Pain Management NUR.210 Chapter 11 PDF

Chapter 11 Pain Management INTRODUCTION Pain is a complex emotional and sensory experience shaped by biological, sociocultural, and psychological factors, including genetics, gender, health status, and life experience. Pain is also defined "unpleasant sensory and emotional experience associated w...

Chapter 11 Pain Management INTRODUCTION Pain is a complex emotional and sensory experience shaped by biological, sociocultural, and psychological factors, including genetics, gender, health status, and life experience. Pain is also defined "unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage." Assessment and treatment of pain is challenging: no one person experiences pain like any other, and the same person may experience pain in different ways, at different times, and under different circumstances. Although pain is the number one reason patients consult a healthcare provider in the United States, pain remains poorly understood, with mixed treatment success. For most patients in pain, a thorough assessment leads to the identification of the source of pain, a diagnosis, and successful treatment. For other patients, the source of their pain is difficult to determine, and a diagnosis is difficult to make. Treatments for many pain problems may bring little in the way of sustained relief or may create side effects that are challenging to manage. Pain disrupts quality of life and represents a significant public health problem. most people experience at least one episode of sustained and unrelieved pain in their lifetime. One in three patients presenting to an emergency department identifies pain as the chief complaint For the hospitalized patient, pain accompanies surgical treatment, traumatic injury, childbirth, and invasive procedures. Often, the medications and treatments given to treat disorders such as cancer and cardiovascular disease cause pain and disability that linger beyond the treatment period. Pain interferes with sleep, activity, and nutrition patterns, as well as relationships and social interactions. Pain contributes to a loss of independence and is frequently linked to the development of anxiety disorders and depression. Nearly 9 of 10 American households have one or more pain relief therapies in their homes, including over-the-counter (OTC) oral medications, analgesic heat rubs, and heating pads. More than 50% of these same households also have prescription pain medications, usually an opioid (opium-based medication used for pain), sharing the medicine cabinet with OTC medications. However, thousands of patients each year fail to satisfactorily manage pain, and the search for pain relief often finds providers who are not knowledgeable about pain management or are unwilling to treat pain that lasts for more than a short acute episode. Relatively few pain specialists are in practice, and they are often concentrated in city centers not easily accessible to rural populations. Health insurance may cover only a portion of the costs associated with comprehensive pain care. The American Pain Society, the American Nurses Association, and The Joint Commission all released standards of care requiring that patients be educated about their right to appropriate assessment and pain management, with a special emphasis on pain management in older adults and patients at the end of life. This emphasis on improved pain management did lead to innovations in pain treatment, including new classes of medications. Significant challenges continue with pain management, with many gaps in translating research findings into evidence-based pain management practice. Most significant is a fundamental shift in the assessment and management of pain that is less focused on relieving all pain and more focused on improving comfort and functional engagement DEFINITIONS OF PAIN \*\*\*\*\*\*\*\*\*\*\*Distinguishing Acute and Chronic Pain Of all the different ways to classify pain, the most common may be a distinction based on pain duration Acute pain is sudden in onset and usually of short duration, presenting immediately following noxious stimuli and tissue damage and continuing for several hours to several weeks. The close association between tissue injury and sudden onset of pain suggests acute pain serves a biological purpose, alerting us to actual or potential tissue damage and prompting withdrawal or avoidance behaviors. Patients frequently describe acute pain as sharp or intense and can generally pinpoint the pain to a well-defined and specific body location. Acute pain is generally responsive to common pain management treatments and predictably resolves as tissue heals. Pain that is present for more than 3 to 6 months, with or without an obvious link to tissue injury, is considered chronic pain. Chronic pain intensity can vary widely; patients describe pain that is achy, dull, stabbing, burning, and icy hot. Patients with chronic pain may also have difficulty localizing chronic pain with more precision than a general region of the body, such as the lower back or legs. Chronic pain is unpredictable in course and resistant to many common pain management approaches and, unlike acute pain, serves no apparent biological purpose. Examples of chronic pain include diabetic peripheral neuropathic pain (pain associated with damage or disease affecting the somatosensory nervous system), phantom limb pain following amputation, and fibromyalgia. Acute or chronic pain that responds to some therapeutic interventions but recurs when therapies reach the effective end of their dose is termed persistent pain. Examples of this type of pain include pain associated with wounds, arthritis, back pain, and some headaches. Although patients with persistent pain may have pain relief with medications, the application of heat, or the application of pressure at specific acupoints, these modalities have time-limited effectiveness, with pain returning as therapies "wear off." Persistent pain can be particularly frustrating for patients and caregivers because pain solutions appear to work, but there is not sustained pain relief. Breakthrough pain is a term used by pain experts without consensus to describe short-term bursts of acute pain that present against a background level of controlled or managed pain. Breakthrough pain can be caused by patient movements, by underlying or escalating pathology, or by being at or near the end of a medication dose. Frequently, breakthrough pain appears for unknown reasons but may be remedied by medication, dose, or schedule modification. Although chronic pain cannot always be linked to a specific tissue injury, some forms of chronic pain coexist with other health problems with enough frequency that a comorbid relationship between certain pathologies and chronic pain must be considered. In chronic malignant pain, for example, rapidly dividing cells associated with cancer growth invade and distort bone and other tissues, causing severe pain. More than two-thirds of cancer patients report moderate to severe pain during their illness, especially as cancer progresses or becomes unresponsive to therapy. For many cancer patients, fear of pain and fear of addiction secondary to pain treatment are almost as debilitating as fear of cancer and its consequences, in spite of evidence that fewer than 5% of cancer patients become addicted to aggressive and largely effective opioid therapy. Cancer is not the only chronic illness in which pain is a regular and constant presence. Most patients with chronic illness report moderate to severe pain, including patients with arthritis, sickle cell anemia, irritable bowel syndrome, fibromyalgia, and lupus erythematosus. Some patients with chronic illness report pain as their primary symptom, including patients with migraine or cluster headaches, chronic oral-facial pain, and postamputation pain. Referred to as nonmalignant or noncancer chronic pain, this type of pain inconsistently responds to common pain treatments, including anti-inflammatory medications and opioids, and is the least likely to be adequately managed, according to patients and pain experts. \*\*\*\*\*\*\*\*\*\*\*Distinguishing Nociceptive and Neuropathic Pain A second useful way to classify pain is by the point of origin. Pain originating in different tissues has unique biological features that shape both its presentation and its responsiveness to therapy. Nociceptive pain results from stimulation of peripheral nerve fibers by noxious stimuli or conditions in superficial skin and tissues, as well as bones, joints, and muscles, or in organs. Specialized receptors on peripheral nerves sense and respond to noxious mechanical stimuli, including pressure and pinprick, as well as to a range of potentially tissue-injuring cold and hot temperatures. Other specialized peripheral neuron receptors sense and respond to noxious chemical stimuli, including acidic or basic substances, as well as many locally released chemicals, including enzymes and growth factors. Nociceptive pain, when originating in superficial tissues, is termed cutaneous pain. Pain originating deeper in the joints, bones, and muscles is called somatic pain, whereas pain that has its origins in the organs is termed visceral pain (Table 11.2). Cutaneous pain tends to be sharp, with intensity varying from mild to severe. It is easily located to a well-defined area. Examples of cutaneous pain include superficial cuts and minor burns and the pain that accompanies some procedures, such as phlebotomy. Somatic pain tends to be dull, achy, and difficult to localize, although the intensity can also vary from mild to severe. Examples of somatic pain include pain associated with inflammatory diseases of the joints such as arthritis, overuse injuries involving the muscle following exercise, trauma, and degenerative diseases of the bone. Visceral pain can be sharp or dull but is relatively difficult to localize. It can begin in any of the large organs in the thoracic or abdominal cavity, although the pain sensation is often present in a location some distance away from the source organ. This is known as referred pain and occurs when nerve fibers from normally high-sensory areas (superficial tissues) and input from normally low-sensory areas (visceral organs) all converge at a similar level of the spinal cord (Fig. 11.2). When visceral organs generate strong pain signals, the brain is not used to processing pain messages from these sites and interprets this input as coming from more superficial sites. Referred pain can be diagnostic for serious disorders and should be evaluated thoroughly. For example, the nurse might recognize acute right shoulder pain referred from the gallbladder in the setting of acute cholecystitis. The most challenging type of pain to assess and manage follows damage or injury to nervous system structures. This neuropathic pain presents with a mixture of both positive and negative symptoms. Patients report shooting, stinging, or "pins and needles" in conjunction with areas lacking feeling or sensation. Peripherally generated neuropathic pain presents in the peripheral tissues but may represent injury or dysfunction anywhere along the nerve pathway that supports that region of the body. Patients with phantom limb pain who have experienced a limb loss often continue to perceive pain, itching, and numbness in the absent limb. The loss of the limb involves a transection through the nerves supplying that limb. These damaged nerves continue to transmit nociceptive messages, often in hyperexcited bursts, that can permanently alter how the brain and spinal cord process incoming and descending pain messages. Even as the brain can visually recognize the loss of the limb, the perception of pain in the missing limb remains. Other examples of peripherally generated neuropathic pain syndromes include diabetic and alcohol-induced neuropathy, chemotherapy-induced neuropathy, and postherpetic neuralgia. Centrally generated neuropathic pain has its origins in injuries to the spinal cord and brain structures. Damage to the nerve roots that enter the spinal cord, the cord itself, or anywhere along ascending or descending central nociceptive pathways disrupts normal pain processing. Some parts of the pain-processing pathways can become hyperactive while others can lose function. New abnormal synaptic connections can form, contributing to sensations of pain that may be felt anywhere in the body. In some primary neurological conditions, such as stroke, Parkinson's disease, or multiple sclerosis, damage to neurons, their supporting myelin, or the nourishing glial cells that surround the brain and spinal tissue also disrupt pain processing. One condition that has features associated with both peripherally generated and centrally generated neuropathic pain is fibromyalgia. Patients complain of pain and stiffness in muscle and joints often accompanied by cognitive dysfunction, fatigue, disturbed sleep, depression, and anxiety. Evidence suggests these symptoms are associated with abnormalities in the brain regions responsible for these body functions, as well as altered neuroendocrine functioning, and may follow either prolonged stress or emotional trauma. Neuropathic pain can last for months to years. The vagueness of complaints, frequently in the absence of diagnosable injury, leads patients on an often-frustrating search for solutions, with many health providers wondering about the truthfulness of patient reports. Some patients with neuropathic pain feel dismissed by their healthcare providers as having mental health concerns and not actual pain. New insights into the biology of pain processing are leading to the broader understanding that neuropathic pain is pathological pain; whether arising out of injury to central or peripheral nervous structures, neuropathic pain represents true dysfunction and disorder in the nervous system. PROCESSING PAIN MESSAGES The Processing of Pain Messages in Acute Pain The peripheral nerves that innervate peripheral tissues have several unique features that allow them to sense and transmit information rapidly across great distances on their way to the spinal cord and brain. Each nerve is composed of a bundle of single nerve fibers surrounded by connective tissue. Each nerve fiber is a long projecting axon for a single nerve cell or neuron leading to a cell body located near the entrance to the spinal cord. Some of these single projecting axons transmitting incoming sensory or afferent information, especially those innervating the distal extremities, can be several meters long. Along the dorsal side of the spinal cord, the cell bodies of these peripheral neurons are grouped in a nodular structure or ganglion called a dorsal root ganglion (DRG; Fig. 11.3A). Each DRG represents a large region of the body, and the chain of DRGs along the dorsal side of the spinal cord represents somatic regions, or dermatomes, on the body (Fig. 11.3B). Dorsal root ganglion neurons are specialized at their terminal ends, along their axons, and in their cell bodies to respond to different sensory stimuli. Some of these DRG neurons have large-diameter myelin-covered axons that are generally responsive to touch and proprioceptive input. Myelin is critical to nervous system functioning, serving as an insulating material that surrounds some nerve fibers to increase the speed at which electrical impulses move along the nerve fiber. Some smaller-diameter DRG neurons have thinly myelinated axons, unmyelinated axons, or free nerve endings that respond to non-noxious temperatures, as well as a wide range of noxious stimuli. Generally, nerve fibers with less myelin conduct sensory information more slowly than larger, fully myelinated fibers. Dorsal root ganglion neurons that selectively respond when stimuli become noxious or potentially injury inducing are called nociceptors. Some nociceptors are sensitive to tissue-injuring cold and hot temperatures, whereas other nociceptors are sensitive to mechanical pressure or pinprick. Still other nociceptors sense the presence of tissue-injuring chemical substances, including acids, bases, and specific injury-induced chemical substances released by the body. Peripheral nociceptive neurons have the ability to convert a cellular response to noxious stimulation into an electrochemical message that is rapidly transmitted to the spinal cord along afferent (sensory) nerve pathways. Once in the spinal cord, peripheral sensory fibers make connections with other specialized pain-processing neurons that then relay pain messages to the brainstem, the forebrain, and finally the cerebral cortex (Fig. 11.4). This structural organization serves to filter, interpret, and influence ascending pain messaging to the brain. It is in the cerebral cortex where these electrochemical nociceptive messages are cognitively interpreted as pain. The pain response is coordinated through many of these same brain and spinal cord structures along descending pain-messaging pathways. Acute pain is generally understood to be a product of this complex series of pain-processing steps. At every connection, or synapse, in the pain-processing system, there are important neurotransmitters that can either boost or inhibit the transmission of pain messages. In classic gate control theory, these neurotransmitters can either "open" or "close" the gate to the transmission of nociceptive information. Pain researchers have a better appreciation of how these neurochemicals either enhance or inhibit pain processing, but further research is needed to explain why patients experiencing similar injuries experience pain in very different ways. Some explanatory models for these individual differences explore the interplay between psychology and physiology, such as the impact of expectations or attention on pain perception and response. Patients may use a common language to describe their pain because of the specific pain pathways activated in specific types of injuries, but pain intensity varies widely from person to person. Clinicians must appreciate these individual differences and avoid bias during subjective pain assessment. \*\*\*\*\*\*\*\*\*\*\*\*Dysfunctional Pain Processing Is the Hallmark of Chronic Pain Evidence suggests that what happens at the beginning of an injury may well shape the pain experience in the long term. In the earliest stages of an injury, damaged cells release a wide range of chemicals, including histamine, bradykinin, and prostaglandins. Some of these locally released chemicals specifically activate local nociceptors to begin transmitting pain messages to the brain and spinal cord. Other locally released chemicals serve to stimulate the inflammatory response, attracting macrophages and other immune cells to begin the process of local tissue repair. Once attracted to the site of injury, activated immune cells in turn release pain-enhancing chemicals into the local injury environment. These pain-enhancing chemicals include cytokines and growth factors. The net result of this local inflammatory response is to increase the sensitivity of injured tissue to any further stimuli. This sensitization of peripheral tissues serves a protective function to try to minimize further tissue damage. For example, patients do not normally find their clothes painful to wear, but following sunburn, patients find that wearing clothes is very painful. This allodynia, or painful response to normally innocuous stimuli, causes patients to limit stimulation to their injured tissue, allowing it to heal more quickly. These same patients are also likely to experience hyperalgesia, an exaggerated response to already painful stimuli. Sunburned patients, for example, rapidly withdraw from a hot surface to protect their already injured tissue from further injury. Peripheral sensitization has the effect of increasing, prolonging, and amplifying the nociceptive messages that reach the spinal cord and brain, sensitizing these central nociceptive structures as well. Some sensitized spinal and brain nerve cells respond by releasing large amounts of pain-enhancing neurotransmitters, whereas other sensitized central nerve cells release large amounts of pain-inhibiting neurotransmitters. Sensitized nerve cells further respond to this increased neurotransmitter release by altering their synaptic relationships with adjacent nerve cells. Some synaptic connections weaken, some new synapses appear, and some abnormal synaptic connections form, changing the balance of excitation and inhibition in pain processing. Some researchers describe the formation of these abnormal or pathological connections as a form of "cellular memory" that explains why pain may linger after all objective measures indicate tissues have healed. This structural and functional reorganization of synapses is what allows nervous systems to respond to new experiences, including injury and disease; however, this synaptic flexibility feature, or plasticity, is also believed to be what contributes to the persistence and treatment resistance of many chronic pain conditions. There is still a great deal that is not known about how this synaptic reorganization occurs. Why, for example, do two people with similar injuries have different long-term pain experiences? One patient may have persistent pain that gradually resolves as the injury heals, whereas another patient goes on to develop debilitating chronic pain. Many chronic pain conditions have no clear-cut injury as a precipitating event, so it is not clear how or why chronic pain develops in such patients. \*\*\*\*\*\*\*\*\*\*\*\*FACTORS SHAPING THE PAIN EXPERIENCE Recent data demonstrate a complex interplay among biological, psychological, and social factors on individual differences in the experience of chronic pain. Some people seem to have a lower threshold for pain, whereas others appear to tolerate a great deal of pain in spite of common anatomy and physiology. Evidence suggests many factors shape the pain experience, including prior experience with pain, expectations of pain, and anxiety, as well as attention to and the situational meaning of that pain for that particular patient. A patient in labor, for example, may be able to endure quite a bit of pain knowing that at the end of this painful experience will be a new life. This same patient in labor, however, may find labor more painful in a subsequent delivery if they had a difficult delivery with a previous birth. The expectation of pain during phlebotomy is often enough to make this procedure quite painful for one person but not painful to another who is distracted and does not expect the procedure. Patients are naturally apprehensive before surgery, but evidence suggests that patients with higher anxiety use more pain medications in the postoperative period. Patients who receive preoperative education about what to expect and reassurances about postoperative pain medication report less preoperative anxiety and use less postoperative pain medications. Patients who normally describe themselves as having a high tolerance for pain find their tolerance influenced by fatigue, nausea, and their ability to cope in the moment. Past history of physical or sexual abuse is associated with increased reports of pain. Environmental factors, such as ambient temperature, humidity, light, and noise, and the presence of other people shape the pain experience. \*\*\*\*\*\*\*\*\*\*\*\*\*Sociocultural Determinants of Pain One of the most powerful influences on the pain experience is the patient's cultural experience. Social mores and customs shape families, the communities of residence, and the larger culture, just as the larger culture, communities, and families shape biology and behavior. People learn how to respond to pain in subtle and obvious ways. In some families, stoicism is valued, whereas in other families, it is acceptable to more demonstrably display pain. Depending on how health and illness are defined within a community, pain may mean different things. A patient's cultural experience may lead to increased faith in Western medicine to diagnose and treat pain, whereas another patient's experiences may reinforce non-Western approaches to managing pain. Limited access to healthcare resources may inspire creative and folk solutions to pain that continue even when access to healthcare is ensured. Evidence suggests that pain assessment and pain management are likely to qualitatively improve pain diagnosis and pain relief when patients and caregivers share a common ethnicity or cultural perspectives. When the cultural background of the caregiver differs from that of the patient, caregivers are more likely to misread or misjudge the intensity and severity of pain. Language barriers between patient and healthcare providers serve to exacerbate cultural differences. Although educational programs for health professionals attempt to infuse cultural sensitivity into standards and practice, most cultural effectiveness is often and inconsistently gained through trial-and-error learning in actual practice. Nurses need to be aware that language and culture shape the pain experience and should incorporate culturally specific and validated assessment tools and population- or pain-specific dosing guidelines into the standards of care. \*\*\*\*\*\*\*\*\*\*\*\*The Influence of Sex and Genetics The term sex refers to purely biological differences between males and females. The term gender encompasses the larger psycho-social-cultural context associated with being masculine or feminine. As such, differences between male and female patients may represent clearly distinct molecular and neurohormonal pain mechanisms, whereas gender differences may reflect the influence of a wide range of cognitive, affective, and sociocultural factors. Modeled and learned behaviors, life history, and factors other than biological differences may influence both pain processing and the pain experience. Gender-role expectations, for example, may discourage men from reporting pain or even seeking regular medical care. On the other hand, women are statistically more likely to have an ongoing relationship with a healthcare professional and may feel freer to report painful symptoms, even as evidence suggests that healthcare professionals may not recognize gender differences in pain presentation or may not take pain complaints from women as seriously as complaints presented by men. In children as young as 5 or 6, masculine and feminine social stereotypes appear to manifest, with boys more likely to say they do not pay attention to pain, whereas girls are more comfortable discussing their pain. There is also evidence to suggest that women in pain utilize a broader range of coping skills than do men, including how they self-medicate, employ palliative behaviors, and use social supports. \*\*\*\*\*\*\*\*\*\*\*\*\*\*Sex differences in pain sensitivities and the pain experience are both clinically and experimentally observed in humans. Inflammatory arthritis, irritable bowel syndrome, and neuropathic pain, for example, are among many pain conditions more prevalent among female patients. Cluster headaches, as well as some muscle and visceral pain syndromes, are more prevalent among male patients (Table 11.3). Prominent meta-analyses of human pain studies found sex-related differences in the majority of selected studies, with evidence suggesting female individuals have lower thresholds for pain, rate noxious stimuli as more painful, and have a lower tolerance for intense pain than do male individuals. Sex-related differences in both clinical and experimental pain generally do not present until after the age of puberty, suggesting a prominent role for sex-linked hormones. Female patients generally report more pain sensitivity to acute pain during all phases of their menstruating adult lives than do postpubescent male patients, although these differences in pain sensitivity seem to lessen after female menopause. Sex and gender differences have also been noted in response to analgesics. Several studies of hospitalized postoperative patients using patient-controlled analgesia (PCA) found that male patients required higher opioid doses to achieve pain relief than did female patients. PCA technology delivers a constant low level of background opioid dose that is supplemented by patients choosing to bolus deliver additional opioids, within preset dosing programming. It is not clear whether this difference in therapeutic response represents sex-influenced differences in opioid metabolism alone, is a manifestation of a larger gender influence on threshold and self-management strategies, or both. Nonopioid analgesia use differs as well, with men reporting more analgesic relief with ibuprofen (Motrin), one of many NSAID compounds. That women can be simultaneously more sensitive to pain and more responsive to most analgesics suggests a number of mechanistic questions about pain that remain underexplored. Few pain disorders feature true inherited dominant or recessive genes, although there are rare sensory and autonomic neuropathies that pass generation to generation, as well as some familial migraine disorders. Case-controlled association studies of unrelated individuals, however, identify thousands of possible genetic variations between individuals that can influence pain thresholds, tolerance, and response to analgesics. Some of these genetic variants might cause a protein to be malformed or to be produced in excess quantities or even result in a critical protein not being produced at all. For example, genes that regulate the production of several inflammatory cytokines, including interleukin-6, interleukin-1, and interleukin-10, vary extensively between people, suggesting differences in how an inflammatory response can shape the pain experience. Genes that play a role in how nerve cells form connections or synapses with adjacent nerve cells also vary widely between people, suggesting that how a nervous system sensitized by injury structurally and functionally restructures synapses may influence who may develop chronic pain. Genes also shape the pharmacodynamics and pharmacokinetics of medication, increasing the likelihood of toxic effects or altering the body's ability to resolve pain. Gene differences in medication metabolism, for example, can vary across sexes, across ethnic groups, and within ethnic groups depending on geography. Genes responsible for some enzymes in medication metabolism pathways, for example, appear in less than 5% of people of Northern European descent and in less than 1% of people from southern Asia but in more than 25% of people of African descent. Understanding how individual genetic differences contribute to pain processing, pain perception, and pain relief is a major research goal, with the promise of targeted or individually designed pain treatments. \*\*\*\*\*\*\*\*\*\*Epigenetics and Pain Cells, particularly neurons, have evolved considerable ability to respond to both external and internal stressors. One critical evolutionary process involves how cells control access to DNA to shape a dynamic cellular response independent from any change in the basic nucleotide sequence of inherited DNA. Epigenetics refers to the cellular processes that allow access to the cell's DNA for transcription, regulation, and production of proteins critical to cell function. Compacting the nearly 2 meters of chromosomal DNA into the relatively small cell nucleus while allowing access for transcription and gene expression requires highly coordinated packaging processes that serve to temporally and functionally control access to DNA throughout the cell cycle. Histones are the chief compacting proteins within the nucleus, forming tight covalent bonds along the DNA backbone that essentially spool the DNA around the histone. The new histone--DNA spool, chromatin, organizes as repeating functional groupings of spooled DNA in a "bead on a string" formation, which can either open or restrict transcriptional access to the DNA as needed to shape a cell's response. It is this functional regulation of gene expression through dynamic remodeling and modification to chromatin that defines epigenetics. For example, the local changes around a cell that result from tissue injury release cellular contents such as histamine into the local tissue environment. This external stress to the cell alters signaling between and within cells that prompts chromatin to unspool a region of DNA, allowing transcription, replication, and the production of anti-inflammatory cytokines and glucocorticoids to respond to the local injury. This access to the DNA, however, is transient and often short-lived, with respooling of the DNA and tightening up of the chromatin access to DNA when no longer needed. Chromatin remodeling processes result from the addition or removal of chemical groups, either to the histone molecule or the DNA molecule, within the chromatin complex. The addition of a methyl group, for example, is called methylation, and the addition of an acetyl group or phosphate group is called acetylation and phosphorylation, respectively. The orchestrated formation and disruption of chromatin that controls transcription also include ways to rapidly and dynamically demethylate and deacetylate protein structures, or remove phosphate groups, as well as recruit a wide range of other modifier proteins in the cell to shape a cellular response. These epigenetic processes have become increasingly important to the evolving science of pain management, representing new targets for pain medications and altering the way injury is managed from moment to moment. Two of the most therapeutically intriguing insights arising from epigenetics research are suggestions that epigenetic mechanisms play a critical role in the transition from acute to chronic pain and that a wide range of environmental factors across the life span serve as epigenetic primers for individual pain and analgesic response. Evidence suggests that more than 1,000 genes in spinal cord neurons are epigenetically regulated within the first minutes to hours following a peripheral nerve injury. Often, these early modifications are followed by more sustained epigenetic processes shaping synaptic connectivity and are implicated in the formation of long-term pathological pain. Sustained DNA methylation, for example, has been linked to accelerated degeneration of vertebral disks in low-back pain in both animal models and human subjects. Sustained histone deacetylation has been identified as a factor driving long-lived neuropathic pain and decreased responsiveness to morphine analgesia. There is also compelling evidence that pain in the neonate, like that experienced by babies in the neonatal intensive care unit (NICU), epigenetically primes the nervous system, creating conditions that support the development of chronic pain later in life. New medications in development that target epigenetic processes include histone deacetylation inhibitors (HDAC inhibitors) that inhibit the removal of acetyl groups to stabilize DNA access and improve anti-inflammatory responses. Surgeons and anesthesiologists now recognize the preoperative, intraoperative, and postoperative periods as a very active time of epigenetic activity with the potential for shaping surgical outcomes. The promise in epigenetics lies in identifying the temporal ordering of chromatin remodeling changes linked to pathology, then therapeutically leveraging the transient and often reversible nature of epigenetic processes to interrupt or otherwise influence a health outcome. \*\*\*\*\*\*\*\*\*\*\*Pain and Older Adults As the proportion of the population over 65 years of age grows, healthcare providers are challenged to assess and manage pain in an increasingly older population of patients. The pain assessment tools used in most healthcare settings were developed and tested with younger adults and may lack reliability and validity as pain measures in older adults. For example, evidence suggests that verbal descriptor scales and numerical rating scales become more difficult to use as patients age, with a higher frequency of incomplete or unscored responses. The evidence further suggests that older patients who are not acculturated to visual analog scales or numerical rating scales in their formal education or who may have mild to moderate cognitive problems demonstrate problems reporting their pain using tools that require a level of abstract reasoning. Some older patients with pain reluctantly report pain, feeling as if pain is to be expected and normal or out of fear that pain signals pathology, leading to a diagnostic process that itself may be painful. The evidence is mixed on the prevalence of pain and pain patterns in older patients. Some studies report that migraine headaches and low-back pain peak in middle age and decrease as patients age. Other studies report an increased incidence in all types of persistent pain, generalized musculoskeletal pain, and fibromyalgia in older patients. More than half of older patients report mild to moderate intermittent pain as they age, with the incidence of all types of pain more common in older adults in long-term care facilities. Many of these studies date from the late 1980s and early 1990s, and relevant new research is needed to quantify pain experiences as patients age. There is no reason to expect that all types of pain will vary the same way as a function of age given that different pain mechanisms are responsible for different types of pain. The differences between older and younger adults are most apparent in acute pain, especially acute pain associated with specific injuries or infections. Conditions that are painful in younger adults, such as urinary tract infections or duodenal ulcers, are likely to manifest as subtle behavioral changes in an older adult, including confusion, aggression, restlessness, or a loss of appetite. The pathophysiological reason for this more subtle clinical presentation is not clear. It is theorized that age-related changes in these target organs or in pain-processing structures in the spinal cord and brain lead to an altered neurochemical response from sensitized nerve cells, changing the way nerve cells form synaptic connections. Instead of pain messages moving along established pain pathways, new synaptic connections are made that divert pain messages to other brain regions. Other types of visceral pain have an atypical presentation in older adults as well, with as many as 30% of adults reporting either no pain with myocardial infarction or referral patterns different from those of younger patients with myocardial pain. Similar atypical presentations are reported for older patients with pancreatitis and appendicitis. Older postoperative patients do, however, report more unrelieved pain, use analgesic agents longer than younger adults, and are more likely to have pain slow their surgical recovery. Inadequate pain control in older adults is associated with greater levels of postoperative confusion, depression of immune and respiratory systems, and increased mortality. Although evidence suggests that common pain treatments, including NSAIDs and opioids, are effective in managing pain in older adults, doses often need to be modified because of age-related changes in medication metabolism. Standard dosing may lead to more toxic side effects, whereas reduced dosages provide effective analgesia. \*\*\*\*\*\*\*\*\*\*\*\*\*\*\*COMPREHENSIVE ASSESSMENT STRATEGIES FOR ACUTE AND CHRONIC PAIN In early 1999, the Veterans Health Administration (VHA) began a system-wide initiative to improve pain management for the nearly 3.5 million veterans cared for nationwide. This VHA program, called "Pain as the 5th Vital Sign," requires measurement and documentation of patients' self-report of pain using a numeric rating scale for all clinical encounters. The American Pain Society soon championed this relatively straightforward way to improve pain management, believing the inclusion of pain assessment when assessing blood pressure, pulse, and respirations would give pain assessment clinical priority. This now familiar and widely accepted approach in most clinical settings asks patients to self-report their pain on a standardized 10-integer verbal or visual analog scale, with 0 representing no pain and 10 representing the worst possible pain. Visual scales are available for patients to use to assist in the communication of their pain score. Pain scores of 4 or higher require a clinician response, including a more comprehensive pain assessment and timely intervention. In the years since this initiative was launched, evidence suggests that the widespread use of numerical rating scales has improved awareness of the importance of pain assessment but has not always translated to improved pain management outcomes for patients. One of the big challenges in using a numeric rating scale is that this asks patients to measure their pain only on the single dimension of intensity and does not allow for a more nuanced self-report. A second challenge to using single-dimension tools such as numeric rating scales is that such tools are not designed to measure the mixed pain that most patients actually experience. As this new decade in pain science is entered, there is a realization that this single-dimension pain scale has likely contributed to patients and caregivers believing the best pain score to have is 0. Pain specialists implicate the 0-to-10 pain-rating system as contributing to both the overprescribing of opioids and the larger opioid misuse epidemic. A new consensus is developing that measuring intensity is only one way to assess pain and analgesia response and that the most effective pain assessment approach is to assess across multiple dimensions of the pain experience. \*\*\*\*\*\*\*\*\*\*\*\*\*Measuring Pain Intensity The most commonly used pain assessment tools provide valuable and useful information to clinicians about pain intensity. When serially administered over the course of hours to days, these tools reliably measure pain levels in a single patient, allowing staff to implement pain management strategies and measure treatment response. Examples of unidimensional assessment tools include numeric rating scales, verbal rating scales, and visual analog scales. Verbal rating scales ask patients to rate their pain by looking at a list of descriptive words ordered from least to most intense (no pain, mild, moderate, and severe). Patients then select the one word that best describes their pain, with the evaluator assigning a point value that corresponds to the descriptor (no pain = 0, severe = 3). Visual analog scales are structured with a 10-cm horizontal or vertical line with labeled endpoints. One end of the scale is marked "no pain," and the other end is marked "worst pain ever" or uses a similar phrase to indicate intense pain. Patients place a mark on the line to indicate their level of current pain or indicate their pain by moving a sliding indicator, with the evaluator measuring the distance in centimeters from the low end of the scale as a numerical index of pain intensity. Often the patient is asked to evaluate the pain on not just one visual analog scale but several similarly constructed scales to assess different dimensions of pain besides intensity. Some of these other dimensions of pain include how disturbing or unpleasant the pain is, how close to the surface or how deep the pain is, and how disruptive the pain is to activities of daily living. These tools are reliable for measuring many types of acute pain, with evidence suggesting verbal rating scales are more effective with older people than the more common numeric rating scales (Fig. 11.5). All of these unidimensional measures of pain are sensitive to measuring treatment response to both pharmacological and nonpharmacological interventions for many forms of acute pain, including burns, postoperative pain, and chronic noncancer pain. Although evidence suggests unidimensional scales may be less effective as measures of chronic pain or mixed acute and chronic pain, there is a clinical preference for numeric rating scales. Most clinicians find them easy to explain and relatively quick to administer; patients also find they are minimally intrusive and conceptually simple to understand. Visual analog scales can be more difficult to administer in many clinical settings, requiring preprinted forms and writing implements as well as a patient whose vision and hearing are largely intact so that instructions are understood and followed. Patients with motor or physical impairments also have difficulty using visual analog scales. Some of these barriers to using visual analog scales were addressed with the introduction of the visual analog thermometer (Fig. 11.6). Another useful approach to visual analog measures is to use cartoon faces expressing degrees of discomfort, unhappiness, and pain. Explanations are provided that direct the patient to choose the facial image that best describes how they are feeling, with each face associated with a specific score for quantification. Examples include the Wong-Baker FACES tool geared mostly to preverbal populations, such as children, and the FACES pain scale used with older adults with expressive aphasia. Such tools have not been found to be an effective assessment tool for patients with cognitive impairments or to bridge language and cultural differences. Patients from different ethnic backgrounds or who speak languages other than English may not understand or may not view the facial imagery in a qualitatively useful way for assessment. Barriers to effective use of numerical rating scales, verbal rating scales, and visual analog scales include clinicians who doubt the accuracy of self-report. Some clinicians believe that including a subjective numerical assessment of pain at the same time objective data such as blood pressure and heart rate are collected overstates the qualitative usefulness of pain assessment information, especially because this measures only a single dimension of pain. Often these doubts about the accuracy of self-reports arise from the failure of unidimensional measures to support assessment and effective pain management in complex pain situations, such as in patients with chronic pain or addictions or at the end of life. Although pain intensity is an important aspect of the pain experience, it is not the only dimension of pain important to patients and therefore should not be the only dimension of pain important to clinicians. \*\*\*\*\*\*\*\*\*\*\*\*\*\*The Focused Pain Assessment OPQRST-AAA One critical aspect of pain assessment that is underemphasized in most healthcare settings relying on unidimensional measures of pain is the follow-up required to make effective use of this screening measure. Although these tools often advise intervention at pain levels 4 and above, these tools are not designed to recommend specific pain measures. Clinicians have a range of therapeutic options available to them and require more information to appropriately evaluate clinical manifestations and choose an intervention. OPQRST-AAA is a useful mnemonic to use to evaluate pain symptoms, with each letter representing an important area of assessment. O: Onset of pain. When the pain first begins is critical to understanding whether the pain is more acute or chronic in nature. Ask patients to describe what they were doing when the pain first started and whether the pain onset was sudden, gradual, or ongoing. Follow-up questions include "What do you believe is causing this pain?" P: Provocation. External factors such as movement and clinician examination can elicit a pain response. Ask the patient whether any specific factor, such as turning in bed, sitting, or walking, makes the pain worse. Q: Quality of pain. Descriptive words or phrases, such as sharp, dull, stabbing, burning, or crushing, can give clinicians insight into the pain experience for patients. Open-ended questions such as "Can you describe your pain to me?" can be particularly effective at drawing out pain descriptors. In an urgent situation, leading questions such as "Is your pain sharp or stabbing?" can generate specific and immediate assessment information. R: Region and radiation. The location of the pain and whether it radiates or moves to other body areas can be diagnostically significant, especially for deep somatic and visceral pain. Ask patients to point to areas on their body where they feel the pain. Sometimes it can be helpful to ask patients if they can trace the borders of their pain to help localize the extent of the pain. S: Severity of pain. The terms severity and intensity are often used interchangeably and generally mean the degree of discomfort associated with pain. Numerical rating scales are often used to gauge patient perception of pain intensity. Frequently, patients use this opportunity to compare this pain to a pain they experienced previously, as in "This is much worse than when I broke my arm" or "This is worse than childbirth." Patients also describe their pain in terms of how it limits their activities, such as "I cannot sleep" or "I cannot sit for long periods." These are important subjective comments that are worth noting in an assessment summary. T: Time and duration. As with onset of pain, the length of time a patient reports pain is diagnostically significant. Ask patients how long the pain condition they are experiencing has been going on and whether it has happened before. Follow-up questions include whether the pain condition has changed for the better or worse since they first had the pain. AAA: Aggravating/Alleviating factors and Associated clinical manifestations. Ask patients if there is anything they do that makes the pain better or worse. Sometimes focused questions will help them reflect, for example, "If you change your position, does this make the pain better?" or "Does sitting up help you feel better?" Follow-up questions include "Have you taken any medications that help you feel better?" or "Did you use a heating pad or put an ice pack on the area, and did it make it feel better or worse?" and "Do you have any other symptoms such as nausea, sweating, or odd sensations you can describe?" A brief interview using the OPQRST-AAA mnemonic can be conducted in less than 5 minutes and can occur simultaneously with other assessment activities. The information gained through this structured questioning approach clarifies the nature of the pain experienced by the patient and informs the clinician's review and selection of effective therapeutic interventions. Other approaches to more comprehensive pain assessment include using assessment tools that ask the patient to evaluate pain on several dimensions, including the functional impact of pain. Examples of this more comprehensive tool include the McGill Pain Inventory and the Multidimensional Pain Inventory. The use of such structured tools to assess dimensions of pain beyond intensity with structured OPQRST-AAA interviewing techniques yields more complete pain assessments to guide diagnoses and treatment decisions. \*\*\*\*\*\*\*\*\*\*\*\*\*Physical Examination There are many situations when a screening tool or serial measure, such as a numerical rating scale or the OPQRST-AAA mnemonic, yields insufficient information to support the diagnosis and management of pain. For example, some patients may not be able to verbally measure or communicate their pain. Other patients present with complex pain conditions that are not easily measured using unidimensional scales or qualified solely through subjective answers to structured interview questions. Selected physical assessment techniques tailored to the pain complaint in conjunction with observational pain assessment tools can support bedside diagnosis to help clinicians choose appropriate therapeutic interventions. The most useful of these techniques for bedside clinicians may be palpation and assessment of range of motion (ROM). Muscle groups in the area of the pain should be palpated, and both verbal and nonverbal response to this palpation should be recorded. Clinicians should also record responses to any assessments of joint flexion, extension, side bending, and extremity lifting to determine whether pain is experienced with movement or whether there are any functional limitations. Consultation with members of the health team may lead to more extensive bedside testing, including a tailored neurological examination consisting of cranial nerve assessments and sensory testing of sensitivity to light touch, pressure, and pinprick, as well as reflexes. A more extensive assessment of motor function may include tests for motor weakness, coordination, balance, and loss of endurance. Many acute care settings provide comprehensive pain teams composed of physicians, nurse specialists, physical therapists, pharmacists, and social workers. These comprehensive pain teams should be consulted early in the presence of complex pain for the best clinical outcomes. \*\*\*\*\*\*\*\*\*\*\*\*\*NURSING MANAGEMENT OF PAIN Patient and Nurse: The Therapeutic Partnership Pain is so common to the patient experience that intervening to improve comfort and reduce suffering is central to the practice of nursing. When patients present with pain, it is frequently a nurse who first assesses the clinical presentation. It is also nurses who are often first to propose a remedy and to encourage self-management strategies. However, it is the critical role nurses play in understanding the larger context and impact of clinical manifestations, such as pain, that is at the core of what nurses are and what nurses do. Although nurses, physicians, and other health team members work collaboratively to diagnose and treat health problems, it is nurses who are charged with recognizing the physiological and psychosocial responses to health problems that symptoms represent. Nurses are also charged with developing and implementing a comprehensive plan to address symptoms and the impact of those symptoms. Effective interventions begin with comprehensive assessments of clinical manifestations of pain as well as functional health patterns. Specific tools or inventory forms are regularly used to collect initial or baseline data that establish physiological stability, the risk for physiological instability, and patient habits and routines. This data-collection step is critical to beginning to narrow down the range of risk for nursing diagnoses, identifying actual nursing diagnoses, and determining collaborative care problems with other disciplines. Although relatively few questions on most baseline assessment forms directly ask patients about their pain, in fact, most questions on comprehensive assessments are gathering pain-related information useful to planning effective interventions. Questions that ask patients how they perceive their health and well-being or that assess their knowledge of health practices add context to questions and answers about self-management of pain and adherence to prescribed treatment. Questions that determine usual patterns of food and fluid intake, as well as appetite and food preferences, add perspective to objective data gathered about weight lost or gained. In similar ways, questions that determine activity and exercise patterns, sleep--rest patterns, role and relationship patterns, and coping and stress tolerance patterns help nurses understand the larger impact of symptoms such as pain. This subjective portrait of a patient's health status is combined with physical assessment findings and other objective data to drive the identification of priority nursing diagnoses and a comprehensive plan of care. \*\*\*\*\*\*\*\*\*\*\*\*\*The Care-Planning Process for Managing Acute and Chronic Pain The reasoning process that guides the nurse from data collection to nursing diagnoses begins with listing individual signs, symptoms, and health needs. Next, the nurse evaluates the significance of individual pieces of data, sorting them into significance clusters or diagnostic cues. These diagnostic cues help nurses formulate diagnostic hypotheses. Diagnostic hypotheses represent inferences or tentative explanations for specific pieces or clusters of data cues that require further investigation. To confirm a diagnostic hypothesis, nurses may need to validate the accuracy and reliability of key pieces of data, distinguish normal from abnormal findings, and recognize inconsistencies and possible information gaps. Nurses, for example, may need to recheck a blood pressure or follow up a patient interview with a corroborative family interview. \*\*\*\*\*\*\*\*\*\*Nursing Diagnoses for Patients in Pain The thinking language nurses use to organize and focus nursing care is the nursing process, organized around prioritized nursing diagnoses. A well-developed and well-constructed nursing diagnosis defines and shapes problem solving. When nurses identify a problem such as anxiety, insomnia, or delayed surgical recovery, they are choosing a diagnostic label that represents their reasoned conclusions arising out of data collection and data validation. This same process of reasoned evaluation of assessment data leads to the identification of related factors that have either caused or contributed to the identified health problem. The value of diagnostic labels and the identification of related factors are often underappreciated. Not only do diagnostic labels focus nursing attention on prioritized care problems and define patient goals in the care-planning process, but the identification of related factors also guides critical interventions. It may seem self-evident that the grimacing postoperative patient reporting a variable 2/10 to 9/10 level in their pain should be diagnosed as being in acute pain, with the care goal being improved patient comfort. However, if this same patient is also breathing shallowly, guarding with incisional pain, and presenting with a decreased oxygen saturation level even on supplemental oxygen, the diagnostic label of ineffective respiratory function represents a more completely reasoned evaluation of a comprehensive assessment. Rather than being the primary problem, in this circumstance the acute pain the patient is experiencing is part of the related factors that are shaping the larger diagnosis of ineffective respiratory function. The nursing plan of care would include management of pain in either diagnosis. However, the nursing goal for this patient is not necessarily to improve comfort; rather, it is to improve respiratory functioning and gas exchange. Nurses who too narrowly diagnose either acute or chronic pain for their patients in pain run the risk of missing priority care problems by failing to acknowledge the significant impact pain has on life and health, as well as the risk of not choosing an intervention appropriate to meeting the larger care priority. A refocus on understanding how to optimize and improve system functioning also has the benefit of increasing reliance on a broader range of pain management options, lessening overuse of pharmacological remedies, and reframing patient expectancy on improving comfort and not total pain relief. For patients in pain, the impact is far ranging. The activation of pain-processing networks in the brain and spinal cord engages hormonal responses and stimulates sympathetic and parasympathetic nervous system responses. Elevations of heart rate and blood pressure may be seen as a result of pain, which can exacerbate preexisting health conditions such as heart failure or kidney impairment. Pain may limit the ability of someone to work or engage in previously enjoyable social situations. Pain may limit partner intimacy and alter interpersonal relationships. Pain may cause patients to question their beliefs, their values, and their self-worth. Pain may disrupt sleep or affect a patient's appetite. Pain medications may alter elimination patterns or compromise the physiological integrity of vital organs such as the liver or kidney. In order to develop a comprehensive plan of care for the patient in pain, it is critical to once again review how clinical manifestations affect functional health patterns. Many site-based comprehensive assessment forms use some organizing framework to understand the impact that the clinical presentation has on the well-being of the patient and the patient's family unit. This wide-ranging impact is reflected in the diversity of diagnostic labels that can focus nursing diagnoses for patients who are in pain (Box 11.1). Identifying which diagnostic label best defines the patient's priority nursing problems rests with the reasoned interpretation of data cues, including the patient's subjective report of problem urgency, as well as clinician interpretation of physiological stability. So not only must the diagnostic label be appropriately identified for each patient, but a focused nursing diagnosis must also identify the correct etiology (or "related to factors" that are part of the diagnostic statement), or nurses run the risk of not intervening appropriately or wasting both nursing time and resources on ineffective interventions. \*\*\*\*\*\*\*\*\*\*Measuring the Effectiveness of Care Although data gathered through physical assessment, review of critical laboratory values, and structured questioning provide the evidence necessary to support the diagnostic labels that focus problem solving, this same evidence is used to measure both the success of nursing interventions and, ultimately, problem resolution. The nurse must provide both targeted pain medications and non--medication-based therapies designed to address the pain, such as thoughtful positioning and appropriately resourced assisted ambulation that promotes effective pulmonary hygiene. Organizing physical activity in the daytime combined with clustered nursing activities at night is an intervention designed to promote sleep and rest. When these care organizing strategies are combined with thoughtful use of massage and relaxation techniques, as well as pharmacologically appropriate medications to promote pain and sleep, nurses increase the likelihood that patients sleep more regularly and restfully. The success of nursing interventions and focused problem solving can be measured both by observational reports from night staff about the length of sleep periods overnight and by subjective reports from the patient about the quality of that sleep. \*\*\*\*\*\*\*\*\*\*\*\*\*Monitoring the Risks and Benefits of Nonopioid Analgesic Use The broad benefits associated with nonopioid use need to be balanced with the risks associated with these therapies, including the risks associated with the mechanism of action and with the mechanisms of metabolic clearance. Aspirin, in addition to effects on prostaglandin synthesis, inhibits platelet aggregation, thus its secondary use for cardiovascular prophylaxis in patients at high risk for myocardial infarction or cerebrovascular accident (stroke). The reduced ability for platelets to aggregate following aspirin intake increases the risk for bleeding from wounds, incisions, and even minor cuts or scrapes. Patients taking aspirin as well as other anti-inflammatory medications, including most NSAIDs, are also at increased risk for thrombocytopenia (low platelet count). This side effect is not well understood, but the relationship between medication intake and the onset of reduced platelet counts suggests that thrombocytopenia may result from an immune response to these medications in patients with a heightened systemic inflammatory response following injury. A drop in platelet counts can occur fairly quickly and is likely to reoccur with subsequent use of the medication. Cyclooxygenase (COX) is an enzyme critical in the synthesis of prostaglandin. Aspirin and most NSAIDs interfere with prostaglandin synthesis by COX inhibition. There are two major COX isoenzyme variations, COX-1 and COX-2. These COX isoenzymes have similar functions, but inhibition of different COX isoenzymes has a different physiological effect and presents different side effects (or risk profiles). Cyclooxygenase-1 isoenzymes are present in every cell type throughout the body. Their role in producing nearly constant levels of prostaglandins and related molecules helps maintain physiological homeostasis in many organs, including the lungs, kidneys, and stomach. Inhibition of COX-1 by NSAIDs is particularly harmful to the gastrointestinal tract, disrupting the protective lining of the stomach and increasing the risk for gastrointestinal ulcers and bleeding even at recommended dosages and with short-term use. Inhibition of prostaglandin synthesis can also compromise uterine wall integrity, and for this reason, NSAIDs are discouraged in the third trimester of pregnancy to minimize the risk for premature labor. Cyclooxygenase-2 isoenzymes are produced only by activated immune cells, including macrophages. The anti-inflammatory and antipyretic effects of aspirin and NSAIDs are believed to be largely associated with COX-2 inhibition. To address the risk associated with COX inhibition, several NSAID compounds have been developed that leave COX-1 enzyme function intact but selectively block COX-2. These compounds, including celecoxib (Celebrex), have limited benefit for managing acute pain because of their slow absorption and slow elimination, but they are effective at managing chronic osteoarthritis pain. Acetaminophen has a similar analgesia effect as aspirin, although acetaminophen has few anti-inflammatory effects. Acetaminophen is believed to also activate one of the body's own natural pain-inhibiting neurochemical systems in the peripheral and central nervous systems, the cannabinoid system, to inhibit pain processing and minimize structural and functional reorganizing of central pain-processing synapses. Acetaminophen also inhibits COX, with specific selectivity for COX-2, but has few if any anti-inflammatory effects. Acetaminophen is metabolized in the liver and excreted in the kidneys. When used at therapeutic dose limits of 1,000 mg per single dose and 3,000 mg in 24 hours, acetaminophen is generally safe for use in patients with healthy livers. Doses need to be adjusted for patients with liver impairments or not used at all. Extra precautions need to be taken to educate patients about taking OTC acetaminophen with any other OTC or prescription products. Patients may not be aware, for example, that OTC cold preparations and prescription pain medications, such as Tylox and Vicodin, also contain acetaminophen. The risk of accidental overdose leading to liver failure has been associated with cumulative acetaminophen doses of greater than 3,000 mg per day. Significant drug--drug interactions are also noted in patients taking nonopioid analgesics and prescription medications (Table 11.5). Because many of the nonopioids, including aspirin, acetaminophen, and NSAIDs, are OTC, patients may self-treat minor aches and pains but not appreciate the interaction effects with other common prescription medications, including insulins, antihypertensive medications, and diuretics. \*\*\*\*\*\*\*\*\*\*\*\*\*Corticosteroids Corticosteroids are naturally occurring steroid hormones produced in the adrenal cortex. These steroids are involved with the body's stress response to illness and injury and play a role in the body's immune response and inflammation. Synthetic steroid hormones, such as prednisone (Deltasone) and hydrocortisone (Cortef), are used as anti-inflammatory agents to treat arthritis, bone pain, and painful dermatitis, as well as visceral pain conditions, including lupus erythematosus, sarcoidosis, and inflammatory bowel disease. They are also successfully used to treat acute inflammation and pain following nerve and spinal cord injuries and are used as adjuvant (increasing effectiveness of other medications) therapy for pain control in cancer patients. Corticosteroids work by blocking the synthesis of pro-inflammatory molecules, such as prostaglandin and leukotrienes. Corticosteroids can be delivered at low doses in topical creams, ointments, and drops. Higher doses can be given orally, inhaled, directly injected in targeted regions such as joints, or delivered intravenously. Secondary effects of steroid use include improved appetite and mood, which can also shape the pain experience. High-dose or sustained corticosteroid use is associated with several side effects, including hyperglycemia, weight gain, myopathies, and Cushing's syndrome, as well as mental status changes, including delirium and psychosis. Dosage adjustments can minimize side effects; tapered discontinuation of corticosteroids is preferred over the sudden cessation of medication to prevent adrenal suppression and steroid withdrawal syndrome. Corticosteroids should not be used in combination with NSAIDs to minimize the risk of gastrointestinal bleeding, especially in older adults and/or anticoagulated patients. \*\*\*\*\*\*\*\*\*\*\*\*Local Anesthetics Local anesthetic agents are pharmacological substances, either topically applied or injected into nerves and tissue, that eliminate sensation and pain without the loss of consciousness associated with general anesthesia. Local anesthetics are generally used in a defined location to accommodate minor surgery or to regionally target pain. Lidocaine (Xylocaine) is the most commonly used local anesthetic medication. Lidocaine alters the excitability of neurons by blocking fast voltage-gated sodium (Na+) channels in the cell membranes responsible for propagating pain messages along nociceptive pathways. It acts quickly, usually within 10 minutes, and can last as long as 2 hours. Bupivacaine (Marcaine) is more potent and longer lasting than lidocaine and is used often as an injection for nerve blocks and as an epidural anesthetic. Bupivacaine also carries a greater risk for central nervous system and cardiac toxicity, so doses must be carefully adjusted. It can take as long as 20 minutes for bupivacaine to achieve anesthesia, but the effects can last as long as 8 hours when given as an epidural. Bupivacaine can also be injected into the tissues around a surgical wound intraoperatively, providing pain relief for as long as 20 hours. Local anesthetics relax vascular muscle walls, bringing increased blood flow into the region. This increased blood flow can increase systemic medication absorption, which shortens effective anesthesia times. To maximize local anesthetic effectiveness, these anesthetic agents are often combined with short-acting vasoconstricting agents such as epinephrine. This allows the anesthetic agent to stay regionally active for a longer period of time and limits potential systemic toxicity from too-rapid absorption. Local vasoconstriction also reduces bleeding in the area of injection. Epinephrine-lidocaine combinations, however, are not recommended for small, confined, vascular-rich areas, such as the penis, fingers, or toes, where local vascular constriction can cause inadequate blood flow and tissue necrosis. Local anesthetics are also diluted and compounded into sprays, pastes, and creams that can be applied to minor burns and abrasions. A commonly used mixture of local anesthetics (EMLA) is a combination ointment consisting of 2.5% lidocaine and 2.5% prilocaine and is applied to provide superficial dermal anesthesia for venipuncture, IV catheter insertion, and minor wound debridement. Applied 45 to 60 minutes before a procedure and covered with an occlusive dressing, EMLA provides up to 2 hours of local anesthesia once the occlusive dressing is removed. Dilute lidocaine anesthetic sprays and lozenges help soothe sore throats and aid in anesthetizing oral mucous membranes in preparation for tracheal or nasogastric intubation. \*\*\*\*\*\*\*\*\*\*\*\*\*\*Topical Rubefacients Rubefacients are topically applied substances that cause local dilation of blood vessels and reddening of the skin, producing local sensations of coolness and warmth that many people find soothing. Examples of rubefacients include rubbing alcohol, menthol-containing ointments and creams, salicylates (e.g., aspirin), and oil of wintergreen. Products such as Icy Hot and Bengay, which contain menthol, and aspirin-containing creams, such as Aspercreme and Myoflex, are used to treat low-back pain and general muscle aches associated with activity. Many homemade and folk recipes contain herbal rubefacients such as horseradish, nettle, garlic, cloves, rosemary oil, and turpentine. Rubefacients are believed to relieve pain by serving as a counterirritant. Rubefacients are often compounded to have a strong "medicinal" smell that is also believed to distract or offset the pain and are the most widely purchased OTC pain remedies after oral nonopioid analgesics. Rubefacients should not be used to treat painful dermatitis following radiation treatment because radiation damages epithelial cells and alters the permeability of the vascular bed, and the use of topical rubefacients can worsen radiation-induced dermatitis. Capsaicin, the active ingredient in chili peppers, is frequently used in topical ointments and dermal patches to produce localized, soothing warm and hot sensations. Capsaicin is believed to activate specific temperature-sensitive receptors on peripheral neurons, causing a rapid propagation of warm and hot impulses to the spinal cord. At the level of the spinal cord, these heat impulses cause rapid release and emptying of stores of a pro-pain neurotransmitter called substance P. Until these neurotransmitter stores recover, which could be as long as 6 to 8 hours, these particular peripheral neurons cannot induce a pain response. In patient comparison studies, the evidence in support of capsaicin heat for providing effective pain relief is stronger than for the heat produced by other rubefacients. At low concentrations, capsaicin (Capzasin, Tiger Balm) is used to treat minor musculoskeletal aches and pains, including arthritis, backache, muscle strains, and sprains. At higher concentrations, capsaicin-containing ointments and patches have been used to treat the postherpetic neuralgia associated with shingles as well as other peripheral neuropathies. Gloves should be worn when applying capsaicin ointments and patches to avoid clinician exposure, and they should not be applied to open or broken skin. At higher doses, face masks, protective eyewear, and gloves are recommended for clinician safety. Capsaicin creams are not recommended immediately after hot baths or showers, nor are they recommended to be used with heating pads because the additional heat may allow for overabsorption of the medication. Opioids Considered primary in the treatment and management of acute pain, opioids are among the oldest known substances used for the treatment of pain. It is increasingly recognized that opioids are much less effective in managing the pathologies underlying most chronic pain conditions, and their use in chronic pain should be carefully evaluated. Opioids work by binding to opioid receptors that are located primarily in the brain, in the spinal cord, and along peripheral nerves and the gastrointestinal tract. These opioid receptors are classified as delta-, kappa-, and mu-type receptors (Table 11.6), with the physiological effect of opioids dependent on the location, type, and binding affinity between medication and receptor. Some opioid receptors located in ascending pain-transmission pathways are activated by opioid medications and block the effects of pro-pain neurotransmitters, including substance P and glutamate. Other opioid receptors located in descending pain pathways are activated by opioid medications and enhance naturally occurring pain-inhibiting processes. It is the action of opioids on receptors in other brain regions, such as the hypothalamus and pituitary gland, that produces the autonomic effects seen with opioids, including pupil constriction, dry mouth, lowered body temperature, and reduced sensitivity to cold. Opioid activation of receptors in the brainstem mutes the activity of the sympathetic nervous system and causes relaxation, sedation, slowed breathing, and reductions in anxiety. Other effects of opioids on brain receptors activate the chemoreceptor trigger zone, which can induce nausea and vomiting. Opioids are used in the treatment of moderate to severe pain and are often administered to postoperative patients (Box 11.2). Although most often administered via the oral route in the outpatient setting, opioids may be given via the IV, subcutaneous, intraspinal, transdermal, rectal, and epidural routes. Oral dosages may provide the most consistent therapeutic levels of these medications if administered at appropriate intervals. Patients may not receive adequate pain relief because of a fear of side effects or fear of addiction, which is not the same as tolerance. Tolerance is characterized by the need for increasing doses of medication to get the same pain results. Addiction is characterized by a compulsive behavioral pattern to take a medication for both its physiological and psychic effects without regard for the negative consequences associated with continued medication ingestion. The growth in addiction, particularly to new synthetic opioid formulations, over the last 5 years has reached epidemic proportions. The numbers of patients addicted to opioids tripled in the years between 2003 and 2014, with the number of opioid overdose deaths annually now exceeding those dying from gun violence and motor vehicle deaths combined. Although there has been a national initiative to limit opioid-prescribing patterns, opioid overdose deaths are cited as a significant contributing factor to the recent drop in life expectancy, the first such drop in more than 50 years. There is existing evidence that opioids should not be initiated in the management of chronic pain, even for those at low risk for developing addiction. When already prescribed for chronic pain, a carefully individualized treatment plan should be developed, and while abrupt cessation or downtitration of opioids should be avoided, opioid antagonists can be used in conjunction with treatment of opioid use disorder if this is a concern. In the setting of acute pain, opioids should be used sparingly unless pain is severe, and then should be prescribed in short courses of less than 1 week, at which point reevaluation is advised. Patients receiving opioids are at risk for several side effects, particularly related to actions at the mu receptor sites, and prevention and management of these effects are central to any plan of care for patients receiving opioids. Respiratory depression is the most critical adverse side effect of opioids and requires close patient monitoring, especially after IV administration. The American Pain Society's 2020 guidelines for nursing highlight the importance of monitoring for sedation and respiratory depression in all hospitalized patients, with focused attention on those at high risk. Importantly, risk can be stratified across patients (e.g., impaired pulmonary, cardiac, or renal function), treatment parameters (e.g., first 24 hours after initiating opioids in the naïve patient), and across environment of care levels (e.g., ineffective interprofessional communication). Opioids also carry risk for gastrointestinal side effects. Nausea and vomiting are relatively common and usually develop shortly after the first doses. In the postoperative patient, assessment for nausea and vomiting is particularly important because it increases the risk of aspiration. Patients experiencing pain often have decreased physical activity and oral intake; these circumstances, along with the effects of opioids on the gastrointestinal system, increase constipation. Laxatives and stool softeners are almost always indicated to assist in the prevention or treatment of constipation. Other receptor-mediated adverse effects of opioids include urinary retention and pruritus. Opioids acting on opioid receptors in synaptically reorganized dysfunctional pain pathways can paradoxically increase pain in patients with chronic pain. This receptor response in patients who have taken opioids long term or who may also be addicted to opioids can confound the assessment and management of pain in this population, often leading to skepticism about pain severity and judgmental labeling of patients as "drug seeking." Consultation with pain management experts can assist providers in safe and appropriate pain management in this challenging pain circumstance (see Evidence-Based Practice: Opioid Use in Pain Management). Morphine (Roxanol) is considered the gold standard of opioids and is used in the treatment of acute pain. Oral morphine agents are available in both short-acting and controlled-release (MS Contin) forms. In the acute setting, particularly with severe pain, and in the postoperative setting, IV morphine is common. Hydromorphone (Dilaudid) is another opioid used in the treatment of severe pain and is five times more potent than morphine (Fig. 11.7). Available only in short-release forms, this medication is frequently used in the treatment of acute pain, particularly via the IV route. Fentanyl, roughly 100 times the potency of morphine, is another effective short-acting opioid available in IV form in the inpatient setting for acute pain. Its transdermal patch route is effective for longer-term management of severe pain often in the context of cancer or other life-limiting illness. Synthetic opioids include different preparations of oxycodone, including the extended-release form branded as OxyContin. This potent opioid, although originally marketed as having low addiction risk, is highly addictive given its low cost and wide prescriptive availability. Until recently, this single agent was identified as being the most commonly abused opioid and responsible for a significant number of overdose deaths. Appropriately prescribed to manage short-term acute pain, this medication represents a significant treatment advantage over other commonly prescribed opioids; however, tighter prescription controls have not necessarily reduced opioid overdose deaths. Patients who previously have been taking OxyContin and find themselves addicted but without a ready source of that medication have switched their opioid of choice to cheaper and often illegally obtained heroin and fentanyl. Opioid overdose deaths remain a significant public health concern. \*\*\*\*\*\*\*\*\*\*\*\*\*\*Atypical Analgesics Adrenergic Agonists Clonidine (Catapres) is a direct-acting alpha-2 adrenergic agonist used to treat high blood pressure. Its side effects of analgesia and sedation prompted clinical trials to evaluate clonidine for pain relief. Oral dosing of clonidine for pain management has limited benefit for the treatment of acute and chronic pain because doses sufficient to produce pain relief create excessive sedation. Intrathecal and epidural infusions of clonidine, however, have been used to treat cancer pain and neuropathic pain, as well as chronic pain in patients who have become tolerant to opioids. Clonidine activates alpha-2 receptors at the level of the spinal cord to reduce cellular excitability and has been demonstrated to potentiate the action of local anesthetics and opioids. A related compound, tizanidine (Zanaflex), used to treat muscle spasticity, has proven effective at treating some forms of myofascial pain and peripheral neuropathy. Tricyclic Antidepressants and Selective Norepinephrine Reuptake Inhibitors Tricyclic antidepressants (TCAs) comprise a large class of medications that modulate the effects of serotonin and the related neurotransmitter norepinephrine in the central nervous system. First used to treat mood disorders and major depression in the 1960s, TCAs became more widely used to treat pain with the discovery of the critical role of serotonin and norepinephrine in modulating naturally occurring opioids in descending pain pathways. Tricyclic antidepressants largely affect the reuptake of serotonin or norepinephrine at the level of the individual synapse in the brain, with the net effect being an increase in the amount of neurotransmitter available, enhancement of neurotransmission, and changes in the level of naturally occurring opioids in the central nervous system. The most commonly prescribed TCAs, amitriptyline (Elavil), clomipramine (Anafranil), desipramine (Norpramin), imipramine (Tofranil), and nortriptyline (Pamelor), have proven effective at managing neuralgias, fibromyalgia, and migraine headaches, as well as the pain associated with irritable bowel syndrome, post-traumatic stress disorders, and neuropathies. Although doses for pain relief are generally lower than those prescribed to treat depression, the stabilization of mood that accompanies TCA use is generally viewed as a positive outcome for patients with pain who also report depression. Duloxetine, a selective norepinephrine reuptake inhibitor (SNRI), has shown potential benefit in neuropathic pain as well, and may be considered when treating concomitant pain and depression. TCAs and SNRIs are used commonly for neuropathic pain, but have varying efficacy across patients and are not without side effects. Glutamate Receptor Antagonists and Gamma-Aminobutyric Acid Agonists Glutamate is the principal excitatory neurotransmitter in the central nervous system. At the level of the spinal cord, glutamate interacts with several different receptors, including the N-ethyl-D-aspartic acid (NMDA) receptor. Calcium movement across NMDA receptors in spinal cord neurons is thought to influence how spinal neurons form synaptic connections with adjacent neurons, critically shaping "cellular memory" for pain. Blocking the activation of NMDA receptors is thought to limit the formation and permanency of abnormal synaptic connections. Ketamine (Ketalar) is the most commonly used medication to block glutamate activation of the NMDA receptor and has been successfully used to treat chronic pain resistant to most other analgesics. It is particularly useful at suppressing the central sensitization associated with surgical incisions and postherpetic neuralgia. Dose ranges for ketamine that produce analgesia are only slightly below dose ranges that produce pronounced hallucinations and ataxia; therefore, its use is largely restricted to anesthesia suites or emergency departments as part of pre-anesthesia induction or emergency sedation. Recent research has demonstrated that ketamine can be a life-saving therapy in depression that is nonresponsive to other antidepressant therapy. Although ketamine is an older and well-established analgesic, the overlap of brain regions shaping depression and chronic pain suggest that ketamine, and synthetic metabolites of ketamine in the body, may hold new and exciting promise in treating chronic pain. Dilute topical preparations of ketamine in combination with other anesthetics and anti-inflammatory agents have been used to treat nerve pain and painful dermatitis following radiation for cancer treatment. The most common topical preparation includes 10% ketamine, 10% of the NSAID ketoprofen, and 5% lidocaine. Other topical ketamine preparations combine ketamine with clonidine, TCAs including amitriptyline and tramadol, and the local anesthetic mepivacaine. Medications closely related to ketamine are being evaluated in clinical trials to treat chronic pain syndromes. Amantadine (Symadine), commonly used to treat viral syndromes and the symptoms of Parkinson's disease, has demonstrated promising results in the treatment of neuropathic pain in cancer patients. Memantine (Namenda), used to treat the memory loss associated with Alzheimer's disease, is also in clinical trials, with significant reductions reported in diabetic neuropathic pain. When pain messages originating in the periphery reach the spinal cord, both excitatory and inhibitory neurotransmitters are released at synaptic connections. Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the central nervous system. When GABA interacts with specific receptors in the pain-processing systems, it changes the electrical conductivity from neuron to neuron, inhibiting pain processing. When injury leads to more permanent restructuring of pain synapses and dysfunctional cellular memory, it is often because there are fewer functional pain inhibition connections. Synthetic medications can be used to mimic the action of GABA by activating GABA receptors more widely, increasing pain inhibition. The most commonly prescribed GABA receptor agonist is baclofen (Lioresal). It is generally used to treat spastic movement disorders associated with spinal cord injury, multiple sclerosis, and amyotrophic lateral sclerosis. It has proven effective for the treatment of pain following nerve crush injuries, spinal cord injuries, and complex peripheral neuropathies in which the underlying cause may be difficult to determine. Ion-Channel Blockers Following the development of successful ion-channel--blocking agents, such as lidocaine, and the identification of other ion channels critical to pain processing, there has been great clinical interest in a broader ion-channel blockade to control pain. The anticonvulsant medications phenytoin (Dilantin), carbamazepine (Tegretol), and lamotrigine (Lamictal) are nonselective Na+-channel blockers effective at treating neuropathic pain and trigeminal neuralgia. They must be used cautiously in patients also taking oral anticoagulants, including warfarin (Coumadin), because these can increase the therapeutic effect of anticoagulants (increasing the risk of bleeding) or cause toxicity. Tricyclic antidepressants, in addition to their effects on serotonin reuptake, block Na+ channels as a secondary mechanism of action, limiting the propagation of pain messages, which may also help to explain their analgesic activity. Gabapentin (Neurontin) and pregabalin (Lyrica) are novel anticonvulsant medications with analgesic effects. Although gabapentin was initially synthesized to mimic the inhibitory neurotransmitter GABA, it is not believed to activate GABA receptors; instead, the analgesic mechanism of action is believed to be its binding to a subunit of ion channels that gate local calcium flow, limiting the propagation of pain messages. Both gabapentin and pregabalin, a more potent second-generation form of gabapentin, have proven effective at treating diabetic neuropathic pain and neuropathic pain following nerve injuries in the lower back. Other ion channels that influence calcium movement in pain-processing neurons and thus the propagation of pain messages have also been identified as potential analgesia targets. Blockers of L-type calcium channels, including nimodipine (Nimotop), verapamil (Calan), and diltiazem (Cardizem), allow for reduced doses of opioids when treating cancer patients, as well as a reduced need for postoperative analgesia following abdominal surgery (Table 11.7). \*\*\*\*\*\*\*\*\*\*\*\*\*\*\*Decision Making for Effective Dose, Route, and Medication Choice In spite of gains in pharmacology and a growing body of evidence to guide the best pain practices, too many patients wake each day in chronic pain, too many postoperative patients experience unrelieved pain that slows their recovery, and too many patients suffer at the end of life. Part of the challenge in balancing the risks and benefits of intervention is acknowledging that significant variability exists among individual patients in analgesia response. The therapeutic goal is to choose medications that provide the best pain relief with the fewest adverse effects for the individual. There are many factors to consider when making a therapeutic medication choice, including (1) the type, intensity, and duration of a patient's pain; (2) the patient's age, gender, and general health; (3) the potential for pain relief and side effects based on mechanism of action and analgesia potency; (4) the potential for drug--drug interactions with current medications; and (5) the potential to improve or worsen comorbid health conditions. Effective pain management depends on understanding how the body releases medications from their formulation and how medications enter the circulation and are distributed throughout the body's tissues, as well as how medications are metabolized and excreted from the body. Identical medications can produce different results depending on the route of administration. Inhaled steroids, for example, provide more targeted treatment in the bronchial tree with fewer systemic effects than if the same steroid is delivered orally or intravenously. Although oral medications are preferred by most patients because they are more convenient and do not involve sterile procedures or potentially painful injections, many medications cannot be formulated for therapeutically effective gastrointestinal absorption into the bloodstream. Although many oral medications do have the benefit of being able to be compounded for sustained release, many dosing errors have been associated with improper crushing of sustained-released medications, both by patients at home and by clinicians who may not be aware of sustained-release formulations. Oral medications are also frequently compounded with dyes and pharmacologically inert substances that are allergenic for many people. Over-the-counter oral analgesics, for example, should be used cautiously in patients with a significant allergy history or a documented allergy to red and yellow dyes. In addition to the mouth serving as a convenient entry to the gastrointestinal tract, the mouth is also an area of very vascular-rich tissue, allowing medication access through the mucosa. Some opioids, such as buprenorphine (Buprenex) or methadone (Methadose), can be formulated for sublingual doses, compounded into a lozenge, or packaged as a lollipop. The Actiq lollipop contains the opioid fentanyl and is particularly effective at treating breakthrough pain between scheduled doses of other medications. Oxycodone oral concentrate (20 mg/mL) can be administered sublingually, which is particularly useful in treating acute pain in those unable to swallow. The rectal route can also be an effective route of administration for many patients, although it is associated with the most variable absorption and peak-onset effects. The rectal route also can stimulate bowel evacuation in patients with low levels of bowel continence, with a subsequent loss of unabsorbed medication, minimizing effective dosing. The IV route of administration is reliable in emergency situations or when a rapid therapeutic effect is desired, but its use is often more limited to care settings and not as readily available for home use. Intravenous medications have the advantage, however, of being able to deliver both a bolus dose of medication or continuous infusions. Bolus dosing provides for a relatively rapid onset of pain relief, usually within 5 to 7 minutes, whereas continuous infusions allow for a steady level of medication that keeps plasma concentrations of the medication more constant. Continuous infusions may allow for lower cumulative levels of medication to be delivered, which has the potential to reduce medication side effects. In addition to IV delivery of medications, other infusion devices can deliver pain medication via subcutaneous tissues. Small 25- to 30-gauge needles can be placed into the subcutaneous tissues and connected to a small refillable medication reservoir. Some patients can also have implanted subcutaneous medication reservoirs with tunneled infusion systems under the skin to continuously deliver small doses of medications. These infusion sites need to be continually monitored for redness, swelling, signs of medication leakage, and the formation of dependent edema in the affected extremity. Pain relief can be variable with these delivery systems, and sites generally need to be rotated every 6 to 7 days to minimize infection and tissue trauma. Transdermal patches comfortably provide both targeted and systemic pain relief, although there are relatively few pain medications currently formulated for transdermal administration. The most common pain medication delivered by transdermal patch is fentanyl (Duragesic). Patients and families do appreciate the ability to self-medicate using this delivery system, with sustained medication delivery limiting the frequency of breakthrough pain. As with all opioids, the risk of opioid-induced respiratory depression must be mitigated by close monitoring of respiratory status; transdermal fentanyl patches require close monitoring without dose increase over 24 to 72 hours, allowing the drug to reach steady state. Transdermal patches may be applied to any clean, dry skin surface, although areas on the upper back and chest are recommended to minimize dislodging of the patch. It is important to remove old patches when new ones are applied so that patients are not overmedicated. New patches should be placed on rotating skin sites to minimize skin irritation. One important factor to consider with transdermal patches is that these sustained-release delivery devices can require up to 24 to 72 hours before effective pain relief is achieved, and often patients require a supplemental analgesic in the interim. Intrathecal, epidural, or targeted injections into joints or nerve roots allow for regional analgesia with fewer systemic side effects but require specialist assessment and administration. Delivering medications directly into and around the spinal cord allows medications to act directly on specialized pain receptors and pain-processing networks of synapses to inhibit pain. The advantages of this targeted therapy include a generally longer duration of analgesia and at lower doses than can be achieved by other delivery methods. Often, targeted spinal analgesics combine an opioid with a local anesthetic to maximize pain relief by inhibiting several pain pathways. Side effects of targeted spinal analgesia and anesthesia include urinary retention and pruritus. Respiratory status must be closely monitored with targeted spinal opioid delivery and continued for several hours after discontinuation of therapy. Delayed respiratory depression has been noted, and patients should remain on continuous pulse oximeter monitoring for 8 to 12 hours after the medication has been discontinued. Frequent peripheral neurological and skin assessments should be performed with continuous targeted spinal analgesia, especially if opioids are combined with local anesthetic agents. Patients will have reduced sensation in the lower extremities and may not be able to readjust their position in response to pressure or other noxious stimulation. These patients should also have blood pressure monitored as well. Vascular tone can be affected by targeted spinal anesthesia, causing some pooling of blood in lower extremities, leading to lower systemic blood pressures and feelings of light-headedness. Epidural catheters are placed in the small space outside the dura mater of the spinal cord and are generally used for long-duration analgesia delivery, including pain relief for patients in labor and some lower-extremity procedures. Implanted catheters connected to refillable reservoirs or pumps are used for days to months to provide long-lasting pain relief for patients with chronic pain. Intrathecal injections are usually single injections directly into the cerebrospinal fluid, bathing the spinal column with short-duration effects of 30 minutes to 8 hours. Injections of corticosteroids and