1. Nonsteroidal anti-inflammatory drugs (NSAIDs, Table 38.1) can effectively treat mild to moderate pain, particularly pain associated with inflammatory conditions. Drugs classified as NSAIDs have diverse chemical structures, but all share the ability to inhibit the enzyme cyclooxygenase (COX) and thereby inhibit the formation of prostaglandins from arachidonic acid. Combination therapy with the addition of NSAIDs to opioid during the perioperative period can often provide synergistic analgesia and reduce opioid-related side effects. Although it is important to avoid NSAIDs in patient populations at significant risk for toxicity, many patients having surgery can benefit from their addition.
   1. Mechanism of action. The apparent mechanism for analgesia produced by the NSAIDs is the prevention of neuronal sensitization by diminishing prostaglandin production. Type I cyclooxygenase (COX-1) is a constitutively expressed enzyme that is present in varying amounts in most cells at a fairly constant level. COX-1 serves a key role in cellular homeostasis and is the primary form of the enzyme present in platelets, the kidney, stomach, and vascular smooth muscle. COX-2 -selective inhibitors, developed with the goal to reduce side effects such as gastrointestinal (GI) bleeding associated with NSAIDs, have also been associated with a increase in the risk of adverse cardiovascular effects (eg, myocardial infarction and stroke). COX-2 inhibitors should be used with caution when cardiovascular risk factors are present and are contraindicated during coronary artery bypass graft surgery. Celecoxib is now the only available COX-2 inhibitor in the United States. For an overview of the NSAIDs according to their inhibition of COX and their selectivity for the COX-2 isoenzyme, see Table 38.1.

      Table 38-1 Classification of Common NSAIDs Based on COX Inhibition and Selectivity

      Aspirin Irreversible inhibition of both COX-1 and COX-2 Ibuprofen, naproxen Reversible, competitive inhibition of both COX-1 and COX-2 Ketorolac Nonselective COX-1 and COX-2 inhibition Indomethacin Slower, time-dependent, but reversible inhibition of both COX-1 and COX-2 Celecoxib Slow, time-dependent, and highly selective COX-2 inhibition

   2. Toxicity from NSAIDs impacts primarily the GI, renal, hematologic, and hepatic systems.
      1. GI system. Dyspepsia is the most common side effect, and nonselective NSAIDs lead to asymptomatic ulcers in 20% to 25% of users within 1 week of administration. Complicated ulcers, including perforated ulcers, upper GI bleeding, and obstruction occur in a significant number of long-term NSAID users. Factors that increase the risk of NSAID-induced GI toxicity are shown in Table 38.2.

         Table 38-2 Risk Factors That Increase the Risk of NSAID-Induced GI Toxicity

         Age over 60 y Prior history of peptic ulcer disease Steroid use Alcohol use Use of multiple NSAIDs The first 3 mo of use

      2. Renal impairment occurs in some patients taking NSAIDs and results from reduction in renal perfusion due to inhibition of prostaglandin synthesis. In patients with contraction of their intravascular volume (eg, congestive heart failure, acute blood loss, and hepatic cirrhosis), renal perfusion is maintained through the vasodilatory effects of prostaglandins. Renal toxicity may manifest as acute interstitial nephritis or nephrotic syndrome. Acute renal failure occurs in as many as 5% of patients using NSAIDs; renal impairment typically resolves with the discontinuation of NSAID therapy but, rarely, progresses to end-stage renal disease. Factors that increase the risk of NSAID-induced renal toxicity are shown in Table 38.3.

         Table 38-3 Factors That Increase the Risk of NSAID-Induced Renal Toxicity

         Hypovolemia Acute blood loss Chronic diuretic use Low cardiac output (congestive heart failure) Hepatic cirrhosis Preexisting renal insufficiency

      3. Hematologic toxicity associated with NSAIDs takes the form of inhibition of normal platelet function. Platelet activation is blocked by the inhibitory effects of NSAIDs on cyclooxygenase and the secondary decrease of prostaglandin conversion to thromboxane A₂ (a platelet activator). Aspirin irreversibly acetylates cyclooxygenase, and thus, the platelet inhibition resulting from aspirin use persists for the 7 to 10 days required for new platelet formation. Nonaspirin NSAIDs induce reversible platelet inhibition that resolves when most of the drug has been eliminated. A recent metanalysis suggests that the effect of ketorolac on platelet function does not necessarily result in clinically appreciable postoperative bleeding.
      4. Hepatic toxicity may also result from NSAID use. Minor elevations in hepatic enzyme levels appear in 1% to 3% of patients. The mechanism appears to be immunologic or metabolic-mediated direct hepatocellular injury, with dose-related toxicity occurring with both acetaminophen and aspirin. Periodic assessment of liver function is recommended in those on long-term NSAID therapy.
      5. Inhibition of normal bone formation has been reported in both clinical and animal models. The clinical relevance to NSAID use in the immediate post–orthopedic surgery period and following acute fractures requires further study; despite the frequent use of NSAIDs to provide analgesia after orthopedic surgery and injury, there is little evidence that they dramatically affect healing.
   3. Clinical uses. NSAIDs are used most widely to treat the pain and inflammation associated with rheumatic and degenerative arthritides. They also serve as a useful adjunct to opioids for providing control of acute pain, often reducing opioid requirements and opioid-related side effects in the postoperative period. Numerous agents are available for oral administration, and several are available without prescription. Thus, they are among the most common first-line analgesics.
   4. Available formulations. Ketorolac and diclofenac are parenteral NSAIDs approved for clinical use in the United States. Both are potent analgesics and antipyretics, and several studies have demonstrated their usefulness in treating moderate postoperative pain. Ketorolac and diclofenac are nonselective NSAIDs, and despite a parenteral form, intravenous administration is still associated with GI toxicity similar to other orally administered NSAIDs. Familiarity with the dosing and administration of several oral NSAIDs as well as the parenteral formulations is an important tool for those treating acute pain. For a summary of comparative efficacy and dosages of commonly used nonopioid analgesics, see Table 38.4.

      Table 38-4 Selected Nonopioid Analgesics and Comparative Efficiency

      Drug Special Nonopioid Analgesic Dosage and Comparative Efficiency to Standards Common Brand Names Average Analgesic Dose (mg) Dose Interval (h) Maximum Daily Dose (mg) Analgesic Efficacy Compared With Standards Plasma Half-Life (h) Comments Acetaminophen Tylenol numerous 500-1000 PO, PR, or IV 4-6 4000 Comparable to aspirin 650 mg 2-3 Use with caution in presence of alcoholism or liver disease Rectal suppository available Aspirin (Salicylate) Numerous 500-1000 PO 4-6 4000 0.25 Because of risk of Reye syndrome, do not use in children under 12 y with possible viral illness Rectal suppository available Ibuprofen (Propionic acid) Advil numerous 200-400 PO 4-6 2400 Superior at 200 mg to aspirin 650 mg 2-2.5 Naproxen Naprosyn 500 PO initial 250 PO 6-8 1250 12-15 Indomethacin Indocin 25 PO 8-12 100 Comparable to aspirin 650 mg 2 Not routinely used because of high incidence of side effects Ketorolac (Pyrrolacetic acid) Toradol 15-30 IV or IM 6 150 first day, 120 thereafter Comparable to 6-12 mg morphine 6 Do not take >5 d Diclofenac (Phenyl acetic acid) Dyloject 75-150 IV or IM 24 150 daily 1-2 h Do not take >2 d Celecoxib (COX-2 inhibitor) Celebrex 100-200 PO 12 400 Not to be taken if allergic to sulfa

2. Acetaminophen is a para-aminophenol derivative with analgesic and antipyretic properties similar to NSAIDs. The exact mechanism by which acetaminophen exerts its effects has yet to be fully understood. Acetaminophen does not produce any significant peripheral inhibition of prostaglandin production. Acetaminophen causes no significant GI toxicity or platelet dysfunction, and there are few side effects within the normal dose range. Acetaminophen is entirely metabolized by the liver, and minor metabolites are responsible for the hepatotoxicity associated with overdose. The most common oral analgesics used to treat moderate to severe pain incorporate acetaminophen in combination with one of the opioids. Standing per os, per rectum, or IV dosing of 1 g of acetaminophen every 6 hours (<4 g/d) can be a very useful adjunct in the postoperative setting and can significantly improve pain and reduce opioid requirements.
3. Ketamine is an atypical dissociative anesthetic and potent analgesic that is an N-methyl-d-aspartate receptor (NMDA) receptor antagonist, which may play a role in decreasing central sensitization in the development of chronic pain. In contrast to opioids, spontaneous respiration and airway reflexes are relatively well maintained. Hypersalivation is a common side effect that can be eased by coadministration of an antisialagogue such as glycopyrrolate. Ketamine causes indirect stimulation of the sympathetic nervous system by inducing a catecholamine release. In high doses, ketamine causes a “dissociative” state and is associated with unpleasant side effects such as nightmares, which may be attenuated by concomitant administration of benzodiazepines. Use of ketamine as an adjuvant anesthetic has been shown to result in decreased opioid requirements in the immediate postoperative period in a majority of studies without significant increase in adverse outcomes and is especially useful in the management of perioperative pain in patients on chronic opioid therapy. Ketamine infusions (2.5-10 μg/kg/min) can be used as an intraoperative anesthetic adjunct for pain and has been shown to reduce opiate consumption in complex spine surgery up to 48 hours postoperatively. A Cochrane review of perioperative ketamine demonstrated both reduced pain and opioid consumption, increased time to first analgesic, and decreased postoperative nausea and vomiting, at the consequence of increased dysphoric side effects (hallucinations, unpleasant dreams, nystagmus). Ketamine bolus can also be used in the immediate postoperative period as a rescue analgesic, especially after opioid rescue has failed. Patients should be premedicated with a benzodiazepine to mitigate dysphoria and be monitored on telemetry (bolus 10-30 mg). A Cochrane review reported that 27 of 37 studies also demonstrated a significant reduction in postoperative pain with the use of ketamine.
4. Opiates and opioids. Opiates are among the most universally effective agents available for treating acute pain. Morphine, the prototypical opiate, is derived from the milk of the scored seed pod of the Oriental poppy, Papaver somniferum. Several other compounds can be derived directly through the chemical modification of morphine. Those drugs derived directly from morphine are termed the opiates. Other synthetic compounds have been produced that act via opiate receptors—all compounds that act via opiate receptors are termed the opioids. Although opioids form the cornerstone of effective acute pain management, they have significant side effects, and their long-term effectiveness is limited by tolerance, physical dependence, and the possibility of addiction. Common prescribing practices in the United States have led to an epidemic of prescription opioid misuse and abuse. Overdoses involving opioids killed nearly 47,000 people in 2018, and 32% of those deaths involved prescription opioids. Significant reform in physicians’ prescribing patterns represents the first step in addressing this public health issue. Opioids are extremely useful for treating acute pain; although they are in widespread clinical use, their long-term effectiveness for treating chronic, noncancer pain is less clear.
   1. Metabolism. Following injection, morphine rapidly undergoes hepatic conjugation with glucuronic acid; morphine remains largely in the ionized form at physiologic pH and is highly protein bound. The plasma concentration attained after an identical dose of morphine increases progressively with increasing age of patients. The plasma concentration of morphine correlates poorly with its pharmacologic effect. Analgesia and depressed ventilation correlate more closely with the cerebrospinal fluid (CSF) concentration. Of the metabolites morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G), M-6-G, although produced in smaller amounts (a ratio of 1:9 in M-6-G:M-3-G), is pharmacologically active producing both analgesia and respiratory depression via interaction with μ-opioid receptors. As a result, prolonged respiratory depression can occur in patients with renal failure as M-6-G elimination is significantly impaired. Unlike fentanyl, histamine release follows IV morphine administration resulting in a decrease in systemic vascular resistance and blood pressure.
   2. Side effects associated with opioid analgesics
      1. Respiratory depression. Opioids cause a dose-dependent reduction in the responsiveness of the brain stem respiratory centers to increases in arterial carbon dioxide tension (PaCO₂) that manifests as a reduction in breathing rate and at high doses, apnea.
      2. Sedation. Mediated through the limbic system.
      3. Pupillary constriction. Excitatory action on the autonomic segment of the Edinger-Westphal nucleus of the occulomotor nerve.
      4. Nausea and vomiting. Direct stimulation of the chemoreceptor trigger zone within the area postrema in the medulla.
      5. Constipation. Reduction in the propulsive peristaltic contractions of the small and large intestines.
      6. Bradycardia. Central stimulation of the vagal nucleus within the medulla.
   3. Tolerance. With continued use of substantial amounts of opioids, larger doses of the drug are required over time to produce the same physiologic effects. This phenomenon is called tolerance and is characteristic of the entire class of opioids.
   4. Physical dependence. The precipitation of a distinct withdrawal (abstinence) syndrome when the opioid is discontinued. Manifestations of opioid withdrawal include diaphoresis, hypertension, tachycardia, abdominal cramping, and nausea and vomiting. Physical dependence occurs in any individual given sufficient doses of opioid for extended periods of time and is not synonymous with the complex disease that is addiction, although it can contribute to the neurobiological mechanisms driving compulsive opioid-seeking behaviors.
   5. Opioid-induced hyperalgesia (OIH). This refers to a paradoxical increase in painful stimuli with opioid administration. This is thought to be secondary to the upregulation of compensatory pain pathways, of which the central glutaminergic system plays a central role. Discerning between OIH and tolerance is challenging, and as such, one must rule out an exacerbation of the patient’s pain syndrome before considering OIH as a contributor. Strategies to address OIH once it occurs include opioid rotation and gradual dose reduction.
   6. Forms of opioids
      1. Oral opioids are common agents used for the control of mild to moderate pain in those who are able to continue oral intake. Many agents are available as combination preparations containing an opioid along with acetaminophen. The duration of analgesic action for the orally administered opioids is similar and in the range of 3 to 4 hours. Commonly used oral opioids are listed in Table 38.5. In those with opioid tolerance or greater than average opioid requirements, oral opioid alone (without acetaminophen) should be used to avoid hepatic toxicity.

         Table 38-5 Common Oral Opioid and Opioid/Acetaminophen Combinations Used to Treat Mild to Moderate Pain

         Drug Equianalgesic Oral Dose (mg) How Supplied Acetaminophen — 325-, 500-, 625-mg tabs; 500-mg/15-mL elixir Codeine 60 15-, 30-, 60-mg tabs; 15-mg/5-mL elixir Acetaminophen with codeine — 300–15-, 300–30-, 300–60-mg tabs; 120–12/5-mL elixir Hydrocodone 60 (Available only in combination with acetaminophen) Acetaminophen with hydrocodone — 500–2.5-, 500–5-, 500–7.5-, 660–10-mg tabs; 500–7.5/15-mL elixir Oxycodone 10 5-mg tabs; 5-mg/5-mL elixir Acetaminophen with oxycodone — 325–5-, 500–5-mg tabs; 325–5/5-mL elixir Morphine 10 15-, 30-mg tabs; 10-, 20-mg/5-mL elixir Hydromorphone 2 2-, 4-, 8-mg tabs; 5-mg/5-mL elixir

      2. Intravenous (IV) opioids. Control of moderate to severe pain or treatment of those who are unable to tolerate oral intake often requires the use of IV opioids. The pharmacokinetic profiles of opioid analgesics administered intramuscularly are similar but somewhat more erratic owing to variations in the muscle blood flow compared with that seen with IV administration; however, there is significant discomfort with intramuscular (IM) administration. There is no maximum dose for any of the pure opioid agonists (either orally or parenterally), and the dose can be increased until acceptable analgesia is produced or intolerable side effects ensue. Patients who require large doses of opioids should be closely monitored during initial dose titration as marked respiratory depression and apnea may occur unexpectedly.
5. Muscle relaxants: Medications used in the treatment of pain associated with musculoskeletal systems and spasms have varying mechanisms of action and unique safety and side-effect profiles. These include but are not limited to GABA-B agonists such as baclofen, α₂-agonists such as tizanidine, 5-HT2 antagonists such as cyclobenazeprine, and even benzodiazpenes such as diazepam. The mechanisms of action, side effects, and suggested dosing can be found in Table 38.6.

   Table 38-6 Muscle Relaxants Used in the Management of Pain Related to Muscular Spasm

   Name Mechanism Suggested Dose Caution Baclofen GABA-B receptor agonist Starting dose: 5 mg PO up to 3 times daily Increase by 5 mg every 3 d, to max dose of 80 mg daily No hepatic or renal dose adjustments Transient dizziness, withdrawal syndromes, interactions with CNS depressants Tizanidine Central α-2 receptor agonist 2-4 mg PO 3 times daily Increase as tolerated up to maximum dose of 36 mg daily Caution in renal or hepatic impairment; dose adjustments necessary Hypotension, mild LFT elevation, and transient withdrawal syndrome with abrupt discontinuation Diazepam GABA-A receptor agonist 2 mg PO 2-3 times daily Contraindicated in hepatic impairment Sedation, potential for dependence, withdrawal syndromes with abrupt discontinuation, interaction with CNS depressants Cyclobenzaprine Centrally acting 5HT2 receptor antagonist 5 mg PO 3 times daily Can be increased to 7.5 or 10 mg PO 3 times daily for up to 3 wk Use avoided in hepatic impairment, elderly patients. Long-term use not recommended Anticholinergic effects including dizziness, dry mouth, visual disturbances, ocular hypertension, constipation, urinary retention, cardiac conduction disturbances

1. Gabapentin: Meta-analyses of preoperative use of gabapentin (250-500 mg) has shown decreased opioid use for 24 hours (by 35%), decreased pain at rest and with movement, decreased pruritus, nausea, and vomiting, but at the cost of increased dizziness and sedation.
2. α₂-Agonists: α₂-Agonists such as dexmedetomidine have been shown to decrease the risk of nausea and morphine consumption in the first 24 hours postoperatively without increased recovery times in abdominal surgery, and has also shown benefits in reducing pain scores and morphine consumption in the first 24 hours after cardiothoracic, breast, and bariatric surgery.
3. Lidocaine (IV): Meta-analyses of IV lidocaine infusion demonstrate decreased morphine consumption in both open and laparoscopic abdominal surgery. In addition, this review found moderate decreases in pain at both rest and with movement, time to first flatus and bowel movement (7 and 12 hours, respectively), as well as hospital stay. Proposed mechanisms suggest that lidocaine exerts its effects not only through sodium channel blockade but also through interactions with inflammatory signaling cascades and inhibition of excitatory responses in wide dynamic range neurons. Additional studies have shown benefits in reducing opioid consumption in the ambulatory surgery setting and in thoracic surgery patients who are nonneuraxial candidates. Of note, although lidocaine did not show remarkable differences in opioid consumption in the perioperative setting in breast surgery, patients had a lower rate of chronic pain at 3 and 6 months, respectively. Similar studies in spine surgery show a decrease in postoperative pain 1 and 3 months after complex spine surgery. Lidocaine infusions can also be continued postoperatively for inpatient management of pain in conjunction with interdisciplinary support between pain service anesthesiologists, surgeons, and nursing staff, provided appropriate monitoring for signs of lidocaine toxicity as well as anesthesiology staff who can be available at all times to specifically address concerns relating to lidocaine infusion use is present. Intralipid emulsion should be readily available if lidocaine infusions are to be considered. At our institution, the acute pain service is routinely consulted on these patients, and nurses are given specific instructions on how to reach the service at any time.

1. Patient-controlled analgesia (PCA) utilizes patient self-administration of opioid analgesia via a patient-activated infusion device. This method for delivering analgesics has evolved with the introduction of computer-controlled, programmable infusion pumps. The PCA paradigm holds that the timely administration of small intermittent doses of analgesics will allow maintenance of optimal plasma drug concentration while minimizing side effects and periods of poor analgesia associated with intermittent IV or IM administration. Typical PCA devices can be programmed to deliver a specified dose of opioid and then “lockout” further administration for a specified interval. Guidelines for PCA administration of common opioid analgesics are shown in Table 38.7. PCA provides superior analgesia in many settings where hospitalized patients experience acute pain. Patients are very accepting of this technology and are typically quite satisfied with the close degree of control of pain that PCA allows. The addition of a basal infusion to the PCA dosing regimen for opioid-tolerant patients is generally not recommended. Routinely including a basal infusion does not improve analgesia but increases the total opioid dose used and the frequency of opioid-related side effects.
   1. Advantages of PCA: PCA allows each patient to control their own pain relief, provides for rapid administration of analgesic immediately on patient request, has a high degree of patient acceptance and satisfaction, and reduces total opioid dose and related side effects.

      Table 38-7 Guidelines for Opioid Administration via IV PCA

      Drug (Concentration) Typical Demand Dose (Range) Typical Lockout Interval (Range) Morphine (1 mg/mL) 1 mg (0.5-3 mg) 10 min (5-12 min) Meperidinea (10 mg/mL) 10 mg (5-30 mg) 10 min (5-12 min) Fentanyl (10 μg/mL) 10 μg (10-20 μg) 10 min (5-10 min) Hydromorphone (0.2 mg/mL) 0.2 mg (0.1-0.5 mg) 10 min (5-10 min)

      ^a Use of meperidine has diminished, as this agent has an active metabolite, normeperidine, which can accumulate and lead to central nervous system excitation and seizures at very high doses.

   2. Disadvantages of PCA: PCA requires the patient’s ability to understand and follow directions, requires enough mobility to utilize the PCA option, requires availability of specific infusion pumps, and is subject to programming errors that can cause overdosing or underdosing.
2. Neuraxial analgesia. The pharmacology and clinical use of intrathecal and epidural opioids and local anesthetics has been covered extensively in Chapter 20. In this section, we will focus on the practical aspects for using neuraxial techniques to provide postoperative analgesia. The combined use of thoracic epidural analgesia with general anesthesia (when compared with general anesthesia with IV opioids) has demonstrated many advantages for abdominal and thoracic surgery including decreased length of hospitalization, improved postoperative pain control with less sedation, improved respiratory function, accelerated recovery of bowel function, improved lower-extremity blood flow, and reduced stress response. In addition, the use of thoracic epidurals has shown to decrease mortality in elderly thoracic trauma patients as compared with parenteral medications in the setting of two or more rib fractures.
   1. Intrathecal opioids can provide prolonged analgesia after a single injection. When a surgical procedure is to be carried out using spinal anesthesia, the addition of an opioid to the local anesthetic serves as a practical and effective means for improving postoperative analgesia. The technique is limited by the frequency of side effects at higher doses and the inability to provide complete analgesia for more extensive and painful procedures. There are two general classes of opioids used for spinal analgesia: those that are hydrophilic (eg, morphine) and those that are lipophilic (eg, fentanyl and sufentanil).
      1. Hydrophilic opioids are slower in onset (peak analgesic effect occurs between 20 and 60 minutes) but persist at significant levels within the CSF for prolonged periods of time. The prototypic hydrophilic agent is morphine. Although it produces prolonged analgesia, it has also been associated with a small incidence of delayed respiratory depression occurring as late as 18 to 20 hours after administration. This is believed to be due to the persistence of significant levels of the drug within the CSF for up to 24 hours and the rostral spread of drug within the CSF. Morphine 0.1 to 0.3 mg can provide analgesia for up to 8 to 24 hours; however, patients should remain hospitalized and observed periodically to detect and promptly treat delayed respiratory depression with this agent. The depression of ventilation can be difficult to detect because patients may demonstrate a relatively normal respiratory rate; however, hypoxemia detected by pulse oximetry, PaCO₂ (with bimodal peak of approximately 6 and 18 hours) detected by blood gas, and clinically depressed level of consciousness can point to undesired respiratory effects.
      2. Lipophilic opioids have a rapid onset (peak analgesic effect within 5-10 minutes), greater systemic absorption, and a short duration of analgesic action (2-4 hours). Delayed respiratory depression has not been observed with the lipophilic opioids. Fentanyl 10 to 25 μg or, less commonly, sufentanil 2.5 to 10 μg is often combined with small doses of local anesthetic to provide surgical anesthesia and postoperative analgesia for outpatient surgery.
   2. Epidural opioids. Opioid analgesics also provide effective analgesia when administered into the epidural space. They can be administered as single-bolus injections, but it is far more common to place a catheter and administer combinations of opioid and low-dose local anesthetic to provide for continuous analgesia following surgery. It is imperative to understand the dermatomal extent of analgesia that can be expected from each agent and to place the injection at or near the midpoint of the dermatomal location of the surgical incision.
      1. Hydrophilic agents such as morphine or hydromorphone can be placed in the lumbar region and still provide analgesia for incisions that extend to the thoracic region, whereas fentanyl will not spread to the same extent.
      2. Local anesthetics provide analgesia only within the dermatomes adjacent to the site of injection. When administering combined opioid and local anesthetic infusions via an epidural catheter, we suggest an initial bolus to establish analgesia, prior to starting an infusion.
   3. Continuous epidural infusion and patient-controlled epidural analgesia (PCEA). Continuous epidural infusions of opioids or opioid–local anesthetic combinations result in fewer fluctuations in the concentration of the analgesic drug and allows for patient-controlled supplementation via PCEA using programmable infusion pumps identical to those used for IV PCA. As discussed above, IV PCA relies on the patient-administered intermittent bolus doses to provide analgesia, and continuous infusions are seldom needed. In contrast, when using PCEA, the continuous infusion provides most of the analgesia, and small intermittent patient-administered doses are used to supplement its effect. There is evidence that patients can safely receive epidural opioids while on the regular hospital ward, provided that an anesthesiology-based acute pain service is responsible for all adjustments of analgesic and sedative medications.
   4. Adverse effects associated with neuraxial opioid administration including sedation, pruritus, nausea, and vomiting, and urinary retention are common in patients receiving epidural or intrathecal opioids. Standing orders should be in place for addressing these common, minor side effects. Suggested standing orders for management of common side effects associated with neuraxial opioid administration are shown in Table 38.8.

      Table 38-8 Pharmacologic Management of Common Side Effects Associated With Neuraxial Opioid Administration

      Adverse Effect Standing Orders for Treatment Nausea Ondansetron 1-4 mg IV or dolasetron 12.5 mg IV Nalbuphine 1-3 mg IV or butorphanol 0.25-0.5 mg IV every 4 h as needed Pruritus Diphenhydramine 25-50 mg IV every 4 h as needed Nalbuphine 1-3 mg IV or butorphanol 0.25-0.5 mg IV every 4 h as needed Urinary retention Keep indwelling urinary catheter in place until discontinuation of the epidural analgesia Sedation or respiratory depression Notify acute pain service immediately, for respiratory rate less than 6/min Place supplemental oxygen 4 L/min via nasal cannula Administer naloxone 0.4 mg IV

   5. Treatment of inadequate analgesia in patients receiving continuous epidural infusions requires a systematic approach. A member of the acute pain service should be immediately available to assess the patient and determine the cause for inadequate analgesia. A common algorithm for responding to inadequate analgesia in patients receiving epidural analgesia is shown in Table 38.9. Daily management of the patient receiving epidural analgesia requires a systematic approach aimed at assuring safe and effective pain treatment. A suggested daily checklist that will guide patient management is shown in Table 38.10.

      Table 38-9 Suggested Management of Inadequate Analgesia in Patients Receiving Continuous Epidural Analgesia

      Assess the patient directly at the bedside to determine the cause for inadequate analgesia. If the patient is unable to respond in a timely fashion, consider alternate means for providing analgesia (eg, order a one-time IV dose of opioid by telephone; consider discontinuing epidural infusion and beginning IV PCA). Examine the patient for signs of a unilateral block or a dislodged or disconnected epidural catheter. Administer a bolus dose of the opioid or opioid–local anesthetic combination in use for continuous infusion. Choose the dose based on the severity of pain and use between ½ and 1 h worth of the medication (eg, 4- to 8-mL bolus of fentanyl 4 μg/mL/bupivacaine 0.0625% in a patient receiving 8 mL/h). If there is no improvement in pain relief within 20-30 min, consider test dosing the epidural catheter with 10 mL of 2% lidocaine. Do not administer a test dose unless the patient can be attended continuously and monitored with blood pressure checks at least every 5 min for 20 min after the bolus is given. Means for treating hypotension must be readily available (IV access and ready availability of a vasopressor such as ephedrine or phenylephrine). If no sensory or motor block appears within 20 min, replace or discontinue epidural catheter and begin an alternate means for providing analgesia (eg, IV PCA). If a bilateral sensory or motor block develops, readminister an epidural bolus of the medication in use for continuous infusion and increase the epidural infusion rate. Be alert for causes of inadequate analgesia (eg, a lumbar epidural catheter in use for pain following thoracotomy). Consider changing the opioid in use if the catheter location is suboptimal or there is an extensive incision.

      Table 38-10 Suggested Daily Checklist for Daily Management of Patients Receiving Epidural Analgesia

      Examine the nursing record for adjustments and supplemental analgesics as well as medications for side effects. Check vital signs for evidence of persistent fever or hypotension. Assess for adequate analgesia and side effects by directly questioning the patient. Be alert for sedation, pruritus, nausea and vomiting, and urinary retention. Examine the patient to detect signs of unilateral block or excessive sensory or motor block. Examine the epidural catheter site for signs of infection and the presence of an intact occlusive dressing. Interrogate the infusion pump to assess the patient’s use of supplemental doses, assure that it is properly programmed. Examine the infusion bag directly to be certain the medication ordered is what the patient is receiving. Document your interaction in detail in the patient’s chart and order any changes needed. Include when you anticipate changing or discontinuing therapy.

   6. Complications associated with epidural analgesia. Although the goal of epidural analgesia is to provide pain relief and minimize side effects, there are several serious complications associated with its use.
      1. Catheter migration into the intrathecal space can lead to increasing levels of sensory block and total spinal anesthesia.
      2. Indwelling epidural catheters can become infected directly at the skin entry site or through hematogenous seeding of the catheter tip within the epidural space. Superficial site infection is common and rarely needs treatment beyond the removal of the catheter. Extension of a superficial infection or direct seeding of the catheter tip to produce an epidural abscess is rare.
      3. Epidural hematoma formation is also uncommon but may follow epidural placement in a patient receiving systemic anticoagulants. Both epidural abscess and hematoma present with worsening back pain and neurologic deficit (urinary retention and sensory and motor loss in the lower extremities). The recognition and management of these complications are discussed in detail in Chapter 20.
3. Continuous peripheral nerve blocks using catheters are continuing to gain popularity in the inpatient as well as the ambulatory setting. The focus in this chapter is to outline a strategy for management of continuous nerve catheters in the postoperative period. For placement of peripheral nerve blocks, see Chapter 21. The availability of lightweight and sophisticated infusion pumps has greatly facilitated the use of continuous perineural infusions of local anesthetics. Ultrasound is now commonly used to guide catheter placement. Advances in technology and the emergence of the literature supporting continuous perineural infusions for improved postoperative analgesia and recovery have led to more widespread use of continuous perineural infusions of local anesthetics.
   1. Specific indications for continuous peripheral nerve blocks vary in terms of surgical site. For example, femoral and popliteal fossa nerve catheters are commonly used following below-the-knee amputations. Similarly, brachial plexus blocks using continuous infusion have also proven effective for surgery on the shoulder and upper extremity.
   2. Choice of drug, concentration, and infusion rate will depend on the target nerve or plexus, the surgical procedure, as well as the individual patient’s response. Infusion rates can be fixed or variable including the possibility of a bolus (patient-controlled regional anesthesia). Continuous peripheral nerve blocks are carried out by infusing local anesthetic alone (for example, 0.1% bupivacaine or 0.2% ropivacaine) at a rate of 5 to 10 mL/h.
   3. Management of continuous peripheral nerve catheters. Since the extremity will have decreased sensitivity for the duration of the block, care should be taken to prevent injury to exposed nerves. A properly fitted sling, brace, and thorough patient education are paramount to provide adequate protection. Given the high cumulative dose of local anesthetic, caution should be used in patients with renal failure and the drug should be avoided in those with hepatic failure. Daily follow-up of hospitalized patients with a perineural catheter should include close attention to specific aspects shown in Table 38.11.

      Table 38-11 Checklist for Daily Follow-Up of Patients With Perineural Catheters

      Inspect the catheter insertion site to assess for signs of infection, leaks, and catheter dislocation. Assure that ongoing analgesia is adequate. Assess the patient for signs of excessive motor and/or sensory block. Assess the patient for signs or symptoms of local anesthetic toxicity (local anesthetic toxicity is rare in the context of continuous perineural infusion, but the daily dose and any associated side effects should be assessed daily).

   4. Use of perineural catheters in ambulatory patients. Perineural catheters have been successfully employed in the ambulatory care setting. This requires careful patient selection, comprehensive patient education, and the implementation of a protocol for patient follow-up. Patient education should involve the patient’s caregiver and include instructions on how to operate the pump, signs of catheter-related complications (such as infection, migration, and leak), and signs of local anesthetic toxicity. Patients should be aware of the expected time for resolution of the block and should understand the necessity to abstain from driving or operating machinery. A plan for breakthrough pain management should be in place. Daily follow-up should be arranged, and provisions for immediate contact with an anesthesiologist should be available.

Patients with opioid tolerance or dependence represent a unique challenge to the anesthesiologist in the perioperative period. In contrast to the term addiction, dependence is defined by the World Health Organization as a cluster of physiological, behavioral, and cognitive phenomena in which the overwhelming desire and use of a substance, such as an opioid, takes on higher priority than other behaviors that once had value. Tolerance may or may not be present.

1. Perioperative management of patients with opioid tolerance or a history of opioid dependence. Concepts to consider when managing patients who have been taking large doses of opioids for chronic pain and those with current or previous history of an opioid use disorder are shown in Table 38.12.

   Table 38-12 Managing Patients With Opioid Tolerance or With Current or Previous Dependence

   Consider use of regional anesthesia (spinal opioids and epidural infusions) to improve analgesia and minimize systemic opioid effects. Use adjunctive analgesics whenever possible to reduce total opioid requirements (eg, NSAIDs, ketamine). Administer opioids liberally to control pain in the immediate postoperative period. Do not attempt to limit opioid dose or wean opioid analgesics in the immediate postoperative period. Those with significant tolerance will probably require higher-than-average doses to control acute pain. Use preoperative opioid doses as a baseline requirement and administer additional doses beyond this to control acute pain. This baseline requirement can be administered by continuing the preoperative long-acting opioid in addition to the use of a PCA. Consider consultation with a substance abuse specialist during hospitalization for those with ongoing opioid abuse or a history of addiction. Closely coordinate (communicate) the pain management with the patient’s primary care provider before hospital discharge. Although acute escalation in the opioid requirement is often necessary in the perioperative period, a plan for weaning the opioids to their previous levels should be established before the patient is discharged from the hospital.

2. Managing acute pain in patients on buprenorphine maintenance therapy. Buprenorphine, a semisynthetic, potent, and long-acting opioid, has been introduced for ambulatory treatment of patients with opioid dependence. It is a high-affinity partial agonist at the μopioid receptor and antagonist at the ƙ opioid receptor that at higher doses exhibits a plateau effect in regards to euphoria and respiratory depression. When prescribed in the outpatient setting, buprenorphine is often mixed with naloxone (Suboxone) to be taken sublingually. Naloxone has poor bioavailability after oral and sublingual administration; however, if the drug combination is administered intravenously in an attempt for abuse, naloxone is present in high-enough concentrations to precipitate acute withdrawal symptoms in opioid-dependent patients. The addition of naloxone aims at limiting both abuse and diversion of the drug. Buprenorphine alone (Subutex) is used for initial testing prior to initiating a buprenorphine therapy–based maintenance regimen in the opioid-addicted patient. Subutex has also gained some popularity for use in the treatment of chronic pain, owing to its limited abuse potential and significant efficacy as an analgesic agent. There is a paucity of data for the management of patients receiving buprenorphine who present for surgery. In addition to the general principles for managing patients with opioid tolerance or addiction discussed above, specific considerations for the patient receiving buprenorphine are shown in Table 38.13.

   Table 38-13 Perioperative Considerations for the Patient Receiving Long-Term Buprenorphine Treatment

   For patients undergoing elective surgery, data from clinical studies suggest a possible synergistic and additive effect between buprenorphine at low to moderate analgesic doses (8-12 mg SL or less) and full µ-opioid receptor agonists. At doses less 12 mg SL studies suggest an at least 20% µ-opioid receptor availability for binding by full agonists. Furthermore, studies also suggest that 50%-60% receptor occupancy is what is needed to avoid withdrawal symptoms in patients managed on buprenorphine. Thus, our institutional policy is as follows: For surgeries in which postoperative pain is expected to be mild, home dose buprenorphine is recommended to be continued. For those in which moderate to severe pain is expected, the management depends on the buprenorphine dose. For those managed on 16 mg buprenorphine or less, it is recommended to continue the home dose until the day before surgery, and to continue patients on a regimen of 8 mg daily plus additional full opioid agonists and adjunctive pain medications as needed to manage pain postoperatively. Once postoperative pain subsides, patients can resume their home dose. For those managed on greater than 16 mg of buprenorphine, it is recommended that patients titrate down their therapy over time with the goal of 16 mg on the day before surgery with the assistance of the physician responsible for prescribing their opioid agonist therapy. Patients are then maintained on 8 mg daily plus full opioid agonists as needed until the period of acute pain resolves and the home regimen can be reinstated after full agonists are tapered off. Of note, some institutions recommend that buprenorphine therapy be completely discontinued and replaced with a full opioid agonist (eg, morphine and hydromorphone) 48-72 h prior to the scheduled surgery, with full opioid agonist dosages adjusted as needed to treat acute pain in the perioperative period. Buprenorphine maintenance therapy can then be reinstated using an induction protocol, coordinated with the physician primarily responsible for the opioid agonist therapy to ensure safety and supervision of the necessary changes in the therapeutic regimen after the period of acute pain resolves, as the initial dose of buprenorphine can precipitate withdrawal symptoms. For patient requiring urgent or emergent surgery or when prior conversion to a full agonist is not feasible, a short-acting full agonist such as fentanyl can be titrated to effect. As is the case for patients maintained with other opioid agonists, higher-than-usual doses to achieve adequate analgesia are likely to be required. The appropriate dose of fentanyl in a patient taking buprenorphine might also be higher because of the strong affinity of buprenorphine for the μreceptor. After buprenorphine therapy is discontinued, the effects of a full agonist will become more pronounced; once the buprenorphine has been cleared from the body, the dose of the full agonist will need to be reduced over time. Close monitoring of the patient’s response to therapy is required.

3. Managing acute pain in patients on methadone maintenance therapy. Methadone, a synthetic mixed µ-opioid and delta receptor agonist, with NMDA receptor antagonist and serotonin norepinephrine reuptake inhibitor activity, has been used in the treatment of opioid-dependent patients for over 60 years and has found increasing applications in the treatment of cancer-related pain, neuropathic pain, and other chronic pain states. Its long half-life with a biphasic elimination profile exerts an effect both on pain control (8-12 hours) and on withdrawal (30-60 hours). However, variable oral bioavilability (40%-99%), variable hepatic elimination and the phenomena of incomplete cross tolerance, or lack of tolerance to the effects of opioids of other classes makes conversion from oral to IV formulations and calculating equianalgesic doses very challenging. Considering these attributes and its long half-life, titration to reach steady-state levels over days to weeks should only be done with assistance of a pain specialist owing to the risk of delayed respiratory depression. Furthermore, pretreatment EKG should be checked in any patient initiated or titrated on methadone, as QTC prolongation remains a significant concern. Patients who present for surgery should continue their baseline dose methadone on the morning of surgery, and pain should be managed proactively and aggressively in the perioperative period. The general principles for managing patients with opioid tolerance or addiction discussed above apply to these patients as well.