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TREATMENT METHODS

Many options are available for the treatment of postoperative pain, including systemic (i.e., opioid and nonopioid) analgesics and regional (i.e., neuraxial and peripheral) analgesic techniques. By considering patients' preferences and an individualized assessment of the risks and benefits of each treatment modality, the clinician can optimize the postoperative analgesic regimen for each patient. Essential
TABLE 72-1 -- Monitoring and documentation of postoperative analgesia
Analgesic Medication *
Name, concentration, and dose of drug
Settings of PCA device: demand dose, lockout interval, continuous infusion
Amount of drug administered (including number of unsuccessful and successful doses)
Limits set (e.g., 1- and 4-hour limits on dose administered)
Supplemental or breakthrough analgesics
Routine Monitoring
Vital signs: temperature, heart rate, blood pressure, respiratory rate
Analgesia
  Pain at rest and with activity, pain relief
  Use of breakthrough medication
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 covering physician
  Contact information should be provided (24 hours/7 days per week) if problems occur
Emergency analgesic treatment if PCA device fails
CNS, central nervous system; PCA, patient-controlled analgesia.
*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.[2]





aspects for postoperative monitoring for patients receiving various postoperative analgesic treatment methods are listed in Table 72-1 .[2]

Systemic Analgesic Techniques

Opioids
Advantages and Characteristics

Opioid analgesics are one of the cornerstone options for the treatment of postoperative pain. These agents generally exert their analgesic effects through μ receptors in the CNS, although there is evidence that opioids may also act at peripheral opioid receptors[58] (see Chapter 11 ). 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[59] or opioid-related side effects such as nausea, vomiting, sedation, or respiratory depression. Opioids may be administered by subcutaneous, transcutaneous, and transmucosal routes, but the most common routes of postoperative systemic opioid analgesic administration are oral, intravenous, and intramuscular. Opioids also may


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be administered at specific anatomic sites such as the intrathecal or epidural space (see "Single-Dose Neuraxial Opioids" and "Continuous Epidural Analgesia) (see Chapter 43 and Chapter 44 ).

There is wide intersubject and intrasubject variability in the relationships of opioid dose, serum concentration, and analgesic response in the treatment of postoperative pain.[60] Certain routes of administration (e.g., intramuscular) may result in a wider variability in serum drug concentrations than other routes (e.g., intravenous). 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. 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 initiates oral intake and postoperative pain has been stabilized with parenteral opioids. Although oral opioids (typically as part of a combination product that includes an adjuvant such as acetaminophen) are generally prescribed on an "as needed" (PRN) basis postoperatively, there may be a role for sustained-release oral opioids that may provide superior analgesia compared with conventional PRN regimens.[61] [62] [63] Transdermal fentanyl has been used for acute pain management,[64] but transdermal fentanyl cannot be easily titrated, although electrically facilitated delivery of transdermal fentanyl may eventually become useful for treatment of acute pain.[65]


TABLE 72-2 -- Intravenous patient-controlled analgesia regimens
Drug Concentration Size of Bolus * Lockout Interval (min) Continuous Infusion
Agonists


Morphine (1 mg/mL)


  Adult 0.5–2.5 mg 5–10
  Pediatric 0.01–0.03 mg/kg (max = 0.15 mg/kg/hr) 5–10 0.01–0.03 mg/kg/hr
Fentanyl (0.01 mg/mL)


  Adult 10–20 µg 4–10
  Pediatric 0.5–1 µg/kg (max = 4 µg/kg/hr) 5–10 0.5–1 µg/kg/hr
Hydromorphone (0.2 mg/mL)


  Adult 0.05–0.25 mg 5–10
  Pediatric 0.003–0.005 mg/kg (max = 0.02 mg/kg/hr) 5–10 0.003–0.005 mg/kg/hr
Alfentanil (0.1 mg/mL) 0.1–0.2 mg 5–8
Methadone (1 mg/mL) 0.5–2.5 mg 8–20
Meperidine (10 mg/mL) 5–25 5–10
Oxymorphone (0.25 mg/mL) 0.2–0.4 mg 8–10
Sufentanil (0.002 mg/mL) 2–5 µg 4–10
Agonist-Antagonists


Buprenorphine (0.03 mg/mL) 0.03–0.1 mg 8–20
Nalbuphine (1 mg/mL) 1–5 mg 5–15
Pentazocine (10 mg/mL) 5–30 mg 5–15
*All doses are for adult patients unless noted otherwise. Units vary across agents for size of bolus (mg versus mg/kg versus µg versus µg/kg) and continuous infusion (mg/kg/hr versus µg/kg/hr). The anesthesiologist should proceed with titrated intravenous loading doses if necessary to establish initial analgesia. Individual patient's requirements vary widely, with smaller doses typically given for elderly or compromised patients. Continuous infusions are not initially recommended for opioid-naïve adult patients.




Intravenous Patient-Controlled Analgesia

Various factors, including the wide interpatient and intrapatient variability in analgesic needs, variability in serum drug levels (especially with intramuscular injections), and administrative delays may contribute to inadequate postoperative analgesia. There may be difficulty in compensating for these factors with the use of a traditional PRN analgesic regimen. By circumventing some of these issues, intravenous patient-controlled analgesia (PCA) optimizes delivery of analgesic opioids and minimizes the effects of pharmacokinetic and pharmacodynamic variability among individual patients. Intravenous 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.[66] [67] [68] Although some equipment-related malfunctions have been reported, the PCA device itself is relatively free of problems, and most problems related to PCA use result from user or operator errors.[66] [69]

A PCA device can be programmed for several variables, including the demand (bolus) dose, lockout interval, and background infusion ( Table 72-2 ). The optimal demand or bolus dose is integral to intravenous PCA analgesic efficacy 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.[70] Although the optimal demand dose is uncertain, available data suggest that the optimal demand dose for morphine is 1 mg and


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that for fentanyl is 40 µg for opioid-naïve patients; however, the actual dose for fentanyl (10 to 20 µg) is often less in clinical practice.[66] [70] [71] The lockout interval may also affect the analgesic efficacy of intravenous PCA. A lockout interval that is too long may result in inadequate analgesia and decrease the analgesic effectiveness of intravenous 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 may contribute to an increase in medication-related side effects. In essence, the lockout interval is a safety feature of intravenous PCA and, although the optimal lockout interval is unknown, most intervals range from 5 to 10 minutes, and varying the interval within this range appears to have no effect on analgesia or side effects. [66] [72]

Most PCA devices allow the addition of a continuous or background infusion in addition to the demand dose. Initially, routine use of a background infusion was thought to confer certain advantages, including improved analgesia especially during sleep; however, subsequent trials failed to demonstrate any analgesic benefits of a background infusion in opioid-naïve patients.[73] [74] [75] [76] Many studies show that use of a background infusion only increases the analgesic dosage used and incidence of side effects such as respiratory depression.[74] [76] [77] [78] [79] Use of a nighttime background infusion does not improve postoperative sleep patterns, analgesia, or recovery profiles.[80] Although the routine use of continuous or background infusions in intravenous PCA in adult opioid-naïve patients is not recommended, there may be a role for use of a background infusion for opioid-tolerant or pediatric patients (see "Pediatric Patients" and "Opioid-Tolerant Patients").

Compared with traditional PRN analgesic regimens, intravenous PCA provides superior postoperative analgesia, improves patient satisfaction, and may decrease the risk of pulmonary complications; however, it is unclear whether intravenous PCA can provide any economic benefits.[81] [82] An early meta-analysis of 15 randomized trials comparing PRN intramuscular dosing with intravenous PCA revealed that intravenous PCA provided significantly greater analgesic efficacy, but there was only a nonsignificant trend toward reduced analgesic use, occurrence of side effects, and length of hospital stay.[82] A subsequent, larger quantitative systematic review demonstrated that intravenous PCA (versus nonintravenous PCA-administered systemic opioids) improved analgesia and decreased the risk of pulmonary complications without any difference in cumulative opioid consumption, duration of hospital stay, or opioid-related side effects.[81] With regard to economic outcomes, it is not clear whether intravenous PCA is superior to traditional PRN intramuscular opioid administration because the calculations of cost are complex. [83] Although there appears to be no improvement in hospital length of stay with intravenous PCA,[81] intravenous PCA does require less nursing time than intramuscular injections, which may be important with the shift toward using a higher percentage of less-skilled providers on surgical wards.[84] [85] [86]

Intravenous PCA may provide advantages when assessing other patient-related outcomes, such as patient satisfaction, which have become more important as health care organizations use these outcomes as a measure of quality and a tool for marketing purposes. Patients tend to prefer intravenous PCA compared with intravenously, intramuscularly, or subcutaneously administered opioids.[81] [82] [87] Greater patient satisfaction with intravenous PCA may be the result of superior analgesia and of perceived control over analgesic medication administration and avoidance of disclosing pain or securing analgesic medication from nurses.[88] [89] However, the reasons for patient satisfaction are complex, and many factors contribute to or predict satisfaction with intravenous PCA.[87] [88] [89] [90] Patients' willingness to pay for and timing of cessation of intravenous PCA may also influence satisfaction ratings.[91] [92] Although intravenous PCA use overall appears to be associated with greater satisfaction, there are many methodologic issues in the proper assessment of patient satisfaction. [93] [94]

The incidence of opioid-related side effects from intravenous PCA does not appear to differ significantly from that administered intravenously, intramuscularly, or subcutaneously.[81] The rate of respiratory depression associated with intravenous PCA is low (<0.5%) and does not appear to be higher than that with systemic or neuraxial opioids.[79] [95] [96] [97] Factors that may be associated with occurrence of respiratory depression with intravenous PCA include use of a background infusion, advanced age, concomitant administration of sedative or hypnotic agents, and coexisting pulmonary disease such as sleep apnea. [79] [95] [96] Intravenous PCA-related respiratory depression may also be related to errors in programming or administration (i.e., operator error).[98] The incidence of nocturnal hypoxemia in patients receiving intravenous PCA may be reduced with supplemental oxygen administration.[99]

Nonopioid Analgesics
Nonsteroidal Anti-inflammatory Agents

Nonsteroidal anti-inflammatory drugs (NSAIDs), which include aspirin and acetaminophen, consist of a diverse group of analgesic compounds with different pharmacokinetic properties. The primary mechanism by which NSAIDs exert their analgesic effect is through the inhibition of the cyclooxygenase (COX) and synthesis of prostaglandins, which are important mediators for peripheral sensitization and hyperalgesia. Although traditionally viewed primarily as peripherally acting agents, NSAIDs can also exert their analgesic effects through inhibition of spinal COX.[100] [101] 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, and 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 COX-1 and COX-2.[102] The discovery of a COX-3 variant may represent a primary central mechanism by which acetaminophen and other antipyretics decrease pain and fever.[103] [104]

Used as sole agents, NSAIDs generally provide effective analgesia for mild to moderate pain. NSAIDs also are traditionally considered a useful adjunct to opioids for treatment of moderate to severe pain, although some quantitative, systematic reviews suggest that NSAIDs, alone or in combination with opioids, may be more beneficial than previously thought ( Table 72-3 and Fig. 72-1 and Fig. 72-2 ).[105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] NSAIDs may be administered orally or


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TABLE 72-3 -- Relative efficacy of single-dose analgesics to provide more than 50% pain relief for moderate-to-severe postoperative pain
Drug * Mean NNT 95% CI
Codeine (60 mg) + acetaminophen (1000 mg PO)[106] 2.2 1.7–2.9
Diclofenac (50 mg PO)[107] 2.3 2.0–2.7
Rofecoxib (50 mg PO)[108] 2.3 2.0–2.6
Ibuprofen (600 mg PO)[107] 2.4 1.9–3.3
Oxycodone (15 mg PO)[109] 2.4 1.5–4.9
Oxycodone (5 mg) + acetaminophen (325 mg PO)[109] 2.5 2.0–3.2
Ketorolac (10 mg PO)[110] 2.6 2.3–3.1
Ibuprofen (400 mg PO)[107] 2.7 2.5–3.0
Meperidine (100 mg IM)[110] 2.9 2.3–3.9
Morphine (10 mg IM)[111] 2.9 2.6–3.6
Ketorolac (30 mg IM)[110] 3.4 2.5–4.9
Codeine (60 mg) + acetaminophen (600 to 650 mg PO)[112] 3.6 2.9–4.5
Acetaminophen (1000 mg PO)[108] 3.8 3.4–4.4
Aspirin (1000 mg PO)[113] 4.0 3.2–5.4
Aspirin (600 to 650 mg PO)[113] 4.4 4.0–4.9
Dextropropoxyphene (65 mg) + acetaminophen (650 mg PO)[114] 4.4 3.5–5.6
Tramadol (100 mg PO)[115] 4.8 3.4–8.2
Acetaminophen (600 to 650 mg PO)[112] 5.3 4.1–7.2
Tramadol (50 mg PO)[115] 7.1 4.6–18
Dextropropoxyphene (65 mg PO)[114] 7.7 4.6–22
Dihydrocodeine (30 mg PO)[109] 8.1 4.1–540
Codeine (60 mg PO)[115] 9.1 6.0–23.4
CI, confidence interval; IM, intramuscular; NNT, number needed to treat; PO, oral route.
*Data are from several systematic reviews, as referenced.
†NNT in this case refers to the number of patients who must be treated to obtain more than 50% pain relief for moderate-to-severe postoperative pain.[116] NNT conveys statistical and clinical significance, is useful to compare treatment efficacy for different interventions, and summarizes treatment effects in a clinically relevant way.[116] A lower mean NNT number implies greater analgesic efficacy in this example. See Figure 72-1 and Figure 72-2 for a graphic presentation of these data.




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, reducing opioid analgesic requirements, decreasing opioid-related side effects, and facilitating the recovery of patients.[50] [117] [118] As an adjunct to systemic or neuraxial opioid analgesia, NSAIDs can improve postoperative analgesia and reduce opioid requirements by up to 50%, which may result in improvements in surrogate economic measurements and a decrease in overall hospital costs.[119] [120] [121] [122] Use of NSAIDs may facilitate return of gastrointestinal function, reduce nausea, decrease respiratory depression, and improve patient satisfaction, although not all studies consistently demonstrate a reduction in opioid-related side effects with NSAID use.[105] [119] [120]

Despite the analgesic benefits, perioperative use of NSAIDs is associated with a number of side effects, including decreased hemostasis, renal dysfunction, gastrointestinal hemorrhage, and effects on bone healing and osteogenesis. Many of these side effects are related to inhibition of COX and formation of prostaglandins, which mediate many diverse processes throughout the body. Decreased hemostasis from NSAID use is attributed primarily to platelet dysfunction and inhibition of thromboxane A2 (generated by COX-1), which is an important mediator of platelet aggregation and vasoconstriction.[123] [124] The evidence of the effect of NSAIDs on perioperative bleeding is equivocal,[105] [124] [125] and a surveillance study of perioperative ketorolac did not demonstrate a significant increase in operative site bleeding.[126]

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 renal vascular beds and mediate diuretic and natriuretic renal effects.[105] [127] Euvolemic patients with normal renal function are unlikely to be affected; a meta-analysis did not demonstrate any significant reduction in urine volume or cases of postoperative renal failure requiring dialysis.[128] NSAIDs may also have an adverse effect on bone healing and spinal fusion.[129] Perioperative use of NSAIDs is associated with a higher incidence of gastrointestinal bleeding[126] because of NSAID-inhibition of COX-1, which is required for the synthesis of cytoprotective gastric mucosal prostaglandins. [123] Bronchospasm may be induced by NSAIDs (including aspirin) and by acetaminophen, and there may be cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects.[130] [131]

Because the expression of peripheral COX-2 is increased during inflammation, selective inhibition of COX-2 theoretically could provide analgesia without the side effects associated with COX-1 inhibition. COX-2 inhibitors are associated with a lower incidence of gastrointestinal complications[132] and exhibit minimal platelet inhibition even when administered in supratherapeutic doses.[133] Although there does not appear to be a benefit in using COX-2 inhibitors compared with traditional nonselective NSAIDs in reducing the incidence of renal complications,[134] preliminary evidence suggests that COX-2 inhibitors may be an alternative when attempting to avoid the detrimental effects of nonselective NSAIDs on bone healing.[135]

Ketamine

Ketamine is traditionally recognized as an intraoperative anesthetic agent; however, increasing interest in use of low-dose ketamine for postoperative analgesia has developed in part because of its NMDA antagonistic properties, which may be important in attenuating central sensitization and opioid tolerance[136] [137] (see Chapter 10 ). Although the role of low-dose ketamine (<2 mg/kg intramuscularly, <1 mg/kg intravenously, or ≤20 µg/kg/min by intravenous


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Figure 72-1 The mean and 95% confidence intervals for the numbers needed to treat (NNTs) are shown for several nonopioid analgesics from Table 72-3 . The NNTs are derived from trials investigating the efficacy of a single dose of nonopioid analgesic versus placebo in providing more than 50% pain relief for moderate to severe postoperative pain.

infusion) in the treatment of postoperative pain is controversial, perioperative administration of a small dose of ketamine may be a valuable addition to a multimodal analgesic regimen and an adjunct to opioids and local anesthetics by enhancing analgesia and reducing opioid-related side effects.[136] [138] [139] [140] Low-dose ketamine infusions do not appear to cause hallucinations or cognitive impairment, and the incidence of side effects, such as dizziness, itching, nausea, or vomiting, is comparable to that seen


Figure 72-2 The mean and 95% confidence intervals for the number needed to treat (NNTs) are shown for several opioid analgesics from Table 72-3 . The NNTs are derived from trials investigating the efficacy of a single dose of opioid analgesic versus placebo in providing more than 50% pain relief for moderate to severe postoperative pain. The upper end of the 95% confidence interval for dihydrocodeine is actually 540.

with opioids.[141] [142] Ketamine has been administered epidurally and intrathecally,[143] [144] but the neurotoxicity of ketamine is unclear, [145] and the use of neuraxial ketamine is discouraged until further safety data are available.

Tramadol

Tramadol is a synthetic opioid that exhibits weak μ-agonist activity and inhibits reuptake of serotonin and norepinephrine. Although tramadol exerts its analgesic effects


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primarily through central mechanisms, it may exhibit peripheral local anesthetic properties.[146] Tramadol is effective for treating moderate postoperative pain[147] [148] and comparable in analgesic efficacy to aspirin (650 mg) with codeine (60 mg) or ibuprofen (400 mg) (see Table 72-3 and Fig. 72-1 and Fig. 72-2 ).[106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [148] The advantages of tramadol for postoperative analgesia include the relative lack of respiratory depression, major organ toxicity, and depression of gastrointestinal motility and a low potential for abuse.[147] [149] [150] Common side effects (overall incidence of 1.6% to 6.1%) include dizziness, drowsiness, sweating, nausea, vomiting, dry mouth, and headache.[147] [148] Tramadol should be used with caution in patients with seizures or increased intracranial pressure and in those taking monoamine oxidase inhibitors.[148]

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