The noxious stimulus associated with thoracic surgery is among the most severe sources of postoperative pain and carries one of the highest incidences of persistent postsurgical pain (PPSP).^1,2 These procedures can be associated with intense pain throughout the perioperative encounter. In addition, inadequately controlled pain can compromise respiratory function, inhibiting coughing and deep breathing in the postoperative period and leading to atelectasis and pneumonia. The consequences of these acute conditions can negatively impact long-term outcomes, leading to increased patient morbidity and mortality.^3,4

The incidence of severe postoperative pain after thoracic surgery was already documented in the anesthesia literature of the 1960s.⁵ Subsequent investigations have shown that postoperative respiratory compromise was associated with surgical incision site.^6,7 By the 1980s, the benefits of adequate intraoperative and postoperative analgesia on respiratory function were being elucidated.^8,9 Today, pain after thoracic surgery is viewed as multifactorial. Patients experience acute pain in the days after surgery and some develop PPSP.¹⁰ A detailed understanding of the mechanisms of pain after thoracic surgery will allow for optimal management.

The evidence suggests that effective perioperative pain control can improve postoperative pain and recovery, reduce time to extubation, improve pulmonary function and gas exchange, and increase patient satisfaction.^9,11,12 Aggressive pain management strategies have also been identified as a method to reduce the incidence of chronic postthoracotomy pain.^1,10,13,14 In this chapter, we will discuss the pathophysiology of pain after thoracic surgery and how multimodal analgesia (MMA) with systemic and regional anesthesia techniques are used for pain management.

Description of Pain in Thoracic Surgery

Acute pain from thoracic surgery can arise from multiple pathways. Nociceptive, inflammatory, neuropathic, and referred pathways can each produce and modulate pain that becomes a total subjective experience for the patient undergoing thoracic surgery (Table 24.1).

Nociceptive stimuli can be transmitted via somatic afferent fibers or visceral afferent fibers. Nociceptive pain is the pain that results from activation of high-threshold peripheral (nociceptor) neurons by intense mechanical, chemical, or thermal noxious stimuli. It signals the presence, location, intensity, and duration of a noxious stimulus and fades once the peripheral driving force is removed.¹⁵

Nociceptive somatic stimuli are initially gathered by the anterior cutaneous branch (anterior midline to midclavicular line) and the lateral cutaneous branch (midclavicular line to side wall to back) of the intercoastal nerve for afferent transmission to the ipsilateral dorsal horn of the spinal cord. At the spinal cord, somatic afferent fibers ascend via the contralateral anterolateral system in the spinal cord to reach the limbic system of the thalamus and finally terminating at the somatosensory cortex. Skin incision, separation of muscle fibers, retraction of ribs, and the interruption of the parietal pleura all provide nociceptive somatic stimuli that can be perceived by the patient as nociceptive somatic pain.¹⁶

Nociceptive visceral stimuli are transmitted by the phrenic and vagus nerves following injury to the internal organs of the thorax, such as the thymus gland, heart, lungs and its tracheobronchial tree, and visceral pleura. These stimuli can be perceived by the patient as a dull, poorly localized pain.¹⁶

The tissue injury of thoracic surgery activates an inflammatory response. This response can be observed peripherally at nociceptors and centrally at the spinal cord and brain. The peripheral inflammatory response consists of the release of sensitizing inflammatory mediators that decrease the activation threshold of nociceptors that innervate the injured tissue.¹⁶ Examples of inflammatory mediators include prostaglandins, histamine, bradykinin, and potassium. Together, these mediators heighten pain sensitivity and describe the peripheral inflammatory pathway of pain as a component of the pain experience related to thoracic surgery. As a consequence of continued nociception and peripheral sensitization of pain, the central nervous system can undergo sensitization at the spinal cord through activation of N-methyl-D-aspartate (NMDA) receptors in response to central mediators, such as substance P, calcitonin gene-related peptide, and glutamate.¹⁵ Inflammatory pain can present soon after tissue injury and persist for days if inflammation is present. Patients are likely to report a tense, throbbing pain and hyperalgesia to heat with sensory and motor function remaining intact. Inflammatory pain and the related sensitization can be reversed and is the focus of acute pain management after thoracic surgery.

Neuropathic pain can also be produced from nerve injury during thoracic surgery to the intercostal nerves located within the neurovascular bundle at the inferior aspect of each rib (Fig. 24.1). Neuropathic pain has the unique characteristic of combining simultaneous sensory deficit to touch, pressure, and temperature with pain hypersensitivity, such as allodynia, hyperalgesia, or dysesthesia.¹⁵ This new sensory experience can contribute to pain and results from abnormal neuronal function. This hypersensitivity of neuropathic pain, which can spread beyond the distribution of the damaged intercostal nerve, can mask sensory loss. Neuropathic pain can be difficult to discriminate from inflammatory pain because both can arise spontaneously after tissue damage. Patients are likely to report neuropathic pain as a burning pain, spasmodic in onset with sensory loss along the nerve distribution in the affected intercostal space.

Referred pain to the ipsilateral shoulder following thoracic surgery can add to the burden of a patient’s pain experience. Prevalence of ipsilateral shoulder pain was observed to be 97% following thoracotomy.¹⁷ Studies concerning the etiology of this ipsilateral shoulder pain have identified the phrenic nerve as being the most likely source.¹⁸ There is direct evidence that blockade of the periphrenic fat pad at the diaphragm relieves postthoracotomy ipsilateral shoulder pain.^19,20 There is also supporting evidence that interscalene and stellate ganglion blockade have relieved ipsilateral shoulder pain, likely from concomitant blockade of the phrenic nerve that is commonly associated with these blocks.^21,22 ­Irritation or injury of the visceral pleura, the mainstem bronchi, diaphragm, or pericardium will produce sensory input carried by the phrenic nerve. Thoracostomy tubes can also irritate the phrenic nerve and produce ipsilateral shoulder pain.¹⁶ Because the phrenic nerve originates from C3 to C5, pain to the shoulder is thought to be referred most likely from phrenic nerve input at the site of thoracic surgery.

In summary, acute pain in thoracic surgery involves multiple nerve fibers and pathways (nociceptive, inflammatory, neuropathic, and referred) that produce and modulate the pain experienced by a patient. The pain experienced in the perioperative period has the potential to progress to PPSP, defined as discomfort that lasts for more than 3 to 6 months after surgery and wound healing. Furthermore, PPSP can progress to chronic pain with an incidence of 30% to 40% among those undergoing thoracotomy (see Chapter 25).¹⁵ Therefore it is imperative for the perioperative physician to understand and implement strategies to treat pain related to thoracic surgery, both to decrease acute postoperative pain and decrease the incidence of PPSP.

Multimodal Analgesia and Perioperative Analgesic Strategies

MMA incorporates two or more analgesic agents of different pharmacologic classes to provide superior analgesia and reduce individual class side effects. MMA targets various receptors along the pain pathway to block the transmission of nociceptive stimuli. Because the pain following thoracic surgery involves multiple nociceptive fibers and pathways, a multimodal analgesic strategy is recommended.²³ Combination therapy with different nonopioid analgesics can produce additive or synergistic effects, thereby minimizing opioid use and their associated adverse effects.^24,25

MMA has been shown to be superior to traditional opioid-based therapies for a variety of surgical procedures and is an integral component of enhanced recovery after surgery (ERAS) and anesthesia protocols.^23,25–27 An MMA regimen that incorporates regional and systemic anesthesia is strongly recommended by the ERAS Society and European Society of Thoracic Surgeons.²³ Thoracic surgery impairs pulmonary function and the respiratory depressant effects of opioid medications can lead to postoperative complications in this at-risk population. Opioids are also associated with an increase in postoperative nausea/vomiting (PONV), ileus, and can impair ambulation and possibly delay a patient’s recovery from thoracic surgery.²⁸ Nonopioids should be administered on a scheduled basis, reserving opioids for severe pain that is not relieved by other modalities. The advantages and disadvantages of various systemic analgesics are summarized in Table 24.2.

Opioids

Postthoracotomy pain was traditionally managed with opioid-based therapies.¹ Various routes of opioid administration have been investigated, including intramuscular (IM),²⁹ subcutaneous (SC),³⁰ continuous intravenous (IV) infusions,³¹ and epidural administration.³² IV opioids administered via patient-controlled analgesia (PCA) has been shown to be more effective than IM and SC injections and is also associated with higher patient satisfaction and recovery after surgery.^33–36 As discussed later in this chapter, epidural opioids can be administered in combination with local anesthetics or as a single solution. Regardless of the route or mode of administration, opioid-related adverse effects, such as PONV, constipation, sedation, cough suppression, and respiratory depression, have been shown to impede postoperative recovery.²⁴ MMA techniques that focus on opioid minimization have replaced opioid-based therapies as the preferred perioperative pain management strategy.

Acetaminophen

Acetaminophen has been incorporated into many enhanced recovery pathways and has been shown to reduce morphine consumption after major surgery.³⁷ In postthoracotomy patients, acetaminophen has been successful in reducing ipsilateral shoulder pain in patients with a thoracic epidural.¹⁷ It is available in oral, rectal, and IV formulations. IV formulations have greater drug bioavailability, but do not appear to enhance the quality of analgesia when compared with oral formulations.³⁸ IV formulations may be an alternative to patients not tolerating oral intake.³⁸

Acetaminophen is a well-tolerated medication that does not have the cardiovascular, gastrointestinal, and renal adverse effects associated with nonsteroidal antiinflammatory drugs (NSAIDs). High doses of acetaminophen can be hepatotoxic, and the total daily dose should be limited to less than 4000 mg per day. It is considered safe for patients at risk for renal failure.

Nonsteroidal Antiinflammatory Drugs

NSAIDs are a diverse class of analgesics that inhibit prostaglandin production via cyclooxygenase (COX) enzymes. NSAIDs can reduce opioid consumption and when combined with opioids can result in improved analgesia and a reduction in PONV and sedation compared with opioids alone.³⁹ In addition, the combination of NSAIDs and acetaminophen has been shown to be more efficacious than either class of medication alone.⁴⁰ High-quality evidence supports the combination of acetaminophen and NSAIDs for thoracic surgery and is strongly recommended by guidelines published by the ERAS Society.^23,41–43

Several small studies suggested that the antiinflammatory effects of NSAIDs may reduce the efficacy of surgical pleurodesis.⁴⁴ However, a recent randomized trial demonstrated that NSAIDs were noninferior to opioids when assessing pleurodesis efficacy.⁴⁵ NSAIDs may worsen renal function in patients who are elderly, hypovolemic, or have preexisting renal dysfunction. Many patients who undergo thoracic surgery are at risk for these conditions and an examination of their comorbidities should be accessed before administration.²³

Nonselective NSAIDs are associated with an increased risk of major cardiovascular events.⁴⁶ However, these adverse effects are more likely to be of concern with the long-term use of NSAIDs.⁴⁶ Multiple randomized controlled trials (RCTs) have demonstrated that the short-term use of perioperative NSAIDs does not increase the risk of mortality, cardiovascular events, surgical bleeding, or renal dysfunction.⁴⁷ Nevertheless, the U.S. Food and Drug Administration recently expanded its warning about NSAIDs increasing the risk of stroke and heart attack to include all classes of NSAIDs.⁴⁸

N-Methyl-D-Aspartate-Receptor Antagonists

Ketamine is a potent analgesic that mediates its effects through the antagonism of the NMDA receptor. In a large metaanalysis of 70 RCTs, ketamine was shown to reduce postoperative opioid consumption.⁴⁹ The greatest reduction in opioid consumption was seen in upper abdominal and thoracic surgeries. The opioid-sparing effects of ketamine were independent on the dose or timing of ketamine administration or the type of intraoperative opioid used.⁴⁹ In a prospective, randomized double-blinded study after thoracic surgery, the addition of ketamine to a morphine PCA reduced morphine consumption and decreased the number of nocturnal desaturations.⁵⁰

The use of ketamine in thoracic surgery is supported by both the ERAS Society and the 2018 American Society of Regional Anesthesia and Pain Medicine (ASRA) guidelines for IV ketamine for acute pain.^23,51 In the acute pain setting, subanesthetic doses of ketamine are used. Current recommendations state that bolus dosing should not exceed 0.35 mg/kg and infusions should not exceed 1 mg/kg/h in settings without intensive monitoring.⁵¹

Gabapentinoids

Gabapentinoids (gabapentin and pregabalin) are antiepileptic agents commonly used to treat neuropathic pain. Gabapentinoids have analgesic properties mediated by the alpha 2-delta subunits of presynaptic voltage-gated calcium channels and decreased excitatory neurotransmitter release.⁵²

In an RCT that studied its efficacy in postthoracotomy patients, perioperative gabapentin was ineffective in treating acute postthoracotomy pain or for the prevention of persistent postthoracotomy pain.⁵³ In a separate RCT, pregabalin was also ineffective in reducing the incidence of persistent postthoracotomy pain.⁵⁴ Perioperative gabapentinoids are currently not recommended for perioperative pain management in patients undergoing thoracic surgery.²³

Glucocorticoids

Glucocorticoids, including dexamethasone and methylprednisolone, are commonly administered during surgery because of their analgesic, antiemetic, antipyretic, and antiinflammatory properties.⁵⁵ The analgesic effect of dexamethasone is dose-dependent and at intermediate doses (0.11–0.20 mg/kg), a reduction in postoperative pain, opioid consumption, and PONV can be achieved.^56,57 The effect of a single administration of high-dose methylprednisolone (125 mg) in patients undergoing a video-assisted thoracoscopic surgery (VATS) lobectomy was a significant reduction in pain ratings, nausea, and fatigue without an increase in complications.⁵⁸

Glucocorticoids can be considered as part of a multimodal approach to treating PONV, postoperative pain, and airway edema. Compared with the evidence in PONV, the strength of evidence as part of a multimodal analgesic strategy for thoracic surgery is comparatively weak. Nevertheless, dexamethasone has a variety of systemic benefits that are useful in thoracic surgery and is strongly recommended.²³

Intravenous Lidocaine

High-quality evidence supports the use of perioperative intravenous lidocaine infusions for abdominal surgery.⁵⁹ Its utility in thoracic surgery is less clear. In a single, randomized trial of 40 patients, systemic infusions of lidocaine reduced acute postoperative pain and morphine consumption after thoracotomy.⁶⁰ In a separate study, systemic lidocaine failed to demonstrate benefit after VATS.⁶¹ More evidence is needed to determine the utility of perioperative lidocaine infusions for thoracic surgery.

Regional Anesthesia

Several regional anesthetic techniques are available for treating pain after thoracic surgery (Table 24.3). Techniques, such as the thoracic epidural anesthesia (TEA), thoracic paravertebral block (TPVB), and intercostal nerve block (ICNB) have been used for many decades in thoracic surgery and their benefits are well established in the literature.^62–64 In recent years, newer techniques, such as the erector spinae plane (ESP) block and the serratus anterior plane block (SAPB), have been developed. Early studies indicate that these blocks provide good analgesia, but additional evidence into their mechanism of action and safety is needed.⁶⁵

The choice of regional anesthetic technique should be dependent on the surgical approach, clinical circumstances, and the presence or absence of contraindications. For example, coagulopathy is a contraindication for a TEA, TPVB, and ICNB, but the risk-benefit ratio might be more favorable when considering ESP or SAPB. However, current guidelines from the ASRA for patients taking anticoagulants do not address the risks associated with newer blocks, such as ESP or SAPB, and caution should still be exercised because few data are available to guide clinicians.⁶⁶

In the era of enhanced recovery, TEA has for the most part been limited to patients undergoing an open thoracotomy. Patients undergoing minimally invasive procedures ­(robotic-assisted and thoracoscopic surgery) are more likely to ­receive either a TPVB, ICNB, ESPB, or SAPB. Each of these techniques can be performed as either a single injection, repeat injections, or via continuous infusions.

Thoracic Epidural Analgesia

It could be argued that the “gold standard” for analgesia after open thoracotomy is the thoracic epidural. TEA has been shown in multiple studies to provide effective analgesia and an epidural may be used intraoperatively as an infusion or intermittent bolus dosing. Large-scale metaanalyses have concluded that TEA is superior to systemic analgesia for postoperative pain relief.^62,67 TEA also reduces overall opioid consumption, which is often a goal of surgeons, anesthesiologists, and patients alike.⁶² Additional TEA benefits include decreased pulmonary complications, decreased bowel dysfunction, and improved patient satisfaction.⁶⁸

Typically, TEA serves as an adjunct to general anesthesia. Initiation of the epidural infusion intraoperatively is useful in establishing an adequate dermatomal band of analgesia and can reduce the intraoperative opioid requirements, as well as anesthetic requirements.^10,13 TEA infusions may consist of local anesthetic alone, opioid alone, or a combination. The optimal solution is debatable, although some evidence suggests that combining TEA local anesthetics and opioids produces superior analgesia compared with using epidural opioids or local anesthetics alone.⁶² Local anesthetic infusions alone in a multimodal platform with supplemental IV or oral opioids likely produces the most opioid reduction and least opioid-related adverse events. There are many local anesthetic-opioid mixtures using TEA with the common characteristics of long duration of action of the local anesthetic (ropivacaine or bupivacaine) and lipophilicity of the opioid (fentanyl or to a lesser degree ­hydromorphone). In a systematic review comparing various regional anesthetic techniques with systemic opioids, TEA with local anesthetic plus opioid, local anesthetic alone, or lipophilic opioid alone was superior to systemic routes of opioid administration.³² The studies yielded mixed results when comparing TEA with hydrophilic opioids alone and systemic opioid administration.³² Continuous delivery of an opioid by any route of administration, including the epidural route, is associated with a higher rate of respiratory depression than intermittent on-demand opioids. All current acute pain guidelines recommend a multimodal analgesic approach with intermittent delivery of opioids at the lowest possible dose. Thoracic epidural analgesia is best used within the context of MMA minimizing opioids and preferentially using opioids only intermittently as needed. Because patients recovering from thoracic surgery are at an increased risk for respiratory impairment, special consideration should be ­given to reducing overall opioid doses, and it is particularly crucial in patient with myasthenia gravis. Maintenance of analgesia throughout the postoperative period may be administered as a bolus or continuous infusion with the possibility of patient-controlled delivery. TEA is generally continued until chest tubes are removed a few days after surgery.