dose and field, and use of adjuvant chemotherapy and radiation. The majority of patients treated for head and neck cancers or those receiving high-dose chemotherapy develop severe OM. Usually the healing within lesions of OM is evidenced within 2–4 weeks after stoppage of either therapy.

So much so, the OM is a painful and agonizing condition that it has a drastic impact on oral hygiene maintenance, nutritional intake, and quality of life. Current clinical management of OM is largely supportive and aimed at maintaining oral hygiene, pain relief, and nutritional support. A majority of patients with mucositis pain has difficulty in food intake through mouth and a nasogastric tube or gastrostomy tube helps to achieve nutrition. Diet modifications in the form of liquid and soft diet are suggested to facilitate the food intake during the cancer therapy [27].

Maintenance of oral hygiene has an important contribution in the prevention and management of OM; however, it remains a neglected habit. Moreover, a good oral care helps to prevent secondary infection and sepsis in the lesions of OM. Oral hygiene measure such as tooth brushing, flossing, rinsing with sterile water, and using mouth moisturizers helps control pain and bleeding and prevent infections of the oral soft tissue. However, at the same time, caution must be exercised that tooth brushing and flossing do not traumatize the oral mucosa. In case, a patient with OM is unable to tolerate the use of a tooth brush, oral sponges and foam brushes can be used instead.

Simple analgesia, e.g., paracetamol (1 g four times a day) in soluble form used as a mouth rinse will be adequate to control the mild-to-moderate pain of OM. For controlling severe pain, opioid analgesics (e.g., hydromorphone or morphine) can be used. Use of opioids is both logical and appropriate to alleviate the intolerable pain of OM, and strong opioids can be helpful in this direction.

When swallowing pills can be problematic in patients with severe OM, the use of parenteral administration of opioid analgesics is required. For seeking short-term relief in pain of OM, oral rinsing with 2% viscous lidocaine (topical anesthetic) in combination with diphenhydramine and magnesium aluminum hydroxide may allow the patient to eat and maintain oral hygiene. Mucosal-coating agents such as sucralfate, Gelclair®, and Caphosol® by adhering to oral mucosa form a protective coating. This coating aids in patient comfort by shielding the exposed and overstimulated nerve endings [20].

Prevention of OM is also an important aspect to be considered and has involved multiple medications. The updated clinical practice guidelines for the prevention and treatment of mucositis have suggested the use of chemo-preventative agents to prevent and/or reduce severity of OM. The most commonly prescribed preventative agents for OM are ice chips (given 30 minutes prior to chemotherapy) or amifostine (a thiol drug) and keratinocyte growth factor-1 (palifermin). Moreover, the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society for Oral Oncology (ISOO) guidelines for treatment of oral recommends the use of benzydamine for prevention of radiation-induced OM. Benzydamine hydrochloride (HCl) is a cytoprotectant with analgesic, antiinflammatory, and antimicrobial activity. On being used as an oral rinse, it significantly reduced OM-related erythema and ulceration [20].

#### **3.6 Acute necrotizing ulcerative gingivitis (ANUG)**

Acute necrotizing ulcerative gingivitis (ANUG) is an acute infection of the gingiva and is characterized by pain, bleeding, fetid breath, and gingival necrosis. Fever, malaise, and regional lymphadenopathy may be accompanying features. Oral functions including speaking and swallowing become difficult due to intense gingival pain.

Destructive pattern in the form of gingival ulcerations, necrosis, and 'punchedout' ulcerated papillae makes ANUG unique when compared with other periodontal diseases. Initially cratered ulcers affect the tips of interdental papilla, later on spreading along gingival margins. ANUG most commonly affects smokers and stressful immunocompromised individuals. Other risk factors are neglected oral hygiene, sleep deprivation, and malnutrition. ANUG is an opportunistic bacterial infection that is caused by a complex of *fusiforms* and *spirochaetes*.

Maintenance of oral hygiene through self-care and gentle debridement by the dentist is the stepping stone to the successful management of ANUG. Patients may be advised to use mouth rinses, such as warm normal saline or 1.5% hydrogen peroxide or 0.12% chlorhexidine at hourly intervals for the first few days. Analgesics may help to ward off the intense pain associated with ANUG. In order to prevent recurrence of ANUG, the patient must be educated to maintain high personal oral hygiene, to have adequate nutrition, and to get sufficient rest. Antibiotics are indicated in case of systemic involvement. The recommended antibiotics are amoxicillin 500 mg, three times daily for 10 days plus metronidazole 250 mg, three times daily for 10 days. The healed gingival craters can act as stagnation areas where plaque can accumulate and ANUG may reoccur. For correction of superficial craters, gingivectomy and/or gingivoplasty procedures may be helpful. For rehabilitation of deep craters, periodontal flap surgery or regenerative surgery may be considered [28–30].

#### **3.7 Desquamative gingivitis (DG)**

Desquamative gingivitis (DG) is a specific clinical presentation of unknown etiology in which the attached gingiva appears fiery red, glazed, and friable. Desquamative gingivitis may be a clinical manifestation of various mucocutaneous disorders—erythema multiforme, erosive lichen planus, pemphigus, pemphigoid, and psoriasis. DG is characterized by gingival soreness and burning sensation, which worsens on eating spicy and acidic food. The typical clinical feature in severe cases is of desquamation of gingival epithelium. The treatment of DG is aimed at minimizing the gingival injury and irritation. Therefore, the patient should avoid spicy or acidic foods. Oral hygiene maintenance can be helpful in removal of exacerbating factors, particularly dental plaque. However, in order to avoid injury to the friable gingiva, tooth brushing should be done gently with a soft tooth brush or toothette. Use of an anesthetic mouthwash, e.g., benzydamine hydrochloride can be helpful in tackling the pain. Topical therapies are the mainstay of treatment for DG. High potency corticosteroid gels are commonly used as first-line topical therapy. Clobetasole-17-propionate or fluocinonide 0.05% in gel form can be prescribed. Ease of gel application can be facilitated via the use of custom fabricated

**23**

provided the original work is properly cited.

\*Address all correspondence to: smrshaikh@gmail.com

*Management of Odontogenic and Nonodontogenic Oral Pain*

the odontogenic or non-odontogenic oral pain [1].

ship and/or publication of this chapter.

trays. Furthermore, 0.1% triamcinolone orabase can also be used. For complete resolution of DG, it is important that the underlying disease leading to DG is

Odontogenic and nonodontogenic pain may occur due to a variety of factors and

The author declares no potential conflicts of interest with respect to the author-

causes. A differential diagnosis of orofacial pain, distinguishing between odontogenic pathologies and nonodontogenic painful etiologies, is a requisite before taking any clinical or pharmacological decision for pain management. Exactness of differential diagnosis is dependent on a thorough medical and dental history, comprehensive clinical examination, and appropriate investigations. Any decision on pain management should encompass a treatment regimen (e.g. palliative, dental, pharmacological, and psychological) that can adequately address the clinical problem of pain. For the successful accomplishment of a durable pain management, the treatment decisions should be based upon the best-available evidence, consideration of cost-effectiveness, and patient's expectation. Specialist referral is warranted, if the conventional clinical and pharmacological measures fail to control

diagnosed and treated appropriately by specific therapies [31, 32].

*DOI: http://dx.doi.org/10.5772/intechopen.83837*

**4. Conclusion**

**Conflict of interest**

**Author details**

Sameer Shaikh

Saudi Arabia

© 2019 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,

Department of Oral Diagnosis and Oral Medicine, University of Ha'il, Ha'il,

trays. Furthermore, 0.1% triamcinolone orabase can also be used. For complete resolution of DG, it is important that the underlying disease leading to DG is diagnosed and treated appropriately by specific therapies [31, 32].

### **4. Conclusion**

*From Conventional to Innovative Approaches for Pain Treatment*

cantly reduced OM-related erythema and ulceration [20].

infection that is caused by a complex of *fusiforms* and *spirochaetes*.

**3.7 Desquamative gingivitis (DG)**

**3.6 Acute necrotizing ulcerative gingivitis (ANUG)**

or amifostine (a thiol drug) and keratinocyte growth factor-1 (palifermin). Moreover, the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society for Oral Oncology (ISOO) guidelines for treatment of oral recommends the use of benzydamine for prevention of radiation-induced OM. Benzydamine hydrochloride (HCl) is a cytoprotectant with analgesic, antiinflammatory, and antimicrobial activity. On being used as an oral rinse, it signifi-

Acute necrotizing ulcerative gingivitis (ANUG) is an acute infection of the gingiva and is characterized by pain, bleeding, fetid breath, and gingival necrosis. Fever, malaise, and regional lymphadenopathy may be accompanying features. Oral functions including speaking and swallowing become difficult due to intense gingival pain. Destructive pattern in the form of gingival ulcerations, necrosis, and 'punchedout' ulcerated papillae makes ANUG unique when compared with other periodontal diseases. Initially cratered ulcers affect the tips of interdental papilla, later on spreading along gingival margins. ANUG most commonly affects smokers and stressful immunocompromised individuals. Other risk factors are neglected oral hygiene, sleep deprivation, and malnutrition. ANUG is an opportunistic bacterial

Maintenance of oral hygiene through self-care and gentle debridement by the dentist is the stepping stone to the successful management of ANUG. Patients may be advised to use mouth rinses, such as warm normal saline or 1.5% hydrogen peroxide or 0.12% chlorhexidine at hourly intervals for the first few days. Analgesics may help to ward off the intense pain associated with ANUG. In order to prevent recurrence of ANUG, the patient must be educated to maintain high personal oral hygiene, to have adequate nutrition, and to get sufficient rest. Antibiotics are indicated in case of systemic involvement. The recommended antibiotics are amoxicillin 500 mg, three times daily for 10 days plus metronidazole 250 mg, three times daily for 10 days. The healed gingival craters can act as stagnation areas where plaque can accumulate and ANUG may reoccur. For correction of superficial craters, gingivectomy and/or gingivoplasty procedures may be helpful. For rehabilitation of deep craters, periodontal flap surgery or regenerative surgery may be considered [28–30].

Desquamative gingivitis (DG) is a specific clinical presentation of unknown etiology in which the attached gingiva appears fiery red, glazed, and friable. Desquamative gingivitis may be a clinical manifestation of various mucocutaneous disorders—erythema multiforme, erosive lichen planus, pemphigus, pemphigoid, and psoriasis. DG is characterized by gingival soreness and burning sensation, which worsens on eating spicy and acidic food. The typical clinical feature in severe cases is of desquamation of gingival epithelium. The treatment of DG is aimed at minimizing the gingival injury and irritation. Therefore, the patient should avoid spicy or acidic foods. Oral hygiene maintenance can be helpful in removal of exacerbating factors, particularly dental plaque. However, in order to avoid injury to the friable gingiva, tooth brushing should be done gently with a soft tooth brush or toothette. Use of an anesthetic mouthwash, e.g., benzydamine hydrochloride can be helpful in tackling the pain. Topical therapies are the mainstay of treatment for DG. High potency corticosteroid gels are commonly used as first-line topical therapy. Clobetasole-17-propionate or fluocinonide 0.05% in gel form can be prescribed. Ease of gel application can be facilitated via the use of custom fabricated

**22**

Odontogenic and nonodontogenic pain may occur due to a variety of factors and causes. A differential diagnosis of orofacial pain, distinguishing between odontogenic pathologies and nonodontogenic painful etiologies, is a requisite before taking any clinical or pharmacological decision for pain management. Exactness of differential diagnosis is dependent on a thorough medical and dental history, comprehensive clinical examination, and appropriate investigations. Any decision on pain management should encompass a treatment regimen (e.g. palliative, dental, pharmacological, and psychological) that can adequately address the clinical problem of pain. For the successful accomplishment of a durable pain management, the treatment decisions should be based upon the best-available evidence, consideration of cost-effectiveness, and patient's expectation. Specialist referral is warranted, if the conventional clinical and pharmacological measures fail to control the odontogenic or non-odontogenic oral pain [1].

### **Conflict of interest**

The author declares no potential conflicts of interest with respect to the authorship and/or publication of this chapter.

### **Author details**

Sameer Shaikh Department of Oral Diagnosis and Oral Medicine, University of Ha'il, Ha'il, Saudi Arabia

\*Address all correspondence to: smrshaikh@gmail.com

© 2019 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.

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[25] Jimson S, Rajesh E, Krupaa RJ, Kasthuri M. Burning mouth syndrome. Journal of Pharmacy & Bioallied Sciences. 2015;**7**(Suppl 1):S194-S196

[26] Naidu MU, Ramana GV, Rani PU, Mohan IK, Suman A, Roy P. Chemotherapy-induced and/ or radiation therapy-induced oral mucositis—Complicating the treatment of cancer. Neoplasia. 2004;**6**(5):423-431

[27] Raber-Durlacher JE, Elad S, Barasch A. Oral mucositis. Oral Oncology. 2010;**46**:452-460

[28] Malek R, Gharibi A, Khlil N, Kissa J. Necrotizing ulcerative gingivitis. Contemporary Clinical Dentistry. 2017;**8**(3):496-500

[29] Dufty J, Gkranias N, Donos N. Necrotising ulcerative gingivitis: A literature review. Oral Health & Preventive Dentistry. 2017;**15**(4):321-327

[30] Ubertalli JT. Acute Necrotizing Ulcerative Gingivitis (ANUG) (Fusospirochetosis; Trench Mouth; Vincent Infection or Vincent Angina) [Internet]. 2018. Available from: https:// www.msdmanuals.com/professional/ dental-disorders/periodontal-disorders/ acute-necrotizing-ulcerative-gingivitisanug [Accessed: November 15, 2018]

[31] Karagoz G, Bektas-Kayhan K, Unur M. Desquamative gingivitis: A review. Journal of Istanbul University Faculty of Dentistry. 2016;**50**(2):54-60

[32] Maderal AD, Lee Salisbury P, Jorizzo JL. Desquamative gingivitis: Diagnosis and treatment. Journal of the American Academy of Dermatology;**2018**(5):78, 851-861

**24**

*From Conventional to Innovative Approaches for Pain Treatment*

[10] Ubertalli JT. Pulpitis [Internet]. 2018. Available from: http://www. msdmanuals.com/professional/dentaldisorders/common-dental-disorders/ pulpitis [Accessed: November 15,

[11] Marchick M. Chapter 4: Sore throat, dental pain, and other oral issues. In: Desai B, Desai A, editors. Primary Care for Emergency Physicians. Cham:

[12] Rosenberg PA. Chapter 2: Odontogenic and non-odontogenic pain. In: Rosenberg PA, editor. Endodontic Pain: Diagnosis, Causes, Prevention and Treatment. 1st ed . (Endodontic Topics). Heidelberg, Germany: Springer Publishing; 2014. DOI: 10.1007/978-3-642-54701-0

[13] Greenwood M, Corbett I. Dental Emergencies. Chichester, West Sussex: Blackwell Publishing Ltd; 2012. DOI:

[14] Eversole LR. Clinical Outline of Oral Pathology: Diagnosis and Treatment.

Maciulskiene V. Pathogenesis of apical periodontitis: A literature review. Journal of Oral & Maxillofacial

10.1002/9781118702895

4th ed. USA: People's Medical Publishing House; 2011

[15] Graunaite I, Lodiene G,

[16] Patel B. Chapter 1: Pain of odontogenic and non-odontogenic origin. In: Patel B, editor. Endodontic Diagnosis, Pathology and Treatment Planning. Switzerland: Springer International Publishing. p. 2015. DOI:

10.1007/978-3-319-15591-3

2000;**66**(8):440-443

[17] Barzilay I. Splinting teeth—A review of methodology and clinical case reports. Journal of the Canadian Dental Association.

Research. 2011;**2**(4):e1

2018]

Springer; 2017

[1] Odontogenic pain management. International Dental Journal.

[2] Romero-Reyes M, Uyanik JM. Orofacial pain management: Current perspectives. Journal of Pain Research. 2014;**7**:99-115. DOI: 10.2147/JPR.S37593

[3] Clark GT. Chapter 1: The 30 most prevalent chronic painful diseases, disorders, and dysfunctions that occur in the orofacial region. In: Clark GT, Dionne RA, editors. Orofacial Pain: A Guide to Medications and Management. Oxford , England: Wiley-Blackwell; 2012

[4] Hargreaves K, Abbott PV. Drugs for pain management in dentistry. Australian Dental Journal. 2005;**50**(4

[5] Clark GT. Chapter 2: Top 60 most important medications used in an orofacial pain treatment center. In: Clark GT, Dionne RA, editors. Orofacial Pain: A Guide to Medications and Management. Oxford, England: Wiley-

[6] Cawson RA, Odell EW, Porter S. Cawson's Essentials of Oral Pathology and Oral Medicine. 8th ed. Edinburgh:

[7] Shephard MK, Macgregor EA, Zakrzewska JM. Orofacial pain: A guide for the headache physician. Headache. 2014;**54**(1):22-39. DOI: 10.1111/

[8] Regezi JA, Sciubba JJ, Jordan RCK. Oral Pathology: Clinical

Pathologic Considerations. 6th ed. St. Louis, Missouri: Saunders; 2012

[9] Dabuleanu M. Pulpitis (reversible/ irreversible). Journal of the Canadian Dental Association. 2013;**79**:d90

Churchill Livingstone; 2008

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pdf/10.1111/idj.12375

**References**

2018;**68**:20-21. DOI: 10.1111/idj.12375. https://onlinelibrary.wiley.com/doi/

**27**

**1. Introduction**

**Chapter 3**

**Abstract**

in Surgery

*Nicholas Yim and Fereydoun Don Parsa*

opioid-free pain management approach in surgery.

From the Origins of the Opioid

Use (and Misuse) to the Challenge

of Opioid-Free Pain Management

Pain is a physiologic mechanism of the human body. Early cultures believed pain to have demonic and spiritual origins. In the early nineteenth century, morphine was first isolated by the German pharmacist Friedrich Wilhelm Adam Ferdinand Serturner. Since then, synthetic opioids and other derivatives of morphine have been developed for a wide variety of purposes, including pain relief during surgery. Opioids mainly act through the stimulation of μ-receptors, which has inhibitory effects on the propagation of pain signals to the brain. However, opioids also have unwanted side effects like nausea, vomiting, constipation, postoperative sedation, dizziness, and addiction, and are associated with significant morbidity, prolong hospital stays, increase use of medications needed to reverse side effects, and

decrease patient satisfaction. Furthermore, use and abuse of opioids have contributed to an opioid epidemic, especially in the United States since the beginning of the twenty-first century. Opioid-free anesthesia is an alternative aimed at providing pain relief without the opioid-related adverse effects and to enhance recovery. Non-opioid alternatives and preoperative patient education strategies have been shown to be superior in the management of postoperative pain and opioid requirements. Clinicals have embraced these concepts enthusiastically and have begun to incorporate an

**Keywords:** opioids, opioid-free anesthesia, opioid-free pain management, surgery

The perception of pain is an integral part of human existence. Although uncomfortable to the individual, the perception of pain is necessary to protect the body from harm. A painful sensation causes man to seek an explanation for the reason of this discomfort. A brief history of the origins of pain and the development of pain medications is presented, followed by the current understanding of the physiology of pain and modern concern about opioid use. In the second half of the twentieth century, synthetic opioids were introduced to achieve hemodynamic stability during anesthesia. Furthermore, combined with hypnotics and muscle relaxants, the opioids administration is considered a keystone of anesthesia. For instance, a prevalence of 30% of unwanted effects of opioids such as nausea, vomiting, dizziness and constipation has been reported [1].

#### **Chapter 3**

## From the Origins of the Opioid Use (and Misuse) to the Challenge of Opioid-Free Pain Management in Surgery

*Nicholas Yim and Fereydoun Don Parsa*

#### **Abstract**

Pain is a physiologic mechanism of the human body. Early cultures believed pain to have demonic and spiritual origins. In the early nineteenth century, morphine was first isolated by the German pharmacist Friedrich Wilhelm Adam Ferdinand Serturner. Since then, synthetic opioids and other derivatives of morphine have been developed for a wide variety of purposes, including pain relief during surgery. Opioids mainly act through the stimulation of μ-receptors, which has inhibitory effects on the propagation of pain signals to the brain. However, opioids also have unwanted side effects like nausea, vomiting, constipation, postoperative sedation, dizziness, and addiction, and are associated with significant morbidity, prolong hospital stays, increase use of medications needed to reverse side effects, and decrease patient satisfaction. Furthermore, use and abuse of opioids have contributed to an opioid epidemic, especially in the United States since the beginning of the twenty-first century. Opioid-free anesthesia is an alternative aimed at providing pain relief without the opioid-related adverse effects and to enhance recovery. Non-opioid alternatives and preoperative patient education strategies have been shown to be superior in the management of postoperative pain and opioid requirements. Clinicals have embraced these concepts enthusiastically and have begun to incorporate an opioid-free pain management approach in surgery.

**Keywords:** opioids, opioid-free anesthesia, opioid-free pain management, surgery

#### **1. Introduction**

The perception of pain is an integral part of human existence. Although uncomfortable to the individual, the perception of pain is necessary to protect the body from harm. A painful sensation causes man to seek an explanation for the reason of this discomfort. A brief history of the origins of pain and the development of pain medications is presented, followed by the current understanding of the physiology of pain and modern concern about opioid use. In the second half of the twentieth century, synthetic opioids were introduced to achieve hemodynamic stability during anesthesia. Furthermore, combined with hypnotics and muscle relaxants, the opioids administration is considered a keystone of anesthesia. For instance, a prevalence of 30% of unwanted effects of opioids such as nausea, vomiting, dizziness and constipation has been reported [1].

An increased occurrence of confusion and postoperative delirium [2], respiratory depression, increased postoperative pain and opioids consumption with abuse, immunodepression, hyperalgesia and chronic postoperative pain have also been described. Of note, opioid tolerance to analgesia can occur after a single dose. Thus, the management of pain in surgery is currently moving in the direction of the reduction of opioid use preoperatively, perioperatively, and postoperatively. The modern multimodal anesthesia and analgesia with intraoperative hemodynamic stability, immobility and anticipation of postoperative analgesia can be achieved without opioids. The concept of opioid-free anesthesia (OFA) is based on the idea that hemodynamic stability can be obtained without opioids during anesthesia. In particular, OFA is a fascinating multimodal approach to anesthesia which provides the combination of hypnotics, N-methyl-D-aspartate (NMDA) antagonists, local anesthetics, anti-inflammatory drugs and alpha-2 agonists such as dexmedetomidine, and no intra-operative systemic, neuraxial, or intracavitary opioid is administered during anesthesia and the perioperative course. This strategy is aimed to prevent postoperative opioid-related adverse effects and to enhance recovery after surgery.

#### **2. Pain and pain management from ancient cultures to the nineteenth century**

Early theories of the origin of pain, especially from internal diseases, revolved around demonic and religious beliefs. Shamans and sorcerers treated patients with the use of amulets, magic sculptures, talismans, magic ceremonies and rituals to ward off demons and evil spirits. It was believed that spirits and demons should leave the body from the same way it entered, resulting in cultural scarifications to allow bad fluids, spirits and demons to escape. In Egypt, religious ceremonies and prayers were believed to help relieve pain. Incantations to God Horus and other deities were thought to relieve unilateral headaches [3].

Ancient cultures have used leaves of cocoa plant and opium for religious and medical purposes. The earliest anthropological evidence of the use of cocoa leaves was from the pre-Inca culture in Peru, dated to 1300 B.C. The Peruvians used cocoa leaves as a local anesthetic in trepanation operations. Opium was introduced to Egypt around 1500–1300 B.C., and was used as a cream for external application and for the fumigation of toothaches. In India and China, opium was used for the treatment of toothache and joint pain. In these cultures, opium could not be separated from its "recreational" use [3].

In the seventeenth century, physicians began to consider the human body as a machine with different parts in constant motion. The French philosopher Rene Descartes proposed one of the earliest concepts of modern physiology: a movement or touch initiated at the peripheral nerve endings propagated to the brain. This concept, which formed the basis of nineteenth century pain theories, is illustrated by Descartes famous figure [3] of a boy, whose foot is being stimulated by heat from a fire. Several scientific discoveries followed Descartes physiologic concept of pain, including that of Sir Humphrey Davy's reports of pain relief from inhalation of nitrous oxide in 1800 and James Moore's report of opium use for postoperative analgesia in 1784 [3].

#### **3. The era of opioid analgesics and the discovery of anesthesia**

With a better understanding of the physiology and pathways of pain, pharmacologic discoveries, particularly of morphine, were made in the beginning of the nineteenth century. The German pharmacist Friedrich Wilhelm Adam Ferdinand

**29**

systems followed [3].

*From the Origins of the Opioid Use (and Misuse) to the Challenge of Opioid-Free Pain…*

Serturner was the first to isolate morphine from poppy in 1805. He named the substance after Morpheus, the Greek god of sleep. The invention of the hypodermic hollow needles and syringes by Charles Gabriel Pravaz and Alexander Wood in the 1850s allowed the ease of subcutaneous application. While this helped the widespread use of morphine, it also paved way for the use and abuse of morphine that spread rapidly during the American Civil War (1861–1865) and the French-German War (1870–1871). Opioid addiction became known as the "soldier's disease" and

spurred research efforts to find substances with a lower risk of abuse [3].

and several other substances from non-prescription preparations [3].

Stemming from the discovery of morphine, scientists began to experiment and develop different forms of morphine. In 1874 Charles Adler Wright synthesized diacetyl-morphine, which in 1898 was registered under the name of heroin. This drug showed stronger cough suppression but lower analgesic effects when compared to morphine in animal models. Toward the beginning of the twentieth century, addiction to heroin became a growing problem in the USA, and in 1914, the government began implementing stricter regulations, limiting the maximum amount of heroin in preparations. These regulations also prohibited opium, morphine, cocaine,

The development of new opioid analgesics continued. Derivatives of morphine and codeine such as hydromorphone, dihydrocodeine, hydrocodone, oxymorphone, meperidine, and oxycodone emerged at the beginning of the twentieth century. Methadone was developed during World War II in Germany and was used primarily as a substitution therapy in drug addicts. Methadone is a μ-receptor agonist and a noncompetitive NMDA antagonist. The NMDA receptor is involved in the pathophysiology of neuropathic pain. Fentanyl was developed by Paul A.J. Janssen in 1953 and was proved to be approximately 40 times more active than morphine. Subsequently, similar compounds with stronger potency developed, including

The techniques for pain relief, such as spinal cord analgesia, knee surgeries, and different routes of administration for medications, began to develop after further research suggested opioid receptors in the human brain and the demonstration of endogenous opioids, the endorphins and enkephalins, constituting an internal system of pain modulation. Opioid receptors were found in high density in the substantia gelatinosa of the spinal cord, as well as the limbic system and periaqueductal gray area of the brainstem. This led to the reintroduction of spinal opioid application in clinical medicine. Peripheral opioid receptors were demonstrated in the late 1980s, and Stein and colleagues showed reduced operative pain following arthroscopy of the knee joint following intraarticular injection of morphine. Sustained release formula and transdermal route of administration provided a profound impact on the management of chronic pain. It made pain management much more comfortable for the patients, resulting in an improved quality of life. Morphine was available in the sustained release formula in 1983, while fentanyl was available in the transdermal system. Various opioids in sustained release formula and transdermal

Surgical anesthesia experimentations in the nineteenth century allowed for major development in pain-free surgeries. One of particular note was the Dr. William Morton's experimentation with ether as a local anesthetic for a surgical neck operation. The dentist Horace Wells previously used gas during teeth extraction procedures. The first surgical ether anesthetized procedure was by the dentist William Thomas Green Morton at Massachusetts General Hospital, Boston, in 1846. Dr. John C. Warren was the senior surgeon operating on a congenital vascular tumor on the neck of a young man, Gilbert Abbott. To the audience's amazement, Abbott did not cry out in pain during the procedure, and this ushered in the era of painfree surgery [3]. Painters Warren and Lucia Prosperi were commissioned in 2000

*DOI: http://dx.doi.org/10.5772/intechopen.82675*

carfentanil, sufentanil, and alfentanil [3].

#### *From the Origins of the Opioid Use (and Misuse) to the Challenge of Opioid-Free Pain… DOI: http://dx.doi.org/10.5772/intechopen.82675*

Serturner was the first to isolate morphine from poppy in 1805. He named the substance after Morpheus, the Greek god of sleep. The invention of the hypodermic hollow needles and syringes by Charles Gabriel Pravaz and Alexander Wood in the 1850s allowed the ease of subcutaneous application. While this helped the widespread use of morphine, it also paved way for the use and abuse of morphine that spread rapidly during the American Civil War (1861–1865) and the French-German War (1870–1871). Opioid addiction became known as the "soldier's disease" and spurred research efforts to find substances with a lower risk of abuse [3].

Stemming from the discovery of morphine, scientists began to experiment and develop different forms of morphine. In 1874 Charles Adler Wright synthesized diacetyl-morphine, which in 1898 was registered under the name of heroin. This drug showed stronger cough suppression but lower analgesic effects when compared to morphine in animal models. Toward the beginning of the twentieth century, addiction to heroin became a growing problem in the USA, and in 1914, the government began implementing stricter regulations, limiting the maximum amount of heroin in preparations. These regulations also prohibited opium, morphine, cocaine, and several other substances from non-prescription preparations [3].

The development of new opioid analgesics continued. Derivatives of morphine and codeine such as hydromorphone, dihydrocodeine, hydrocodone, oxymorphone, meperidine, and oxycodone emerged at the beginning of the twentieth century. Methadone was developed during World War II in Germany and was used primarily as a substitution therapy in drug addicts. Methadone is a μ-receptor agonist and a noncompetitive NMDA antagonist. The NMDA receptor is involved in the pathophysiology of neuropathic pain. Fentanyl was developed by Paul A.J. Janssen in 1953 and was proved to be approximately 40 times more active than morphine. Subsequently, similar compounds with stronger potency developed, including carfentanil, sufentanil, and alfentanil [3].

The techniques for pain relief, such as spinal cord analgesia, knee surgeries, and different routes of administration for medications, began to develop after further research suggested opioid receptors in the human brain and the demonstration of endogenous opioids, the endorphins and enkephalins, constituting an internal system of pain modulation. Opioid receptors were found in high density in the substantia gelatinosa of the spinal cord, as well as the limbic system and periaqueductal gray area of the brainstem. This led to the reintroduction of spinal opioid application in clinical medicine. Peripheral opioid receptors were demonstrated in the late 1980s, and Stein and colleagues showed reduced operative pain following arthroscopy of the knee joint following intraarticular injection of morphine. Sustained release formula and transdermal route of administration provided a profound impact on the management of chronic pain. It made pain management much more comfortable for the patients, resulting in an improved quality of life. Morphine was available in the sustained release formula in 1983, while fentanyl was available in the transdermal system. Various opioids in sustained release formula and transdermal systems followed [3].

Surgical anesthesia experimentations in the nineteenth century allowed for major development in pain-free surgeries. One of particular note was the Dr. William Morton's experimentation with ether as a local anesthetic for a surgical neck operation. The dentist Horace Wells previously used gas during teeth extraction procedures. The first surgical ether anesthetized procedure was by the dentist William Thomas Green Morton at Massachusetts General Hospital, Boston, in 1846. Dr. John C. Warren was the senior surgeon operating on a congenital vascular tumor on the neck of a young man, Gilbert Abbott. To the audience's amazement, Abbott did not cry out in pain during the procedure, and this ushered in the era of painfree surgery [3]. Painters Warren and Lucia Prosperi were commissioned in 2000

*From Conventional to Innovative Approaches for Pain Treatment*

deities were thought to relieve unilateral headaches [3].

from its "recreational" use [3].

An increased occurrence of confusion and postoperative delirium [2], respiratory depression, increased postoperative pain and opioids consumption with abuse, immunodepression, hyperalgesia and chronic postoperative pain have also been described. Of note, opioid tolerance to analgesia can occur after a single dose. Thus, the management of pain in surgery is currently moving in the direction of the reduction of opioid use preoperatively, perioperatively, and postoperatively. The modern multimodal anesthesia and analgesia with intraoperative hemodynamic stability, immobility and anticipation of postoperative analgesia can be achieved without opioids. The concept of opioid-free anesthesia (OFA) is based on the idea that hemodynamic stability can be obtained without opioids during anesthesia. In particular, OFA is a fascinating multimodal approach to anesthesia which provides the combination of hypnotics, N-methyl-D-aspartate (NMDA) antagonists, local anesthetics, anti-inflammatory drugs and alpha-2 agonists such as dexmedetomidine, and no intra-operative systemic, neuraxial, or intracavitary opioid is administered during anesthesia and the perioperative course. This strategy is aimed to prevent postoperative opioid-related adverse effects and to enhance recovery

**2. Pain and pain management from ancient cultures to the nineteenth** 

Early theories of the origin of pain, especially from internal diseases, revolved around demonic and religious beliefs. Shamans and sorcerers treated patients with the use of amulets, magic sculptures, talismans, magic ceremonies and rituals to ward off demons and evil spirits. It was believed that spirits and demons should leave the body from the same way it entered, resulting in cultural scarifications to allow bad fluids, spirits and demons to escape. In Egypt, religious ceremonies and prayers were believed to help relieve pain. Incantations to God Horus and other

Ancient cultures have used leaves of cocoa plant and opium for religious and medical purposes. The earliest anthropological evidence of the use of cocoa leaves was from the pre-Inca culture in Peru, dated to 1300 B.C. The Peruvians used cocoa leaves as a local anesthetic in trepanation operations. Opium was introduced to Egypt around 1500–1300 B.C., and was used as a cream for external application and for the fumigation of toothaches. In India and China, opium was used for the treatment of toothache and joint pain. In these cultures, opium could not be separated

In the seventeenth century, physicians began to consider the human body as a machine with different parts in constant motion. The French philosopher Rene Descartes proposed one of the earliest concepts of modern physiology: a movement or touch initiated at the peripheral nerve endings propagated to the brain. This concept, which formed the basis of nineteenth century pain theories, is illustrated by Descartes famous figure [3] of a boy, whose foot is being stimulated by heat from a fire. Several scientific discoveries followed Descartes physiologic concept of pain, including that of Sir Humphrey Davy's reports of pain relief from inhalation of nitrous oxide in 1800

and James Moore's report of opium use for postoperative analgesia in 1784 [3].

With a better understanding of the physiology and pathways of pain, pharmacologic discoveries, particularly of morphine, were made in the beginning of the nineteenth century. The German pharmacist Friedrich Wilhelm Adam Ferdinand

**3. The era of opioid analgesics and the discovery of anesthesia**

**28**

after surgery.

**century**

to immortalize this milestone in anesthetic surgery with a painting that became known as the Ether Dome painting.

Further significant steps in anesthesia in surgical environments continued. The use of chloroform in the management of childbirth was introduced into the medical world by Sir James Young Simpson in 1847, the same year physiologist Marie Jean Pierre Flourens had discovered the anesthetic properties of chloroform in animals. Chloroform remained the preferred anesthetic until the end of the nineteenth century even though the use of chloroform resulted in significantly more deaths than with ether [3].

Cocaine in local anesthesia marked another milestone in the advancement of pain management in surgery. During the nineteenth century, Albert Niemann, a scientist from Gottingen, isolated cocaine out of the mixture of alkaloids of the cocoa plant. The extracts became popular for conditions such as toothaches, digestive disorders, hysteria, and melancholia, as well as for being an aphrodisiac. Carl Koller experimented with cocaine as a local anesthetic on frog eyes, other animals, his assistants, and even himself. His paper, which demonstrated cocaine's efficacy, was presented at the Heidelberg Ophthalmological Society in 1884 by his colleague Josef Brettauer. The presentation was widely received and others began experimenting with cocaine's surgical applications [3].

After the Heidelberg presentation, scientists began experimenting with cocaine as a nerve block, in advanced cancer patients, and in spinal cord operations. American surgeon William Steward Halsted [4] began experimenting with cocaine as a nerve block, which opened up new possibilities in surgery anesthetics. Halsted and several of his colleagues eventually became addicted to cocaine during their experimentations with the drug. James Leonard Corning used cocaine as a spinal anesthetic in 1885. Dr. Herbert Snow was the first physician to incorporate cocaine into cancer pain treatment. In 1896, he administered cocaine with opium for pain relief to patients with advanced diseases. He later developed the "Brompton Cocktail," a mixture containing morphine, cocaine, and alcohol. German surgeon August Bier and his colleagues published their clinical results of spinal anesthesia, including intrathecal injections on each other. He introduced intravenous regional anesthesia in 1908. Rudolph Matas administered the first morphine anesthetic to the spinal cord in 1909. Most of the nerve blocking techniques during this time period were developed for surgical anesthesia [3].

Further experimentation with cocaine as an analgesic continued during the nineteenth century, resulting in the development of new local anesthetics including synthetic substitutes. Alfred Einhorn synthesized procaine in 1905. Lofgren and Lundqvist synthesized Lignocaine in 1943. Other local anesthetics followed including cinchocaine and amethocaine in the 1920s, mepivacaine, prilocaine, and bupivacaine in the late 1950s, etidocaine in the 1970s, and ropivacaine in the 1980s [3].

The current understanding of the physiology of pain involves the activation of the nervous system. Noxious stimuli, including intense thermal, mechanical, or chemical stimuli, are recognized by nociceptors in the peripheral nervous system. The threshold for pain activation is relatively high, requiring a large stimulus for signal propagation. The signals either travel through Aδ-fibers, Aβ-fibers, or C-fibers. While the Aδ-fibers and Aβ-fibers are myelinated and transmit "acute, well-localized, fast pain," the C-fibers are unmyelinated and transmit "slow" pain, often described as an ache. The signals travel to the dorsal root ganglion, are transmitted through the spinal cord and synapse on the somatosensory cortex and limbic system. The modification of this pathway by medications aims to reduce or eliminate pain [5].

**31**

to 2010 [7].

*From the Origins of the Opioid Use (and Misuse) to the Challenge of Opioid-Free Pain…*

Although opioids have historically been significant medications in the management of pain, opioids have also been the source of significant public health concern because of the addictive and destructive adverse effects of the medication. During the twentieth century, there were positive attitudes for the use of opioids, as a letter written to the New England Journal of Medicine underscored the safety and low addictive potential of opioid use in chronic pain patients, with subsequent letters and reviews supporting this perspective. With the impression that there was very little risk, particularly of addictive potential, in prescribing opioids for chronic pain, the demand for opioid use increased in clinical settings. However, by 2000, attitudes are beginning to shift and a reduction of opioid use is becoming the trend [5].

The detrimental overuse, abuse and addiction of opioids can precipitate from prolonged treatment of opioids. Opioid tolerance occurs when there is a reduction in the analgesic and sedative effects of these medications. Tolerance to the euphoric effects also develop, further increasing the risk of addiction. Opioid dependence results from the overactivation of the somatomotor cortex and autonomic nervous system due to the increased signaling of the cells while on the inhibitory medications. Cessation of opioid use or the administration of opioid receptor antagonists such as naloxone or naltrexone cause the withdrawal symptoms, including diarrhea,

In the United States, the opioid abuse has reached epidemic proportions and have become a public health issue. The treatment of opioid dependence is unclear, but there have been significant public health prevention efforts to combat the trends of increased abuse and overdose deaths [5]. On the topic of opioid epidemic, the United States Surgeon General Dr. Jerome Adams supports overdose education and awareness, and suggests co-prescribing naloxone to patients on high morphine milligram equivalent who are at risk [6]. Nearly all the U.S. states have laws supporting naloxone provision to lay persons. Further, the U.S. Department of Health and Human Services highlighted naloxone rescue kit access and emergency overdose as a priority to address the opioid crisis. The benefits of naloxone programming have been demonstrated in San Francisco, as well as in North Carolina, where a 70% decline in prescription opioid-related overdose death rates was observed from 2009

The current trend in surgery is in the direction away from general anesthesia that traditionally requires opioids preoperatively, intraoperatively, and postoperatively, and toward a more multi-modal regimen approach with preoperatively patient education, specifically highlighting the interplay between opioids and the

Currently, many surgical operations have been traditionally performed under general anesthesia with adjunct opioid use. The main mechanism of action of opioids is the stimulation of μ receptors, which has inhibitory effects on the propagation of pain signals to the brain [8]. However, there are a wide variety of associated adverse effects of opioids including nausea, vomiting, constipation, postoperative sedation, dizziness, and addiction [9]. Opioid use also carries significant morbidity, prolong hospital stays, increase use of medications needed to reverse side effects, and decrease patient satisfaction [10, 11]. Further, opioids may also cause paradoxical hyperalgesia

vomiting, agitation, hyperalgesia, hyperthermia, and hypertension [5].

**5. Special issues on perioperative opioids administration**

human body's natural pain management system.

**4. The public health issue of prescription opioid abuse**

*DOI: http://dx.doi.org/10.5772/intechopen.82675*

*From the Origins of the Opioid Use (and Misuse) to the Challenge of Opioid-Free Pain… DOI: http://dx.doi.org/10.5772/intechopen.82675*

#### **4. The public health issue of prescription opioid abuse**

*From Conventional to Innovative Approaches for Pain Treatment*

known as the Ether Dome painting.

ing with cocaine's surgical applications [3].

period were developed for surgical anesthesia [3].

than with ether [3].

to immortalize this milestone in anesthetic surgery with a painting that became

Further significant steps in anesthesia in surgical environments continued. The use of chloroform in the management of childbirth was introduced into the medical world by Sir James Young Simpson in 1847, the same year physiologist Marie Jean Pierre Flourens had discovered the anesthetic properties of chloroform in animals. Chloroform remained the preferred anesthetic until the end of the nineteenth century even though the use of chloroform resulted in significantly more deaths

Cocaine in local anesthesia marked another milestone in the advancement of pain management in surgery. During the nineteenth century, Albert Niemann, a scientist from Gottingen, isolated cocaine out of the mixture of alkaloids of the cocoa plant. The extracts became popular for conditions such as toothaches, digestive disorders, hysteria, and melancholia, as well as for being an aphrodisiac. Carl Koller experimented with cocaine as a local anesthetic on frog eyes, other animals, his assistants, and even himself. His paper, which demonstrated cocaine's efficacy, was presented at the Heidelberg Ophthalmological Society in 1884 by his colleague Josef Brettauer. The presentation was widely received and others began experiment-

After the Heidelberg presentation, scientists began experimenting with cocaine

as a nerve block, in advanced cancer patients, and in spinal cord operations. American surgeon William Steward Halsted [4] began experimenting with cocaine as a nerve block, which opened up new possibilities in surgery anesthetics. Halsted and several of his colleagues eventually became addicted to cocaine during their experimentations with the drug. James Leonard Corning used cocaine as a spinal anesthetic in 1885. Dr. Herbert Snow was the first physician to incorporate cocaine into cancer pain treatment. In 1896, he administered cocaine with opium for pain relief to patients with advanced diseases. He later developed the "Brompton Cocktail," a mixture containing morphine, cocaine, and alcohol. German surgeon August Bier and his colleagues published their clinical results of spinal anesthesia, including intrathecal injections on each other. He introduced intravenous regional anesthesia in 1908. Rudolph Matas administered the first morphine anesthetic to the spinal cord in 1909. Most of the nerve blocking techniques during this time

Further experimentation with cocaine as an analgesic continued during the nineteenth century, resulting in the development of new local anesthetics including synthetic substitutes. Alfred Einhorn synthesized procaine in 1905. Lofgren and Lundqvist synthesized Lignocaine in 1943. Other local anesthetics followed including cinchocaine and amethocaine in the 1920s, mepivacaine, prilocaine, and bupivacaine in the late 1950s, etidocaine in the 1970s, and ropivacaine in the 1980s [3]. The current understanding of the physiology of pain involves the activation of the nervous system. Noxious stimuli, including intense thermal, mechanical, or chemical stimuli, are recognized by nociceptors in the peripheral nervous system. The threshold for pain activation is relatively high, requiring a large stimulus for signal propagation. The signals either travel through Aδ-fibers, Aβ-fibers, or C-fibers. While the Aδ-fibers and Aβ-fibers are myelinated and transmit "acute, well-localized, fast pain," the C-fibers are unmyelinated and transmit "slow" pain, often described as an ache. The signals travel to the dorsal root ganglion, are transmitted through the spinal cord and synapse on the somatosensory cortex and limbic system. The modification of this pathway by medications aims to reduce or

**30**

eliminate pain [5].

Although opioids have historically been significant medications in the management of pain, opioids have also been the source of significant public health concern because of the addictive and destructive adverse effects of the medication. During the twentieth century, there were positive attitudes for the use of opioids, as a letter written to the New England Journal of Medicine underscored the safety and low addictive potential of opioid use in chronic pain patients, with subsequent letters and reviews supporting this perspective. With the impression that there was very little risk, particularly of addictive potential, in prescribing opioids for chronic pain, the demand for opioid use increased in clinical settings. However, by 2000, attitudes are beginning to shift and a reduction of opioid use is becoming the trend [5].

The detrimental overuse, abuse and addiction of opioids can precipitate from prolonged treatment of opioids. Opioid tolerance occurs when there is a reduction in the analgesic and sedative effects of these medications. Tolerance to the euphoric effects also develop, further increasing the risk of addiction. Opioid dependence results from the overactivation of the somatomotor cortex and autonomic nervous system due to the increased signaling of the cells while on the inhibitory medications. Cessation of opioid use or the administration of opioid receptor antagonists such as naloxone or naltrexone cause the withdrawal symptoms, including diarrhea, vomiting, agitation, hyperalgesia, hyperthermia, and hypertension [5].

In the United States, the opioid abuse has reached epidemic proportions and have become a public health issue. The treatment of opioid dependence is unclear, but there have been significant public health prevention efforts to combat the trends of increased abuse and overdose deaths [5]. On the topic of opioid epidemic, the United States Surgeon General Dr. Jerome Adams supports overdose education and awareness, and suggests co-prescribing naloxone to patients on high morphine milligram equivalent who are at risk [6]. Nearly all the U.S. states have laws supporting naloxone provision to lay persons. Further, the U.S. Department of Health and Human Services highlighted naloxone rescue kit access and emergency overdose as a priority to address the opioid crisis. The benefits of naloxone programming have been demonstrated in San Francisco, as well as in North Carolina, where a 70% decline in prescription opioid-related overdose death rates was observed from 2009 to 2010 [7].

#### **5. Special issues on perioperative opioids administration**

The current trend in surgery is in the direction away from general anesthesia that traditionally requires opioids preoperatively, intraoperatively, and postoperatively, and toward a more multi-modal regimen approach with preoperatively patient education, specifically highlighting the interplay between opioids and the human body's natural pain management system.

Currently, many surgical operations have been traditionally performed under general anesthesia with adjunct opioid use. The main mechanism of action of opioids is the stimulation of μ receptors, which has inhibitory effects on the propagation of pain signals to the brain [8]. However, there are a wide variety of associated adverse effects of opioids including nausea, vomiting, constipation, postoperative sedation, dizziness, and addiction [9]. Opioid use also carries significant morbidity, prolong hospital stays, increase use of medications needed to reverse side effects, and decrease patient satisfaction [10, 11]. Further, opioids may also cause paradoxical hyperalgesia

due to opioid-induced neural plasticity. This appears to affect both the central and peripheral nervous systems, and may lead to sensitization of the pain pathways [12].

In addition to the wide variety of adverse effects, opioids use may also hamper the effects of the human body's own natural pain killers, endorphins. Opioid administration reduces the production of beta-endorphins and impairs the function of mu-opioid receptors [13]. Beta-endorphins have significant natural analgesic effects and have been proposed to yield 18–33 times greater analgesic potency than morphine. Endorphin release is believed to enhance in response to a stressor, such as sharp pain, and can be quickly utilized to control the pain. The stressor causes the hypothalamus to release corticotrophin-releasing hormone (CRH), a peptide hormone and neurotransmitter, from the periventricular nucleus. CRH stimulates the cleavage of protein proopiomelanocortin (POMC) from basophilic cells, resulting in smaller proteins, one of them being beta-endorphin. In the peripheral nervous system, beta-endorphins bind to the μ receptors on both pre-synaptic and post-synaptic nerve terminals. The binding leads to the release of gamma-aminobutyric acid (GABA), which inhibits the release of substance P, a tachykinin protein involved in the transmission of pain. Endorphins not only have greater analgesic potency than morphine, but also enhances individuals' mood and well-being, due to indirect elevation of dopamine [13]. In the central nervous system, beta-endorphins bind the μ receptors on the pre-synaptic nerve terminals and inhibit release of GABA, which normally inhibits the release of dopamine. The overall effect of beta-endorphins, which is decreased in opioid use, is a decrease in pain and an elevation in wellbeing.

#### **6. The concept of opioid-free anesthesia**

Opioid-free anesthesia is an anesthetic technique without intraoperative systemic, neuraxial or intracavitary opioids, and that avoids perioperative opioids. There are a number of therapeutic uses and indications for opioid-free anesthesia including narcotic history (acute and chronic opioid addiction), opioid intolerance, morbidly obese patients with obstructive sleep apnea, hyperalgesia, history of chronic pain, immune deficiency, oncologic surgery, inflammatory disease, chronic obstructive pulmonary disease, and asthma [14].

Postoperative complications, such as respiratory depression, central muscle rigidity, pharyngeal muscle weakness, obstructed breathing, negative inotropism, nausea, vomiting, ileus and constipation, urinary retention, tolerance and addiction, dizziness, and excessive somnolence, can be reduced or prevented. Decrease histamine release (allergy/anaphylaxis), increase patient satisfaction, and enhanced recovery after surgery and anesthesia (ERAS) are other beneficial effects of opioidfree anesthesia [14–16].

Opioid-free anesthesia should be avoided in patients with allergy to any adjuvant drugs, and should be used cautiously in patients with disorders of autonomic failure, cerebrovascular disease, critical coronary stenosis, acute coronary ischemia, heart block, extreme bradycardia, non-stabilized hypovolemic shock or polytrauma patients, controlled hypotension for minimal blood loss, and elderly patients on beta-blockers.

Interest and use of adjuvant modalities, including ketamine, gabapentinoids, intravenous lidocaine, magnesium sulfate, alpha-2 adrenoreceptor agonists, and beta-blockers, is increasing because of enhanced recovery, particularly in specific patient populations like chronic pain and opioid dependent patients [15].

**33**

recovery.

*From the Origins of the Opioid Use (and Misuse) to the Challenge of Opioid-Free Pain…*

In light of the serious adverse effects associated with opioids, many clinicians are forgoing prescribing opioids excessively and using opioid alternatives for postoperative pain control. These non-opioid alternatives, including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS)/cyclooxygenase-2 (COX-2) inhibitors, gabapentin, local anesthetic infusion pumps, paravertebral or transverse abdominis plane nerve blocks, long-acting local anesthetics, and botulinum toxins, have been shown to produce analgesic effects and decrease opioid use postoperatively. Combinations of non-opioid alternatives have been shown to be superior in the management of postoperative pain and opioid requirements. In 2008, Parsa demonstrated that gabapentin and celecoxib in combination preoperatively for subpectoral breast augmentation was significantly superior than celecoxib alone in reducing postoperative pain and opioid use [17]. Stephan and Parsa have extensive experience using non-opioid modalities of postoperative pain control, which has resulted in significant reduction in opioid administration postoperatively for patients undergoing various plastic

Several other opioid reduction strategies in a surgical setting have been tested and shown to be effective in managing pain and decreasing opioid use. Preoperative patient education has shown to be effective in reducing the opioid requirement postoperatively. Sugai et al. demonstrated that preoperative oral and written education concerning the body's response to pain reduced preoperative and postoperative opioid prescriptions [18]. When comparing patients that had opioid-free procedures to the patients receiving adjunct opioids, Parsa et al. found statistically significant reduction in time from end of operation to discharge, unplanned postoperative hospital admissions, and opioid use in the

Pain treatment and management has come a long way since ancient cultures. Several innovations during the nineteenth century made significant headway in opioid analgesics, and by the end of the twentieth century, hemodynamic stability during anesthesia was achievable through the application of opioids. However, in an era with significant opioid abuse, limiting opioid requirements in postoperative pain management is of greater importance. Opioids are associated with unwanted side effects, including nausea, vomiting, dizziness, constipation, and hyperalgesia. Not only are there several adverse effects with opioid use, including a high addictive potential, opioids also interfere with beta-endorphins, the human body's potent natural analgesic. Opioid-free anesthesia provides a technique that can achieve intraoperative hemodynamic stability, immobility, and postoperative analgesia without opioids, and therefore, in the absence of the significant associated side effects. Judicious utilization of adjuvants like ketamine, gabapentinoids, intravenous lidocaine, magnesium sulfate, alpha-2 adrenoreceptor agonists, and beta-blockers contribute to enhanced recovery in specific patients with chronic pain and opioid dependence. Opioid-free anesthesia and other opioid-free pain relief strategies are essential in the control of the opioid crisis, are key in effective analgesia without unwanted opioid-related side effects, and are needed for postoperative

**7. Opioid alternatives for postoperative pain control**

*DOI: http://dx.doi.org/10.5772/intechopen.82675*

surgery procedures [13].

post-anesthesia care unit [19].

**8. Conclusions**

*From the Origins of the Opioid Use (and Misuse) to the Challenge of Opioid-Free Pain… DOI: http://dx.doi.org/10.5772/intechopen.82675*

#### **7. Opioid alternatives for postoperative pain control**

In light of the serious adverse effects associated with opioids, many clinicians are forgoing prescribing opioids excessively and using opioid alternatives for postoperative pain control. These non-opioid alternatives, including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS)/cyclooxygenase-2 (COX-2) inhibitors, gabapentin, local anesthetic infusion pumps, paravertebral or transverse abdominis plane nerve blocks, long-acting local anesthetics, and botulinum toxins, have been shown to produce analgesic effects and decrease opioid use postoperatively. Combinations of non-opioid alternatives have been shown to be superior in the management of postoperative pain and opioid requirements. In 2008, Parsa demonstrated that gabapentin and celecoxib in combination preoperatively for subpectoral breast augmentation was significantly superior than celecoxib alone in reducing postoperative pain and opioid use [17]. Stephan and Parsa have extensive experience using non-opioid modalities of postoperative pain control, which has resulted in significant reduction in opioid administration postoperatively for patients undergoing various plastic surgery procedures [13].

Several other opioid reduction strategies in a surgical setting have been tested and shown to be effective in managing pain and decreasing opioid use. Preoperative patient education has shown to be effective in reducing the opioid requirement postoperatively. Sugai et al. demonstrated that preoperative oral and written education concerning the body's response to pain reduced preoperative and postoperative opioid prescriptions [18]. When comparing patients that had opioid-free procedures to the patients receiving adjunct opioids, Parsa et al. found statistically significant reduction in time from end of operation to discharge, unplanned postoperative hospital admissions, and opioid use in the post-anesthesia care unit [19].

#### **8. Conclusions**

*From Conventional to Innovative Approaches for Pain Treatment*

pain and an elevation in wellbeing.

free anesthesia [14–16].

beta-blockers.

**6. The concept of opioid-free anesthesia**

obstructive pulmonary disease, and asthma [14].

due to opioid-induced neural plasticity. This appears to affect both the central and peripheral nervous systems, and may lead to sensitization of the pain pathways [12]. In addition to the wide variety of adverse effects, opioids use may also hamper

the effects of the human body's own natural pain killers, endorphins. Opioid administration reduces the production of beta-endorphins and impairs the function of mu-opioid receptors [13]. Beta-endorphins have significant natural analgesic effects and have been proposed to yield 18–33 times greater analgesic potency than morphine. Endorphin release is believed to enhance in response to a stressor, such as sharp pain, and can be quickly utilized to control the pain. The stressor causes the hypothalamus to release corticotrophin-releasing hormone (CRH), a peptide hormone and neurotransmitter, from the periventricular nucleus. CRH stimulates the cleavage of protein proopiomelanocortin (POMC) from basophilic cells, resulting in smaller proteins, one of them being beta-endorphin. In the peripheral nervous system, beta-endorphins bind to the μ receptors on both pre-synaptic and post-synaptic nerve terminals. The binding leads to the release of gamma-aminobutyric acid (GABA), which inhibits the release of substance P, a tachykinin protein involved in the transmission of pain. Endorphins not only have greater analgesic potency than morphine, but also enhances individuals' mood and well-being, due to indirect elevation of dopamine [13]. In the central nervous system, beta-endorphins bind the μ receptors on the pre-synaptic nerve terminals and inhibit release of GABA, which normally inhibits the release of dopamine. The overall effect of beta-endorphins, which is decreased in opioid use, is a decrease in

Opioid-free anesthesia is an anesthetic technique without intraoperative systemic, neuraxial or intracavitary opioids, and that avoids perioperative opioids. There are a number of therapeutic uses and indications for opioid-free anesthesia including narcotic history (acute and chronic opioid addiction), opioid intolerance, morbidly obese patients with obstructive sleep apnea, hyperalgesia, history of chronic pain, immune deficiency, oncologic surgery, inflammatory disease, chronic

Postoperative complications, such as respiratory depression, central muscle rigidity, pharyngeal muscle weakness, obstructed breathing, negative inotropism, nausea, vomiting, ileus and constipation, urinary retention, tolerance and addiction, dizziness, and excessive somnolence, can be reduced or prevented. Decrease histamine release (allergy/anaphylaxis), increase patient satisfaction, and enhanced recovery after surgery and anesthesia (ERAS) are other beneficial effects of opioid-

Opioid-free anesthesia should be avoided in patients with allergy to any adjuvant drugs, and should be used cautiously in patients with disorders of autonomic failure, cerebrovascular disease, critical coronary stenosis, acute coronary ischemia, heart block, extreme bradycardia, non-stabilized hypovolemic shock or polytrauma patients, controlled hypotension for minimal blood loss, and elderly patients on

Interest and use of adjuvant modalities, including ketamine, gabapentinoids, intravenous lidocaine, magnesium sulfate, alpha-2 adrenoreceptor agonists, and beta-blockers, is increasing because of enhanced recovery, particularly in specific

patient populations like chronic pain and opioid dependent patients [15].

**32**

Pain treatment and management has come a long way since ancient cultures. Several innovations during the nineteenth century made significant headway in opioid analgesics, and by the end of the twentieth century, hemodynamic stability during anesthesia was achievable through the application of opioids. However, in an era with significant opioid abuse, limiting opioid requirements in postoperative pain management is of greater importance. Opioids are associated with unwanted side effects, including nausea, vomiting, dizziness, constipation, and hyperalgesia. Not only are there several adverse effects with opioid use, including a high addictive potential, opioids also interfere with beta-endorphins, the human body's potent natural analgesic. Opioid-free anesthesia provides a technique that can achieve intraoperative hemodynamic stability, immobility, and postoperative analgesia without opioids, and therefore, in the absence of the significant associated side effects. Judicious utilization of adjuvants like ketamine, gabapentinoids, intravenous lidocaine, magnesium sulfate, alpha-2 adrenoreceptor agonists, and beta-blockers contribute to enhanced recovery in specific patients with chronic pain and opioid dependence. Opioid-free anesthesia and other opioid-free pain relief strategies are essential in the control of the opioid crisis, are key in effective analgesia without unwanted opioid-related side effects, and are needed for postoperative recovery.

*From Conventional to Innovative Approaches for Pain Treatment*

#### **Author details**

Nicholas Yim and Fereydoun Don Parsa\* Department of Surgery, John A. Burns School of Medicine, University of Hawaii, USA

\*Address all correspondence to: fdparsa@gmail.com

© 2018 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.

**35**

*From the Origins of the Opioid Use (and Misuse) to the Challenge of Opioid-Free Pain…*

retention: Incidence, management and prevention. Drug Safety.

[11] Swegle JM, Logemann C. Management of common opioidinduced adverse effects. American Family Physician. 2006;**74**(8):1347-1354

Patel VB, Manchikanti L. A comprehensive review of opioidinduced hyperalgesia. Pain Physician.

2011;**14**(2):145-161

2016;**75**(3):63-67

2017;**31**(4):547-560

[12] Lee M, Silverman SM, Hansen H,

[13] Stephan BC, Parsa FD. Avoiding opioids and their harmful side effects in postoperative patient: Exogenous opioids, endogenous endorphins, wellness, mood, and their relation to postoperative pain. Hawai'i Journal of Medicine & Public Health.

[14] Sultana A, Torres D, Schumann R. Special indications for Opioid Free Anaesthesia and Analgesia, patient and procedure related: Including obesity, sleep apnoea, chronic obstructive pulmonary disease, complex regional pain syndromes, opioid addiction and cancer surgery. Best Practice & Research. Clinical Anaesthesiology.

[15] Lavand'homme P, Estebe JP. Opioidfree anesthesia: A different regard to anesthesia practice. Current Opinion in Anaesthesiology. 2018;**31**(5):556-561

[16] Lavand-Homme P, Steyaert A. Opioid-free anesthesia opioid side effects: Tolerance and hyperalgesia. Best Practice & Research. Clinical Anaesthesiology. 2017;**31**(4):487-498

[10] Oderda GM, Said Q, Evans RS, et al. Opioid-related adverse drug events in surgical hospitalizations: Impact on costs and length of stay. The Annals of Pharmacotherapy. 2007;**41**(3):400-406

2008;**31**(5):373-388

*DOI: http://dx.doi.org/10.5772/intechopen.82675*

[1] Boer HD, Detriche O, Forget P. Opioid-related side effects:

2017;**31**(4):499-504

**References**

Postoperative ileus, urinary retention, nausea and vomiting, and shivering. A review of the literature. Best Practice & Research. Clinical Anaesthesiology.

[2] Cascella M, Bimonte S. The role of general anesthetics and the mechanisms of hippocampal and extrahippocampal

[3] Sabatowski R, Schafer D, Kasper SM, Brunsch H, Radbruch L. Pain treatment: A historical overview. Current Pharmaceutical Design.

[4] Rankin JS, Halsted WS. Annals of Surgery. 2006;**243**(3):418-425

[6] U.S. Surgeon General Discusses the Opioid Epidemic. https://www. thedoctors.com/articles/u.s.-surgeongeneral-discusses-the-opioid-epidemic/

[7] Fairbairn N, Coffin PO, Walley A. Naloxone for heroin, prescription opioid, and illicitly made fentanyl overdoses: Challenges and innovations responding to a dynamic epidemic. The International Journal on Drug Policy.

[8] Owusu OA, Hamadeh I, Smith M. Review of opioid pharmacogenetics and considerations for pain management. Pharmacotherapy. 2017;**37**(9):1105-1121

[9] Sturkenboom MC, Stricker BH, Bosch R. Drug-induced urinary

[5] Schaefer CP, Tome ME, Davis TP. The opioid epidemic: A central role for the blood brain barrier in opioid analgesia and abuse. Fluids and Barriers of the

dysfunctions in the genesis of postoperative cognitive dysfunction. Neural Regeneration Research.

2017;**12**(11):1780-1785

2004;**10**(7):701-716

CNS. 2017;**14**:32

2017;**46**:172-179

*From the Origins of the Opioid Use (and Misuse) to the Challenge of Opioid-Free Pain… DOI: http://dx.doi.org/10.5772/intechopen.82675*

#### **References**

*From Conventional to Innovative Approaches for Pain Treatment*

**34**

USA

**Author details**

provided the original work is properly cited.

Nicholas Yim and Fereydoun Don Parsa\*

\*Address all correspondence to: fdparsa@gmail.com

© 2018 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,

Department of Surgery, John A. Burns School of Medicine, University of Hawaii,

[1] Boer HD, Detriche O, Forget P. Opioid-related side effects: Postoperative ileus, urinary retention, nausea and vomiting, and shivering. A review of the literature. Best Practice & Research. Clinical Anaesthesiology. 2017;**31**(4):499-504

[2] Cascella M, Bimonte S. The role of general anesthetics and the mechanisms of hippocampal and extrahippocampal dysfunctions in the genesis of postoperative cognitive dysfunction. Neural Regeneration Research. 2017;**12**(11):1780-1785

[3] Sabatowski R, Schafer D, Kasper SM, Brunsch H, Radbruch L. Pain treatment: A historical overview. Current Pharmaceutical Design. 2004;**10**(7):701-716

[4] Rankin JS, Halsted WS. Annals of Surgery. 2006;**243**(3):418-425

[5] Schaefer CP, Tome ME, Davis TP. The opioid epidemic: A central role for the blood brain barrier in opioid analgesia and abuse. Fluids and Barriers of the CNS. 2017;**14**:32

[6] U.S. Surgeon General Discusses the Opioid Epidemic. https://www. thedoctors.com/articles/u.s.-surgeongeneral-discusses-the-opioid-epidemic/

[7] Fairbairn N, Coffin PO, Walley A. Naloxone for heroin, prescription opioid, and illicitly made fentanyl overdoses: Challenges and innovations responding to a dynamic epidemic. The International Journal on Drug Policy. 2017;**46**:172-179

[8] Owusu OA, Hamadeh I, Smith M. Review of opioid pharmacogenetics and considerations for pain management. Pharmacotherapy. 2017;**37**(9):1105-1121

[9] Sturkenboom MC, Stricker BH, Bosch R. Drug-induced urinary

retention: Incidence, management and prevention. Drug Safety. 2008;**31**(5):373-388

[10] Oderda GM, Said Q, Evans RS, et al. Opioid-related adverse drug events in surgical hospitalizations: Impact on costs and length of stay. The Annals of Pharmacotherapy. 2007;**41**(3):400-406

[11] Swegle JM, Logemann C. Management of common opioidinduced adverse effects. American Family Physician. 2006;**74**(8):1347-1354

[12] Lee M, Silverman SM, Hansen H, Patel VB, Manchikanti L. A comprehensive review of opioidinduced hyperalgesia. Pain Physician. 2011;**14**(2):145-161

[13] Stephan BC, Parsa FD. Avoiding opioids and their harmful side effects in postoperative patient: Exogenous opioids, endogenous endorphins, wellness, mood, and their relation to postoperative pain. Hawai'i Journal of Medicine & Public Health. 2016;**75**(3):63-67

[14] Sultana A, Torres D, Schumann R. Special indications for Opioid Free Anaesthesia and Analgesia, patient and procedure related: Including obesity, sleep apnoea, chronic obstructive pulmonary disease, complex regional pain syndromes, opioid addiction and cancer surgery. Best Practice & Research. Clinical Anaesthesiology. 2017;**31**(4):547-560

[15] Lavand'homme P, Estebe JP. Opioidfree anesthesia: A different regard to anesthesia practice. Current Opinion in Anaesthesiology. 2018;**31**(5):556-561

[16] Lavand-Homme P, Steyaert A. Opioid-free anesthesia opioid side effects: Tolerance and hyperalgesia. Best Practice & Research. Clinical Anaesthesiology. 2017;**31**(4):487-498 [17] Parsa AA, Sprouse-Blum AS, Jackowe DJ, Lee M, Oyama J, Parsa D. Combined preoperative use of celecoxib and gabapentin in the management of postoperative pain. Aesthetic Plastic Surgery. 2009;**33**:98-103

[18] Sugai DY, Deptula PL, Parsa AA, Parsa FD. The importance of communication in management of postoperative pain. Hawai'i Journal of Medicine & Public Health. 2013;**72**(6):180-184

[19] Parsa FD, Cheng J, Stephan B, Castel N, Kim L, Murariu D, et al. Bilateral breast reduction without opioid analgesics: A comparative study. Aesthetic Surgery Journal. 2017;**37**(8):892-899

**37**

**Chapter 4**

**Abstract**

patient autonomy

**1. Introduction**

The Utility of Patient-Controlled

in the Emergency Department

*Mark Bender and Linda Papa*

Analgesia for Managing Acute Pain

There is a growing expectation of physicians to treat acute pain more aggressively in the emergency department (ED). This has contributed to an increase in opiate prescribing practices that has resulted in a crisis of medication abuse and misuse. The resultant backlash against physicians has created a void within the realm of acute pain management, as physicians search for a means to treat their patients in a way that is both empathetic and responsible. In an effort to combat this growing epidemic, alternative means of pain control are being explored. Patientcontrolled analgesia devices (PCADs) have been used extensively in multiple fields of medicine and have demonstrated significant clinical utility for treating pain postoperatively; however there is a dearth of evidence to support their use within the acute care setting. Due to this lack of evidence, PCADs have not been widely implemented in the ED. Recent studies have shown that the use of PCADs may improve objective pain scores and increase both patient and nurse satisfaction while reducing the likelihood of developing chronic pain. The economic feasibility of this undertaking remains unclear; however there is strong evidence for the clinical

**Keywords:** pain, emergency department, treatment, patient-controlled analgesia,

Although there are discrepancies in prevalence among different emergency departments (ED), pain is the primary presenting complaint in 45–75% of all ED visits [1]. To put this in perspective, it is important to note just how significantly the landscape of the ED has changed over the last 20 years. Between 1996 and 2015 there was a 46% increase in the utilization of emergency services in the United States with 136 million people seeking emergency care in 2015. This equates to over 100 million patients presenting to the ED in acute pain [2]. As emergency room visits continue to grow every year, so does the need to find effective treatments for patients experiencing such episodes. Currently, the standard of care in most EDs includes the use of intravenous (IV) opiates which are titrated subjectively according to patient complaints; however this is often significantly impacted by outside forces including nursing availability and patient census. Unfortunately, in many

patients-controlled analgesia devices, oligoanalgesia, patient satisfaction,

utility of this modality to treat acute pain in this population.

#### **Chapter 4**

*From Conventional to Innovative Approaches for Pain Treatment*

[17] Parsa AA, Sprouse-Blum AS, Jackowe DJ, Lee M, Oyama J, Parsa D. Combined preoperative use of celecoxib and gabapentin in the management of postoperative pain. Aesthetic Plastic

[18] Sugai DY, Deptula PL, Parsa AA,

[19] Parsa FD, Cheng J, Stephan B, Castel N, Kim L, Murariu D, et al. Bilateral breast reduction without opioid analgesics: A comparative study. Aesthetic Surgery Journal.

Surgery. 2009;**33**:98-103

2013;**72**(6):180-184

2017;**37**(8):892-899

Parsa FD. The importance of communication in management of postoperative pain. Hawai'i Journal of Medicine & Public Health.

**36**

## The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency Department

*Mark Bender and Linda Papa*

#### **Abstract**

There is a growing expectation of physicians to treat acute pain more aggressively in the emergency department (ED). This has contributed to an increase in opiate prescribing practices that has resulted in a crisis of medication abuse and misuse. The resultant backlash against physicians has created a void within the realm of acute pain management, as physicians search for a means to treat their patients in a way that is both empathetic and responsible. In an effort to combat this growing epidemic, alternative means of pain control are being explored. Patientcontrolled analgesia devices (PCADs) have been used extensively in multiple fields of medicine and have demonstrated significant clinical utility for treating pain postoperatively; however there is a dearth of evidence to support their use within the acute care setting. Due to this lack of evidence, PCADs have not been widely implemented in the ED. Recent studies have shown that the use of PCADs may improve objective pain scores and increase both patient and nurse satisfaction while reducing the likelihood of developing chronic pain. The economic feasibility of this undertaking remains unclear; however there is strong evidence for the clinical utility of this modality to treat acute pain in this population.

**Keywords:** pain, emergency department, treatment, patient-controlled analgesia, patients-controlled analgesia devices, oligoanalgesia, patient satisfaction, patient autonomy

#### **1. Introduction**

Although there are discrepancies in prevalence among different emergency departments (ED), pain is the primary presenting complaint in 45–75% of all ED visits [1]. To put this in perspective, it is important to note just how significantly the landscape of the ED has changed over the last 20 years. Between 1996 and 2015 there was a 46% increase in the utilization of emergency services in the United States with 136 million people seeking emergency care in 2015. This equates to over 100 million patients presenting to the ED in acute pain [2]. As emergency room visits continue to grow every year, so does the need to find effective treatments for patients experiencing such episodes. Currently, the standard of care in most EDs includes the use of intravenous (IV) opiates which are titrated subjectively according to patient complaints; however this is often significantly impacted by outside forces including nursing availability and patient census. Unfortunately, in many

cases a baseline pain score is not adequately established which leads to substantial variations in treatment, with the end result being that patients experience increased pain and less satisfaction with their care. Inadequate pain relief, otherwise known as oligoanalgesia, can lead to a myriad of psychological and physiologic consequences which can extend far beyond the initial injury. Thus, early intervention to treat acute pain is integral to effective patient care.

Current guidelines established by the American Academy of Emergency Medicine Physicians suggest that "parenteral opioids should be titrated regardless of the initial dosing regimen (i.e., weight-based, fixed, or nurse-initiated) at 20–30 minutes intervals until pain is relieved to acceptable levels with frequent reassessment and evaluation for development of opioid-related adverse effects." [3] Although this schedule may appear ideal, re-dosing of medication at this frequency requires significant time from nursing staff and physicians and may prove difficult given the demanding pace characteristic of most emergency departments. This is problematic from both a practice and administrative standpoint, as increasing patient volumes are taxing our already overburdened EDs. From a clinical perspective this translates into substantial delays in achieving adequate analgesia and prolonged wait times between doses for patients in acute pain. In light of these issues, it is clear that physicians and ED staff must reconsider their current approach to pain management and explore novel methods to improve treatment efficiency without sacrificing quality.

Within the last 20 years, there have been increasing demands placed on ED physicians and staff to aggressively treat acute pain in an effort to improve patient satisfaction, improve outcomes and meet core measures. Consequently, the "Emergency Department Measure Set" was developed by the Centers for Medicare and Medicaid Services (CMS) and has been adopted by The Joint Commission's ORYX program in order to maintain alignment with CMS reporting requirements [4]. These, and many additional factors, have contributed to an increase in opiate prescriptions which has resulted in a crisis of medication abuse and misuse which continues to plague EDs all over the country. The resultant backlash against both physicians and pharmaceutical companies has created a void within the realm of acute pain management, as physicians search for a means to treat their patients in a way that is both empathetic and responsible. Patient-controlled analgesia, which has long been accepted as an appropriate form of pain management in post-surgical care, has shown promising results in its application in the acute care setting and may prove to be an invaluable tool which may be used for effective multimodal pain control.

Patient-controlled analgesia offers multiple benefits to patients in acute pain. The devices themselves are relatively easy to set up, they reduce delays and treatment variability, and provide patients with increased control of their analgesic needs. Delivery of medication via this method also avoids the peaks and troughs in blood levels associated with irregular bolus dosing and allows for a steady-state concentration within the plasma [5]. By controlling both the frequency and quantity of medication being delivered, patients are able to achieve improved levels of analgesia while minimizing the risk of adverse events. Dynamic systems such as this allow for increased patient autonomy and improved personalization of care without the requirement of additional supervision by staff.

#### **2. The risks of undertreating pain**

Although many patients achieve full resolution of pain after an acute episode, it has been demonstrated that pain may persist in up to 21% of patients being

**39**

patient.

*The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency…*

**3. Background on patient-controlled analgesia devices**

Patient-controlled analgesia devices were first developed in the 1960s in an effort to allow patients to control their pain without the requirement of frequent nursing intervention [8]. The device itself has gone through significant changes with regards to technology, however its basic purpose remains the same. PCADs generally consist of a volumetric pump which contains opiate medications that may be delivered intravenously once a patient presses the button controlling outflow. The device often contains additional control measures including anti-siphon and anti-reflux valves which allow for precision in the quantity of dosing while minimizing the risk of inadvertent medication administration [9]. Physicians may control several variables including the loading dose, demand/bolus dose, lock-out interval and quantity required for continuous infusions [5]. In the initial stage of treatment a bolus or loading dose is commonly administered to establish a baseline degree of analgesia. Afterwards there is a lock-out period during which the pump does not release any additional medication. Patients may continue to press the release trigger during this period of time but no additional doses are released. A number of demand requests are logged by the device and can help guide physicians when attempting to determine an optimal dosing strategy for each individual

Dosing parameters are generally set by the physician and should reflect the level of pain being experienced by the patient as well as the patient's expected length of stay in the ED, body habitus, and previous use and tolerance to analgesics. An optimal dosing strategy is one that would allow for maximum analgesia while minimizing potential side effects. With traditional dosing methods this is difficult to achieve. To remedy this, several protocols have been developed for use in patientcontrolled analgesia which have been demonstrated to be effective in most patients. For instance, a common protocol used in both the US and UK includes a loading dose of 1 mg of morphine followed by a 5 minutes lockout period and subsequent bolus dosing of 1 mg [10]. Lock-out times are an important safety concern among physicians for obvious reasons, however studies show that increments between 5

discharged from the ED [6, 7]. The precise mechanism for the transition from acute to chronic pain is poorly understood, however, the practical implications of this issue are becoming increasingly apparent as the number of patients experiencing chronic pain has reached epic proportions. Patients experiencing traumatic pain and acute abdominal pain are especially at risk for developing chronic pain and these populations make up a significant amount of ED admissions. In addition to the mechanism of injury there is also a myriad of different symptoms which can predispose individuals to developing persistent pain including age, gender, genetics, pain trajectory and pre-existing anxiety/depression [7]. Although many of these cannot be adequately controlled for in an acute setting, pain trajectory is one of the main factors that can be actively affected by emergency physicians and PCADs have shown increasing effectiveness in this regard. A recent study conducted by Rockett et al., demonstrated that utilization of PCADs in the emergency room significantly decreased the number of patients experiencing persistent pain from non-traumatic abdominal injuries, 6 months post-injury. "The study findings suggest that it may be possible to reduce persistent pain (at least in patients with abdominal pain) by delivering better acute pain management" [7]. Consequently, it appears that increased utilization of patient-controlled analgesia may be a viable alternative to our current practice model which can provide increased comfort to both provider and patient while diminishing the number of patients developing persistent pain.

*DOI: http://dx.doi.org/10.5772/intechopen.83427*

#### *The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency… DOI: http://dx.doi.org/10.5772/intechopen.83427*

discharged from the ED [6, 7]. The precise mechanism for the transition from acute to chronic pain is poorly understood, however, the practical implications of this issue are becoming increasingly apparent as the number of patients experiencing chronic pain has reached epic proportions. Patients experiencing traumatic pain and acute abdominal pain are especially at risk for developing chronic pain and these populations make up a significant amount of ED admissions. In addition to the mechanism of injury there is also a myriad of different symptoms which can predispose individuals to developing persistent pain including age, gender, genetics, pain trajectory and pre-existing anxiety/depression [7]. Although many of these cannot be adequately controlled for in an acute setting, pain trajectory is one of the main factors that can be actively affected by emergency physicians and PCADs have shown increasing effectiveness in this regard. A recent study conducted by Rockett et al., demonstrated that utilization of PCADs in the emergency room significantly decreased the number of patients experiencing persistent pain from non-traumatic abdominal injuries, 6 months post-injury. "The study findings suggest that it may be possible to reduce persistent pain (at least in patients with abdominal pain) by delivering better acute pain management" [7]. Consequently, it appears that increased utilization of patient-controlled analgesia may be a viable alternative to our current practice model which can provide increased comfort to both provider and patient while diminishing the number of patients developing persistent pain.

#### **3. Background on patient-controlled analgesia devices**

Patient-controlled analgesia devices were first developed in the 1960s in an effort to allow patients to control their pain without the requirement of frequent nursing intervention [8]. The device itself has gone through significant changes with regards to technology, however its basic purpose remains the same. PCADs generally consist of a volumetric pump which contains opiate medications that may be delivered intravenously once a patient presses the button controlling outflow. The device often contains additional control measures including anti-siphon and anti-reflux valves which allow for precision in the quantity of dosing while minimizing the risk of inadvertent medication administration [9]. Physicians may control several variables including the loading dose, demand/bolus dose, lock-out interval and quantity required for continuous infusions [5]. In the initial stage of treatment a bolus or loading dose is commonly administered to establish a baseline degree of analgesia. Afterwards there is a lock-out period during which the pump does not release any additional medication. Patients may continue to press the release trigger during this period of time but no additional doses are released. A number of demand requests are logged by the device and can help guide physicians when attempting to determine an optimal dosing strategy for each individual patient.

Dosing parameters are generally set by the physician and should reflect the level of pain being experienced by the patient as well as the patient's expected length of stay in the ED, body habitus, and previous use and tolerance to analgesics. An optimal dosing strategy is one that would allow for maximum analgesia while minimizing potential side effects. With traditional dosing methods this is difficult to achieve. To remedy this, several protocols have been developed for use in patientcontrolled analgesia which have been demonstrated to be effective in most patients. For instance, a common protocol used in both the US and UK includes a loading dose of 1 mg of morphine followed by a 5 minutes lockout period and subsequent bolus dosing of 1 mg [10]. Lock-out times are an important safety concern among physicians for obvious reasons, however studies show that increments between 5

*From Conventional to Innovative Approaches for Pain Treatment*

acute pain is integral to effective patient care.

sacrificing quality.

cases a baseline pain score is not adequately established which leads to substantial variations in treatment, with the end result being that patients experience increased pain and less satisfaction with their care. Inadequate pain relief, otherwise known as oligoanalgesia, can lead to a myriad of psychological and physiologic consequences which can extend far beyond the initial injury. Thus, early intervention to treat

Current guidelines established by the American Academy of Emergency Medicine Physicians suggest that "parenteral opioids should be titrated regardless of the initial dosing regimen (i.e., weight-based, fixed, or nurse-initiated) at 20–30

Within the last 20 years, there have been increasing demands placed on ED physicians and staff to aggressively treat acute pain in an effort to improve patient satisfaction, improve outcomes and meet core measures. Consequently, the "Emergency Department Measure Set" was developed by the Centers for Medicare and Medicaid Services (CMS) and has been adopted by The Joint Commission's ORYX program in order to maintain alignment with CMS reporting requirements [4]. These, and many additional factors, have contributed to an increase in opiate prescriptions which has resulted in a crisis of medication abuse and misuse which continues to plague EDs all over the country. The resultant backlash against both physicians and pharmaceutical companies has created a void within the realm of acute pain management, as physicians search for a means to treat their patients in a way that is both empathetic and responsible. Patient-controlled analgesia, which has long been accepted as an appropriate form of pain management in post-surgical care, has shown promising results in its application in the acute care setting and may prove to be an invaluable tool which may be used for effective multimodal pain

Patient-controlled analgesia offers multiple benefits to patients in acute pain. The devices themselves are relatively easy to set up, they reduce delays and treatment variability, and provide patients with increased control of their analgesic needs. Delivery of medication via this method also avoids the peaks and troughs in blood levels associated with irregular bolus dosing and allows for a steady-state concentration within the plasma [5]. By controlling both the frequency and quantity of medication being delivered, patients are able to achieve improved levels of analgesia while minimizing the risk of adverse events. Dynamic systems such as this allow for increased patient autonomy and improved personalization of care without

Although many patients achieve full resolution of pain after an acute episode, it has been demonstrated that pain may persist in up to 21% of patients being

the requirement of additional supervision by staff.

**2. The risks of undertreating pain**

minutes intervals until pain is relieved to acceptable levels with frequent reassessment and evaluation for development of opioid-related adverse effects." [3] Although this schedule may appear ideal, re-dosing of medication at this frequency requires significant time from nursing staff and physicians and may prove difficult given the demanding pace characteristic of most emergency departments. This is problematic from both a practice and administrative standpoint, as increasing patient volumes are taxing our already overburdened EDs. From a clinical perspective this translates into substantial delays in achieving adequate analgesia and prolonged wait times between doses for patients in acute pain. In light of these issues, it is clear that physicians and ED staff must reconsider their current approach to pain management and explore novel methods to improve treatment efficiency without

**38**

control.

and 10 minutes are generally considered safe regardless of the type of medication being used [5]. These parameters can be altered in real time in response to patient feedback. This allows for more dynamic analgesic control which has clear benefits for patients presenting to the ED with acute pain.

It is important to note that there are distinct differences between machine programming parameters for postoperative patients versus those in an emergency setting. A prime example of this is the use of background/continuous infusions. Utilization of this setting allows for increased baseline plasma levels of medication and may improve pain control in certain populations [5]. Although the literature supports this type of treatment in post-operative patients, it may not be ideal for the ED as it requires close maintenance by nursing staff. Additionally, research shows that it does not improve pain control significantly in this patient population and may actually lead to increased incidence of adverse events including respiratory depression and sedation [5]. In another study which specifically examined the use of background infusions in the ED it was also found that manipulation of this setting led to an increased rate of pump programming errors. Although the patients involved in this study did not sustain any long-term side effects, there was an increase in the rate of sedation which further supports that this setting is of limited use in the ED [11].

#### **4. General principles in acute pain management**

The use of opiate medication in acute pain management has been a staple in most busy emergency departments. They work via blockade of μ-opioid receptorchannels which inhibit the transmission of pain in the central nervous system. In general, pure μ agonists have a high degree of variation in terms of dose-response relationships among individuals and require close monitoring by medical staff [1]. Side effects of medications which target μ-opioid receptors include respiratory depression, sedation, nausea, vomiting and pruritus. The frequency of adverse events associated with opiate administration in an acute care setting is difficult to predict and often, a trial of medication is necessary before sensitivities can be established. The disparities among these patients in regard to appropriate analgesic control is multifactorial and includes differences in opiate tolerance, pain severity, previous opiate use, body habitus, height and weight, dosing quantity and the frequency of administration. Many of these factors are difficult to control in a fast-paced environment such as the emergency room. However, utilization of patient-controlled analgesia may help offset these issues by allowing patients to take a more active role in the management of their pain.

Common opiates used in this setting include morphine, hydromorphone, and fentanyl. They are widely available and physicians are familiar with their general dose-response relationships and safety profiles. Although studies have shown that usage of specific opiates does not necessarily correlate with significant differences in pain scores among patients using PCADs, this does not obfuscate the need for appropriate medication selection [5]. Thus, it is important to take an individualized approach when selecting which medication a patient will receive.

#### **4.1 Opiate selection**

#### *4.1.1 Morphine*

Morphine is the most commonly used opiate in EDs which is likely due to its intermediate half-life, moderate strength and familiarity among hospital staff.

**41**

*4.1.3 Fentanyl*

*The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency…*

The average half-life of morphine is 1.5–2 hours with peak intensity usually being established in approximately 90 minutes [12, 13]. This makes it an effective medication for pain control as its effects wear off in a reasonable amount of time and it is generally well tolerated. Analgesic dosing is usually 0.5–3 mg per bolus, with a lockout period of 5–20 minutes [5]. Due to morphine's longer onset of action it could accumulate in the plasma and could result in analgesic stacking if the lockout times are not calibrated appropriately. Although this could theoretically lead to a significant increase in adverse events; it is very rarely seen clinically when administering conventional PCAD level dosages [5]. Additionally, it is important to recall that morphine has a higher degree of histamine release than other opiates in its class. This may preclude it from use in patients that have a history or pruritus or flushing after morphine use. This is, however, only a relative contraindication and may not manifest as readily due to the decreased quantity of medication adminis-

Hydromorphone is a medication that is both incredibly effective but also increasingly maligned by emergency physicians. It has gained notoriety due to its strength and efficacy in acute pain management and it is widely available in most EDs. Unfortunately, these attributes have also made it a popular drug of abuse among pain seekers and physicians remain wary of regular use. It is seven times more potent than morphine and is broken down into a biologically inactive metabolite which makes it an excellent candidate for patients requiring repeat dosing of opioid medications. It also has an improved side effect profile, including diminished histamine release, which results in less pruritus. The time to peak analgesic effect for hydromorphone is approximately 20 minutes and its dose equivalent when compared to morphine ranges from 4–8 to 1 which can make precise conversions difficult [13]. Although hydromorphone is considerably more potent than morphine studies have demonstrated that PCADs utilizing hydromorphone are equally effective in comparison to morphine PCADs when dosing toward equianalgesia [13]. Typical dosing for hydromorphone is 0.1–0.5 mg followed by a 5–15 minutes lockout interval [5]. A recent study comparing the efficacy of morphine and hydromorphone concluded that the side effect profile is similar between morphine and hydromorphone in terms of opiate-related side effects [13]. Additionally, pain control and patient satisfaction were also equivalent. Thus it appears that prioritization of one medication over another should likely be guided by patient history as each drug has a unique side effect profile which may preclude it from usage in certain groups. Unfortunately, due to the past history of hydromorphone misuse in

Fentanyl has long been a preferred drug in ED for patients in severe acute pain as it reaches peak concentrations quickly within 1–2 minutes and has a short half-life (6 minutes) [14]. This makes it an excellent candidate for patients that require timely analgesia without a lengthy period of sedation. Fentanyl is well suited for use with PCADs as repetitive dosing at appropriate lockout intervals has not been shown to lead to excessive accumulation in the plasma and thus, does not result in analgesic stacking [15]. Intravenous dosing of Fentanyl usually consists of 15–50 μg followed by a 3–10 minutes lockout period. Although intravenous administration of this medication remains popular, novel delivery methods have recently been explored which show promising results. Transdermal Fentanyl is becoming

*DOI: http://dx.doi.org/10.5772/intechopen.83427*

tered in each dose.

*4.1.2 Hydromorphone (Dilaudid)*

the ED it will likely remain as a secondary agent.

#### *The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency… DOI: http://dx.doi.org/10.5772/intechopen.83427*

The average half-life of morphine is 1.5–2 hours with peak intensity usually being established in approximately 90 minutes [12, 13]. This makes it an effective medication for pain control as its effects wear off in a reasonable amount of time and it is generally well tolerated. Analgesic dosing is usually 0.5–3 mg per bolus, with a lockout period of 5–20 minutes [5]. Due to morphine's longer onset of action it could accumulate in the plasma and could result in analgesic stacking if the lockout times are not calibrated appropriately. Although this could theoretically lead to a significant increase in adverse events; it is very rarely seen clinically when administering conventional PCAD level dosages [5]. Additionally, it is important to recall that morphine has a higher degree of histamine release than other opiates in its class. This may preclude it from use in patients that have a history or pruritus or flushing after morphine use. This is, however, only a relative contraindication and may not manifest as readily due to the decreased quantity of medication administered in each dose.

#### *4.1.2 Hydromorphone (Dilaudid)*

*From Conventional to Innovative Approaches for Pain Treatment*

for patients presenting to the ED with acute pain.

**4. General principles in acute pain management**

a more active role in the management of their pain.

approach when selecting which medication a patient will receive.

use in the ED [11].

and 10 minutes are generally considered safe regardless of the type of medication being used [5]. These parameters can be altered in real time in response to patient feedback. This allows for more dynamic analgesic control which has clear benefits

It is important to note that there are distinct differences between machine programming parameters for postoperative patients versus those in an emergency setting. A prime example of this is the use of background/continuous infusions. Utilization of this setting allows for increased baseline plasma levels of medication and may improve pain control in certain populations [5]. Although the literature supports this type of treatment in post-operative patients, it may not be ideal for the ED as it requires close maintenance by nursing staff. Additionally, research shows that it does not improve pain control significantly in this patient population and may actually lead to increased incidence of adverse events including respiratory depression and sedation [5]. In another study which specifically examined the use of background infusions in the ED it was also found that manipulation of this setting led to an increased rate of pump programming errors. Although the patients involved in this study did not sustain any long-term side effects, there was an increase in the rate of sedation which further supports that this setting is of limited

The use of opiate medication in acute pain management has been a staple in most busy emergency departments. They work via blockade of μ-opioid receptorchannels which inhibit the transmission of pain in the central nervous system. In general, pure μ agonists have a high degree of variation in terms of dose-response relationships among individuals and require close monitoring by medical staff [1]. Side effects of medications which target μ-opioid receptors include respiratory depression, sedation, nausea, vomiting and pruritus. The frequency of adverse events associated with opiate administration in an acute care setting is difficult to predict and often, a trial of medication is necessary before sensitivities can be established. The disparities among these patients in regard to appropriate analgesic control is multifactorial and includes differences in opiate tolerance, pain severity, previous opiate use, body habitus, height and weight, dosing quantity and the frequency of administration. Many of these factors are difficult to control in a fast-paced environment such as the emergency room. However, utilization of patient-controlled analgesia may help offset these issues by allowing patients to take

Common opiates used in this setting include morphine, hydromorphone, and fentanyl. They are widely available and physicians are familiar with their general dose-response relationships and safety profiles. Although studies have shown that usage of specific opiates does not necessarily correlate with significant differences in pain scores among patients using PCADs, this does not obfuscate the need for appropriate medication selection [5]. Thus, it is important to take an individualized

Morphine is the most commonly used opiate in EDs which is likely due to its intermediate half-life, moderate strength and familiarity among hospital staff.

**40**

**4.1 Opiate selection**

*4.1.1 Morphine*

Hydromorphone is a medication that is both incredibly effective but also increasingly maligned by emergency physicians. It has gained notoriety due to its strength and efficacy in acute pain management and it is widely available in most EDs. Unfortunately, these attributes have also made it a popular drug of abuse among pain seekers and physicians remain wary of regular use. It is seven times more potent than morphine and is broken down into a biologically inactive metabolite which makes it an excellent candidate for patients requiring repeat dosing of opioid medications. It also has an improved side effect profile, including diminished histamine release, which results in less pruritus. The time to peak analgesic effect for hydromorphone is approximately 20 minutes and its dose equivalent when compared to morphine ranges from 4–8 to 1 which can make precise conversions difficult [13]. Although hydromorphone is considerably more potent than morphine studies have demonstrated that PCADs utilizing hydromorphone are equally effective in comparison to morphine PCADs when dosing toward equianalgesia [13]. Typical dosing for hydromorphone is 0.1–0.5 mg followed by a 5–15 minutes lockout interval [5]. A recent study comparing the efficacy of morphine and hydromorphone concluded that the side effect profile is similar between morphine and hydromorphone in terms of opiate-related side effects [13]. Additionally, pain control and patient satisfaction were also equivalent. Thus it appears that prioritization of one medication over another should likely be guided by patient history as each drug has a unique side effect profile which may preclude it from usage in certain groups. Unfortunately, due to the past history of hydromorphone misuse in the ED it will likely remain as a secondary agent.

#### *4.1.3 Fentanyl*

Fentanyl has long been a preferred drug in ED for patients in severe acute pain as it reaches peak concentrations quickly within 1–2 minutes and has a short half-life (6 minutes) [14]. This makes it an excellent candidate for patients that require timely analgesia without a lengthy period of sedation. Fentanyl is well suited for use with PCADs as repetitive dosing at appropriate lockout intervals has not been shown to lead to excessive accumulation in the plasma and thus, does not result in analgesic stacking [15]. Intravenous dosing of Fentanyl usually consists of 15–50 μg followed by a 3–10 minutes lockout period. Although intravenous administration of this medication remains popular, novel delivery methods have recently been explored which show promising results. Transdermal Fentanyl is becoming

increasingly popular in the realm of patient-controlled analgesia, as it has been demonstrated to have increased ease of use (i.e. improved confidence/comfort with the device, dosing, and knowledge/understanding) and less technical issues associated with autonomous administration. Although the transdermal route of delivery has been notorious for inconsistencies in medication delivery/absorption it appears as though transdermal Fentanyl produces results in terms of pain control and patient satisfaction which are on par with morphine [16]. Additionally, studies have also demonstrated that it has an improved side effect profile and has less frequent adverse events associated with its use, including hypotension, hypoventilation, nausea, vomiting, pruritus and tachycardia [17]. As such, it may be a viable alternative for patients who have sensitivities to more traditional medications like morphine.

#### *4.1.4 Meperidine (Demerol)*

Meperidine is another common opiate that has been studied as an alternative to morphine for use in patient-controlled analgesia, however it has limited utility in the ED. Meperidine has numerous disadvantages, including a short duration of action, a very poor analgesic effect at common doses (25–50 mg), abuse potential, and concerning drug interactions. Meperidine has serotonergic and noradrenergic properties and has the potential to induce serotonin syndrome in patients taking selective serotonin reuptake inhibitors and monoamine oxidase inhibitors [18].

A head-to-head comparison was recently done which evaluated meperidine versus morphine use in patients utilizing patient-controlled analgesia who were chronic opiate users presenting to the emergency room in acute pain. Levels of analgesia among the two groups were similar; however, patients using meperidine had a greater likelihood of experiencing withdrawal symptoms afterwards which was reflected in increased COWS scores [19]. Additionally, meperidine has a less favorable side effect profile when compared to morphine as it is broken down into the biologically active metabolite, normeperidine, which is a neurotoxin that can accumulate in the plasma and increases the risk of seizures, delirium, tremors, myoclonus and restlessness [5, 20]. It is important that patients be closely monitored when receiving this medication. Increased need for staff supervision would likely negate many of the benefits which PCADs provide in an acute care setting. For these reasons, meperidine is a poor choice for acute pain and should be used with caution in the ED [5, 21].

#### **4.2 Additional modes of administration**

There are numerous alternative modes of medication administration in patient-controlled analgesia including oral/sublingual, transdermal, intranasal, inhalational, and epidural preparations [22]. Intravenous delivery has remained the most popular route of administration, however, studies have shown promising results for several of these alternatives. Oral/sublingual medication, in particular, may have increased utility in the ED as it has the added benefit of being less invasive than standard IV therapy and may be preferable for some patients who are not candidates for inpatient admission. A meta-analysis of 13 studies demonstrated that sublingual medication administration had less side effects and a statistically significant improvement in global assessment scores (defined as "good" or "excellent") as well as trends which indicated improvements in VAS when compared to both morphine and transdermal Fentanyl [23].

In light of this information, a novel, non-invasive delivery system has recently been developed for the newly FDA approved medication, sufentanil.

**43**

*The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency…*

can be recommended specifically for use in the emergency department.

improves and devices are able to deliver medication more effectively.

the feasibility of its implementation in this setting is limited.

**5. Special populations**

**5.1 Children**

In additional to oral preparations there may be increased utility for medication delivery via the intranasal or inhalation route as these may also decrease the need for IV insertion and reduce overall cost. Unfortunately there are still significant barriers which must be overcome before these devices become commonplace. Inhalational medication, in particular, offers clear benefits as it is non-invasive, has a rapid onset of action and improved bioavailability [8, 26]. It has not been embraced in its current form; however, due to technical issues with regard to medication delivery, and improper patient compliance. Intranasal administration has been plagued by similar issues; however this may change in the future as technology

For the sake of completeness, epidural preparations should be briefly discussed as they are widely utilized in the perioperative and postoperative setting and have been shown to be more effective at controlling pain than intravenous administration [8, 27]. Epidural delivery of medication allows for targeted placement of opiates adjacent to the spinal afferent pain receptors which may diminish the systemic effects seen with oral and intravenous administration. This would initially appear promising for ED physicians as they are continually searching for ways to reduce the quantities of opiates being prescribed to their patients. Unfortunately this requires placement of an epidural catheter by a trained physician (often an anesthesiologist) which would not be feasible within the scope of the emergency department. Thus,

PCAD usage is considered safe for autonomous use in children over 6 who are experiencing acute pain [5]. Studies have demonstrated that PCAD use in this population results in decreased total opiate use, improved analgesia and decreased adverse effects, making it an ideal alternative to standard therapy [28]. One of the main determinants which govern its effective use in this population is the ability of the child to understand how and why the device is being used. The child must be able to understand basic principles regarding their pain as they will be required to follow instructions on how to self-administer medication. Studies have demonstrated that PCAD use in children under 4 is ineffective due to the aforementioned issues; however, children between 4 and 6 may use the device with the caveat that they maintain close nursing oversight. The need for additional monitoring is important for patient safety but this may not be feasible in a busy ED. Parental controlled patient analgesia has been offered as an alternative to this but in order to be effective it requires one-on-one education from nursing staff which also takes

This sublingual delivery device has been specifically designed for use in patientcontrolled analgesia and has demonstrated excellent titratability and a rapid onset of action which makes it attractive for use in the ED [24]. Phase 3 trials have demonstrated that sublingual Sufentanil has greater efficacy for the treatment of pain than IV medications and has less incidence of oxygen desaturation in the populations being studied [24]. Additionally, a recently conducted prospective, randomized double-blind study has shown that patients receiving sublingual Sufentanil have a higher summed pain intensity difference and improved global assessment scores in comparison to placebo [25]. Although this initial data appears promising, further studies must be done in an acute care setting before this device

*DOI: http://dx.doi.org/10.5772/intechopen.83427*

#### *The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency… DOI: http://dx.doi.org/10.5772/intechopen.83427*

This sublingual delivery device has been specifically designed for use in patientcontrolled analgesia and has demonstrated excellent titratability and a rapid onset of action which makes it attractive for use in the ED [24]. Phase 3 trials have demonstrated that sublingual Sufentanil has greater efficacy for the treatment of pain than IV medications and has less incidence of oxygen desaturation in the populations being studied [24]. Additionally, a recently conducted prospective, randomized double-blind study has shown that patients receiving sublingual Sufentanil have a higher summed pain intensity difference and improved global assessment scores in comparison to placebo [25]. Although this initial data appears promising, further studies must be done in an acute care setting before this device can be recommended specifically for use in the emergency department.

In additional to oral preparations there may be increased utility for medication delivery via the intranasal or inhalation route as these may also decrease the need for IV insertion and reduce overall cost. Unfortunately there are still significant barriers which must be overcome before these devices become commonplace. Inhalational medication, in particular, offers clear benefits as it is non-invasive, has a rapid onset of action and improved bioavailability [8, 26]. It has not been embraced in its current form; however, due to technical issues with regard to medication delivery, and improper patient compliance. Intranasal administration has been plagued by similar issues; however this may change in the future as technology improves and devices are able to deliver medication more effectively.

For the sake of completeness, epidural preparations should be briefly discussed as they are widely utilized in the perioperative and postoperative setting and have been shown to be more effective at controlling pain than intravenous administration [8, 27]. Epidural delivery of medication allows for targeted placement of opiates adjacent to the spinal afferent pain receptors which may diminish the systemic effects seen with oral and intravenous administration. This would initially appear promising for ED physicians as they are continually searching for ways to reduce the quantities of opiates being prescribed to their patients. Unfortunately this requires placement of an epidural catheter by a trained physician (often an anesthesiologist) which would not be feasible within the scope of the emergency department. Thus, the feasibility of its implementation in this setting is limited.

#### **5. Special populations**

#### **5.1 Children**

*From Conventional to Innovative Approaches for Pain Treatment*

*4.1.4 Meperidine (Demerol)*

with caution in the ED [5, 21].

**4.2 Additional modes of administration**

both morphine and transdermal Fentanyl [23].

increasingly popular in the realm of patient-controlled analgesia, as it has been demonstrated to have increased ease of use (i.e. improved confidence/comfort with the device, dosing, and knowledge/understanding) and less technical issues associated with autonomous administration. Although the transdermal route of delivery has been notorious for inconsistencies in medication delivery/absorption it appears as though transdermal Fentanyl produces results in terms of pain control and patient satisfaction which are on par with morphine [16]. Additionally, studies have also demonstrated that it has an improved side effect profile and has less frequent adverse events associated with its use, including hypotension, hypoventilation, nausea, vomiting, pruritus and tachycardia [17]. As such, it may be a viable alternative for patients who have sensitivities to more traditional medications like morphine.

Meperidine is another common opiate that has been studied as an alternative to morphine for use in patient-controlled analgesia, however it has limited utility in the ED. Meperidine has numerous disadvantages, including a short duration of action, a very poor analgesic effect at common doses (25–50 mg), abuse potential, and concerning drug interactions. Meperidine has serotonergic and noradrenergic properties and has the potential to induce serotonin syndrome in patients taking selective serotonin reuptake inhibitors and monoamine oxidase inhibitors [18]. A head-to-head comparison was recently done which evaluated meperidine versus morphine use in patients utilizing patient-controlled analgesia who were chronic opiate users presenting to the emergency room in acute pain. Levels of analgesia among the two groups were similar; however, patients using meperidine had a greater likelihood of experiencing withdrawal symptoms afterwards which was reflected in increased COWS scores [19]. Additionally, meperidine has a less favorable side effect profile when compared to morphine as it is broken down into the biologically active metabolite, normeperidine, which is a neurotoxin that can accumulate in the plasma and increases the risk of seizures, delirium, tremors, myoclonus and restlessness [5, 20]. It is important that patients be closely monitored when receiving this medication. Increased need for staff supervision would likely negate many of the benefits which PCADs provide in an acute care setting. For these reasons, meperidine is a poor choice for acute pain and should be used

There are numerous alternative modes of medication administration in patient-controlled analgesia including oral/sublingual, transdermal, intranasal, inhalational, and epidural preparations [22]. Intravenous delivery has remained the most popular route of administration, however, studies have shown promising results for several of these alternatives. Oral/sublingual medication, in particular, may have increased utility in the ED as it has the added benefit of being less invasive than standard IV therapy and may be preferable for some patients who are not candidates for inpatient admission. A meta-analysis of 13 studies demonstrated that sublingual medication administration had less side effects and a statistically significant improvement in global assessment scores (defined as "good" or "excellent") as well as trends which indicated improvements in VAS when compared to

In light of this information, a novel, non-invasive delivery system has recently been developed for the newly FDA approved medication, sufentanil.

**42**

PCAD usage is considered safe for autonomous use in children over 6 who are experiencing acute pain [5]. Studies have demonstrated that PCAD use in this population results in decreased total opiate use, improved analgesia and decreased adverse effects, making it an ideal alternative to standard therapy [28]. One of the main determinants which govern its effective use in this population is the ability of the child to understand how and why the device is being used. The child must be able to understand basic principles regarding their pain as they will be required to follow instructions on how to self-administer medication. Studies have demonstrated that PCAD use in children under 4 is ineffective due to the aforementioned issues; however, children between 4 and 6 may use the device with the caveat that they maintain close nursing oversight. The need for additional monitoring is important for patient safety but this may not be feasible in a busy ED. Parental controlled patient analgesia has been offered as an alternative to this but in order to be effective it requires one-on-one education from nursing staff which also takes

time and cooperation from a third party which may be cumbersome to facilitate. Parental controlled analgesia also has the added detractor that it removes the inherent benefits of patient autonomy which PCADs provide. Thus, it is unlikely to demonstrate a significant benefit over IV morphine for the purposes of acute pain management.

Morphine remains the most commonly used medication for patient-controlled analgesia in the pediatric population [28]. Typical dosing consists of a bolus of 10–20 μg/kg and a lockout period of 7–15 minutes [5]. As with all pain medications there are issues that may arise with prolonged administration of Morphine, which is especially concerning in the pediatric population. Cycling narcotics, especially in children who will be admitted, can help combat some of the sensitivities that are seen in relation to morphine utilization. Switching to medications such as hydromorphone can help decrease side effects like pruritus which may be both uncomfortable and alarming to many children. Hydromorphone, morphine and fentanyl are all considered safe for use in the pediatric population and they may be used interchangeably depending on response to treatment. A recent study found that hydromorphone to morphine switches for patient using PCADS was far more common (88.5% versus 11.5%) than vice versa. The most common reason for switching morphine to hydromorphone in this cohort was due to pruritus and inadequate pain control. Hydromorphone to morphine switches were more commonly due to nausea. Thus, physicians should monitor this population closely and change medications as necessary should any adverse events arise.

#### **5.2 Geriatrics**

Acute pain relief in the elderly can be challenging. Elderly patients presenting to the ED frequently have multiple comorbidities and physiologic issues which can affect the way in which analgesics are metabolized. Acute pain control in the geriatric population is an important topic to address because it is integral to their recovery. Studies have shown that unrelieved episodes of acute pain can result in decreased pulmonary function, sympathetic hyperactivity (including tachycardia and hypertension) and central neural sensitization which can lead to the development of chronic pain [29]. PCAD use is well suited for this population as it allows for individualized dosing, decreased fluctuations in opiate plasma concentration and improved pain control [30]. A recent study by Egbert which included 83 high-risk elderly men, demonstrated that PCAD use had improved analgesia without a concomitant increase in adverse events such as sedation. Additionally, the patient-controlled analgesia group reported that the PCAD was easier to use than traditional therapy [30].

Drug choice is important in the elderly as the pharmacokinetics and pharmacodynamic profile of opiate medications changes throughout the aging process. As we age there is an increase in body fat and decrease in total body water which alters drug metabolism. Therefore, fat soluble drugs such as fentanyl and meperidine have a higher volume of distribution and a longer duration of action which make them less attractive for use in this population [29]. Morphine is the most widely used medication for PCADs in the elderly and studies have demonstrated that the optimal loading dose is 1.0–1.5 mg/dose which should be followed by similar bolus dosing after a 5–7 minutes lockout period. It is important to note that water soluble drugs such as morphine have a higher plasma concentration in elderly patients due to their redsuced volume of distribution as well as increased levels of free active drug due to reduced albumin synthesis. As such, continuous infusions are contraindicated in this population as there is an increased frequency of adverse events, namely respiratory depression and hypotension [29].

**45**

*The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency…*

Pain control is notoriously difficult in patients who chronically use opiates and they often remain undertreated [31]. Although PCAD use in this population remains controversial, it may prove effective when used selectively [32]. Unlike patients who are opiate naive, bolus dosing in chronic opioid users may necessitate periodic re-adjustments, as larger doses are usually required with shorter lockout periods [31]. By providing these patients with a more uniform dose of medication ED physicians can avoid sedation while also decreasing the propensity for anxiety and cravings that occur frequently with IV therapy. Some physicians may also be worried about the potential for increased medication administration, should patients attempt to tamper with the device. This is usually not possible with standard pumps though, as they contain safety precautions and redundancies within the structure of the device which limit the potential for abuse. It should be noted however, that the "wrist-watch" type of PCAD contains a reservoir which is less secure than standard devices and it has a fixed lockout schedule which makes it less

In regards to medication selection, morphine is a commonly used medication which remains effective, albeit at higher concentrations, even in patients that have developed a tolerance. Studies which directly evaluated morphine use in ED patients receiving patient-controlled analgesia are limited but, as noted previously, there is a clear benefit to using morphine over other alternatives for numerous reasons [19]. Hydromorphone is another alternative that might initially seem appealing, however there is a push to limit its use in the ED, especially for chronic opioid users, so it is unlikely that it would gain widespread acceptance. Alternatively, one medication which has shown good efficacy for the treatment of acute pain is oral transmucosal fentanyl. Studies show that this medication is effective in chronic opioid users with breakthrough pain and may be a viable alternative for patients where morphine is initially ineffective or patient sensitivities preclude its use [10].

One of the more divisive topics relating to PCAD implementation in the emergency room relates to risk of abuse and reliance on opiates by patients provided with opiate analgesia. Initial systematic reviews regarding this subject demonstrated that patients using PCADs in the postoperative setting required less opiates than those undergoing standard therapy [8]. Unfortunately this does not appear to be the case for patients presenting to the ED. Evaluation of the most current randomized controlled trials for PCAD use in this population have demonstrated that patients receiving this therapy utilize a greater quantity of opiates than those receiving intravenous morphine [11, 33]. A recent study done by Bijur which included 636 patients presenting to the ED in acute pain, demonstrated that patients utilizing a PCAD required significantly more morphine (12.0 mg ± 4.3 versus 6.1 mg ± 2.9; 95% CI: 5.9 [5.2–6.4]) than those in the standard therapy group [11]. This data may seem worrisome at first but, as previously discussed, patients presenting to the ED with acute pain are notoriously undertreated. As such, the increased utilization of opiates in this population may reflect that patients need higher levels of analgesia

**6. Benefits of patient-controlled analgesia use in the ED**

than provided by standard measures of nurse administered analgesia.

In an effort to mollify this effect, recent studies have evaluated the efficacy of adding non-opiate medications to traditional PCAD formulations, with the

*DOI: http://dx.doi.org/10.5772/intechopen.83427*

attractive for use in this population [31].

**6.1 Opiate utilization**

**5.3 Chronic opiate users**

*The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency… DOI: http://dx.doi.org/10.5772/intechopen.83427*

#### **5.3 Chronic opiate users**

*From Conventional to Innovative Approaches for Pain Treatment*

medications as necessary should any adverse events arise.

namely respiratory depression and hypotension [29].

management.

**5.2 Geriatrics**

traditional therapy [30].

time and cooperation from a third party which may be cumbersome to facilitate. Parental controlled analgesia also has the added detractor that it removes the inherent benefits of patient autonomy which PCADs provide. Thus, it is unlikely to demonstrate a significant benefit over IV morphine for the purposes of acute pain

Morphine remains the most commonly used medication for patient-controlled analgesia in the pediatric population [28]. Typical dosing consists of a bolus of 10–20 μg/kg and a lockout period of 7–15 minutes [5]. As with all pain medications there are issues that may arise with prolonged administration of Morphine, which is especially concerning in the pediatric population. Cycling narcotics, especially in children who will be admitted, can help combat some of the sensitivities that are seen in relation to morphine utilization. Switching to medications such as hydromorphone can help decrease side effects like pruritus which may be both uncomfortable and alarming to many children. Hydromorphone, morphine and fentanyl are all considered safe for use in the pediatric population and they may be used interchangeably depending on response to treatment. A recent study found that hydromorphone to morphine switches for patient using PCADS was far more common (88.5% versus 11.5%) than vice versa. The most common reason for switching morphine to hydromorphone in this cohort was due to pruritus and inadequate pain control. Hydromorphone to morphine switches were more commonly due to nausea. Thus, physicians should monitor this population closely and change

Acute pain relief in the elderly can be challenging. Elderly patients presenting to the ED frequently have multiple comorbidities and physiologic issues which can affect the way in which analgesics are metabolized. Acute pain control in the geriatric population is an important topic to address because it is integral to their recovery. Studies have shown that unrelieved episodes of acute pain can result in decreased pulmonary function, sympathetic hyperactivity (including tachycardia and hypertension) and central neural sensitization which can lead to the development of chronic pain [29]. PCAD use is well suited for this population as it allows for individualized dosing, decreased fluctuations in opiate plasma concentration and improved pain control [30]. A recent study by Egbert which included 83 high-risk elderly men, demonstrated that PCAD use had improved analgesia without a concomitant increase in adverse events such as sedation. Additionally, the patient-controlled analgesia group reported that the PCAD was easier to use than

Drug choice is important in the elderly as the pharmacokinetics and pharmacodynamic profile of opiate medications changes throughout the aging process. As we age there is an increase in body fat and decrease in total body water which alters drug metabolism. Therefore, fat soluble drugs such as fentanyl and meperidine have a higher volume of distribution and a longer duration of action which make them less attractive for use in this population [29]. Morphine is the most widely used medication for PCADs in the elderly and studies have demonstrated that the optimal loading dose is 1.0–1.5 mg/dose which should be followed by similar bolus dosing after a 5–7 minutes lockout period. It is important to note that water soluble drugs such as morphine have a higher plasma concentration in elderly patients due to their redsuced volume of distribution as well as increased levels of free active drug due to reduced albumin synthesis. As such, continuous infusions are contraindicated in this population as there is an increased frequency of adverse events,

**44**

Pain control is notoriously difficult in patients who chronically use opiates and they often remain undertreated [31]. Although PCAD use in this population remains controversial, it may prove effective when used selectively [32]. Unlike patients who are opiate naive, bolus dosing in chronic opioid users may necessitate periodic re-adjustments, as larger doses are usually required with shorter lockout periods [31]. By providing these patients with a more uniform dose of medication ED physicians can avoid sedation while also decreasing the propensity for anxiety and cravings that occur frequently with IV therapy. Some physicians may also be worried about the potential for increased medication administration, should patients attempt to tamper with the device. This is usually not possible with standard pumps though, as they contain safety precautions and redundancies within the structure of the device which limit the potential for abuse. It should be noted however, that the "wrist-watch" type of PCAD contains a reservoir which is less secure than standard devices and it has a fixed lockout schedule which makes it less attractive for use in this population [31].

In regards to medication selection, morphine is a commonly used medication which remains effective, albeit at higher concentrations, even in patients that have developed a tolerance. Studies which directly evaluated morphine use in ED patients receiving patient-controlled analgesia are limited but, as noted previously, there is a clear benefit to using morphine over other alternatives for numerous reasons [19]. Hydromorphone is another alternative that might initially seem appealing, however there is a push to limit its use in the ED, especially for chronic opioid users, so it is unlikely that it would gain widespread acceptance. Alternatively, one medication which has shown good efficacy for the treatment of acute pain is oral transmucosal fentanyl. Studies show that this medication is effective in chronic opioid users with breakthrough pain and may be a viable alternative for patients where morphine is initially ineffective or patient sensitivities preclude its use [10].

#### **6. Benefits of patient-controlled analgesia use in the ED**

#### **6.1 Opiate utilization**

One of the more divisive topics relating to PCAD implementation in the emergency room relates to risk of abuse and reliance on opiates by patients provided with opiate analgesia. Initial systematic reviews regarding this subject demonstrated that patients using PCADs in the postoperative setting required less opiates than those undergoing standard therapy [8]. Unfortunately this does not appear to be the case for patients presenting to the ED. Evaluation of the most current randomized controlled trials for PCAD use in this population have demonstrated that patients receiving this therapy utilize a greater quantity of opiates than those receiving intravenous morphine [11, 33]. A recent study done by Bijur which included 636 patients presenting to the ED in acute pain, demonstrated that patients utilizing a PCAD required significantly more morphine (12.0 mg ± 4.3 versus 6.1 mg ± 2.9; 95% CI: 5.9 [5.2–6.4]) than those in the standard therapy group [11]. This data may seem worrisome at first but, as previously discussed, patients presenting to the ED with acute pain are notoriously undertreated. As such, the increased utilization of opiates in this population may reflect that patients need higher levels of analgesia than provided by standard measures of nurse administered analgesia.

In an effort to mollify this effect, recent studies have evaluated the efficacy of adding non-opiate medications to traditional PCAD formulations, with the

expectation there would be a level of opiate sparing and analgesic synergy. One of the most commonly studied of these additives is the NMDA inhibitor, Ketamine. This medication is of particular interest to emergency physicians as it is widely available and used frequently in both the pediatric and adult populations in procedures such as rapid-sequence intubation and procedural sedation. It has a favorable pharmacokinetic profile in terms of pain management as it has both intrinsic analgesic properties and opiate sparing effects via antagonism of NMDA receptors [5, 34]. Unfortunately, research on this subject has been mixed as some studies have shown that it may not provide a significant reduction in pain scores and has an increased incidence of deleterious side effects [5, 35, 36]. Clonidine has also been used as an additive in PCADs and initially showed some benefits in regard to nausea reduction in certain post-operative patients but this has not been reliably reproduced in subsequent studies [5, 34, 37].

One medication which has shown promise for use with PCADs is dexmedetomidine. This medication is a "highly selective α2-adrenoreceptor agonist, with analgesic, anxiolytic, and sedative properties, but without effects on respiratory function." [5, 38] In a recent study it was shown that adding dexmedetomidine to PCADs with morphine resulted in improved analgesia, decreased nausea and significant morphine sparing, without significantly impacting patients hemodynamic status [5, 39]. Thus, it would appear that this medication would be particularly wellsuited for use in the ED. Optimal dosing of this medication has not been definitively established, however the concentration used in this study consisted of 5 μg/mL with the PCAD being programmed to deliver 1 mL per demand bolus followed by a 5-minute lockout period. Formulations such as this are determined by the pharmacokinetic properties of the medication being studied and mixtures of these medications generally require additional assistance by pharmacy staff. This would likely add additional hard costs with regard to medication preparation but this may be a viable option for patients with a labile hemodynamic status (such as the elderly, septic or traumatically injured) where the analgesic benefits of increased dosing may be tempered by the fear of respiratory depression or hypotension. Additionally, these additives would offer a clear benefit for chronic opiate users where opiate sparing may be of increased importance.

#### **6.2 Pain reduction**

The perception of pain is highly subjective and varies greatly among individuals and makes it difficult to measure in precise terms. That being said, multiple formal measures have been created to objectively measure reductions in pain, namely the Visual Analogue Scale score (VAS score) and Numeric Rating Scales (NRS). These tools are of primary importance to both patients and physicians in objectifying levels of pain. Studies show that improvement in pain scores are directly correlated with patient satisfaction which can significantly influence the clinical course of patients experiencing an episode of acute pain [40]. Although it is well established that PCADs reduce pain scores in the post-operative setting there has been some controversy as to whether this would hold true for ED patients, as they often do not have as much time to convalesce from injuries. In reviewing the literature it appears that eight randomized controlled trials have been done which specifically examined the effect that patient-controlled analgesia had on pain scores in patients presenting to the ED. Five out of the eight studies in question have shown statistically significant results which favor PCAD use over conventional intravenous therapy. Two of the remaining studies demonstrated a downward trend which favored PCADs (although this did not reach the threshold for statistical significance) and only one study showed no difference [9, 11, 33, 41–46]. Unfortunately there is

**47**

*The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency…*

significant heterogeneity among these studies and due to the wide range of presenting complaints there are many confounding factors which must be accounted for. That being said, the initial data appears to support the use of PCADs over standard

Patient satisfaction is becoming ever more important in clinical medicine. It is imperative that physicians maximize their ability to take care of patients in an empathetic manner which utilizes principles of patient autonomy and shared decision making. Studies have demonstrated that PCADs are preferred by many patients in comparison with both IV and IM preparations and patient satisfaction with this type of treatment is generally high [5, 9, 11, 33, 41–46]. In a recent systematic review of 21 trials which included 1260 postoperative patients, it was shown that patients had increased satisfaction with PCAD use in all of the studies that were included in the cohort [8]. Additionally, a meta-analysis done on the same group showed that patients preferred PCADs significantly more than standard therapy [8]. Studies which have been conducted that have evaluated patient satisfaction for patients presenting to the emergency room have also shown similar results, with the overwhelming majority of studies showing a clear preference for PCADs [9, 11, 33, 41–46]. This is likely due to several factors including faster time to analgesia, decreased need of nursing assistance and an increased sense of autonomy and

In addition to patient satisfaction it is important to remember that proper implementation of this technology requires cooperation across multiple disciplines. As such, the support of physician extenders, nurses, and hospital pharmacists is integral to patient care and should not be overlooked. Relatively few studies have addressed this issue directly but current evidence shows that PCADs are generally well received by nursing staff. One study in particular demonstrated that patientcontrolled analgesia regiments were rated as "good to excellent" more frequently than those utilizing traditional intravenous therapy (69% versus 54%) and the majority of nursing staff would use them again in the future (77%) [41].

The majority of studies which have examined PCAD use in the emergency setting have found that there were similar rates of side effects such as nausea, vomiting, pruritus and drowsiness when compared to those receiving standard therapy [9, 11, 33, 41–46]. However, two studies showed PCADs to have a slightly increased risk of adverse events, including hypotension and hypoventilation, although neither group experienced any long-term sequelae in connection with these events. Additionally, these effects were transient and did not require the use of reversal with naloxone [9, 11]. When evaluating the literature it appears that the preponderance of adverse events associated with PCAD use have been due to factors which are inherent to all sustained opioid use and would likely be minimized with appropriate monitoring by staff. It is important to note that certain subgroups of patients may be prone to respiratory depression with patient-controlled analgesia. Studies have shown that elderly patients, patients with obstructive sleep apnea, and those using concurrent analgesics are at particular risk, and are vulnerable to the sedative

Although it appears that PCADs are safe in this patient population, there are unique characteristics associated with this technology which require special attention

*DOI: http://dx.doi.org/10.5772/intechopen.83427*

therapy for patients presenting to the ED with acute pain.

**7. Drawbacks of patient-controlled analgesia use**

effects which occur with repeated dosing [22].

**6.3 Patient autonomy and patient satisfaction**

control over one's pain [44].

significant heterogeneity among these studies and due to the wide range of presenting complaints there are many confounding factors which must be accounted for. That being said, the initial data appears to support the use of PCADs over standard therapy for patients presenting to the ED with acute pain.

#### **6.3 Patient autonomy and patient satisfaction**

*From Conventional to Innovative Approaches for Pain Treatment*

duced in subsequent studies [5, 34, 37].

sparing may be of increased importance.

**6.2 Pain reduction**

expectation there would be a level of opiate sparing and analgesic synergy. One of the most commonly studied of these additives is the NMDA inhibitor, Ketamine. This medication is of particular interest to emergency physicians as it is widely available and used frequently in both the pediatric and adult populations in procedures such as rapid-sequence intubation and procedural sedation. It has a favorable pharmacokinetic profile in terms of pain management as it has both intrinsic analgesic properties and opiate sparing effects via antagonism of NMDA receptors [5, 34]. Unfortunately, research on this subject has been mixed as some studies have shown that it may not provide a significant reduction in pain scores and has an increased incidence of deleterious side effects [5, 35, 36]. Clonidine has also been used as an additive in PCADs and initially showed some benefits in regard to nausea reduction in certain post-operative patients but this has not been reliably repro-

One medication which has shown promise for use with PCADs is dexmedetomidine. This medication is a "highly selective α2-adrenoreceptor agonist, with analgesic, anxiolytic, and sedative properties, but without effects on respiratory function." [5, 38] In a recent study it was shown that adding dexmedetomidine to PCADs with morphine resulted in improved analgesia, decreased nausea and significant morphine sparing, without significantly impacting patients hemodynamic status [5, 39]. Thus, it would appear that this medication would be particularly wellsuited for use in the ED. Optimal dosing of this medication has not been definitively established, however the concentration used in this study consisted of 5 μg/mL with the PCAD being programmed to deliver 1 mL per demand bolus followed by a 5-minute lockout period. Formulations such as this are determined by the pharmacokinetic properties of the medication being studied and mixtures of these medications generally require additional assistance by pharmacy staff. This would likely add additional hard costs with regard to medication preparation but this may be a viable option for patients with a labile hemodynamic status (such as the elderly, septic or traumatically injured) where the analgesic benefits of increased dosing may be tempered by the fear of respiratory depression or hypotension. Additionally, these additives would offer a clear benefit for chronic opiate users where opiate

The perception of pain is highly subjective and varies greatly among individuals and makes it difficult to measure in precise terms. That being said, multiple formal measures have been created to objectively measure reductions in pain, namely the Visual Analogue Scale score (VAS score) and Numeric Rating Scales (NRS). These tools are of primary importance to both patients and physicians in objectifying levels of pain. Studies show that improvement in pain scores are directly correlated with patient satisfaction which can significantly influence the clinical course of patients experiencing an episode of acute pain [40]. Although it is well established that PCADs reduce pain scores in the post-operative setting there has been some controversy as to whether this would hold true for ED patients, as they often do not have as much time to convalesce from injuries. In reviewing the literature it appears that eight randomized controlled trials have been done which specifically examined the effect that patient-controlled analgesia had on pain scores in patients presenting to the ED. Five out of the eight studies in question have shown statistically significant results which favor PCAD use over conventional intravenous therapy. Two of the remaining studies demonstrated a downward trend which favored PCADs (although this did not reach the threshold for statistical significance) and only one study showed no difference [9, 11, 33, 41–46]. Unfortunately there is

**46**

Patient satisfaction is becoming ever more important in clinical medicine. It is imperative that physicians maximize their ability to take care of patients in an empathetic manner which utilizes principles of patient autonomy and shared decision making. Studies have demonstrated that PCADs are preferred by many patients in comparison with both IV and IM preparations and patient satisfaction with this type of treatment is generally high [5, 9, 11, 33, 41–46]. In a recent systematic review of 21 trials which included 1260 postoperative patients, it was shown that patients had increased satisfaction with PCAD use in all of the studies that were included in the cohort [8]. Additionally, a meta-analysis done on the same group showed that patients preferred PCADs significantly more than standard therapy [8]. Studies which have been conducted that have evaluated patient satisfaction for patients presenting to the emergency room have also shown similar results, with the overwhelming majority of studies showing a clear preference for PCADs [9, 11, 33, 41–46]. This is likely due to several factors including faster time to analgesia, decreased need of nursing assistance and an increased sense of autonomy and control over one's pain [44].

In addition to patient satisfaction it is important to remember that proper implementation of this technology requires cooperation across multiple disciplines. As such, the support of physician extenders, nurses, and hospital pharmacists is integral to patient care and should not be overlooked. Relatively few studies have addressed this issue directly but current evidence shows that PCADs are generally well received by nursing staff. One study in particular demonstrated that patientcontrolled analgesia regiments were rated as "good to excellent" more frequently than those utilizing traditional intravenous therapy (69% versus 54%) and the majority of nursing staff would use them again in the future (77%) [41].

#### **7. Drawbacks of patient-controlled analgesia use**

The majority of studies which have examined PCAD use in the emergency setting have found that there were similar rates of side effects such as nausea, vomiting, pruritus and drowsiness when compared to those receiving standard therapy [9, 11, 33, 41–46]. However, two studies showed PCADs to have a slightly increased risk of adverse events, including hypotension and hypoventilation, although neither group experienced any long-term sequelae in connection with these events. Additionally, these effects were transient and did not require the use of reversal with naloxone [9, 11]. When evaluating the literature it appears that the preponderance of adverse events associated with PCAD use have been due to factors which are inherent to all sustained opioid use and would likely be minimized with appropriate monitoring by staff. It is important to note that certain subgroups of patients may be prone to respiratory depression with patient-controlled analgesia. Studies have shown that elderly patients, patients with obstructive sleep apnea, and those using concurrent analgesics are at particular risk, and are vulnerable to the sedative effects which occur with repeated dosing [22].

Although it appears that PCADs are safe in this patient population, there are unique characteristics associated with this technology which require special attention and education for both patients and staff. Programming errors can occur, especially when staff are unfamiliar with the equipment which can lead to over-sedation and respiratory depression. In a large randomized study conducted in the ED by Bijur et al. there were a similar number of adverse events among patients assigned to the PCAD group versus those receiving standard IV therapy. However, the PCAD group had 11 pump programming errors, 10 of which were due to nursing staff unintentionally giving patients background infusions. None of the patients in question were subject to any long-term side effects. Additionally, following staff remediation and education, no additional errors were seen [11]. One way to address this in the ED would be to have special teams which are trained specifically in PCAD usage and implementation. Studies which have examined the effect of using specially trained support staff have demonstrated that there are less adverse events and a greater likelihood of being able to transition to oral opiates (rather than IM) when staff are trained appropriately [5, 47]. Thus, it appears that many of these events may be mitigated by improving education and regular training among providers and support staff.

There are some additional factors relating to patient perceptions which are unique to this modality and may influence its effectiveness in regard to pain control. Chumbley and colleagues found that many patients had reservations about using PCADs with 22% of patients fearing addiction and 30% fearing overdose [44, 48]. The study goes on to explain that lack of education likely played a large role in this and a patient's psychological background and coping abilities were also involved in influencing their response to treatment [44]. Intrinsic issues such as these are more difficult to control for in an acute setting and are largely related to preconceived notions that patients have prior to presenting to the ED. It is likely that these variables could be minimized if providers were to make an effort to first educate the patients regarding PCAD use and set reasonable expectations regarding pain control prior to the initiation of care.

#### **8. Economics**

Although patient safety maintains primacy in the hierarchy of prioritization with regard to the implementation of new technology, economic considerations play an important role when determining the feasibility of its widespread clinical utility. With regard to PCADs there are both hard costs, in terms of the device itself, length of stay and medication, as well as soft costs, such as time saved by staff and patient satisfaction, which must be considered when analyzing the cost-effectiveness of this modality. Although current research clearly demonstrates that there are improvements in patient satisfaction and an objective reduction in pain scores in patients receiving patient-controlled analgesia, it is difficult to quantify how these benefits translate in terms of savings. As such, clear cost-benefit ratios remain difficult to establish. Due to this complexity, a multivariate approach must be used when evaluating the benefits that PCADs offer in an acute care setting.

Although device costs vary among distributors it is safe to assume that the cost of obtaining the device and subsequent maintenance would be greater than that of traditional therapy. A study by Pritchard et al., which evaluated specific costs associated with the device including depreciation, electrical testing, calibration/ rebuild costs, and servicing demonstrated that the annual costs of a PCAD was approximately \$1573 which equates to \$4.34 per day [49]. In addition to these initial capital expenditures relating to acquiring the device, there is mounting evidence that patients receiving patient-controlled analgesia in the ED also require a greater quantity of opiates than those receiving IV therapy [9, 33, 42, 44, 46]. These increased costs are also compounded by additional administrative challenges which

**49**

**9. Conclusion**

**Conflict of interest**

materials discussed in this manuscript.

*The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency…*

require nursing staff, physicians and pharmacy to coordinate care in a novel manner

pain is the ability of this modality to save valuable staff time. This translates to increased productivity for both nursing staff and physicians which has the propensity to further increase RVUs and improve overall savings. For example, a recent study by Chan et al., demonstrated that PCAD utilization could save an average of 10–13 minutes of treatment time within specific post-operative groups [50]. Literature on costs related to length of stay, on the other hand, appears equivocal. A review of the literature shows that four randomized controlled trials have been done which specifically evaluated length of stay in the ED relative to PCAD use. Two studies reported an increase in length of stay and two reported a reduction [9, 33, 41, 43]. None of the studies reached statistical significance, therefore the question of whether patient-controlled analgesia reduces length of stay remains unanswered. The PASTIES study was a large scale randomized trial which evaluated the effectiveness of patient-controlled analgesia in the ED for patients suffering from traumatic injuries and non-traumatic abdominal pain [9, 33]. This study evaluated patients presenting to the ED who were subsequently admitted to the hospital, thus, providing important follow-up information on patient outcomes after their initial ED care. Subsequent PASTIES studies have since been published which have evaluated the costs associated with PCAD use in this cohort. These studies are important to this discussion as they are the only studies to date which have specifically evaluated the economic feasibility of patient-controlled analgesia in the ED. According to the study there were significant reductions in pain, particularly in patients with acute abdominal pain, however, this came at increased cost. Patients with traumatic injuries incurred an additional \$21.79–\$23.10 per 12 hours; and non-traumatic abdominal pain incurred an additional \$23.67–\$25.09 per 12 hours [49]. Although these costs were significant within the scope of this study, they may be negligible as improvements in patient satisfaction may eventually translate into improved reimbursement. As such, further studies must be done in the future to determine the true financial feasibility of PCAs in this type of setting.

One factor which clearly favors the use of PCADs in patients experiencing acute

Use of patient-controlled analgesia has been demonstrated to be both safe and effective for acute pain management in the ED. It offers a means of pain control which is more patient-centered and allows for a greater degree of shared decision making while simultaneously improving baseline analgesia. Recently, a few small scale studies have shown that the use of patient-controlled analgesia in the acute care setting may improve objective pain scores and increase both patient and nurse satisfaction. However, the economic feasibility for utilization of this modality within the scope of the emergency room remains unclear. As always, medication selection should be guided by clinical presentation and patient response. In conclusion, this technology appears to provide a promising alternative to standard therapy, however, additional studies must be done before more broad recommenda-

The authors have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or

tions can be made regarding widespread implementation.

*DOI: http://dx.doi.org/10.5772/intechopen.83427*

which may be difficult to implement in many EDs.

#### *The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency… DOI: http://dx.doi.org/10.5772/intechopen.83427*

require nursing staff, physicians and pharmacy to coordinate care in a novel manner which may be difficult to implement in many EDs.

One factor which clearly favors the use of PCADs in patients experiencing acute pain is the ability of this modality to save valuable staff time. This translates to increased productivity for both nursing staff and physicians which has the propensity to further increase RVUs and improve overall savings. For example, a recent study by Chan et al., demonstrated that PCAD utilization could save an average of 10–13 minutes of treatment time within specific post-operative groups [50]. Literature on costs related to length of stay, on the other hand, appears equivocal. A review of the literature shows that four randomized controlled trials have been done which specifically evaluated length of stay in the ED relative to PCAD use. Two studies reported an increase in length of stay and two reported a reduction [9, 33, 41, 43]. None of the studies reached statistical significance, therefore the question of whether patient-controlled analgesia reduces length of stay remains unanswered.

The PASTIES study was a large scale randomized trial which evaluated the effectiveness of patient-controlled analgesia in the ED for patients suffering from traumatic injuries and non-traumatic abdominal pain [9, 33]. This study evaluated patients presenting to the ED who were subsequently admitted to the hospital, thus, providing important follow-up information on patient outcomes after their initial ED care. Subsequent PASTIES studies have since been published which have evaluated the costs associated with PCAD use in this cohort. These studies are important to this discussion as they are the only studies to date which have specifically evaluated the economic feasibility of patient-controlled analgesia in the ED. According to the study there were significant reductions in pain, particularly in patients with acute abdominal pain, however, this came at increased cost. Patients with traumatic injuries incurred an additional \$21.79–\$23.10 per 12 hours; and non-traumatic abdominal pain incurred an additional \$23.67–\$25.09 per 12 hours [49]. Although these costs were significant within the scope of this study, they may be negligible as improvements in patient satisfaction may eventually translate into improved reimbursement. As such, further studies must be done in the future to determine the true financial feasibility of PCAs in this type of setting.

#### **9. Conclusion**

*From Conventional to Innovative Approaches for Pain Treatment*

control prior to the initiation of care.

**8. Economics**

and education for both patients and staff. Programming errors can occur, especially when staff are unfamiliar with the equipment which can lead to over-sedation and respiratory depression. In a large randomized study conducted in the ED by Bijur et al. there were a similar number of adverse events among patients assigned to the PCAD group versus those receiving standard IV therapy. However, the PCAD group had 11 pump programming errors, 10 of which were due to nursing staff unintentionally giving patients background infusions. None of the patients in question were subject to any long-term side effects. Additionally, following staff remediation and education, no additional errors were seen [11]. One way to address this in the ED would be to have special teams which are trained specifically in PCAD usage and implementation. Studies which have examined the effect of using specially trained support staff have demonstrated that there are less adverse events and a greater likelihood of being able to transition to oral opiates (rather than IM) when staff are trained appropriately [5, 47]. Thus, it appears that many of these events may be mitigated by improving education and regular training among providers and support staff. There are some additional factors relating to patient perceptions which are unique to this modality and may influence its effectiveness in regard to pain control. Chumbley and colleagues found that many patients had reservations about using PCADs with 22% of patients fearing addiction and 30% fearing overdose [44, 48]. The study goes on to explain that lack of education likely played a large role in this and a patient's psychological background and coping abilities were also involved in influencing their response to treatment [44]. Intrinsic issues such as these are more difficult to control for in an acute setting and are largely related to preconceived notions that patients have prior to presenting to the ED. It is likely that these variables could be minimized if providers were to make an effort to first educate the patients regarding PCAD use and set reasonable expectations regarding pain

Although patient safety maintains primacy in the hierarchy of prioritization with regard to the implementation of new technology, economic considerations play an important role when determining the feasibility of its widespread clinical utility. With regard to PCADs there are both hard costs, in terms of the device itself, length of stay and medication, as well as soft costs, such as time saved by staff and patient satisfaction, which must be considered when analyzing the cost-effectiveness of this modality. Although current research clearly demonstrates that there are improvements in patient satisfaction and an objective reduction in pain scores in patients receiving patient-controlled analgesia, it is difficult to quantify how these benefits translate in terms of savings. As such, clear cost-benefit ratios remain difficult to establish. Due to this complexity, a multivariate approach must be used when

Although device costs vary among distributors it is safe to assume that the cost of obtaining the device and subsequent maintenance would be greater than that of traditional therapy. A study by Pritchard et al., which evaluated specific costs associated with the device including depreciation, electrical testing, calibration/ rebuild costs, and servicing demonstrated that the annual costs of a PCAD was approximately \$1573 which equates to \$4.34 per day [49]. In addition to these initial capital expenditures relating to acquiring the device, there is mounting evidence that patients receiving patient-controlled analgesia in the ED also require a greater quantity of opiates than those receiving IV therapy [9, 33, 42, 44, 46]. These increased costs are also compounded by additional administrative challenges which

evaluating the benefits that PCADs offer in an acute care setting.

**48**

Use of patient-controlled analgesia has been demonstrated to be both safe and effective for acute pain management in the ED. It offers a means of pain control which is more patient-centered and allows for a greater degree of shared decision making while simultaneously improving baseline analgesia. Recently, a few small scale studies have shown that the use of patient-controlled analgesia in the acute care setting may improve objective pain scores and increase both patient and nurse satisfaction. However, the economic feasibility for utilization of this modality within the scope of the emergency room remains unclear. As always, medication selection should be guided by clinical presentation and patient response. In conclusion, this technology appears to provide a promising alternative to standard therapy, however, additional studies must be done before more broad recommendations can be made regarding widespread implementation.

#### **Conflict of interest**

The authors have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

*From Conventional to Innovative Approaches for Pain Treatment*

#### **Author details**

Mark Bender and Linda Papa\* Orlando Health, Orlando, FL, United States

\*Address all correspondence to: lpstat@aol.com

© 2019 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.

**51**

*The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency…*

[8] McNicol ED, Ferguson MC, Hudcova J. Patient controlled opioid analgesia versus non-patient controlled opioid analgesia for postoperative pain. Cochrane Database of Systematic Reviews. 2015;**6**:CD003348

[9] Smith JE, Rockett M, Creanor S, Squire R, et al. PAin SoluTions In the Emergency Setting (PASTIES)—Patient controlled analgesia versus routine care in emergency department patients with pain from traumatic injuries: Randomised trial. British Medical

[10] Fine PG, Marcus M, De Boer AJ, Van der Oord B. An open label study of oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough cancer pain. Pain. 1991;**45**(2):149-153

[11] Bijur PE, Mills AM, Chang AK, et al. Comparative effectiveness of patientcontrolled analgesia for treating acute pain in the emergency department. Annals of Emergency Medicine.

[12] FDA. Prescribing information for Morphine Sulfate Injection. Vol. 2018.

[13] Hong D, Flood P, Diaz G. The side effects of morphine and hydromorphone patient-controlled analgesia. Anesthesia and Analgesia.

[14] Fookes C, Puckey M, Stewart J, Anderson LA. Fentanyl, Fentanyl Citrate, Fentanyl Hydrochloride. AHFS DI Essentials™. Vol. 2018. Bethesda: American Society of Health-System Pharmacists; 2018. Selected Revisions October 22, 2018. https://www.drugs. com/monograph/fentanyl-fentanylcitrate-fentanyl-hydrochloride.

[15] Lehmann KA, Heinrich C, van Heiss R. Balanced anesthesia and

Journal. 2015;**350**:h2988

2017;**70**(6):809-818, e2

Lake Forest: FDA; 2011

2008;**107**(4):1384-1389

html#moreResources

*DOI: http://dx.doi.org/10.5772/intechopen.83427*

[1] Motov SM, Nelson LS. Advanced concepts and controversies in emergency department pain

management. Anesthesiology Clinics.

[2] McCaig LF, Stussman BJ. National Hospital Ambulatory Medical Care Survey: 1996 Emergency department summary. Advance Data;**1997**(293):1-20

[3] Motov S, Strayer R, Hayes B, et al., editors. AAEM White Paper on Acute Pain Management in the Emergency Department. Vol. 2018. Milwaukee: American Academy of Emergency Medicine; 2017. Position Statement

[4] Specifications Manual for National Hospital Inpatient Quality Measures. Emergency Department. Version 5.4 ed., Vol. 2018: Centers for Medicare & Medicaid Services and the Joint Commission, 2018; The Specifications Manual for National Hospital Inpatient Quality Measures includes the measure sets: ED, IMM, STK, SUB, TOB, and VTE. https://www.jointcommission.org/ specifications\_manual\_for\_national\_ hospital\_inpatient\_quality\_measures.aspx

[5] Ellen M, Soffin MD, Spencer S, Liu MD. Patient-controlled analgesia. In: Benzon H, Raja SN, editors. Essentials of Pain Medicine. Philadelphia: Elsevier;

Donaldson GW. Resolution of acute pain following discharge from the emergency department: The acute pain trajectory. The Journal of Pain. 2012;**13**(3):235-241

[7] Rockett M, Creanor S, Squire R, et al. The impact of emergency department patient-controlled analgesia (PCA) on the incidence of chronic pain following trauma and non-traumatic abdominal pain. Anaesthesia. 2018;**74**:69-73. https://www.ncbi.nlm.nih.gov/

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*The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency… DOI: http://dx.doi.org/10.5772/intechopen.83427*

#### **References**

*From Conventional to Innovative Approaches for Pain Treatment*

**50**

**Author details**

Mark Bender and Linda Papa\*

provided the original work is properly cited.

Orlando Health, Orlando, FL, United States

\*Address all correspondence to: lpstat@aol.com

© 2019 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,

[1] Motov SM, Nelson LS. Advanced concepts and controversies in emergency department pain management. Anesthesiology Clinics. 2016;**34**(2):271-285

[2] McCaig LF, Stussman BJ. National Hospital Ambulatory Medical Care Survey: 1996 Emergency department summary. Advance Data;**1997**(293):1-20

[3] Motov S, Strayer R, Hayes B, et al., editors. AAEM White Paper on Acute Pain Management in the Emergency Department. Vol. 2018. Milwaukee: American Academy of Emergency Medicine; 2017. Position Statement

[4] Specifications Manual for National Hospital Inpatient Quality Measures. Emergency Department. Version 5.4 ed., Vol. 2018: Centers for Medicare & Medicaid Services and the Joint Commission, 2018; The Specifications Manual for National Hospital Inpatient Quality Measures includes the measure sets: ED, IMM, STK, SUB, TOB, and VTE. https://www.jointcommission.org/ specifications\_manual\_for\_national\_ hospital\_inpatient\_quality\_measures.aspx

[5] Ellen M, Soffin MD, Spencer S, Liu MD. Patient-controlled analgesia. In: Benzon H, Raja SN, editors. Essentials of Pain Medicine. Philadelphia: Elsevier; 2018. pp. 117-122, e2

[6] Chapman CR, Fosnocht D, Donaldson GW. Resolution of acute pain following discharge from the emergency department: The acute pain trajectory. The Journal of Pain. 2012;**13**(3):235-241

[7] Rockett M, Creanor S, Squire R, et al. The impact of emergency department patient-controlled analgesia (PCA) on the incidence of chronic pain following trauma and non-traumatic abdominal pain. Anaesthesia. 2018;**74**:69-73. https://www.ncbi.nlm.nih.gov/ pubmed/30367688

[8] McNicol ED, Ferguson MC, Hudcova J. Patient controlled opioid analgesia versus non-patient controlled opioid analgesia for postoperative pain. Cochrane Database of Systematic Reviews. 2015;**6**:CD003348

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[10] Fine PG, Marcus M, De Boer AJ, Van der Oord B. An open label study of oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough cancer pain. Pain. 1991;**45**(2):149-153

[11] Bijur PE, Mills AM, Chang AK, et al. Comparative effectiveness of patientcontrolled analgesia for treating acute pain in the emergency department. Annals of Emergency Medicine. 2017;**70**(6):809-818, e2

[12] FDA. Prescribing information for Morphine Sulfate Injection. Vol. 2018. Lake Forest: FDA; 2011

[13] Hong D, Flood P, Diaz G. The side effects of morphine and hydromorphone patient-controlled analgesia. Anesthesia and Analgesia. 2008;**107**(4):1384-1389

[14] Fookes C, Puckey M, Stewart J, Anderson LA. Fentanyl, Fentanyl Citrate, Fentanyl Hydrochloride. AHFS DI Essentials™. Vol. 2018. Bethesda: American Society of Health-System Pharmacists; 2018. Selected Revisions October 22, 2018. https://www.drugs. com/monograph/fentanyl-fentanylcitrate-fentanyl-hydrochloride. html#moreResources

[15] Lehmann KA, Heinrich C, van Heiss R. Balanced anesthesia and

patient-controlled postoperative analgesia with fentanyl: Minimum effective concentrations, accumulation and acute tolerance. Acta Anaesthesiologica Belgica. 1988;**39**(1):11-23

[16] Lindley P, Ding L, Danesi H, Jones JB. Meta-analysis of the ease of care from a patients' perspective comparing fentanyl iontophoretic transdermal system versus morphine intravenous patient-controlled analgesia in postoperative pain management. Journal of Perianesthesia Nursing. 2017;**32**(4):320-328

[17] Viscusi ER, Grond S, Ding L, Danesi H, Jones JB, Sinatra RS. A comparison of opioid-related adverse events with fentanyl iontophoretic transdermal system versus morphine intravenous patient-controlled analgesia in acute postoperative pain. Pain Management. 2016;**6**(1):19-24

[18] Alvarado-Rivera O. Meperidine: Friend or foe? Pharmacy Times. 2016;**2018**. https:// www.pharmacytimes.com/ contributor/orlando-alvaradorivera-pharmd-ms/2016/09/ meperidine-friend-or-foe

[19] Solhi H, Sanaei-Zadeh H, Solhi S, Azizi Nadian MA, Gharibi M, Sadeghi Sedeh B. Meperidine (pethidine) versus morphine in acute pain management of opioid-dependent patients. Open Access Emergency Medicine. 2016;**8**:57-59

[20] Fogarty T, Murray GB. Psychiatric presentation of meperidine toxicity. Journal of Clinical Psychopharmacology. 1987;**7**(2):116-117

[21] Simopoulos TT, Smith HS, Peeters-Asdourian C, Stevens DS. Use of meperidine in patient-controlled analgesia and the development of a normeperidine toxic reaction. Archives of Surgery. 2002;**137**(1):84-88

[22] Macintyre PE. Safety and efficacy of patient-controlled analgesia. British Journal of Anaesthesia. 2001;**87**(1):36-46

[23] Katz P, Takyar S, Palmer P, Liedgens H. Sublingual, transdermal and intravenous patient-controlled analgesia for acute post-operative pain: Systematic literature review and mixed treatment comparison. Current Medical Research and Opinion. 2017;**33**(5):899-910

[24] Minkowitz HS. A review of sufentanil and the sufentanil sublingual tablet system for acute moderate to severe pain. Pain Management. 2015;**5**(4):237-250

[25] Jove M, Griffin DW, Minkowitz HS, Ben-David B, Evashenk MA, Palmer PP. Sufentanil sublingual tablet system for the management of postoperative pain after knee or hip arthroplasty: A randomized, placebo-controlled study. Anesthesiology. 2015;**123**(2):434-443

[26] Thipphawong JB, Babul N, Morishige RJ, et al. Analgesic efficacy of inhaled morphine in patients after bunionectomy surgery. Anesthesiology. 2003;**99**(3):693-700; discussion 6A

[27] Block BM, Liu SS, Rowlingson AJ, Cowan AR, Cowan JA Jr, Wu CL. Efficacy of postoperative epidural analgesia: A meta-analysis. Journal of the American Medical Association. 2003;**290**(18):2455-2463

[28] DiGiusto M, Bhalla T, Martin D, Foerschler D, Jones MJ, Tobias JD. Patient-controlled analgesia in the pediatric population: Morphine versus hydromorphone. Journal of Pain Research. 2014;**7**:471-475

[29] Lavand'Homme P, De Kock M. Practical guidelines on the postoperative use of patient-controlled analgesia in the elderly. Drugs & Aging. 1998;**13**(1):9-16

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[38] Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia.

[39] Lin TF, Yeh YC, Lin FS, et al. Effect of combining dexmedetomidine and morphine for intravenous patientcontrolled analgesia. British Journal of Anaesthesia. 2009;**102**(1):117-122

[40] Brown T, Shetty A, Zhao DF, Harvey N, Yu T, Murphy M. Association between pain control and patient satisfaction outcomes in the emergency department setting. Emergency Medicine Australasia.

[41] Gonzalez ER, Bahal N, Hansen LA, et al. Intermittent injection vs patient-controlled analgesia for sickle cell crisis pain. Comparison in patients in the emergency department.

Archives of Internal Medicine.

Emergency Medicine Journal.

[44] Rahman NH, DeSilva T. A

Medicine. 2012;**43**(6):951-957

randomized controlled trial of patientcontrolled analgesia compared with boluses of analgesia for the control of acute traumatic pain in the emergency department. The Journal of Emergency

[45] Birnbaum A, Schechter C, Tufaro V, Touger R, Gallagher EJ, Bijur P. Efficacy

[42] Evans E, Turley N, Robinson N, Clancy M. Randomised controlled trial of patient controlled analgesia compared with nurse delivered

analgesia in an emergency department.

[43] Melzer-Lange MD, Walsh-Kelly CM, Lea G, Hillery CA, Scott JP. Patientcontrolled analgesia for sickle cell pain crisis in a pediatric emergency department. Pediatric Emergency Care.

1991;**151**(7):1373-1378

2005;**22**(1):25-29

2004;**20**(1):2-4

1999;**54**(2):146-165

2018;**30**(4):523-529

*DOI: http://dx.doi.org/10.5772/intechopen.83427*

[30] Egbert AM, Parks LH, Short LM, Burnett ML. Randomized trial of postoperative patient-controlled analgesia vs intramuscular narcotics in frail elderly men. Archives of Internal Medicine. 1990;**150**(9):1897-1903

[31] Mehta V, Langford R. Acute pain management in opioid

2009;**3**(2):10-14

329-344; quiz 344-7

dependent patients. Reviews in Pain.

[32] Iocolano CF. Perioperative pain management in the chemically dependent patient. Journal of Perianesthesia Nursing. 2000;**15**(5):

[33] Smith JE, Rockett M, Creanor S, et al. PAin SoluTions In the Emergency Setting (PASTIES)—Patient controlled

[34] Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-Daspartate (NMDA) receptors in pain: A review. Anesthesia and Analgesia.

[35] Burstal R, Danjoux G, Hayes C, Lantry G. PCA ketamine and morphine

[36] Reeves M, Lindholm DE, Myles PS, Fletcher H, Hunt JO. Adding ketamine to morphine for patient-controlled analgesia after major abdominal

surgery: A double-blinded, randomized

[37] Striebel WH, Koenigs DI, Kramer JA. Intravenous clonidine fails to reduce postoperative meperidine requirements.

controlled trial. Anesthesia and Analgesia. 2001;**93**(1):116-120

Journal of Clinical Anesthesia.

1993;**5**(3):221-225

after abdominal hysterectomy. Anaesthesia and Intensive Care.

analgesia versus routine care in emergency department patients with non-traumatic abdominal pain: Randomised trial. British Medical

Journal. 2015;**350**:h3147

2003;**97**(4):1108-1116

2001;**29**(3):246-251

*The Utility of Patient-Controlled Analgesia for Managing Acute Pain in the Emergency… DOI: http://dx.doi.org/10.5772/intechopen.83427*

[30] Egbert AM, Parks LH, Short LM, Burnett ML. Randomized trial of postoperative patient-controlled analgesia vs intramuscular narcotics in frail elderly men. Archives of Internal Medicine. 1990;**150**(9):1897-1903

*From Conventional to Innovative Approaches for Pain Treatment*

[22] Macintyre PE. Safety and efficacy of patient-controlled analgesia. British Journal of Anaesthesia.

[23] Katz P, Takyar S, Palmer P, Liedgens

intravenous patient-controlled analgesia for acute post-operative pain: Systematic literature review and mixed treatment comparison. Current Medical Research and Opinion. 2017;**33**(5):899-910

sufentanil and the sufentanil sublingual tablet system for acute moderate to severe pain. Pain Management.

[25] Jove M, Griffin DW, Minkowitz HS, Ben-David B, Evashenk MA, Palmer PP. Sufentanil sublingual tablet system for the management of postoperative pain after knee or hip arthroplasty: A randomized, placebo-controlled study. Anesthesiology. 2015;**123**(2):434-443

H. Sublingual, transdermal and

[24] Minkowitz HS. A review of

[26] Thipphawong JB, Babul N, Morishige RJ, et al. Analgesic efficacy of inhaled morphine in patients after bunionectomy surgery. Anesthesiology. 2003;**99**(3):693-700;

[27] Block BM, Liu SS, Rowlingson AJ, Cowan AR, Cowan JA Jr, Wu CL. Efficacy of postoperative epidural analgesia: A meta-analysis. Journal of the American Medical Association.

[28] DiGiusto M, Bhalla T, Martin D, Foerschler D, Jones MJ, Tobias JD. Patient-controlled analgesia in the pediatric population: Morphine versus hydromorphone. Journal of Pain

2003;**290**(18):2455-2463

Research. 2014;**7**:471-475

1998;**13**(1):9-16

[29] Lavand'Homme P, De Kock M. Practical guidelines on the

postoperative use of patient-controlled analgesia in the elderly. Drugs & Aging.

2001;**87**(1):36-46

2015;**5**(4):237-250

discussion 6A

patient-controlled postoperative analgesia with fentanyl: Minimum

accumulation and acute tolerance. Acta Anaesthesiologica Belgica.

[16] Lindley P, Ding L, Danesi H, Jones JB. Meta-analysis of the ease of care from a patients' perspective comparing fentanyl iontophoretic transdermal system versus morphine intravenous patient-controlled analgesia in postoperative pain management. Journal of Perianesthesia Nursing.

[17] Viscusi ER, Grond S, Ding L, Danesi H, Jones JB, Sinatra RS. A comparison of opioid-related adverse events with fentanyl iontophoretic transdermal system versus morphine intravenous patient-controlled analgesia in acute postoperative pain. Pain Management.

[18] Alvarado-Rivera O. Meperidine:

[19] Solhi H, Sanaei-Zadeh H, Solhi S, Azizi Nadian MA, Gharibi M, Sadeghi Sedeh B. Meperidine (pethidine) versus morphine in acute pain management of opioid-dependent patients. Open Access Emergency Medicine. 2016;**8**:57-59

[20] Fogarty T, Murray GB. Psychiatric presentation of meperidine toxicity. Journal of Clinical Psychopharmacology.

[21] Simopoulos TT, Smith HS, Peeters-Asdourian C, Stevens DS. Use of meperidine in patient-controlled analgesia and the development of a normeperidine toxic reaction. Archives

of Surgery. 2002;**137**(1):84-88

Friend or foe? Pharmacy Times. 2016;**2018**. https:// www.pharmacytimes.com/ contributor/orlando-alvaradorivera-pharmd-ms/2016/09/ meperidine-friend-or-foe

effective concentrations,

1988;**39**(1):11-23

2017;**32**(4):320-328

2016;**6**(1):19-24

1987;**7**(2):116-117

**52**

[31] Mehta V, Langford R. Acute pain management in opioid dependent patients. Reviews in Pain. 2009;**3**(2):10-14

[32] Iocolano CF. Perioperative pain management in the chemically dependent patient. Journal of Perianesthesia Nursing. 2000;**15**(5): 329-344; quiz 344-7

[33] Smith JE, Rockett M, Creanor S, et al. PAin SoluTions In the Emergency Setting (PASTIES)—Patient controlled analgesia versus routine care in emergency department patients with non-traumatic abdominal pain: Randomised trial. British Medical Journal. 2015;**350**:h3147

[34] Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-Daspartate (NMDA) receptors in pain: A review. Anesthesia and Analgesia. 2003;**97**(4):1108-1116

[35] Burstal R, Danjoux G, Hayes C, Lantry G. PCA ketamine and morphine after abdominal hysterectomy. Anaesthesia and Intensive Care. 2001;**29**(3):246-251

[36] Reeves M, Lindholm DE, Myles PS, Fletcher H, Hunt JO. Adding ketamine to morphine for patient-controlled analgesia after major abdominal surgery: A double-blinded, randomized controlled trial. Anesthesia and Analgesia. 2001;**93**(1):116-120

[37] Striebel WH, Koenigs DI, Kramer JA. Intravenous clonidine fails to reduce postoperative meperidine requirements. Journal of Clinical Anesthesia. 1993;**5**(3):221-225

[38] Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia. 1999;**54**(2):146-165

[39] Lin TF, Yeh YC, Lin FS, et al. Effect of combining dexmedetomidine and morphine for intravenous patientcontrolled analgesia. British Journal of Anaesthesia. 2009;**102**(1):117-122

[40] Brown T, Shetty A, Zhao DF, Harvey N, Yu T, Murphy M. Association between pain control and patient satisfaction outcomes in the emergency department setting. Emergency Medicine Australasia. 2018;**30**(4):523-529

[41] Gonzalez ER, Bahal N, Hansen LA, et al. Intermittent injection vs patient-controlled analgesia for sickle cell crisis pain. Comparison in patients in the emergency department. Archives of Internal Medicine. 1991;**151**(7):1373-1378

[42] Evans E, Turley N, Robinson N, Clancy M. Randomised controlled trial of patient controlled analgesia compared with nurse delivered analgesia in an emergency department. Emergency Medicine Journal. 2005;**22**(1):25-29

[43] Melzer-Lange MD, Walsh-Kelly CM, Lea G, Hillery CA, Scott JP. Patientcontrolled analgesia for sickle cell pain crisis in a pediatric emergency department. Pediatric Emergency Care. 2004;**20**(1):2-4

[44] Rahman NH, DeSilva T. A randomized controlled trial of patientcontrolled analgesia compared with boluses of analgesia for the control of acute traumatic pain in the emergency department. The Journal of Emergency Medicine. 2012;**43**(6):951-957

[45] Birnbaum A, Schechter C, Tufaro V, Touger R, Gallagher EJ, Bijur P. Efficacy

of patient-controlled analgesia for patients with acute abdominal pain in the emergency department: A randomized trial. Academic Emergency Medicine. 2012;**19**(4):370-377

[46] Rahman NH, DeSilva T. The effectiveness of patient control analgesia in the treatment of acute traumatic pain in the emergency department: A randomized controlled trial. European Journal of Emergency Medicine. 2012;**19**(4):241-245

[47] Stacey BR, Rudy TE, Nelhaus D. Management of patient-controlled analgesia: A comparison of primary surgeons and a dedicated pain service. Anesthesia and Analgesia. 1997;**85**(1):130-134

[48] Chumbley GM, Hall GM, Salmon P. Patient-controlled analgesia: An assessment by 200 patients. Anaesthesia. 1998;**53**(3):216-221

[49] Pritchard C, Smith JE, Creanor S, et al. The cost-effectiveness of patientcontrolled analgesia vs. standard care in patients presenting to the Emergency Department in pain, who are subsequently admitted to hospital. Anaesthesia. 2017;**72**(8):953-960

[50] Chan VW, Chung F, McQuestion M, Gomez M. Impact of patientcontrolled analgesia on required nursing time and duration of postoperative recovery. Regional Anesthesia. 1995;**20**(6):506-514

**55**

Section 2

Chronic Pain: Advanced

Treatments

## Section 2
