section epub:type=”chapter” id=”c0155″ role=”doc-chapter”> This chapter provides an overview of the fundamental concepts of pain management. Basic physiological concepts are presented involving both nociceptive and neuropathic pain. A comprehensive approach to assessment of pain includes function and comfort. A variety of tools for pain assessment are included. Pain management is explored through a multimodal approach including nonopioid, opioid, and coanalgesic medications. Basic nonpharmacologic interventions that can be used in the perioperative setting are presented. Pain management challenges among patients with preexisting chronic pain and substance use disorder are explored. multimodal analgesia; nonopioids; nonpharmacologic; opioids; pain; substance use disorder Pain is one of the most common reasons people seek health care. Despite an abundance of research and improvements in analgesics and drug delivery technology, the prevalence and societal cost of pain continues to rise.1,2 Nurses, the only members of the health care team present at the patient bedside around the clock, are experts in assessment, medication administration, and patient education. These characteristics have led to the distinction of nurses as the patient’s primary pain manager.3 The presence and actions of nurses are critical to ensuring that patients receive the best possible pain relief available. Definitions Multimodal Analgesia Combinations of medications with different underlying mechanisms are intentionally prescribed and administered to allow lower doses of each of the medications, reduce the potential for analgesic adverse effects, and provide comparable or greater pain relief than can be achieved with any single analgesic. Neuropathic Pain Pain that results from or is a direct result of an injury, disease, or lesion affecting the somatosensory system. It can involve harm to the peripheral nervous system (PNS) and/or central nervous system (CNS). Nociceptive Pain Pain that results from the normal functioning of physiologic systems leading to the perception of noxious stimuli (tissue injury) as being painful. Opioid Naive An individual who has not recently taken enough opioid on a regular enough basis to become tolerant to the effects of an opioid. Titration The process of adjusting the dose of an analgesic within the prescribed parameters. The International Association for the Study of Pain revised the definition of pain as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”4 This definition describes pain as a complex multifactorial phenomenon that affects a person’s psychosocial, emotional, and physical functioning. The definition of pain applied in the clinical setting reinforces that pain is a highly personal and subjective experience described by Margo McCaffery as: “Pain is whatever the experiencing person says it is, existing whenever they says it does.”5 Although many accepted guidelines consider the patient’s report to be the most reliable indicator of pain and the gold standard of pain intensity, it is imperative to consider the various factors that contribute to the pain experience.2,4,6–8 Pain is usually described as being acute or chronic (persistent).5,9 Acute and chronic pain differ from one another primarily in their duration. For example, tissue damage as a result of surgery, trauma, or burns produces acute pain that is expected to have a relatively short duration and to resolve with normal healing. Chronic or persistent pain can occur from an underlying medical condition such as peripheral neuropathy from diabetes, cancer pain from tumor growth, or osteoarthritis pain from joint degeneration, and it can persist throughout the person’s life. Some medical conditions can produce both acute and chronic pain. For example, some patients with cancer have continuous chronic pain and also experience periodic acute exacerbations of pain (called breakthrough pain) and/or they endure repetitive painful procedures during cancer treatment. Pain is increasingly classified by its inferred pathology as being either nociceptive pain or neuropathic pain9 (Table 31.1). Nociceptive pain refers to the normal functioning of physiologic systems that leads to the perception of noxious stimuli (tissue injury) as being painful. This explains why nociception is described as “normal” pain transmission. Pain from surgery, trauma, burns, and tumor growth are examples of nociceptive pain. Patients often describe this type of pain as “aching,” “cramping,” or “throbbing.” GI, Gastrointestinal; HIV, human immunodeficiency virus. From Pasero C, McCaffery M. Pain assessment and pharmacologic management. St. Louis, MO: Elsevier; 2011. Copyright Pasero C, McCaffery M. Used with permission. The most recent definition of neuropathic pain is that it is pain resulting from the somatosensory system, or as a specific outcome resulting from a lesion or disease of that system.9 Examples include postherpetic neuralgia, diabetic neuropathy, phantom pain, and poststroke pain syndrome. Patients with neuropathic pain often describe their pain with distinctive words such as “cold,” “burning,” “sharp,” and “shooting.” Some patients have “mixed pain,” which is a combination of nociceptive and neuropathic pain and is usually chronic in nature.9–11 For example, a patient may have nociceptive pain as a result of tumor growth and also report radiating sharp and shooting neuropathic pain if the tumor is pressing against a nerve plexus. Sickle cell disease pain is often a combination of nociceptive pain from the clumping of sickled cells and resulting perfusion deficits and neuropathic pain from nerve ischemia. Some painful conditions and syndromes are not easily categorized as either nociceptive or neuropathic. Although not officially designated as such, these are sometimes referred to as mixed pain syndromes and include fibromyalgia and some low back and myofascial pain.11 Nociception includes four specific processes: transduction, transmission, perception, and modulation. Fig. 31.1 illustrates these processes, and an overview of each follows. The steps of pain signaling are as follows: Step 1: Transduction: A sharp needle-like object pricks the finger. Nerve endings get stimulated. Step 2: Transmission: The nerve from finger is connected to gray matter of spinal cord. The signal is received by brain then. Step 3: Perception: Pain is experienced. Step 4: Modulation: Pain signal is altered. Signals are received from brain to gray matter of spinal cord. Transduction refers to the processes by which noxious stimuli activate primary afferent neurons called nociceptors, which are located throughout the body in skin, subcutaneous tissue, and visceral and somatic structures (see Fig. 31.1).9 These neurons have the ability to respond selectively to noxious stimuli generated as a result of tissue damage from mechanical (e.g., incision, tumor growth), thermal (e.g., burn, frostbite), chemical (e.g., toxins, chemotherapy), and infectious sources.12,13 Noxious stimuli cause the release of a number of excitatory compounds (e.g., serotonin, bradykinin, histamine, substance P, prostaglandins), which facilitate the movement of pain along the pain pathway.8 These substances are collectively referred to as inflammatory soup.13 Prostaglandins are a particularly important group of compounds that accompanies tissue injury and initiates inflammatory responses which increase tissue swelling and pain at the site of injury.14 They are formed when the enzyme phospholipase breaks down phospholipids into arachidonic acid, and arachidonic acid, in turn, is acted upon by the enzyme cyclooxygenase (COX) to produce prostaglandins (Fig. 31.2). The two best characterized isoenzymes of COX are COX-1 and COX-2; they have an important role in producing the effects of the nonopioid analgesics, which act peripherally and centrally to inhibit the COX isoenzymes. Nonsteroidal anti-inflammatory drugs (NSAIDs) work primarily by blocking the formation of prostaglandins in the periphery. The nonselective NSAIDs, such as ibuprofen, naproxen, diclofenac, and ketorolac, inhibit both COX-1 and COX-2, whereas the COX-2–selective NSAIDs, such as celecoxib, inhibit only COX-2. As Fig. 31.2 illustrates, both types of NSAIDs produce anti-inflammatory and pain relief through the inhibition of COX-2. Although the exact underlying mechanisms of action of acetaminophen continue to be investigated,15,16 acetaminophen is a known COX inhibitor that has minimal peripheral effect, is not anti-inflammatory, and can both relieve pain and reduce fever by preventing the formation of prostaglandins in the CNS.8,16 Flow chart for enzyme pathway: C O X-1 and C O X-2 is as follows: • The chart begins with phospholipids, followed by phospholipase, arachidonic acid, and cyclooxygenase (C O X) (enzyme that converts arachidonic acid to prostaglandins). • Cyclooxygenase leads to C O X-1 (constitutive, always present) and C O X-2 (induced, present with tissue injury). • C O X-1 leads to prostaglandins, followed by G l protection and platelet function. • C O X-2 leads to prostaglandins, followed by pain and inflammation. Other types of analgesics work by partially blocking transduction as well. For example, sodium channels are closed and inactive at rest but undergo changes in response to membrane depolarization. Transient channel opening leads to an influx of sodium and subsequent nerve conduction.17 Local anesthetics are capable of blocking sodium channels and reducing the nerve’s ability to generate an action potential. Anticonvulsants also affect the flux of other ions, such as calcium and potassium, to reduce transduction and produce pain relief (Fig. 31.3). Side view of brain shows brainstem nuclei, thalamic nuclei, and brain cortex, marked 4, 5, and 6, respectively. • Brainstem nuclei: Hyperexcitability, changes in synaptic efficacy, reorganization of afferent projections, reorganization of afferent maps. • Thalamic nuclei: Hyperexcitability, changes in ion channels, changes in synaptic efficacy, reorganization of afferent maps. • Brain cortex (sensory and motor): Increased excitability, changes in synaptic efficacy, reorganization of somatotopic maps. At the bottom, injured peripheral nerve, drug neurons, motoneurons, and spinal cord are marked 1, 2, 2 prime, and 3, respectively. • Injured peripheral nerve: Hyperexcitability regenerating axons, ectopic discharges, neurotrophic deprivation. • D R G neurons: Hyperexcitability, ectopic discharges, changes in ion channels, changes in neuropeptides. • Motoneurons: Hyperexcitability, changes in ion channels, dendrite remodeling. • Spinal cord: Reorganization of afferent projections, sensitization of spinal neurons, changes in synaptic efficacy, decrease in inhibitory neurons. Transmission is the second process involved in nociception. Effective transduction generates an action potential transmitted along the A-delta (δ) and C fibers.8 A-δ fibers are lightly myelinated and faster conducting than the unmyelinated C fibers. The endings of A-δ fibers detect thermal and mechanical injury and allow relatively quick localization of pain and a rapid reflex withdrawal from the painful stimulus. Unmyelinated C fibers are slow conductors and respond to mechanical, thermal, and chemical stimuli. They yield poorly localized, often aching or burning pain. A-beta (β) fibers are the largest of the fibers and do not normally transmit pain but do respond to touch, movement, and vibration.8 Afferent information passes through the cell body of the dorsal root ganglia (see Fig. 31.1), which lie outside of the spinal cord, to synapses in the dorsal horn of the spinal cord. An action potential is generated, and the impulse ascends up to the spinal cord and transmits information to the brain, where pain is perceived. Extensive modulation occurs in the dorsal horn via complex neurochemical mechanisms. The primary A-δ fibers and C fibers release a variety of transmitters including glutamate, neurokinin, and substance P. Glutamate binds to the N-methyl-d-aspartate (NMDA) receptor and promotes pain transmission. Endogenous and therapeutically administered opioids bind to opioid receptor sites in the dorsal horn to block substance P and thereby produce analgesia.8 The third broad process involved in nociception is perception. Perception, the result of the neural activity associated with transmission of noxious stimuli,8,18 involves the conscious awareness of pain and requires activation of higher brain structures for the occurrence of awareness, emotions, and drives associated with pain (see Fig. 31.1). Physiology of pain perception has been poorly understood. The authors of a recent systematic review explored physiology of the perception of acute pain evidenced by functional resonance imaging (fMRI).8a Research supports the idea that perception of pain can be modified by mind-body therapies such as distraction, imagery, and mirror therapy, which are based on the belief that brain processes can strongly influence pain perception.8,18 Modulation of afferent input generated in response to noxious stimuli occurs at every level from the periphery to the cortex with involved processes and numerous neurochemicals.14 For example, serotonin and norepinephrine are central inhibitory neurotransmitters released in the spinal cord and brainstem by descending fibers of the modulatory system (see Fig. 31.1). Some antidepressants provide pain relief by blocking the body’s reuptake of serotonin and norepinephrine, extending their availability to fight pain. Endogenous opioids are located throughout the PNS and CNS, and, like therapeutically administered opioids, they inhibit neuronal activity by binding to opioid receptors. As an example, Fig. 31.1 shows that the dorsal horn of the spinal cord, which is densely populated with opioid receptors, is the primary action site of epidural opioids. Neuropathic pain is sustained by mechanisms driven by injury, damage to, or dysfunction of the PNS or CNS. In contrast to nociceptive pain, neuropathic pain is abnormal processing of stimuli.12,19 Whereas nociceptive pain involves tissue damage or inflammation, neuropathic pain can occur in the absence of either. Neuropathic pain, even when acute, reflects a pathophysiology that serves no useful purpose.8 A discussion of some of the peripheral and central mechanisms that initiate and maintain neuropathic pain follows. Extensive research is ongoing to better define these mechanisms. Neuropathic pain can develop at any point from the periphery to the CNS. For example, when nerve endings are injured, changes occur that involve a number of processes. These processes involve the release of a variety of substances that function as excitatory inflammatory mediators including prostaglandin, bradykinin, histamine, and cytokines. Hypersensitivity develops as the sodium channel ions accumulate in response to injury. The threshold for nerve depolarization is then lowered, which leads to an increased response to stimuli and ectopic discharges. Hyperexcitable nerve endings in the periphery can become damaged, leading to abnormal reorganization in the nervous system, an underlying mechanism of some neuropathic pain states.8,12 Subsequent to the initial nerve damage, chemically mediated ion changes can lead to cortical reorganization, central and peripheral sensitization, which are believed to contribute to the maintenance of neuropathic pain. The Special Interest Group on Neuropathic Pain (NewPSIG) rated gabapentoids, serotonin and norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) as first-line pharmaceutical interventions with tramadol, lidocaine patches, and capsaicin 8% patches as second-line and botulinum toxin as third-line interventions for neuropathic pain12,20 (Fig. 31.4). Mechanism of peripheral sensitization is as follows: Cellular membrane is embedded with different colored T r k A, K 2 P, B K or E P 2, A S I C, and P 2 X 3. An arrow from cell points outside toward substance P C G R P. Different colored chemical mediators are released at the site of injury. Macrophage above at the site of tissue releases I L-1 beta, N G F, L I F, I L-6, and T N F-alpha. Mast cells release histamine, bradykinin, and P G E sub 2. Tissue damage releases adenosine, H positive, and A T P. Platelets also leads to A T P. To the right, immune cell with multi-lobed nuclei is depicted. Central mechanisms also have a role in establishing neuropathic pain. Central sensitization is a complex process that is still being studied to gain fuller understanding. It can be understood as an amplified neuronal response in the CNS with pain hypersensitivity complex changes induced by incoming barrages of nociceptors.8,20,21 The accumulation of intracellular ions causes spinal neurons to become highly sensitized and fire rapidly in a process called wind-up that occurs early in the process.8,20 Extensive release and binding of excitatory neurotransmitters, such as glutamate, activate the NMDA receptor and cause an increase in intracellular calcium levels into the neuron, resulting in pain. Local anesthetics and anticonvulsants can block ion channels and inhibit abnormal pain sensation. As with injured peripheral neurons, synaptic reorganization and anatomic changes can also occur in the CNS. These are thought to be sustained by an increased responsiveness of central neurons to relatively mild peripheral stimuli.20 For example, injury to a nerve route can lead to reorganization in the dorsal horn of the spinal cord. Nerve fibers can invade other areas and create abnormal sensations in the area of the body served by the injured nerve. Allodynia or pain from a normally non-noxious stimulus (e.g., touch) is one such abnormal sensation and a common feature of neuropathic pain. In patients with allodynia, the mere weight of clothing or bed sheets can be excruciatingly painful. The ability of the nervous system to change structure and function as a result of noxious stimuli is called neuroplasticity.21 Another underlying mechanism called central disinhibition occurs when control mechanisms along the inhibitory (modulatory) pathways are lost or suppressed, leading to abnormal excitability of central neurons.22 Likely, there are multiple causes of disinhibition including dysfunction of the gamma-aminobutyric acid (GABA) pathways. GABA is the most abundant neurotransmitter in the CNS and composes a major inhibitory neurotransmitter system. Increased GABA function may help to relieve neuropathic pain. Benzodiazepines, such as midazolam, enhance GABA function, resulting in analgesia for pathologic conditions like muscle spasm.20,22 Literally every system in the body is affected by unrelieved pain; the harmful effects are numerous (Table 31.2). Unrelieved pain triggers and prolongs the stress response, causing the release of excessive amounts of hormones such as cortisol, catecholamines, and glucagon; insulin and testosterone levels decrease.23 This increased endocrine activity initiates a number of metabolic processes that can result in weight loss, tachycardia, increased respiratory rate, shock, and even death. Persistent unrelieved pain has been linked to infections and increased tumor growth; however, empirical studies to support these clinical reports are needed.23–26 ACTH, Adrenocorticotrophic hormone; ADH, antidiuretic hormone; down arrow (↓), decreased; GH, growth hormone; up arrow (↑), increased. From Pasero C, McCaffery M. Pain Assessment and Pharmacologic Management. St. Louis, MO: Elsevier; 2011. Copyright Pasero C, McCaffery M. Used with permission. Effects on the cardiovascular (CV) system include increased postoperative blood loss26 and hypercoagulation,22 which can lead to myocardial infarction and stroke. The respiratory system is affected by small tidal volumes and decreases in functional lung capacity, which can lead to pneumonia, atelectasis, and an increased need for mechanical ventilation.27,28 Every surgical procedure has the potential to produce persistent (chronic) postsurgical pain.27 Although it is not possible to predict which patient will develop persistent postsurgical pain inguinal hernia repair, amputation, and thoracic, cardiac, and breast surgery are among those identified as high risk for this complication.8,29,31 Multiple factors are thought to contribute to the development of persistent postsurgical pain, including nerve injury from the surgical procedure, preexisting pain, psychosocial factors, genetic susceptibility, and severe postoperative pain.29–31 Persistent postsurgical pain may have nociceptive, inflammatory, and neuropathic components, indicating a need for a multimodal treatment approach.23,30 Similar to other complex pain syndromes, it can be difficult to treat and last a lifetime. The gold standard for assessing the existence and intensity of pain is the patient’s self-report.32 A comprehensive pain assessment provides the foundation for good pain control and includes obtaining the following information from the patient: Many patients are unable to provide a report of their pain using the customary self-report pain rating tools, placing them at higher risk for undertreated pain than those who can report.32 These patients are collectively called patients unable to self-report40 and include infants, toddlers, and patients who are cognitively impaired, critically ill (intubated, unresponsive), comatose, imminently dying, receiving neuromuscular blocking agents, or sedated from anesthesia and other medications given during surgery. When patients are unable to self-report pain using traditional methods, an alternative approach based on the Hierarchy of Pain Measures is recommended.32,40,41 The key components of the hierarchy are to: (1) be cognizant of potential causes of pain (e.g., trauma, surgery); (2) attempt to obtain self-report; (3) observe behaviors of the patient; (4) obtain any reports by relatives or caregivers; and (5) conduct an analgesic trial.40 See Box 31.2 for detailed information on each component of the Hierarchy of Pain Measures. Self-report is at the top of the hierarchy and should be attempted even in patients who present challenges in assessment.40 Many patients with mild to moderate cognitive impairment can self-report when clinicians implement fairly simple measures (see Box 31.1). Several behavioral pain assessment tools exist to facilitate assessment in patients who are not able to self-report pain; however, patients must be carefully evaluated for their ability to respond with the requisite behaviors in the selected tool.40,41 For example, tools that require assessment of body movement as a pain indicator should not be used in patients who are unable to move such as those receiving a neuromuscular blocking agent. According to the hierarchy, pain can be assumed to be present in these patients, justified by research showing that endotracheal intubation, ventilation, and suctioning—all required in patients receiving a neuromuscular blocking agent—are painful.40–43 It is equally important to understand that the score obtained from the use of a behavioral pain assessment tool helps to identify the presence of pain, but the score is a behavioral score and not a pain intensity rating. Simply put, if the patient cannot report the intensity of the pain, the intensity is not known.2,41,44 It is also most important to remember that the absence of behavior does not mean the absence of pain. Although nurses who care for patients with acute pain at times rely on vital signs to assess pain, these physiologic signs are considered poor indicators of pain.12,45,46 Many factors other than pain can influence changes in vital signs, and patients quickly adapt physiologically despite the presence of pain. The primary message is that the absence of an elevated blood pressure or heart rate does not mean the absence of pain. After initiation of the pain management plan, pain is reassessed and documented on a regular basis as a way to evaluate the effectiveness of treatment. At a minimum, pain should be reassessed with each new report of pain and before and after administration of analgesics.32 The frequency of reassessment depends on the stability of the patient’s pain and the pharmacokinetics and pharmacodynamics of the medication and is guided by institutional policy. For example, in the postanesthesia care unit (PACU), reassessment may be necessary as often as every 10 minutes when pain is unstable during opioid titration but can be done every 4 to 8 hours in patients with stable pain 24 hours after surgery. It is strongly recommended that sedation and respiratory status is reassessed with each reassessment of pain. The quality of patients’ pain control should be addressed when patients are discharged from one clinical area to another. Many PACUs establish the criterion that patients must achieve a pain rating of 4 on a scale of 0 to 10 or better before discharge; however, the expectation that all patients must be discharged from a given clinical unit with pain ratings less than an arbitrary number is unrealistic. This can lead to the unsafe administration of additional opioid doses to patients who are excessively sedated and is widely discouraged.7 Patient-specific assessment of each patient in totality is needed for safe postoperative care with fewer complications.47 Achieving optimal pain relief is best viewed on a continuum with the primary objective being to provide both effective and safe analgesia.7,39,48 Optimal pain control is the responsibility of every member of the health care team and begins with analgesic titration in the PACU followed by continued prompt assessment and analgesic administration after discharge from the PACU to achieve pain ratings allowing patients to meet their functional goals with relative ease. Although it may not always be possible to achieve a patient’s pain rating goal within the short time the patient is in an area like the PACU, this goal provides direction for ongoing analgesic care. Important information to give to the nurse assuming care of the patient on the clinical unit is the patient’s pain rating goal, how close the patient is to achieving it, what has been done thus far to achieve it (analgesics and doses), and how well the patient has tolerated analgesic administration (adverse effects). Pain is a complex phenomenon involving multiple underlying mechanisms. This characteristic underscores the importance of using more than one analgesic to manage pain, an approach called multimodal analgesia.49 Multimodal analgesia involves intentionally using a combination of pharmacologic and nonpharmacologic interventions and is recommended for the treatment of all types of pain.28,49,50 A multimodal regimen combines medications with different underlying mechanisms; this allows lower doses of each medication in the treatment plan, which reduces the potential for each to produce adverse effects.39 Furthermore, multimodal analgesia can result in comparable or greater pain relief than can be achieved with any single analgesic. Multimodal analgesia should be the rule rather than the exception in pain treatment. The most common analgesics used for postoperative pain management are nonopioid analgesics (e.g., acetaminophen, NSAIDs), opioid analgesics (e.g., morphine, hydromorphone, fentanyl, and oxycodone), local anesthetics, and coanalgesic preparations. A multimodal approach in the perioperative setting may combine agents from each of these analgesic groups to provide effective pain relief and help minimize adverse effects. Unless contraindicated, all surgical patients should routinely be given acetaminophen and an NSAID in scheduled doses throughout the postoperative course. Although there has been recent debate about the benefit of preemptive analgesia, evidence suggests that it is preferable to initiate these medications preoperatively with the goal to reduce surgical pain.51 Opioid analgesics are added to manage moderate to severe postoperative pain in most patients. For some major surgical procedures, a local anesthetic is administered with an opioid epidurally or alone by continuous peripheral nerve block. An anticonvulsant medication may be added to the treatment plan as well to better control postoperative pain and possibly prevent the development of chronic pain situations.30 Alpha-2 agonists have substantial analgesic effect with fewer side effects than opioids including respiratory depression.52 Multimodal analgesia is the recommended approach for the management of postoperative pain.50 As the patient’s primary pain managers, perianesthesia nurses can ensure the prescription of analgesics such as nonopioids that are appropriate for the multimodal pain treatment plan. Perioperative administration of the nonopioid medications and nonpharmacologic interventions can improve postoperative pain control, reduce opioid requirements and opioid-induced nausea and vomiting, and facilitate patient participation in important recovery activities without increasing the risk of bleeding in the surgical patient. Nurses need to remain current with research and literature as new integrative multimodal analgesia information becomes available. One principle of pain management is to use the oral route of administration whenever feasible.39 When the oral route is not possible (e.g., patients who cannot swallow, can receive nothing by mouth, or are nauseated), other routes of administration are used. In the perioperative setting, the intravenous (IV) route is the first-line route of administration for analgesic delivery; patients are transitioned postoperatively to the oral route as tolerated. Other methods to manage pain use catheter techniques, such as intraspinal analgesia and continuous peripheral nerve block infusions. Nurses have an extensive role in the successful management of these therapies.3,53 The American Society for Pain Management Nursing (http://www.aspmn.org) provides guidelines for nurses who care for patients experiencing pain. Topical local anesthetics can be used for acute procedural pain. Other second-line routes of local anesthetic administration, such as transdermal and subcutaneous, are generally reserved for management of chronic pain. The primary disadvantages of transdermal medication delivery are that the skin serves as both a barrier and a reservoir. There is significant lag time before the effects of the medication are felt after transdermal patch application, and the medication continues to enter the systemic circulation for a variable period after the patch is removed.53 The nonopioid analgesic group includes acetaminophen and NSAIDs. There are two categories of NSAIDs: the nonselective NSAIDs (e.g., ibuprofen, naproxen, diclofenac, ketorolac), which inhibit both COX-1 and COX-2, and the COX-2–selective NSAIDs (e.g., celecoxib), which inhibit only COX-2 (see Fig. 31.2). Nonopioids are flexible analgesics used for a wide spectrum of painful conditions. They are appropriate alone for mild to some moderate nociceptive-type pain (e.g., from surgery or trauma) and are added to opioids, local anesthetics, or anticonvulsants as part of a multimodal analgesic regimen for more severe nociceptive pain.54 Acetaminophen and an NSAID can be given concomitantly, and there is no need for staggered doses.54,55 Acetaminophen is versatile in that it can be given via multiple routes of administration including oral, rectal, and IV. IV acetaminophen is approved for treatment of pain and fever in adults and children aged 2 years and older and is given by a 15-minute infusion in single or repeated doses. It can be given alone for mild to moderate pain or moderate to severe pain with adjunctive opioid analgesics and has been shown to be well tolerated and to produce a significant opioid dose-sparing effect and superior pain relief when compared with placebo. Postoperative nausea and vomiting (PONV) has been reduced with IV acetaminophen.56 Although it is argued that no specific advantage has been proven for the oral versus IV use of acetaminophen, the faster onset of action, bypassing the first-pass effect with the liver and increased pharmacodynamic and pharmacokinetic predictability are benefits of IV administration.16 The maximum daily dose for IV acetaminophen is the same as for oral acetaminophen (e.g., 1000 mg every 6 hours, for maximum of 4000 mg in adults; 3000 mg in older adults and adolescents weighing more than 50 kg; 15 mg/kg every 6 hours in adults, adolescents, and children weighing less than 50 kg). For surgical pain, an NSAID can be added to both acetaminophen and opioid as part of a multimodal plan, with the combination most often resulting in improved analgesia with fewer side effects and less opioid consumption.57 A meta-analysis of perioperative multimodal analgesia, the inclusion of NSAID and acetaminophen together were more effective than a single nonopioid in reducing opioid consumption.58 This is likely related to the opioid-sparing effects of NSAIDs. Ketorolac, ibuprofen, and meloxicam are available in IV formulation. Research has shown all three IV NSAID formulations to be effective for postoperative pain following a wide variety of surgical procedures.59 Although further clinical experience and research are needed with IV ibuprofen, it is less COX-1 selective than ketorolac,60 which may result in fewer adverse effects than ketorolac (see Fig. 31.2). A multicenter study (n = 300) investigated patients with various types of surgeries. When the majority of patients (84%) were given a single preoperative dose of IV ibuprofen, they reported reduced pain and used more than 30% less opioid. The remaining patients were given two or more doses. The most common adverse event was infusion site pain.61 Acetaminophen is considered a relatively safe and effective component of postoperative multimodal analgesia.54,62,63 Its most serious complication is hepatotoxicity (liver damage) as a result of overdose. In the healthy adult, a maximum daily dose under 4000 mg is rarely associated with liver toxicity; however, there are some recommendations for adult doses not to exceed 3000 mg or 3250 mg per 24 hours.64 Concerns about accidental overdose of IV acetaminophen in children are related to errors in unintended inaccurate dosing and accidental unsupervised ingestions; however, the latter have been reduced with flow restrictors on bottles of the elixir formulation.65 Because in first-pass models there was 50% less acetaminophen exposure to the liver with IV acetaminophen when compared with oral, there may be less risk with the IV route.16,66 Its lack of effect on platelet aggregation and low incidence of gastrointestinal (GI) adverse effects make acetaminophen the analgesic of choice in individuals with renal insufficiency.67 Acetaminophen is the recommended medication for mild to moderate pain by the National Kidney Foundation.68 Acetaminophen has been shown to increase the international normalized ratio when administered with warfarin, but the likelihood of surgical bleeding as a result of perioperative acetaminophen intake is thought to be low.69,70 The investigators of a multicenter research study (n = 547) comparing acetaminophen with the NSAID diclofenac reported that acetaminophen was comparable to the analgesic benefit of diclofenac alone or in combination with acetaminophen.71 The NSAIDs reportedly have significantly more adverse effects than acetaminophen including bleeding, oliguria, renal dysfunction, and gastric toxicity/ulceration.72–74 Although many surgeons have concern regarding NSAIDs with increased risk of bleeding, the risks are likely dose-related and less concerning when dosed appropriately.75 The authors of a recent evidenced-based review of the literature concluded that prescribers need to consider factors specific to both the individual patient and the particular procedure to guide the cautious use of NSAIDs perioperatively.76 The primary underlying mechanism of NSAID-induced gastric ulceration is the inhibition of COX-1, which leads to a reduction in GI-protective prostaglandins62 (see Fig. 31.2). This effect is systemic rather than local and can occur regardless of the route of administration of the NSAID.54 GI adverse effects are also related to the dose and duration of NSAID therapy; the higher the NSAID dose and the longer the duration of NSAID use, the higher the risk of cumulative GI toxicity.74 This fact underscores the importance of administering the lowest dose for the shortest time necessary. Risk factors include advanced age (older than 60 years), presence of prior ulcer disease, and CV disease and other comorbidities. The use of a COX-2–selective NSAID (e.g., celecoxib) or the least ulcerogenic-nonselective NSAID (e.g., ibuprofen) is recommended if not contraindicated by CV risk.54 All NSAIDs carry a risk of CV adverse effects through prostaglandin inhibition, and the risk is increased with COX-2 inhibition whether it is produced by those labeled COX-2–selective NSAIDs (e.g., celecoxib) or those that are nonselective inhibitors of both COX-1 and COX-2 (e.g., ibuprofen, naproxen, ketorolac).54 One proposed underlying mechanism for this adverse effect is that any medication that inhibits COX-2 will have prothrombotic effects, and those that inhibit COX-2 to a much greater extent than COX-1 will promote thrombosis more than others because of a disturbance in the physiologic balance between thromboxane A2, which promotes platelet aggregation, and prostacyclin, which antagonizes platelet aggregation.77,78 Research study results continue to show elevated CV risk with both COX-1– and COX-2–selective NSAIDs.79,80 Earlier studies led to a 2005 black box warning from the U.S. Food and Drug Administration against the use of NSAIDs after coronary artery bypass graft surgery.81 Most nonselective NSAIDs increase bleeding time through inhibition of COX-1. This is both medication- and dose-related; therefore, the lowest dose of nonopioids with minimal or no effect on bleeding time should be used in patients or procedures with high risk for surgical bleeding. Options include acetaminophen and celecoxib.54 The authors of one systematic review of 12 studies involving 6581 patients reported that of those who received NSAIDs (n = 1785), moderate to severe bleeding occurred in 5.7% compared with 2.2% of the controls (n = 4796).82 With regard specifically to the NSAID ketorolac, meta-analyses have not demonstrated an association between ketorolac and bleeding perioperatively.83 NSAID-induced renal toxicity is relatively rare in otherwise healthy adults given NSAIDs during the short-term perioperative period.16 In addition to potential negative renal effects, NSAIDs can also have an untoward effect by increasing blood pressure through inhibition of prostaglandins negatively affecting the renal vasculature.84 Individuals with acute or chronic volume depletion or hypotension rely on prostaglandin synthesis to maintain adequate renal blood flow, and NSAID inhibition of prostaglandin synthesis in such patients can cause acute renal failure (ARF).85 In addition to older adults, patients at increased risk for ARF include those with cardiac failure, liver disease, diabetes, sepsis, systemic lupus erythematous, preexisting hypertension, preexisting renal impairment, advanced age, or left ventricular dysfunction and those being treated with angiotensin-converting enzyme inhibitors.16,54 Evidence demonstrates that NSAID-induced renal damage is related to both the dose and the duration used.84 Older adults and anyone with risk factors for ARF should be assessed frequently for adverse renal effects during perioperative NSAID therapy. Since the effects are dose dependent and greater with patients with comorbidities and at risk for complication, it is again important for prescription to be patient specific. It is generally recommended to avoid NSAIDs in patients with chronic renal failure and in any patient with a creatinine clearance less than 30 mL/min.84 Acetaminophen is a better choice in patients with significant renal risk. The inflammatory process is initiated when bone is fractured just as it is with any other tissue trauma. Prostaglandins have a central role in bone healing, providing a balance between bone formation and resorption.85 Despite the safe use of NSAIDs for decades to control pain associated with fracture, concerns have been raised about their use under these circumstances.54 Unfortunately, there is a scarcity of well-designed studies that examine the effects of NSAIDs on bone healing in humans, and the results are inconsistent.54 The studies that have been performed are retrospective in design and present conflicting findings. Evidence indicates that the effect on bone healing appears to be related to not only dosage and duration but also the timing of administration postoperatively with the most detrimental effect being during the early postoperative phase (e.g., 2–3 days).54,85 There have also been few studies evaluating NSAIDs and spinal fusion. In an effort to offer a balanced appraisal of existing limited data, several researchers have agreed that short-term use of an NSAID after skeletal surgery, for a period less than 2 weeks, can be considered safe and an option unless a patient has a comorbid condition that could negatively affect fracture healing.54 Since many spine surgeons may be reluctant to use NSAIDs postoperatively, acetaminophen and gabapentin in combination with preoperative education that includes setting realistic postoperative expectations are important components of their multimodal analgesia plan of care.86 First-line opioids for treatment of immediate postoperative pain are morphine, hydromorphone, and fentanyl. At a steady state (when equal amounts of a medication are entering and exiting the body), all opioids have similar characteristics, but differences are noted when administration is by bolus technique53 (Table 31.3). IV, Intravenous. * Doses are approximately equal to one another in terms of pain relief. From Pasero C, McCaffery M. Pain Assessment and Pharmacologic Management. St. Louis, MO: Elsevier; 2011.
31: Pain Management
Abstract
Keywords
Definition of pain
Types and categories of pain
Nociception and analgesic action sites
Transduction
Transmission
Perception
Modulation
Pathophysiology of neuropathic pain
Peripheral Mechanisms
Central Mechanisms
Harmful effects of unrelieved pain
Domains Affected
Specific Responses to Pain
Endocrine
↑ ACTH, ↑ cortisol, ↑ ADH, ↑ epinephrine, ↑ norepinephrine, ↑ GH, ↑ catecholamines, ↑ renin, ↑ angiotensin II, ↑ aldosterone, ↑ glucagon, ↑ interleukin-1, ↓ insulin, ↓ testosterone
Metabolic
Gluconeogenesis, hepatic glycogenolysis, hyperglycemia, glucose intolerance, insulin resistance, muscle protein catabolism, ↑ lipolysis
Cardiovascular
↑ Heart rate, ↑ cardiac workload, ↑ peripheral vascular resistance, ↑ systemic vascular resistance, hypertension, ↑ coronary vascular resistance, ↑ myocardial oxygen consumption, hypercoagulation, deep vein thrombosis
Respiratory
↓ Flows and volumes, atelectasis, shunting, hypoxemia, ↓ cough, sputum retention, infection
Genitourinary
↓ Urinary output, urinary retention, fluid overload, hypokalemia
Gastrointestinal
↓ Gastric and bowel motility
Musculoskeletal
Muscle spasm, impaired muscle function, fatigue, immobility
Cognitive
Reduction in cognitive function, mental confusion
Immune
Depression of immune response
Developmental
↑ Behavioral and physiologic responses to pain, altered temperaments, higher somatization, infant distress behavior, possible altered development of the pain system, ↑ vulnerability to stress disorders, addictive behavior, and anxiety states
Future pain
Debilitating chronic pain syndromes: postmastectomy pain, postthoracotomy pain, phantom pain, postherpetic neuralgia
Quality of life
Sleeplessness, anxiety, fear, hopelessness, ↑ thoughts of suicide
Pain assessment: the foundation
Challenges in Assessment
Reassessment of Pain
Pain Control on a Continuum
Multimodal analgesia: pharmacologic management of pain
Implications for practice
Routes of Administration
Nonopioid Analgesics
Adverse Effects of Nonopioids
Opioid Analgesics
Drug
Onset (min)
Peak (min)
Duration (h)
IV Equianalgesic Dose*
Morphine
5–10
15–30
3–4
10 mg
Fentanyl
3–5
10–15
2
100 mcg
Hydromorphone
5
10–20
3–4
1.5 mg
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