Choice of Opioid

Factors that affect the choice of opioid are speed of onset, duration of action, overall efficacy, and the type and frequency of side effects. If side effects prevent adequate analgesia, other opioids or nonopioid adjuvants should be used. Patient preferences based on past experiences and desired analgesia should also be considered.

Historically, meperidine (pethidine) has been a popular opioid for postoperative analgesia. However, the American College of Obstetricians and Gynecologists (ACOG) and the American Pain Society have discouraged the use of meperidine in obstetric patients because of the accumulation of normeperidine in the neonate and its subsequent effect on neurobehavioral scores. Table 27.2 shows commonly used alternatives to meperidine with equianalgesic doses.

Intravenous Patient-Controlled Analgesia

Intramuscular and subcutaneous opioids are inexpensive, easy to administer, and associated with a long history of safety but are not commonly used in the United States because of the need for repeated painful injections, delayed (and sometimes erratic) absorption of drug, and an inconsistent analgesic response caused by variation in plasma opioid concentration. Intravenous patient-controlled analgesia (PCA) allows patients to control their own pain management by self-administering small doses of intravenous opioids. A 2015 meta-analysis concluded that PCA is often preferred by patients compared with nurse-administered analgesia on request, and PCA was shown to provide better pain control and increased patient satisfaction compared with non–patient-controlled methods. The American Society of Anesthesiologists (ASA) Task Force for Acute Pain Management in the Perioperative Setting recommended that “these modalities [epidural or intrathecal opioids, systemic opioid PCA, and peripheral regional techniques] should be used in preference to intramuscular opioids ordered ‘as needed.’ ” The American Pain Society has recommended the use of intravenous opioid PCA when parenteral administration of analgesics is necessary and the oral route is not available.

PCA has been used via the intravenous and epidural routes after cesarean delivery. A study that compared intravenous and epidural PCA using fentanyl reported higher pain scores and greater fentanyl consumption with the intravenous route, although patient satisfaction was similar in the two groups. In another study that compared intravenous versus epidural PCA using hydromorphone, drug requirement was 3- to 4-fold higher in the intravenous group; the two groups had similar pain and sedation scores, but patients in the intravenous group reported more frequent drowsiness and less pruritus. Studies that compared intravenous morphine PCA to single-shot epidural morphine administration for postcesarean analgesia showed that analgesia and patient satisfaction were better and sedation was less with epidural morphine, although the incidence of pruritus was higher.

Side Effects and Safety Considerations

The goal of opioid administration is to achieve maximum analgesia with minimal side effects. It is important to monitor the respiratory rate and sedation level before giving an additional dose or adjusting the PCA bolus dose. Patients with comorbidities such as hepatic or renal dysfunction (e.g., occurring with severe preeclampsia), morbid obesity, and/or obstructive sleep apnea are particularly susceptible to the respiratory depressant effects of opioids; these patients may need special alterations to pain management, especially the use of multimodal analgesia (see later discussion).

Health care professionals who prescribe PCA should (1) be able to evaluate candidates for PCA (e.g., mental state, level of consciousness, patient understanding); (2) know drug selection criteria, dosing schedules, lockout periods, and infusion devices; (3) be able to provide patient education on pain management and the use of PCA; (4) understand when to alter PCA settings and when to give or withhold additional (rescue) doses of medications; and (5) be able to respond to side effects and adverse events. Observational studies of nonobstetric cohorts have reported an incidence of respiratory depression with intravenous PCA of 0% to 11.5%, which is equivalent to or higher than that reported for neuraxial opioids.

In December 2004, The Joint Commission issued a Sentinel Event Alert on PCA “by proxy” (i.e., when other individuals, including family members, become involved in drug administration by PCA). The Joint Commission acknowledged that PCA is a safe and effective method of controlling pain when used as prescribed; however, serious adverse events, including oversedation, respiratory depression, and death, can result when analgesia is delivered “by proxy.” The Joint Commission made the following recommendations: (1) develop criteria for selecting appropriate candidates for PCA, (2) carefully monitor patients, (3) teach patients and family members about the proper use of PCA and the dangers of others pressing the button for the patient, (4) alert staff to the dangers of administering a dose outside a prescribed protocol, and (5) consider placing warning tags on all PCA delivery pendants stating “only the patient should press this button.” The PCA settings (drug, demand dose, lockout interval, 4-hour limit, and the rate of continuous infusion, if used) are documented on a flow sheet, and any changes in PCA settings clearly documented.

Infusion Pump Settings

Programmable PCA parameters include drug choice, bolus dose, maximum dose, and lockout interval ( Table 27.3 ). Owen et al. performed several PCA investigations in patients undergoing abdominal surgery. In an assessment of PCA morphine demand bolus doses (0.5, 1, or 2 mg with a 5-minute lockout interval), more patients in the 0.5-mg group had inadequate pain relief, whereas those in the 2-mg group had more side effects, including respiratory depression (respiratory rate less than 10 breaths/min). These outcomes correlated with the total dose of self-administered morphine. Although the role of the lockout interval was not addressed in this study, the investigators suggested that inadequate analgesia could be produced by lockout intervals that are too long or demand doses that are too small. By contrast, larger doses or shorter lockout intervals might lead to more opioid-related side effects.

Although patients who experience inadequate analgesia would be expected to make more PCA demands, this is often not the case. Patients may be afraid to administer too much opioid or anticipate more severe side effects. Additionally, it has been suggested that patients are discouraged by an inadequate analgesic effect or they may expect a delayed response.

Continuous basal (background) infusions are not necessary in opioid-naïve women. The American Pain Society does not recommend routine use of basal infusions of opioid in opioid-naïve patients; most evidence does not demonstrate improved analgesia compared with patients who receive no basal infusion. Basal infusions of opioids are associated with an increased incidence of nausea and vomiting, and some studies have shown an increased risk for respiratory depression. Parker et al. compared a group receiving an intravenous PCA morphine regimen (bolus dose 2 mg) with a group receiving the same intravenous PCA regimen and a night-time continuous infusion (1 mg/h). There were no differences between groups in postoperative pain, sleep pattern, demand or delivered bolus dose per hour, opioid consumption, or recovery from surgery. The use of a continuous infusion resulted in six errors during the programming of the device. Three patients required discontinuation of the continuous infusion because of significant oxyhemoglobin desaturation. The ASA Task Force on Acute Pain Management concluded that special caution should be taken when a continuous infusion is used because of the potential for adverse effects from opioid accumulation.

During PCA, the ratio of patient demands to delivered bolus doses appears to be a good measure of analgesia and is strongly correlated with pain scores. A high ratio likely reflects patient misunderstanding or inadequate analgesia; a ratio close to 1 signifies adequate pain relief. Analgesia may be improved by an increase in the bolus dose, a shorter lockout interval, or a change of opioid.

Because of the significant morbidity associated with high doses of opioids, use of these drugs should invoke the application of algorithms for pain assessment, management, and monitoring. Acute postoperative pain is limited in duration; therefore, a plan should be devised for the transition from intravenous opioids to oral analgesic agents when the patient’s pain is controlled and she is able to take medication by mouth.

Oral Opioid Analgesia

Some investigators have advocated the use of oral analgesics rather than intravenous PCA as there is seldom a requirement for a prolonged fasting period after cesarean delivery. Most evidence suggests intravenous administration of opioids is not superior to oral opioids for postoperative analgesia. In fact, patients randomized to oral oxycodone experienced less pain, nausea, and drowsiness 6 hours after cesarean delivery compared with those who received intravenous PCA morphine. Dieterich et al. found intravenous PCA and oral opioids provided similar degrees of satisfaction and pain scores after cesarean delivery. Therefore, when tolerated, oral administration of opioids may be the preferred route of administration. Advantages of this approach are cost savings, facilitation of early mobility, and, perhaps, greater patient satisfaction. Long-acting oral opioids are not recommended in the immediate postoperative period.

Acetaminophen

Acetaminophen is used extensively for postoperative analgesia and provides an opioid-sparing effect of approximately 10% to 20%. A 2012 meta-analysis identified four randomized controlled trials evaluating acetaminophen and its effect on opioid consumption after major surgery; only one study included obstetric patients. The meta-analysis showed that acetaminophen was less effective than NSAIDs for decreasing opioid consumption and postoperative nausea and vomiting (PONV). A comparison of intravenous acetaminophen with oral ibuprofen in postcesarean patients found similar pain scores, opioid consumption, and patient satisfaction. The combination of NSAIDs and acetaminophen has been shown to be synergistic in human experimental pain studies.

In 2009, the U.S. Food and Drug Administration (FDA) lowered the recommended maximum daily dose of acetaminophen from 4000 mg to 3250 mg because of concern for toxicity. Avoiding opioid/acetaminophen combination medication is recommended to decrease unnecessary opioid use and avoid exceeding recommended maximum doses of acetaminophen. The change forced the replacement of combination oral opioid-acetaminophen analgesics with scheduled acetaminophen and as-needed opioids for postcesarean analgesia. Valentine et al. performed a retrospective medical record review of women who underwent cesarean delivery before and after a change in clinical practice at their institution. All patients in their study received spinal anesthesia containing intrathecal morphine 0.2 mg and scheduled NSAIDs for 48 h postoperatively. After the change, the women received oral acetaminophen 650 mg every 6 h for 48 h postoperatively with oral oxycodone administered as needed for breakthrough pain. The scheduled acetaminophen cohort used less opioid than the historical as-needed cohort in the first 48 hours ( Fig. 27.2 ).

Opioid use in milligram intravenous morphine equivalents after cesarean delivery in 24-hour increments in patients who received scheduled acetaminophen with as-needed opioid (dark bars) versus patients who received as-needed combination opioid-acetaminophen (light bars). Data are mean (bar) and standard deviation (whisker). *Significant difference between groups ( P < .001).

(Redrawn from Valentine AR, Carvalho B, Lazo TA, Riley ET. Scheduled acetaminophen with as-needed opioids compared to as-needed acetaminophen plus opioids for post-cesarean pain management. Int J Obstet Anesth. 2015;24:210–216.)

Intravenous acetaminophen has gained popularity, with earlier and higher plasma and cerebrospinal fluid levels compared with more slowly absorbed oral acetaminophen. However, in patients with a functioning gastrointestinal system, there is no documented analgesic advantage of intravenous versus oral administration.

Nonsteroidal Antiinflammatory Drugs

NSAIDs suppress inflammation by inhibition of the cyclooxygenase (COX) enzymes and are a key component of multimodal analgesia. They are effective for perineal pain after vaginal delivery and postcesarean abdominal pain; when co-administered with opioids, they produce a 30% to 50% opioid-sparing effect that can reduce opioid-related side effects. A 2016 systematic review and meta-analysis showed that the use of NSAIDs resulted in lower pain scores up to 24 hours postoperatively, less opioid consumption, and less sedation after cesarean delivery. Fixed-interval dosing of NSAIDs provides more effective analgesia and results in better patient satisfaction than on-demand dosing.

Ibuprofen is one of the most widely used NSAIDs that is available without prescription. Because it nonselectively inhibits COX-1 and COX-2 isoenzymes, in addition to its anti-inflammatory, analgesic, and antipyretic properties, ibuprofen also inhibits platelet adhesion and causes renal artery vasoconstriction and gastrointestinal irritation. Therefore, NSAID use in patients at risk for hemorrhage and renal failure warrants caution. Nonetheless, in most parturients without risk factors for hemorrhage or renal failure, use of NSAIDs is considered safe. Because of limited transfer to breast milk, NSAIDs are particularly beneficial for lactating mothers. In a small study (oral ibuprofen 400 mg every 6 hours for 24 hours), less than 1 mg of ibuprofen was excreted in breast milk in a 36-hour period. Many centers administer 600 to 800 mg every 6 to 8 hours as a standard dose. Ibuprofen is approved as a therapeutic drug for children and therefore is considered compatible with breast-feeding.

Oral naproxen 500 mg every 12 hours has been shown to reduce incisional pain compared with placebo and decrease opioid consumption ( Fig. 27.3 ).

Effect of naproxen on requirement for oral codeine after cesarean delivery: oral codeine use in milligram equivalents (expressed as mean) over time by group.

(From Angle PJ, Halpern SH, Leighton BL, et al. A randomized controlled trial examining the effect of naproxen on analgesia during the second day after cesarean delivery. Anesth Analg. 2002;95:741–745.)

Diclofenac has also been extensively studied; rectal suppositories (100 mg twice a day) decreased morphine consumption (14 mg versus 22 mg in 32 hours) compared with placebo after cesarean delivery. A single rectal dose of diclofenac 100 mg prolonged the mean time to first analgesic administration by more than 5 hours in patients who received intrathecal morphine. Patients who received intrathecal morphine doses as small as 0.025 mg required no rescue analgesic when intramuscular diclofenac 75 mg was administered every 8 hours. Munishankar et al. randomized patients who received spinal anesthesia with bupivacaine and fentanyl to receive one of three analgesic modalities: acetaminophen, diclofenac, or diclofenac and acetaminophen. Women who received both diclofenac and acetaminophen required less morphine than those who received acetaminophen alone ( Fig. 27.4 ).

Morphine consumption in milligrams in consecutive 4-hour periods after cesarean delivery in women randomized to receive acetaminophen (paracetamol), diclofenac, or both. Data were analyzed using repeated measures analysis of variance; patients in the acetaminophen/diclofenac group used less morphine per 4-hour period than patients in the acetaminophen but not the diclofenac group.

(Redrawn from Munishankar B, Fettes P, Moore C, McLeod GA. A double-blind randomised controlled trial of paracetamol, diclofenac or the combination for pain relief after caesarean section. Int J Obstet Anesth. 2008;17:9–14).

Lowder et al. showed that ketorolac decreased pain scores at 2, 3, 4, 6, 12, and 24 hours after cesarean delivery and also decreased opioid consumption. Ketorolac previously had a “black box” warning that it was “contraindicated in nursing mothers,” but current recommendations are to use it with caution. The American Academic of Pediatrics (AAP) considers NSAIDs safe for nursing mothers. Use of NSAIDs in pregnant and breast-feeding women is discussed in detail in Chapter 14 .

Cyclooxygenase-2-Selective Inhibitors

COX-2–selective inhibitors have a potential benefit compared with traditional nonselective NSAIDs in that they have minimal effects on platelet adhesion and thus are less likely to interfere with blood clot formation and contribute to hemorrhage. This category of NSAIDs has similar analgesic effectiveness and opioid dose-sparing to traditional NSAIDs in nonobstetric settings. However, in the setting of cesarean delivery, they do not appear to be as effective as NSAIDs. Additionally, concerns about the potential to increase the risk for cardiovascular and thrombotic events, combined with the baseline elevated risk for these events during pregnancy and postpartum, have prevented COX-2 inhibitors from playing a major role in postpartum analgesia. Celecoxib is the only widely available COX-2–selective inhibitor in the United States. The breast milk content of parecoxib and its primary active metabolite valdecoxib was very low, and neonatal neurologic and adaptive scores were normal, after a single 40-mg intravenous dose following cesarean delivery.

Alpha ₂ -Adrenergic Receptor Agonists

Alpha ₂ -adrenergic receptor agonists have been used for the treatment of acute and chronic pain in nonobstetric patients. Intravenous dexmedetomidine has been used as an adjunct to opioids as a component of general anesthesia for cesarean delivery. Dexmedetomidine is excreted in breast milk in extremely small concentrations; the relative infant dose was 0.034%. Neuraxial clonidine has been used for labor analgesia but is not commonly used for postcesarean analgesia. The epidural formulation of clonidine carries a “black box” warning from the FDA because of the incidence of hypotension at higher intrathecal doses.

Magnesium Sulfate

Peripartum magnesium sulfate therapy is used for tocolysis for preterm labor, seizure prophylaxis in women with preeclampsia, and fetal neuroprotection in women at risk for preterm delivery. A 2013 meta-analysis of trials of intra­venous magnesium for the treatment of acute postoperative pain after nonobstetric surgery performed with general anesthesia concluded that magnesium sulfate administration resulted in a small reduction in postoperative pain scores and a substantial reduction in opioid use, although the incidence of nausea and vomiting was not reduced. The use of intra­venous magnesium as an adjunct to postcesarean analgesia has not been rigorously studied.

Gabapentin

Gabapentin is an anticonvulsant that has analgesic properties, particularly in the setting of neuropathic pain. It has been extensively studied in the management of chronic pain and for postoperative analgesia where it is associated with more rapid opioid cessation. However, its role in opioid-naïve patients after cesarean delivery is less clear. As part of a multimodal analgesic regimen in patients undergoing cesarean delivery, a preoperative dose of oral gabapentin 600 mg was associated with lower pain scores with movement and at rest; however, the incidence of sedation was greater in the gabapentin group than in the placebo group (19% versus 0%). In a follow-up study, two doses of gabapentin (300 mg and 600 mg) were compared with placebo in the hope of finding an efficacious dose associated with less sedation. Unfortunately, the trial failed to show efficacy in either gabapentin group. These results were confirmed by Monks et al. in a randomized trial comparing perioperative gabapentin (600 mg preoperatively followed by 200 mg every 8 hours for 2 days) with placebo when added to a multimodal postcesarean analgesic regimen. Gabapentin produced a clinically insignificant improvement in analgesia (difference in 100-mm visual analog scale pain score on movement –7 mm, 95% confidence interval [CI] –13 to 0; P = .047) after cesarean delivery but was associated with a higher incidence of sedation.

Gabapentin may play a role in postcesarean analgesia in patients with chronic pain and those with opioid tolerance.

Ketamine and Dextromethorphan

Ketamine, an N -methyl- d -aspartate (NMDA) antagonist, has analgesic properties and may play a role in the treatment of acute postoperative pain and prevention or reversal of central sensitization. An evaluation of low-dose ketamine for postcesarean analgesia compared intravenous ketamine 0.15 mg/kg, intrathecal fentanyl 10 µg, ^a

a The Institute of Safe Medicine Practices (ISMP) has recommended that health care providers never use µg as an abbreviation for micrograms, but rather they should use mcg ( http://www.ismp.org/tools/errorproneabbreviations.pdf , Accessed June 2018). The use of the symbol µg is frequently misinterpreted and involved in harmful medication errors. The abbreviation may be mistaken for mg (milligrams), which would result in a 1000-fold overdose. The symbol µg should never be used when communicating medical information, including pharmacy and prescriber computer order entry screens, computer-generated labels, labels for drug storage bins, and medication administration records. However, most scholarly publications have continued to use the abbreviation µg. The editors have chosen to retain the use of the abbreviation µg throughout this text. However, the editors recommend the use of the abbreviation mcg in clinical practice.

A 2015 systematic literature review and meta-analysis included seven studies of ketamine use during spinal anesthesia and five during general anesthesia. Intravenous ketamine in the setting of spinal anesthesia delayed the time to first opioid request and reduced pain after cesarean delivery with no differences in the incidence of nausea, vomiting, pruritus, and psychomimetic effects.

Central Nervous System Penetration

Opioids administered epidurally must penetrate the dura, pia, and arachnoid membranes to reach the dorsal horn and activate the spinal opioid receptors. The arachnoid layer is the primary barrier to drug transfer into the spinal cord. Drug movement through this layer is passive and depends on the physicochemical properties of the opioid (see Chapter 13 ). Drugs penetrating this arachnoid layer must first move into a lipid bilayer membrane, then traverse the hydrophilic cell, and finally partition into other cell membranes before entering the cerebrospinal fluid (CSF). Opioids that are highly lipid soluble (e.g., sufentanil, fentanyl) can easily pass through the hydrophobic cell membrane. However, these drugs have difficulty crossing through the hydrophilic cellular fluid. In contrast, drugs that are less lipid soluble (e.g., morphine) have a greater challenge crossing the cell membrane, but can easily traverse the cell interior. Thus, opioid penetration of the arachnoid mater is dependent on the drug’s lipid solubility. Highly lipid-soluble drugs have poor CSF bioavailability because of (1) poor penetration through the arachnoid layer, (2) rapid absorption and sequestration by epidural fat, and (3) rapid uptake by epidural veins.

Some investigators have questioned the neuraxial specificity of lipophilic opioids given epidurally and have suggested that the primary analgesic effect occurs via vascular uptake, systemic absorption, and redistribution of the drug to supraspinal sites. Earlier studies suggested that parenteral fentanyl provides analgesia equivalent to that provided by epidural fentanyl, but more recent evidence suggests that epidural fentanyl provides analgesia via a spinal mechanism. Cohen et al., comparing a continuous infusion of intravenous fentanyl with epidural fentanyl after cesarean delivery, reported improved analgesia and less supplemental analgesic consumption despite lower plasma fentanyl levels with epidural administration. The difference may relate to speed of administration. There is evidence that bolus administration of lipophilic opioids has both spinal and supraspinal effects. Sadurni et al. randomized 30 patients undergoing abdominal surgery to receive intraoperative analgesia with boluses of fentanyl administered by either the thoracic epidural or intravenous route; patients who received epidural fentanyl required lower intraoperative fentanyl doses compared with those who received it by the intravenous route, suggesting that epidural fentanyl has a spinal as well as supraspinal effect. Additionally, after the administration of an epidural bolus of sufentanil 50 µg in a dog model, CSF concentration of sufentanil was 140 times greater than that found in plasma, and the amount detected in cisternal CSF was only 5% of that measured in lumbar CSF.

Hydrophilic morphine has a greater CSF bioavailability, with better penetration into the CSF and less systemic absorption than the lipid-soluble opioids. A bolus dose of epidural morphine 6 mg results in a peak plasma concentration of 34 ng/mL at 15 minutes after administration and a peak CSF concentration of approximately 1000 ng/mL at 1 hour. A poor correlation between the analgesic effect and plasma levels of morphine has been observed after epidural administration, indicating a predominantly spinal location of action. Intrathecal administration allows for injection of the drug directly into the CSF. This is a more efficient method of delivering opioid to spinal cord receptors than epidural or parenteral administration. A bolus dose of intrathecal morphine 0.5 mg resulted in a CSF concentration higher than 10,000 ng/mL, with barely detectable plasma concentrations.

Distribution and Movement of Opioids within the Central Nervous System

The movement and distribution of opioids within the central nervous system (CNS) follows specific patterns. Movement in the spinal cord is such that lipophilic agents (e.g., fentanyl) are taken up by the white matter with much greater affinity than hydrophilic agents (e.g., morphine), and less drug will reach the gray matter of the dorsal horn. Within the epidural space (and subsequently epidural fat or veins), lipophilic agents are more likely to be absorbed and transported from the epidural space to the systemic circulation. Rostral spread in the CSF is determined by CSF drug bioavailability and the drug concentration gradient; hydrophilic opioids (e.g., morphine) are associated with more rostral spread.

Although opioid dose, volume of injectate, and degree of ionization are important variables, lipid solubility plays the key role in determining the onset of analgesia, the dermatomal spread, and the duration of activity ( Table 27.4 ). Highly lipid-soluble opioids penetrate the spinal cord more rapidly and have a quicker onset of action than more water-soluble agents. The duration of activity is affected by the rate of clearance of the drug from the sites of activity. Lipid-soluble opioids are rapidly absorbed from the epidural space, whereas hydrophilic agents remain in the CSF and spinal tissues for a longer time.

Intrathecal and epidural opioids often produce analgesia of greater intensity than similar doses administered parenterally. The gain in potency is inversely proportional to the lipid solubility of the agent used. Hydrophilic opioids exhibit the greatest gain in potency; the potency ratio for intrathecal to systemic morphine is approximately 1 : 100.