Acute Postoperative Pain

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 .

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.

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).