Short Abstract:
Although the name, acute postoperative pain, implies strictly the care provided after a surgical procedure and in practice often interpreted as the time in which the patient remains in the hospital. Acute postoperative pain care is an essential component of the patient’s perioperative and longitudinal care. Optimal postoperative pain management involves interventions well before the surgery as a part of surgical planning, immediately prior to the procedure, throughout the intraoperative period, the immediate postoperative time and into the out of hospital recovery period. In this chapter, we discuss evidenced based strategies and approaches to address the pain in these phases of care. Special populations such as opioid tolerant patients or those with systemic health conditions that affect responsiveness to analgesics are covered. And finally approaches to development of an inpatient pain service are discussed.
Keywords
Inpatient Pain Inpatient Pain, Ketamine Ketamine, Perioperative Perioperative, Sub-Anesthetic Sub-Anesthetic, Regional Anesthesia Regional Anesthesia
Key Points
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The process of nociception is a dynamic process (i.e., neuroplasticity) with multiple points of modulation. Persistent noxious input may result in relatively rapid neuronal sensitization and possibly persistent pain.
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Postoperative pain, especially when poorly controlled, results in harmful acute effects (i.e., adverse physiologic responses) and chronic effects (i.e., delayed long-term recovery and chronic pain).
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By preventing central sensitization, preventative analgesia may reduce acute and chronic pain. Although studies overwhelmingly support the concept of preemptive analgesia, the evidence from clinical trials is equivocal, mostly because of methodological issues.
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Multimodal analgesia entails use of multiple classes of analgesic drugs (acetaminophen, gabapentinoids, nonsteroidal antiinflammatory drugs [NSAIDs], ketamine, and others) to act on different receptors along the pain pathway. Different drugs act synergistically to enhance analgesia and reduce side effects resulting from use of an individual class of drugs. Use of multimodal analgesia is recommended whenever feasible.
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By allowing individual titration of analgesic drugs, use of patient-controlled analgesia (oral, subcutaneous, iontophoretic, intravenous, paravertebral, or epidural) may provide several advantages over traditional provider-administered analgesia (e.g., intramuscular or intermittent intravenous injections) in the management of postoperative pain.
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The incidence of respiratory depression from opioids is not significantly different among the various routes of administration (i.e., oral, intravenous vs. intramuscular vs. subcutaneous vs. neuraxial). Appropriate monitoring of patients receiving opioid analgesics is essential to detect those with opioid-related side effects, such as respiratory depression. When compared with systemic opioids, perioperative epidural analgesia may confer several advantages, including a facilitated return of gastrointestinal function and decrease in the incidence of pulmonary complications, coagulation-related adverse events and cardiovascular events, especially in higher-risk patients or procedures. However, the risks and benefits of epidural analgesia should be evaluated for each patient, and appropriate monitoring protocols should be used during postoperative epidural analgesia.
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Epidural analgesia is not a generic entity because different catheter locations (catheter-incision congruent vs. catheter-incision incongruent), durations of postoperative analgesia, and analgesic regimens (local anesthetics vs. opioids) may differentially affect perioperative morbidity.
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Postoperative pain management should be tailored to the needs of special populations (e.g., opioid-tolerant, pediatric, and obese patients, as well as those with obstructive sleep apnea) who may have different anatomic, physiologic, pharmacologic, or psychosocial issues.
Acknowledgment
The editors, publisher, and Drs. Robert W. Hurley, Nabil M. Elkassabany, and Christopher L. Wu would like to thank Dr. Jamie D. Murphy for her contribution to this chapter in the prior edition of this work. It has served as the foundation for the current chapter.
Fundamental Considerations
A revolution in the management of acute postoperative pain has occurred during the past four decades. Widespread recognition of the undertreatment of acute pain by clinicians, economists, and health policy experts has led to the development of a national clinical practice guideline for management of acute pain by the Agency for Healthcare Quality and Research (formerly the Agency for Health Care Policy and Research) of the U.S. Department of Health and Human Services. This landmark document includes acknowledgment of the historical inadequacies in perioperative pain management, importance of good pain control, need for accountability for adequate provision of perioperative analgesia by health care institutions, and a statement on the need for involvement of specialists in appropriate cases. In addition, several professional societies including American Society of Anesthesiologists (ASA), The Joint Commission, American Society of Regional Anesthesia and Pain Medicine, and American Pain Society have developed clinical practice guidelines for acute pain management or provided new pain management standards. With their knowledge of and familiarity with pharmacology, various regional anesthetic techniques, and the neurobiology of nociception, anesthesiologists are prominently associated with the clinical and research advances in acute postoperative pain management. Anesthesiologists developed the concepts of acute pain services (APS) (inpatient pain services), application of evidence-based practice to acute postoperative pain, and creation of innovative approaches to acute pain medicine (APM), all of which are a natural extension of the anesthesiologist’s role as a “perioperative physician,” consultant, and therapist throughout the institution, in addition to being a highly skilled expert in the operating room. Provision of effective analgesia for surgical and other medical patients is an important component of this multidimensional role. An area that is often challenging in the acute perioperative pain services (PPS) is the management of patients with acute surgical pain in addition to a baseline chronic pain. These patients are often not well served by the arbitrary distinction of “acute” versus “chronic” pain services in hospitals. Anesthesiologists are well trained to manage acute pain in the patient with concomitant chronic pain as a result of the strength of chronic pain curricula in current anesthesiology training programs. Although this chapter focuses on the patient who has acute perioperative pain, acute management of chronic pain in the hospitalized setting is discussed in Chapter 51 , “Management of the Patient with Chronic Pain.”
Pain Pathways and the Neurobiology of Nociception
Surgery produces tissue injury with consequent release of histamine and inflammatory mediators such as peptides (e.g., bradykinin), lipids (e.g., prostaglandins), neurotransmitters (e.g., serotonin), and neurotrophins (e.g., nerve growth factor). Release of inflammatory mediators activates peripheral nociceptors, which initiate transduction and transmission of nociceptive information to the central nervous system (CNS) and the process of neurogenic inflammation in which release of neurotransmitters (e.g., substance P and calcitonin gene-related peptide) in the periphery induces vasodilatation and plasma extravasation. Noxious stimuli are transduced by peripheral nociceptors and transmitted by A-delta and C nerve fibers from peripheral visceral and somatic sites to the dorsal horn of the spinal cord, where integration of peripheral nociceptive and descending modulatory input (i.e., serotonin, norepinephrine, γ-aminobutyric acid, enkephalin) occurs. Further transmission of nociceptive information is determined by complex modulating influences in the spinal cord. Some impulses pass to the ventral and ventrolateral horns to initiate segmental (spinal) reflex responses, which may be associated with increased skeletal muscle tone, inhibition of phrenic nerve function, or even decreased gastrointestinal motility. Others are transmitted to higher centers through the spinothalamic and spinoreticular tracts, where they induce supra-segmental and cortical responses to ultimately produce the perception of and affective component of pain.
Continuous release of inflammatory mediators in the periphery sensitizes functional nociceptors and activates dormant ones. Sensitization of peripheral nociceptors may occur and is marked by a decreased threshold for activation, increased rate of discharge with activation, and increased rate of basal (spontaneous) discharge. Intense noxious input from the periphery may also result in central sensitization (“persistent postinjury changes in the CNS that result in pain hypersensitivity”) and hyperexcitability (“exaggerated and prolonged responsiveness of neurons to normal afferent input after tissue damage”). Such noxious input may lead to functional changes in the dorsal horn of the spinal cord and other consequences that may later cause postoperative pain to be perceived as more painful than it would otherwise have been. The neural circuitry in the dorsal horn is extremely complex, and we are just beginning to elucidate the specific role of the various neurotransmitters and receptors in the process of nociception. However, it seems that certain receptors (e.g., N -methyl-D-aspartate [NMDA]) may be especially important for the development of chronic pain after an acute injury, although other neurotransmitters or second messenger effectors (e.g., substance P, protein kinase C) may also play important roles in spinal cord sensitization and chronic pain. Our understanding of the neurobiology of nociception has progressed from the hard-wired system proposed by Descartes in the 17th century to the current view of neuroplasticity in which dynamic integration and modulation of nociceptive transmission take place at several levels. There still are many gaps in our knowledge of the specific roles of various receptors, neurotransmitters, and molecular structures in the process of nociception.
An understanding of the neurobiology of nociception is important for appreciating the transition from acute to chronic pain. The traditional dichotomy between acute and chronic pain is arbitrary because acute pain may quickly transition into chronic pain. Noxious stimuli can produce expression of new genes (which are the basis for neuronal sensitization) in the dorsal horn of the spinal cord within 1 hour and these changes are sufficient to alter behavior within the same timeframe. Also, the intensity of acute postoperative pain is a significant predictor of chronic postoperative pain. Control of perioperative pain (e.g., preventive analgesia) and the manner in which it is implemented (e.g., multimodal perioperative pain management) may be important in facilitating short- and long-term patient convalescence after surgery.
Acute and Chronic Effects of Postoperative Pain
Uncontrolled postoperative pain may produce a range of detrimental acute and chronic effects. The attenuation of perioperative pathophysiology that occurs during surgery through reduction of nociceptive input to the CNS and optimization of perioperative analgesia may decrease complications and facilitate recovery during the immediate postoperative period and after discharge from the hospital.
Acute Effects
The perioperative period has a variety of pathophysiologic responses that may be initiated or maintained by nociceptive input. At one time, these responses may have had a beneficial teleological purpose; however, the same response to the iatrogenic nature of modern-day surgery may be harmful. Uncontrolled perioperative pain may enhance some of these perioperative pathophysiologies and increase patient morbidity and mortality. Attenuation of postoperative pain, especially with certain types of analgesic regimens, may decrease perioperative morbidity and mortality.
Transmission of nociceptive stimuli from the periphery to the CNS results in the neuroendocrine stress response, a combination of local inflammatory substances (e.g., cytokines, prostaglandins, leukotrienes, tumor necrosis factor-α) and systemic mediators of the neuroendocrine response. The dominant neuroendocrine responses to pain involve hypothalamic-pituitary-adrenocortical and sympathoadrenal interactions. Suprasegmental reflex responses to pain result in increased sympathetic tone, increased catecholamine and catabolic hormone secretion (e.g., cortisol, adrenocorticotropic hormone, antidiuretic hormone, glucagon, aldosterone, renin, angiotensin II), and decreased secretion of anabolic hormones. The effects include sodium and water retention and increased levels of blood glucose, free fatty acids, ketone bodies, and lactate. A hypermetabolic, catabolic state occurs as metabolism and oxygen consumption are increased and metabolic substrates are mobilized from storage depots. The extent of the stress response is influenced by many factors, including the type of anesthesia and intensity of the surgical injury, with the extent of the stress response being proportional to the degree of surgical trauma. The negative nitrogen balance and protein catabolism may impede convalescence; however, attenuation of the stress response and postoperative pain may facilitate and accelerate the patient’s recovery postoperatively.
The neuroendocrine stress response may enhance detrimental physiologic effects in other areas of the body. The stress response is likely a factor in the postoperative development of hypercoagulability. Enhancement of coagulation (i.e., decreased levels of natural anticoagulants and increased levels of procoagulants), inhibition of fibrinolysis, and increased platelet reactivity and plasma viscosity may enhance the incidence of postoperative hypercoagulable-related events such as deep venous thrombosis, vascular graft failure, and myocardial ischemia. The stress response may also enhance postoperative immunosuppression, the extent of which correlates with the severity of surgical injury. Hyperglycemia from the stress response may contribute to poor wound healing and depression of immune function.
Uncontrolled postoperative pain may activate the sympathetic nervous system and thereby contribute to morbidity or mortality. Sympathetic activation may increase myocardial oxygen consumption, which may be important in the development of myocardial ischemia and infarction, and may decrease myocardial oxygen supply through coronary vasoconstriction and attenuation of local metabolic coronary vasodilation. Activation of the sympathetic nervous system may also delay return of postoperative gastrointestinal motility, which may develop into paralytic ileus. Although postoperative ileus is the result of a combination of inhibitory input from central and local factors, an increase in sympathetic efferent activity, such as from uncontrolled pain, may decrease gastrointestinal activity and delay return of gastrointestinal function.
Nociceptors are activated after surgical trauma and may initiate several detrimental spinal reflex arcs. Postoperative respiratory function is markedly decreased, especially after upper abdominal and thoracic surgery. Spinal reflex inhibition of phrenic nerve activity is an important component of this decreased postoperative pulmonary function. However, patients with poor postoperative pain control may breathe less deeply, have an inadequate cough, and be more susceptible to the development of postoperative pulmonary complications. Activation of nociceptors may also initiate spinal reflex inhibition of gastrointestinal tract function and delay return of gastrointestinal motility.
Many detrimental postoperative pathophysiologic effects can occur in the perioperative period and can activate nociceptors and the stress response. Uncontrolled pain may activate the sympathetic nervous system, which can cause a variety of potentially harmful physiologic responses that may adversely increase morbidity and mortality. Nociceptor activation may also result in several detrimental inhibitory spinal reflexes. Control of the pathophysiologic processes associated with acute postoperative pain may attenuate the stress response, sympathetic outflow, and inhibitory spinal reflexes and contribute to improvements in morbidity, mortality, and patient-reported outcomes (e.g., health-related quality of life [HRQL], patient satisfaction).
Chronic Effects
Chronic persistent postsurgical pain (CPSP) is a largely unrecognized problem that may occur in 10% to 65% of postoperative patients (depending on the type of surgery), with 2% to 10% of these patients experiencing severe CPSP. Poorly controlled acute postoperative pain is an important predictive factor in the development of CPSP. The transition from acute to chronic pain occurs very quickly, and long-term behavioral and neurobiologic changes occur much sooner than was previously thought. CPSP is relatively common after procedures such as limb amputation (30%-83%), thoracotomy (22%-67%), sternotomy (27%), breast surgery (11%-57%), and gallbladder surgery (up to 56%). Although the severity of acute postoperative pain may be an important predictor in the development of CPSP, a causal relationship has not been definitively established, and other factors (e.g., area of postoperative hyperalgesia) may be more important in predicting the development of CPSP. One such factor may be the severity of the patient’s preoperative pain. Patients with more intense levels of preoperative pain may also develop a degree of CNS sensitization predisposing them to the increased likelihood of higher postoperative pain and the subsequent development of chronic pain. Thus, it is important that APS clinicians understand chronic pain conditions and involve themselves in the patient’s preoperative care. The increased involvement of the APM team in preoperative anesthesia clinics or services can positively attenuate the incidence and severity of postoperative pain.
Control of acute postoperative pain may improve long-term recovery or patient-reported outcomes (e.g., quality of life). Patients whose pain is controlled in the early postoperative period (especially with the use of continuous epidural or peripheral catheter techniques) may be able to actively participate in postoperative rehabilitation, which may improve short- and long-term recovery after surgery. Optimizing treatment of acute postoperative pain can improve HRQL. Postoperative chronic pain that develops as a result of poor postoperative pain control may interfere with patients’ activities of daily living.
Preventive Analgesia
The older terminology of “preemptive” analgesia referred to an analgesic intervention that preceded a surgical injury and was more effective in relieving acute postoperative pain than the same treatment following surgery. The precise definition of preemptive analgesia is one of the major controversies in this area of medicine and contributes to the question of whether preemptive analgesia is clinically relevant. Definitions of preemptive analgesia include what is administered before the surgical incision, what prevents the establishment of central sensitization resulting from incisional injury only (i.e., intraoperative period), what prevents central sensitization resulting from incisional and inflammatory injury (i.e., intraoperative and postoperative periods), or the entire perioperative period encompassing preoperative interventions, intraoperative analgesia, and postoperative pain management (i.e., preventive analgesia). The first two definitions are relatively narrow and may contribute to the lack of a detectable effect of preemptive analgesia in clinical trials. The rationale for preemptive analgesia was based on the inhibition of the development of central sensitization. Effectively, noxious input initiated by surgical procedures induced a state of CNS hyperactivity that accentuates pain. Although a very popular and discussed theory, a single analgesic treatment (either peripheral or neuraxial) before the incision does not reduce postoperative pain behaviors beyond the expected duration of the analgesic effect. When the block of nociceptive afferents diminishes, the surgical injury is able to reinitiate central sensitization. Clinical trials have been negative. For these reasons, this terminology has fallen out of favor.
As stated previously, intense noxious input (e.g., postoperative pain from the periphery) can change the CNS (i.e., central sensitization) to induce “pain hypersensitivity” and hyperexcitability (i.e., exaggerated and prolonged responsiveness of neurons to normal afferent input after tissue damage). Preventive analgesia is aimed at inhibiting the development of this type of chronic pain. This definition broadly includes any regimen given at any time during the perioperative period that controls pain-induced sensitization. Central sensitization and hyperexcitability can develop after the surgical incision in a patient who has no history of preoperative pain.
In contrast, some patients may already have existing acute or chronic pain and developed central sensitization prior to the surgical incision. These patients with preexisting pain may have even more intense pain in the postoperative period. This augmentation of preexisting pain can occur in the acutely hospitalized and even in those patients in subacute or chronic outpatient settings. Preventing the establishment of altered central processing by analgesic treatment may result in short-term (e.g., reduction in postoperative pain and accelerated recovery) and long-term (e.g., reduction in chronic pain and improvement in HRQL benefits during a patient’s convalescence). Unfortunately, many clinical studies (e.g., trials) lack clarity of study design and clear terminology of preemptive versus preventative analgesia.
Timing of the intervention may not be as clinically important as other aspects of preventive analgesia (i.e., intensity and duration of the intervention). An intervention administered before the surgical incision is not preventative if it is incomplete or insufficient such that central sensitization is not prevented. Incisional and inflammatory injuries are important in initiating and maintaining central sensitization. Confining the definition of preventative analgesia to only the intraoperative (incisional) period is not relevant or appropriate because the inflammatory response lasts well into the postoperative period and continues to maintain central sensitization.
Maximal clinical benefit is observed when there is complete multi-segmental blockade of noxious stimuli with extension of this into the postoperative period. Preventing central sensitization with intensive multimodal analgesic interventions could theoretically reduce the intensity or even eliminate acute postoperative pain/hyperalgesia and chronic pain after surgery.
Multimodal Approach to Perioperative Recovery/Enhanced Recovery after Surgery
The analgesic benefits of controlling postoperative pain are generally maximized when a multimodal strategy to facilitate the patient’s convalescence is implemented. Yet, postoperative pain treatment may not provide major improvements in some outcomes because it is unlikely that a unimodal intervention can be effective in addressing a complex problem such as perioperative outcomes. The complex nature of nociception and mixed mechanisms of generating surgical pain are also responsible for failure of unimodal analgesia to adequately address postoperative pain. Principles of a multimodal analgesia include using multiple strategies and drug classes to manage patient expectation and control postoperative pain to allow early mobilization, enteral nutrition, and to attenuate the perioperative stress response. These strategies include: patient education, local anesthetic-based techniques (local infiltration, peripheral nerve blocks, and neuraxial analgesia), and a combination of analgesic drugs that act via different mechanisms on different receptors within the pain transmission pathway to provide synergistic effect, superior analgesia, and physiologic benefits.
A multimodal approach to perioperative recovery to control postoperative pathophysiology and facilitate rehabilitation is an integral part of almost all enhanced recovery after surgery (ERAS) pathways and will result in accelerated recovery and decreased length of hospitalization. One of the key components of a multimodal analgesic regimen within any ERAS pathway is the minimization of opioid use and side effects from opioids by utilizing nonopioid analgesics and techniques. Patients undergoing major abdominal or thoracic procedures and who participate in a multimodal strategy have a reduction in hormonal and metabolic stress, preservation of total-body protein, shorter times to tracheal extubation, lower pain scores, earlier return of bowel function, and earlier fulfillment of intensive care unit discharge criteria when compared to patients receiving traditional pain management. ERAS pathways integrate the most recent evidence from surgery, anesthesiology, nociceptive neurobiology, and pain treatment, and transforms traditional care programs into effective postoperative rehabilitation pathways. This approach will decrease perioperative morbidity, costs of care, decrease the length of hospital stay, and improve patient satisfaction without compromising safety. ERAS pathways are more common in adult surgical patients, although there is increasing interest in utilizing ERAS in pediatric patients. Widespread implementation of these programs requires multidisciplinary collaboration, change in the traditional principles of postoperative care, additional resources, and expansion of the traditional APS, which may be limited in the current economic climate.
Treatment Methods
Many options are available for the treatment of postoperative pain, including systemic (i.e., opioid and non-opioid) analgesics and regional (i.e., neuraxial and peripheral) analgesic techniques. By considering patients’ preferences and making an individualized assessment of the risks and benefits of each treatment modality, the clinician can optimize the postoperative analgesic regimen for each patient. Essential aspects of postoperative monitoring of patients receiving various postoperative analgesic treatment methods are listed in Box 81.1 .
Analgesic Medication ∗
∗ Postoperative analgesia includes systemic opioids and regional analgesic techniques. This list incorporates some of the important elements of preprinted orders, documentation, and intravenous PCA and epidural analgesia daily care described in the ASA Practice Guidelines for Acute Pain Management.
Medication, concentration, and dose of drug
Settings of PCA device: demand dose, lockout interval, continuous basal infusion
Amount of drug administered (including number of unsuccessful and successful doses)
Limits set (e.g., 1- and 4-h limits on dose administered)
Supplemental or breakthrough analgesics
Routine Monitoring
Vital signs: temperature, heart rate, blood pressure, respiratory rate, average pain score
Pain score at rest and with activity, pain relief
Side Effects
Cardiovascular: hypotension, bradycardia, or tachycardia
Respiratory status: respiratory rate, level of sedation
Nausea and vomiting, pruritus, urinary retention
Neurologic Examination
Assessment of motor block or function and sensory level
Evidence of epidural hematoma
Instructions Provided
Treatment of side effects
Concurrent use of other CNS depressants
Parameters for triggering notification of the covering physician
Provision of contact information (24 hr/7 day per week) if problems occur
Emergency analgesic treatment if the PCA device fails
CNS , Central nervous system; PCA , patient-controlled analgesia.
Systemic Analgesic Techniques
Opioids
Advantages and Characteristics
Opioid analgesics are one of the cornerstone options for the treatment of postoperative pain. They generally exert their analgesic effects through μ-receptors in the CNS, although opioids may also act at peripheral opioid receptors. A theoretical advantage of opioid analgesics is that there is no analgesic ceiling. Realistically, the analgesic efficacy of opioids is typically limited by the development of tolerance or opioid-related side effects such as nausea, vomiting, sedation, or respiratory depression. Opioids may be administered by the subcutaneous, transcutaneous, transmucosal, or intramuscular route, but the most common routes of postoperative systemic opioid analgesic administration are oral and intravenous (IV). Opioids may also be administered at specific anatomic sites such as the intrathecal or epidural space (see later sections, “Single-Dose Neuraxial Opioids” and “Continuous Epidural Analgesia”).
There is wide intersubject and intrasubject variability in the relationship of opioid dose, serum concentration, and analgesic response in the treatment of postoperative pain. Serum drug concentrations may exhibit wider variability with certain routes of administration (e.g., intramuscular) than with others (e.g., IV). In general, opioids are administered parenterally (intravenously or intramuscularly) for the treatment of moderate to severe postoperative pain, in part because these routes provide a more rapid and reliable onset of analgesic action than the oral route does. Parenteral opioid administration may be necessary in patients who are unable to tolerate oral intake postoperatively. The transition from parenteral to oral administration of opioids usually occurs after the patient resumes oral intake and postoperative pain has been stabilized with parenteral opioids.
Intravenous Patient-Controlled Analgesia
Various factors, including the aforementioned broad interpatient and intrapatient variability in analgesic needs, variability in serum drug levels (especially with intramuscular injection), and administrative delays, may contribute to inadequate postoperative analgesia. A traditional prescribed as-needed (PRN) analgesic regimen probably cannot compensate for these limitations. By circumventing some of these issues, IV patient-controlled analgesia (PCA) optimizes delivery of analgesic opioids and minimizes the effects of pharmacokinetic and pharmacodynamic variability in individual patients. IV PCA is based on the premise that a negative-feedback loop exists; when pain is experienced, analgesic medication is self-administered, and when pain is reduced, there are no further demands. When the negative-feedback loop is violated, excessive sedation or respiratory depression may occur. Although some equipment-related malfunctions can occur, the PCA device itself is relatively free of problems, and most problems related to PCA use result from user or operator error.
A PCA device can be programmed for several variables, including the demand (bolus) dose, lockout interval, and background infusion ( Table 81.1 ). An optimal demand or bolus dose is integral to the efficacy of IV PCA because an insufficient demand dose may result in inadequate analgesia, whereas an excessive demand dose may result in a higher incidence of undesirable side effects such as respiratory depression. Although the optimal demand dose is uncertain, the data available suggest that the optimal demand dose is 1 mg for morphine and 40 μg for fentanyl in opioid-naïve patients; however, the actual dose for fentanyl (10-20 μg) is often less in clinical practice. The lockout interval may also affect the analgesic efficacy of IV PCA. A lockout interval that is too long may result in inadequate analgesia and decrease the effectiveness of IV PCA. A lockout interval that is too short allows the patient to self-administer another demand dose before feeling the full analgesic effect of the previous dose and thus may contribute to an increase in medication-related side effects. In essence, the lockout interval is a safety feature of IV PCA, and although the optimal lockout interval is unknown, most intervals range from 5 to 10 minutes, depending on the medication in the PCA pump; varying the interval within this range appears to have no effect on analgesia or side effects.
Drug Concentration | Size of Bolus ∗ | Lockout Interval (min) | Continuous Infusion |
---|---|---|---|
Agonists | |||
| |||
| 0.5-2.5 mg | 5-10 | — |
| 0.01-0.03 mg/kg (max, 0.15 mg/kg/h) | 5-10 | 0.01-0.03 mg/kg/h |
| |||
| 10-20 μg | 4-10 | — |
| 0.5-1 μg/kg (max, 4 μg/kg/h) | 5-10 | 0.5-1 μχg/kg/h |
| |||
| 0.05-0.25 mg | 5-10 | — |
| 0.003-0.005 mg/kg (max, 0.02 mg/kg/h) | 5-10 | 0.003-0.005 mg/kg/h |
| 0.1-0.2 mg | 5-8 | — |
| 0.5-2.5 mg | 8-20 | — |
| 0.2-0.4 mg | 8-10 | — |
| 2-5 μg | 4-10 | — |
Agonist-Antagonists | |||
| 0.03-0.1 mg | 8-20 | — |
| 1-5 mg | 5-15 | — |
| 5-30 mg | 5-15 | — |
∗ All doses are for adult patients unless noted otherwise. Units vary across agents for size of the bolus (mg vs. mg/kg vs. mcg vs. μg/kg) and continuous infusion (mg/kg/h vs. μχg/kg/h). The anesthesiologist should proceed with titrated intravenous loading doses if necessary to establish initial analgesia. Individual patient requirements vary widely, with smaller doses typically given to elderly or compromised patients. Continuous infusions are not initially recommended for opioid-naïve adult patients.
Most PCA devices allow administration of a continuous or background infusion in addition to the demand dose. Initially, routine use of a background infusion predicted certain advantages, including improved analgesia, especially during sleep; however, analgesic benefits of a background infusion have not been successful in opioid-naïve patients. A background infusion only increases the analgesic dosage used and the incidence of adverse respiratory events in the postoperative period, especially in adult subjects. Furthermore, use of a nighttime background infusion does not improve postoperative sleep patterns, analgesia, or recovery profiles. Although routine use of continuous or background infusion as part of IV PCA in adult opioid-naïve patients is not recommended, a background infusion in opioid-tolerant or pediatric patients may be effective (see later sections, “Opioid-Tolerant Patients” and “Pediatric Patients”) (also see Chapter 24).
When compared with traditional PRN analgesic regimens, IV PCA provides superior postoperative analgesia and improves patient satisfaction, but the presence of economic benefits is not clear. A metaanalysis revealed that IV PCA (vs. as-needed opioids) provides significantly better analgesia and patient satisfaction; however, these patients used more opioids and had a more frequent incidence of pruritus than those treated with PRN opioids, but there was no difference in the incidence of adverse events. With regard to economic outcomes, whether IV PCA is less expensive than traditional PRN intramuscular opioid administration is not clear because the calculations of cost are complex.
IV PCA may provide advantages when assessing other patient-related outcomes such as patient satisfaction; these outcomes have become more important as healthcare organizations use them as a measure of quality and a tool for marketing purposes. Patients usually prefer IV PCA over intravenously, intramuscularly, or subcutaneously administered PRN opioids. Greater patient satisfaction with IV PCA may be the result of superior analgesia and perceived control over the administration of analgesic medications and avoidance of disclosing pain or securing analgesic medication from nurses; however, the reasons for patient satisfaction are complex and many factors may contribute to or predict satisfaction with IV PCA. Although IV PCA use overall creates better satisfaction, the proper assessment of patient satisfaction can be complex.
The incidence of opioid-related adverse events from IV PCA is not different from that of PRN opioids administered intravenously, intramuscularly, or subcutaneously. The rate of respiratory depression associated with IV PCA is infrequent (approximately 1.5%) and is not more frequent than that with PRN systemic or neuraxial opioids. Factors that may influence the frequency and intensity of respiratory depression with IV PCA include use of a background infusion, advanced age, concomitant administration of sedative or hypnotic drugs, and coexisting pulmonary disease such as obstructive sleep apnea (OSA). IV PCA-related respiratory depression may also be caused by errors in programming or administration (i.e., operator error).
Non-Opioids
Nonsteroidal Antiinflammatory Agents
Nonsteroidal antiinflammatory drugs (NSAIDs) consist of a diverse group of analgesic compounds with different pharmacokinetic properties. The primary mechanism by which NSAIDs exert their analgesic effect is through inhibition of cyclooxygenase (COX) and synthesis of prostaglandins, which are important mediators of peripheral sensitization and hyperalgesia. In addition to being peripherally acting analgesics, NSAIDs can also exert their analgesic effects through inhibition of spinal COX. The discovery of at least two COX isoforms (i.e., COX-1 is constitutive and COX-2 is inducible) with different functions (i.e., COX-1 participates in platelet aggregation, hemostasis, and gastric mucosal protection, whereas COX-2 participates in pain, inflammation, and fever) has led to the development of selective COX-2 inhibitors that differ from traditional NSAIDs, which block both COX-1 and COX-2. The discovery of a COX-3 variant may represent a primary central mechanism by which acetaminophen and other antipyretics decrease pain and fever; however, the precise relationship between COX-3 and acetaminophen is still uncertain.
NSAIDs given alone generally provide effective analgesia for mild to moderate pain. NSAIDs are also traditionally considered a useful adjunct to opioids for the treatment of moderate to severe pain. Yet, some quantitative, systematic reviews suggest that NSAIDs, alone or in combination with opioids, may be more beneficial than previously thought ( Table 81.2 and Fig. 81.1 ). NSAIDs may be administered orally or parenterally and are particularly useful as components of a multimodal analgesic regimen by producing analgesia through a different mechanism from that of opioids or local anesthetics. Several meta-analyses have examined the analgesic efficacy of NSAIDs (including COX-2 inhibitors) and acetaminophen when added to IV PCA with opioids. Surprisingly and importantly, NSAIDs resulted in a statistically significant (but probably not clinically meaningful) reduction in pain scores. Although all regimens significantly decreased morphine consumption, only NSAIDs reduced risk for the opioid-related side effects of nausea, vomiting, and sedation.
Drug ∗ | Mean NNT † | 95% CI |
---|---|---|
Acetaminophen (1000 mg PO) | 3.8 | 3.4-4.4 |
Aspirin (600-650 mg PO) | 4.4 | 4.0-4.9 |
Aspirin (1000 mg PO) | 4.0 | 3.2-5.4 |
Diclofenac (50 mg PO) | 2.3 | 2.0-2.7 |
Diclofenac (100 mg PO) | 1.9 | 1.6-2.2 |
Ibuprofen (600 mg PO) | 2.4 | 1.9-3.3 |
Ketorolac (10 mg PO) | 2.6 | 2.3-3.1 |
Ketorolac (30 mg IM) | 3.4 | 2.5-4.9 |
Naproxen (550 mg PO) | 2.7 | 2.3-3.3 |
Celebrex (200 mg PO) | 3.5 | 2.9-4.4 |
Celebrex (400mg PO) | 2.1 | 1.8-2.5 |
Tramadol (100 mg PO) | 4.8 | 3.8-6.1 |
Gabapentin (600 mg PO) | 11 | 6.0-35 |
Codeine (60 mg) + acetaminophen (600-650 mg PO) | 4.2 | 3.4-5.3 |
Oxycodone (5 mg) + acetaminophen (325 mg PO) | 2.5 | 2.0-3.2 |
Codeine (60 mg PO) | 16.7 | 11.0-48.0 |
Morphine (10 mg IM) | 2.9 | 2.6-3.6 |
Oxycodone (15 mg PO) | 2.4 | 1.5-4.9 |
∗ Data obtained in part and modified from Bandolier with permission. http://www.bandolier.org.uk/booth/painpag/Acutrev/Analgesics/lftab.html .
† NNT in this case refers to the number of patients who must be treated to obtain greater than 50% relief of moderate to severe postoperative pain. NNT conveys statistical and clinical significance, is useful in comparing the efficacy of different interventions, and summarizes treatment effects in a clinically relevant manner. A lower mean NNT implies greater analgesic efficacy in this example. CI , confidence interval; IM , intramuscular; NNT , number needed to treat; PO , oral route.
Perioperative use of NSAIDs has several side effects, including decreased hemostasis, renal dysfunction, and gastrointestinal hemorrhage. Inhibition of COX and the formation of prostaglandins cause many of the side effects, which mediate many diverse processes throughout the body. Decreased hemostasis from NSAID use is from platelet dysfunction and inhibition of thromboxane A2 (generated by COX-1), an important mediator of platelet aggregation and vasoconstriction. Evidence of the effect of NSAIDs on perioperative bleeding is equivocal; a surveillance study of perioperative ketorolac administration did not demonstrate a significant increase in operative site bleeding. Whether NSAIDs may also have a deleterious effect on bone healing and osteogenesis is controversial. Although NSAIDs have been used following acetabular/hip fractures and hip replacement surgery to reduce heterotopic ossification, the short-term effect of NSAIDs on other skeletal tissues is less clear. Two recent systematic reviews indicated that when examining the highest-quality studies, there was no increased risk of nonunion with NSAID exposure. Certainly, a short-term NSAID regimen can be used for treatment of post-fracture pain without significantly increasing the risk of disrupted healing. A brief (<14 days) exposure to normal-dose NSAIDs (e.g., ketorolac <120 mg/day) was safe after spinal fusion; however, use of large-dose ketorolac (>120 mg/day) increased the risk of nonunion, suggesting a dose-dependent effect of perioperative NSAIDs on spinal fusion healing. Spine surgeons will more commonly err on the conservative side and refuse to have postoperative spine fusion patients receive NSAIDs.
Perioperative NSAID-induced renal dysfunction may occur in high-risk patients, such as those with hypovolemia, abnormal renal function, or abnormal serum electrolytes, because prostaglandins dilate the renal vascular beds and mediate diuretic and natriuretic renal effects. NSAIDs should not be withheld in patients with normal preoperative renal function, as euvolemic patients with normal renal function are unlikely to be affected, although NSAIDs may cause a clinically unimportant transient reduction in renal function in the early postoperative period in patients with normal preoperative renal function. Gastrointestinal bleeding may be more likely with NSAID intake because of inhibition of COX-1, which is required for the synthesis of cytoprotective gastric mucosal prostaglandins. Bronchospasm may be induced by NSAIDs (including aspirin). Because expression of peripheral COX-2 is increased during inflammation, selective inhibition of COX-2 could theoretically provide analgesia without the side effects associated with COX-1 inhibition. COX-2 inhibitors have a less frequent incidence of gastrointestinal complications and exhibit minimal platelet inhibition, even when administered in supratherapeutic doses. However, long-term use of COX-2 inhibitors has an excess cardiovascular risk such that rofecoxib was withdrawn from the market. The cardiovascular risks of COX-2 inhibitors are heterogeneous and influenced by many factors such as the specific medication, dosage, and patient characteristics. Issues surrounding the perioperative use of COX-2 inhibitors are slightly different from those of longer-term use of COX-2 inhibitors. The perioperative use of potent COX-2 inhibitors resulted in a higher rate of cardiovascular events in high-risk (coronary artery bypass grafting) but not lower-risk (major noncardiac surgery) patients. Celecoxib, a COX-2 inhibitor, has less COX-2 selectivity than other more potent COX-2 inhibitors (rofecoxib) and is still clinically available. Nissen and associates conducted a randomized controlled trial (RCT) of 24,081 patients randomly assigned to celecoxib, naproxen, or ibuprofen and found that celecoxib was noninferior to ibuprofen or naproxen with regard to cardiovascular safety. Liu and associates studied 10,873 patients admitted for total joint arthroplasty and concluded that perioperative use of NSAIDs was not associated with increased risk of postoperative myocardial ischemia and may reduce the hospital length of stay.
Another controversial topic regarding NSAIDs is the association with postoperative bleeding. It is not surprising that several metaanalyses indicate that COX-2 inhibitors, which exhibit minimal platelet inhibition even when administered in supratherapeutic doses, are not associated with an increase in perioperative bleeding. More recent metaanalyses also indicate that traditional NSAIDs (ibuprofen, ketorolac) are not associated with an increase in perioperative bleeding. Finally, some studies have been published suggesting a link between NSAIDs and anastomotic leak, but most studies are flawed or have preexisting selection bias and a metaanalysis did not demonstrate a statistically significant increase in incidence of anastomotic dehiscence with NSAIDs. Newer formulations of NSAIDs are approved for treatment of acute postoperative pain (IV ibuprofen, and intranasal ketorolac ). Cost of the new drugs remains to be an issue, especially in today’s cost-conscious healthcare environment.
Acetaminophen
Acetaminophen has been used for several decades and is believed to have a central role of action in analgesia. It has antipyretic and antiinflammatory properties. Its mechanism of action is through activation of descending serotonergic pathways in the CNS and via the inhibition of prostaglandin synthesis. It is used most often in conjunction with other medications as part of a multimodal analgesia protocol. Maximum recommended dose is 4 gm/day in adult patients. The US Food and Drug Administration (FDA) approved IV acetaminophen formulation for use in the United States in 2011. Sinatra and colleagues studied the efficacy of IV acetaminophen after joint arthroplasty in a placebo-controlled study. The study group had decreased pain scores, used fewer opioids, had a longer median time to morphine rescue compared to placebo, and were more satisfied with pain management. A metaanalysis of 865 patients enrolled in four clinical trials addressing the impact of addition of IV acetaminophen to multimodal analgesia after total hip and knee arthroplasty concluded that there was a significant decrease in pain score and opioid consumption on POD 1 to 3. Nausea and vomiting were decreased in the groups who received acetaminophen. However, the quality of the studies included in the analysis was questioned. Peak plasma concentration is achieved faster after IV versus oral administration of acetaminophen. Evidence to support the premise that increased bioavailability would enhance clinical efficacy is lacking. Cost effectiveness of the IV formulation and patient ability to tolerate oral intake, based on the targeted surgery, should be accounted for when considering integrating IV acetaminophen into a multimodal analgesia protocol. Data from 2013 show that the average increase in cost to hospitals adopting IV acetaminophen can be significant, based on its use.
Gabapentinoids
Gabapentin and pregabalin, antiepileptic drugs also used in the treatment of neuropathic pain, interact with calcium channel α 2 -delta ligands to inhibit calcium influx and subsequent release of excitatory neurotransmitters. However, oral pregabalin is absorbed more rapidly and has more absolute bioavailability (≥90% vs. <60%) than gabapentin. Despite these differences, oral gabapentin improves the analgesic efficacy of opioids both at rest and with movement, and reduces opioid consumption and opioid-related side effects, but with a possibly increased incidence of side effects such as sedation and dizziness. A metaanalysis investigating the analgesic efficacy of pregabalin for acute postoperative pain demonstrated use of pregabalin was associated with a decrease in opioid consumption and opioid-related side effects, but no difference in pain intensity. Another meta-analysis suggested that perioperative administration of pregabalin may provide additional analgesia in the short term but also results in an increase in side effects such as dizziness/light-headedness or visual disturbances.
Although gabapentinoids are commonly used as part of a multimodal analgesic regimen, it should be noted that there have been recent publications questioning the analgesic benefits of gabapentinoids. Several studies have noted that the quality of evidence for a clinically relevant benefit of gabapentinoids is low and the serious adverse events in available trials were poorly reported. When examining trials with low risk of bias, gabapentinoids may actually have a minimal opioid-sparing effect but the risk of serious adverse events seems increased, as the use of gabapentin is associated with increased rates of respiratory depression among patients undergoing laparoscopic surgery. Finally, gabapentinoids may not provide any additional analgesia for some surgical procedures including total hip arthroplasty. The use of gabapentinoids should be considered on an individual basis after surgery.
Ketamine
Ketamine is traditionally recognized as an intraoperatively administered anesthetic; however, small subanesthetic dose (analgesic) ketamine can facilitate postoperative analgesia because of its NMDA-antagonistic properties, which may be important in attenuating central sensitization and opioid tolerance. Ketamine can be administered orally, intravenously (PCA or as a continuous infusion), subcutaneously, or intramuscularly. A systematic review of perioperative ketamine use found that perioperative analgesic doses of ketamine reduce rescue analgesic requirements and pain intensity. In addition, perioperative ketamine reduced 24-hour PCA morphine consumption and postoperative nausea or vomiting and had minimal adverse effects. A subsequent systematic review found that IV ketamine for postoperative analgesia was an effective adjunct for postoperative analgesia, particularly in patients undergoing painful procedures such as upper abdominal, thoracic, and major orthopedic surgeries. The administration of ketamine in postoperative pediatric patients is also associated with decreased postoperative pain intensity. One potential concern is the possible impact of ketamine’s amnestic effects on the neuropharmacologic and cognitive level of patients with use of perioperative ketamine infusions. Although possible, these effects infrequently occur when the medication is given in analgesic doses. Ketamine has also been given epidurally and intrathecally, but racemic mixtures of ketamine are neurotoxic, and therefore the use of neuraxial racemic ketamine is strongly discouraged. Although further studies are needed to elucidate the specific parameters (e.g., dose, duration of use) for ketamine in the perioperative period, this analgesic can be considered on an individual basis as part of a multimodal approach to postoperative analgesia.
Tramadol
Tramadol is a synthetic opioid that exhibits weak μ-agonist activity and inhibits reuptake of serotonin and norepinephrine, although the relative degree of contribution of each modality to postoperative analgesia is not certain. Although tramadol exerts its analgesic effects primarily through central mechanisms, it may have peripheral local anesthetic properties and has been used as an adjunct for brachial plexus block. Tramadol is effective in treating mild to moderate postoperative pain and is comparable in analgesic efficacy to aspirin (650 mg), with codeine (60 mg), or ibuprofen (400 mg) (see Table 81.2 and Fig. 81.1 ). The addition of acetaminophen to tramadol (vs. tramadol alone) may decrease the incidence of side effects of tramadol without reducing its analgesic efficacy. Use of tramadol in IV PCA results in similar pain scores when compared with that from IV PCA opioids; however, the side effect profile is different between the two groups (i.e., a more frequent incidence of postoperative nausea/vomiting but lower pruritus with tramadol). Advantages of tramadol for postoperative analgesia include a relative lack of respiratory depression, major organ toxicity, depression of gastrointestinal motility, and a theoretically lower potential for abuse. Common side effects (overall incidence of 1.6%-6.1%) include dizziness, drowsiness, sweating, nausea, vomiting, dry mouth, and headache. Tramadol should be used with caution in patients with seizures or increased intracranial pressure and is contraindicated in those taking monoamine oxidase inhibitors.
Regional Analgesic Techniques
A variety of neuraxial (primarily epidural) and peripheral regional analgesic techniques may be used for the effective treatment of postoperative pain. In general, the analgesia provided by epidural and peripheral techniques (particularly when local anesthetics are used) is site-specific and superior to that with systemic opioids, and use of these techniques may even reduce morbidity and mortality. However, as with all approaches, the risks and benefits should be compared, especially regarding the controversies about use of these techniques in the presence of various anticoagulants.
Single-Dose Neuraxial Opioids
Administration of a single dose of opioid may be efficacious as a sole or adjuvant analgesic drug when administered intrathecally or epidurally. One of the most important factors in determining the clinical pharmacology for a specific opioid is its degree of lipophilicity (vs. hydrophilicity) ( Table 81.3 ). Once they have reached the cerebrospinal fluid (CSF) through direct intrathecal injection or gradual migration from the epidural space, hydrophilic opioids (i.e., morphine and hydromorphone) tend to remain within the CSF and produce a delayed but longer duration of analgesia, along with a generally more frequent incidence of side effects because of the cephalic or supraspinal spread of these compounds. Neuraxial administration of lipophilic opioids, such as fentanyl and sufentanil, provides a rapid onset of analgesia, and their rapid clearance from CSF may limit cephalic spread and the development of certain side effects such as delayed respiratory depression. The site of analgesic action for hydrophilic opioids is overwhelmingly spinal, but the primary site of action (spinal vs. systemic) for single-dose neuraxial lipophilic opioids is not as certain.
Property | Lipophilic Opioids | Hydrophilic Opioids |
---|---|---|
Common drugs | Fentanyl, sufentanil | Morphine, hydromorphone |
Onset of analgesia | Rapid onset (5-10 min) | Delayed onset (30-60 min) |
Duration of analgesia ∗ | Shorter duration (2-4 h) | Longer duration (6-24 h) |
CSF spread | Minimal CSF spread | Extensive CSF spread |
Site of action | Spinal ± systemic | Primarily spinal ± supraspinal |
Side effects | ||
Nausea and vomiting | Lower incidence with lipophilic than with hydrophilic opioids | |
Pruritus | Lower incidence with lipophilic than with hydrophilic opioids | |
Respiratory depression | Primarily early; minimal delay | Both early (<6 h) and delayed (>6 h) possible |
∗ The duration of analgesia varies. CSF , Cerebrospinal fluid.
The differences in pharmacokinetics between lipophilic and hydrophilic opioids may influence the choice of opioid aiming to optimize analgesia and minimize side effects for a particular clinical situation. Single-dose intrathecal administration of a lipophilic opioid may be useful in situations (e.g., ambulatory surgical patients) in which rapid analgesic onset (minutes) is combined with a moderate duration of action (<4 hours). Single-dose hydrophilic opioid administration provides effective postoperative analgesia and may be useful in patients monitored on an inpatient basis, for whom a longer duration of analgesia would be beneficial.
Single-dose epidural administration of lipophilic and hydrophilic opioids is used to provide postoperative analgesia, with considerations generally similar to those discussed for single-dose intrathecal administration of opioids. A single bolus of epidural fentanyl may be administered to provide rapid postoperative analgesia; however, diluting the epidural dose of fentanyl (typically 50-100 μg) in at least 10 mL of preservative-free normal saline will decrease the onset and prolong the duration of analgesia, possibly as a result of an increase in initial spread and diffusion of the lipophilic opioid. Single-dose epidural morphine is effective for postoperative analgesia and use of a single-dose hydrophilic opioid may be especially helpful in providing postoperative epidural analgesia when the epidural catheter’s location is not congruent with the surgical incision (e.g., lumbar epidural catheter for thoracic surgery). Smaller doses of epidural morphine may be required for elderly patients and thoracic catheter sites. Commonly used dosages for intrathecal and epidural administration of neuraxial opioids are provided in Table 81.4 .
Drug | Intrathecal or Subarachnoid Single Dose | Epidural Single Dose | Epidural Continuous Infusion |
---|---|---|---|
Fentanyl | 5-25 μg | 50-100 μg | 25-100 μg/h |
Sufentanil | 2-10 μg | 10-50 μg | 10-20 μg/h |
Alfentanil | — | 0.5-1 mg | 0.2 mg/h |
Morphine | 0.1-0.3 mg | 1-5 mg | 0.1-1 mg/h |
Hydromorphone | — | 0.5-1 mg | 0.1-0.2 mg/h |
Extended-release morphine ∗ | Not recommended | 5-15 mg | Not recommended |
∗ See package insert for details on dosage and administration.
Continuous Epidural Analgesia
Analgesia delivered through an indwelling epidural catheter is a safe and effective method for management of acute postoperative pain. Postoperative epidural analgesia can provide analgesia superior to that of systemic opioids ( Fig. 81.2 ). Of note, however, epidural analgesia is not a generic term but incorporates a wide range of options, including the choice and dose of analgesic drugs, location of catheter placement, and onset and duration of perioperative use. Although this section focuses on the postoperative management of epidural analgesia, intraoperative use of the epidural catheter as part of a combined epidural-general anesthetic technique results in less pain and faster patient recovery immediately after surgery than general anesthesia followed by systemic opioids does. Each of these options may affect the quality of postoperative analgesia, patient-reported outcomes, and even rates of morbidity and mortality.
Analgesic Drugs
Local Anesthetics
Epidural infusion of local anesthetic alone may be used for postoperative analgesia, but in general it is not as effective in controlling pain as local anesthetic-opioid epidural analgesic combinations are. The precise location of action of local anesthetics in the epidural space is not clear, and potential sites include the spinal nerve roots, dorsal root ganglion, or spinal cord itself. Epidural infusion of local anesthetic alone may be warranted for postoperative analgesia in an attempt to avoid opioid-related side effects; however, the sole use of local anesthetics is less common than the use of a local anesthetic-opioid combination because of a significant failure rate (from regression of sensory blockade and inadequate analgesia) and relatively high incidence of motor block and hypotension.
Opioids for Epidural Infusion
Opioids may be used alone for postoperative epidural infusion and do not generally cause motor block or hypotension from sympathetic blockade. There are differences between continuous epidural infusion (CEI) of lipophilic (e.g., fentanyl, sufentanil) and hydrophilic (e.g., morphine, hydromorphone) opioids. The analgesic site of action (spinal vs. systemic) of CEI of lipophilic opioids is not clear. Although some data suggest a benefit from epidural (vs. IV) infusion of lipophilic opioids, the overall advantage of administering CEI of lipophilic opioids alone is marginal.
The analgesic site of action for continuous hydrophilic opioid infusion is primarily spinal. Continuous infusion of a hydrophilic opioid may be especially useful for providing postoperative analgesia when the site of catheter insertion is not congruent with the site of surgery or when side effects (e.g., hypotension, motor block) are attributed to the epidural local anesthetic. Use of a continuous infusion rather than intermittent boluses of epidural morphine may result in superior analgesia with fewer side effects. CEI of hydrophilic opioids may provide analgesia superior to that of traditional PRN administration of systemic opioids.
Local Anesthetic-Opioid Combinations
Use of a local anesthetic and an opioid in an epidural infusion may have advantages over infusions consisting of a local anesthetic or opioid alone. When compared with a local anesthetic or opioid alone, a local anesthetic-opioid combination provides superior postoperative analgesia (including improved dynamic pain relief), limits regression of sensory blockade, and possibly decreases the dose of local anesthetic administered, although the effect on the incidence is uncertain. CEI of a local anesthetic-opioid combination also provides analgesia superior to that of IV PCA with opioids. It is unclear whether the analgesic effect of the local anesthetic and opioid in epidural analgesia is additive or synergistic. The choice of local anesthetic for CEI varies. In general, bupivacaine or ropivacaine is chosen because of the differential and preferential clinical sensory blockade with minimal impairment of motor function. Concentrations used for postoperative epidural analgesia are lower than those used for intraoperative anesthesia. The choice of opioid also varies, although many clinicians prefer a lipophilic opioid (e.g., fentanyl, sufentanil) to allow rapid titration of analgesia. Use of a hydrophilic opioid (morphine, hydromorphone) as part of a local anesthetic-opioid epidural analgesic regimen may also provide effective postoperative analgesia. The optimal local anesthetic and opioid dose that provides the lowest pain scores with the fewest medication-related side effects is unknown and further investigation is needed to determine the optimal combinations for other types of surgical procedures with different epidural catheter insertion sites and to compare the efficacy of these optimal continuous infusions with patient-controlled epidural analgesia (PCEA).
Adjuvant Drugs
A variety of adjuvants may be added to epidural infusions to enhance analgesia while minimizing side effects, but none has gained widespread acceptance. Two of the more studied adjuvants are clonidine and epinephrine. Clonidine mediates its analgesic effects primarily through the spinal dorsal horn α 2 -receptors on primary afferents and interneurons, as well as the descending noradrenergic pathway, and the epidural dose typically used ranges from 5 to 20 μg/h. Clinical application of clonidine is limited by its side effects: hypotension, bradycardia, and sedation. Hypotension and bradycardia are both dose dependent. Epidural administration of NMDA antagonists, such as ketamine, can theoretically be useful in attenuating central sensitization and potentiating the analgesic effect of epidural opioids, but additional safety and analgesic data are needed.
Location of Catheter Insertion
Insertion of the epidural catheter congruent to the incisional dermatome (i.e., catheter-incision–congruent analgesia) ( Table 81.5 ) results in optimal postoperative epidural analgesia by infusing analgesics to the appropriate incisional dermatomes, providing superior analgesia, minimizing side effects (e.g., lower extremity motor block and urinary retention), and decreasing morbidity. When compared with catheter-incision–congruent epidural analgesia, catheter-incision–incongruent epidural analgesia (e.g., low lumbar catheter placement for thoracic procedures) results in increased pain and early removal of the epidural catheter because of ineffective analgesia. By targeting delivery of analgesic drugs to the appropriate dermatomes, catheter-incision–congruent epidural analgesia may result in smaller drug requirements and decreased medication-related side effects. There is a more frequent incidence of lower extremity motor block with the use of lumbar epidural catheters, and an earlier-than-anticipated termination of epidural analgesia may also result. Use of a high thoracic epidural for abdominal or thoracic surgery does not inhibit sympathetic nerve activity in the lower extremities and may result in a relatively infrequent incidence of urinary retention, thus diminishing the need for routine bladder catheterization. Placement of thoracic epidural catheters is relatively safe, and a more frequent incidence of neurologic complications is not documented with placement of a thoracic (vs. lumbar) epidural catheter. Furthermore, the benefits of epidural analgesia in decreasing morbidity in patients undergoing abdominal and thoracic surgery are seen only with thoracic (congruent), not lumbar (incongruent) epidural catheter placement.
Location of Incision | Examples of Surgical Procedures | Congruent Epidural Catheter Placement |
---|---|---|
Thoracic | Lung reduction, radical mastectomy, thoracotomy, thymectomy | T4-8 |
Upper abdominal | Cholecystectomy, esophagectomy, gastrectomy, hepatic resection, Whipple procedure | T6-8 |
Middle abdominal | Cystoprostatectomy, nephrectomy | T7-10 |
Lower abdominal | Abdominal aortic aneurysm repair, colectomy, radical prostatectomy, total abdominal hysterectomy | T8-11 |
Lower extremity | Femoral-popliteal bypass, total hip or total knee replacement | L1-4 |
Side Effects of Neuraxial Analgesic Drugs
Many medication-related (opioid and local anesthetic) side effects can occur with the use of postoperative epidural analgesia, but before automatically ascribing the cause to the epidural analgesic regimen, other causes should be considered, such as small intravascular volume, bleeding, and low cardiac output leading to hypotension and cerebrovascular accident, pulmonary edema, and evolving sepsis leading to respiratory depression. Standing orders and nursing protocols for analgesic regimens, neurologic monitoring, treatment of side effects, and physician notification about critical variables should be standard for all patients receiving neuraxial and other types of postoperative analgesia (see Box 81.1 ).
Hypotension
The local anesthetics used in an epidural analgesic regimen may block sympathetic fibers and contribute to postoperative hypotension. Although the precise incidence of postoperative hypotension with postoperative epidural analgesia is uncertain, a systematic review of studies investigating postoperative analgesia found a mean (95% CI) incidence of hypotension for epidural analgesia as 5.6 (3.0%-10.2%). Strategies to treat noncritical hypotension caused by epidural analgesia include decreasing the overall dose of local anesthetic administered (by decreasing the rate or concentration), infusing an opioid epidural alone because it is unlikely that neuraxial opioid administration would contribute to postoperative hypotension, and treating the underlying cause of the decrease in blood pressure.
Motor Block
Use of local anesthetics for postoperative epidural analgesia may also contribute to lower extremity motor block in approximately 2% to 3% of patients, and this may lead to the development of pressure sores in the heels. A metaanalysis noted a mean incidence of motor block of 3.2% with PCEA. A lower concentration of local anesthetic and catheter-incision–congruent placement of epidural catheters for abdominal or thoracic procedures may decrease the incidence of motor block. Although motor block resolves in most cases after stopping the epidural infusion for approximately 2 hours, persistent or increasing motor block should be evaluated promptly, and spinal hematoma, spinal abscess, and intrathecal catheter migration should be considered as part of the differential diagnosis.
Nausea and Vomiting
Nausea and vomiting associated with neuraxial administration of single-dose opioid occurs in up to 50% of patients, and the cumulative incidence in those receiving continuous infusions of opioid may be as high as 80%. The overall data (neuraxial opioids and/or local anesthetic combined) suggest that the incidence of postoperative vomiting is similar between epidural analgesia and systemic opioids, although female patients will exhibit a more frequent incidence regardless of analgesic modality. The incidence of neuraxial opioid-related nausea and vomiting may be dose dependent, although a recent metaanalysis suggested that a larger dose (≥0.3 mg) of intrathecal morphine did not increase the risk of postoperative nausea or vomiting compared to smaller dose (<0.3 mg) of intrathecal morphine. Nausea and vomiting from neuraxial opioids may be related to the cephalad migration of opioid within the CSF to the area postrema in the medulla. Use of fentanyl alone or in combination with a local anesthetic in an epidural infusion is associated with a less frequent incidence of nausea and vomiting than infusions of morphine are. A variety of drugs have been used successfully to treat neuraxial opioid-induced nausea and vomiting, including naloxone, droperidol, metoclopramide, dexamethasone, ondansetron, and transdermal scopolamine.
Pruritus
Pruritus is one of the most common side effects of epidural or intrathecal administration of opioids, with an incidence of approximately 60% versus about 15% to 18% for epidural local anesthetic administration or systemic opioids. A systematic review of studies investigating postoperative analgesia found a mean (95% CI) incidence of pruritus for epidural analgesia as 16.1 (12.8%-20%) versus 13.8 (10.7%-17.5%) for IV opioid PCA. Although the cause of neuraxial opioid-induced pruritus is uncertain, peripheral histamine release is not the cause but may be related to central activation of an “itch center” in the medulla or activation of opioid receptors in the trigeminal nucleus or nerve roots with cephalad migration of the opioid. It is unclear whether the incidence of neuraxial opioid-related pruritus is dose dependent. Many drugs have been evaluated for the prevention and treatment of opioid-induced pruritus, which can be difficult to manage and quite bothersome for some patients. IV naloxone, naltrexone, nalbuphine, and droperidol appear to be efficacious for the pharmacologic control of opioid-induced pruritus. Serotonin receptor antagonists may also be an effective modality in the prevention of neuraxial opioid-induced pruritus. The use of epidural morphine is associated with postpartum reactivation of herpes simplex labialis.
Respiratory Depression
Neuraxial opioids used in appropriate doses are not associated with a more frequent incidence of respiratory depression than that seen with systemic administration of opioids. The incidence of respiratory depression with neuraxial administration of opioids is dose dependent and typically ranges from 0.1% to 0.9%. The incidence of respiratory depression, as defined by a slow respiratory rate, should be less than 1%. The precise incidence of respiratory depression in actual clinical practice may be difficult to determine, as there are many criteria (e.g., respiratory rate, oxygen saturation, partial pressure of carbon dioxide, and need to administer respiratory stimulants/reversal drugs) that have been used to define respiratory depression. Neuraxial lipophilic opioids cause less delayed respiratory depression than hydrophilic opioids, although administration of lipophilic opioids may cause early significant respiratory depression. Delayed respiratory depression is primarily associated with the cephalad spread of hydrophilic opioids, which typically occurs within 12 hours after injection of morphine. Risk factors for respiratory depression with neuraxial opioids include increasing dose, increasing age, concomitant use of systemic opioids or sedatives, possibility of prolonged or extensive surgery, and the presence of comorbid conditions (e.g., OSA). Clinical assessments, such as the respiratory rate, may not reliably predict a patient’s ventilatory status or impending respiratory depression. Treatment with naloxone (and airway management if necessary) is effective in 0.1- to 0.4-mg increments; however, because its clinical duration of action is relatively short in comparison to the respiratory depressant effect of neuraxial opioids, continuous infusion of naloxone (0.5-5 μg/kg/h) may be needed. Practice guidelines for the prevention, detection, and management of respiratory depression associated with neuraxial opioid administration have been published.
Urinary Retention
Urinary retention associated with the neuraxial administration of opioids is the result of an interaction with opioid receptors in the spinal cord that decreases the detrusor muscle’s strength of contraction. The incidence of urinary retention is more frequent with neuraxially administered opioids than when given systemically. Urinary retention does not depend on the opioid dose and may be treated with the use of low-dose naloxone, although at the risk of reversing the analgesic effect. Urinary retention occurred in 23.0% of patients, with the most frequent rate in those receiving epidural analgesia. However, the exact incidence of urinary retention seen clinically may be difficult to determine because patients who undergo major surgical procedures are often routinely catheterized.
Patient-Controlled Epidural Analgesia
Epidural analgesia has traditionally been delivered at a fixed rate or as a CEI; however, the administration of epidural analgesia through a patient-controlled device (PCEA) has become more common. Like IV PCA, PCEA allows individualization of postoperative analgesic requirements and may have several advantages over CEI, including lower drug use and better patient satisfaction. PCEA may also provide analgesia superior to that afforded by IV PCA.
PCEA is a relatively safe and effective technique for postoperative analgesia on routine surgical wards. Observational data from two series of over 1000 patients each reveal that more than 90% of patients with PCEA receive adequate analgesia, with a median pain score of 1 (of a possible 10) at rest and 4 with activity. The incidence of side effects is 1.8% to 16.7% for pruritus, 3.8% to 14.8% for nausea, 13.2% for sedation, 4.3% to 6.8% for hypotension, 0.1% to 2% for motor block, and 0.2% to 0.3% for respiratory depression. These rates are favorable and comparable to those reported with CEI.
The optimal PCEA analgesic solution and delivery parameters are unclear. Use of a continuous or background infusion in addition to the demand dose is more common with PCEA than with IV PCA and may provide analgesia superior to that of the use of a demand dose alone. In general, most acute pain specialists have gravitated toward a variety of low-concentration local anesthetic-opioid combinations ( Table 81.6 ) in an attempt to improve analgesia while minimizing side effects, such as motor block and respiratory depression. As for CEI, addition of an opioid to the local anesthetic can provide analgesia superior to that of either analgesic alone. A lipophilic opioid is usually chosen because its rapid analgesic effect and shorter duration of action may be more suitable for use with PCEA. Use of lower concentrations of a local anesthetic (e.g., bupivacaine, ropivacaine) may provide excellent analgesia without significant motor block.