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Opioids remain the mainstay of acute pain treatment, despite concerns about their side effects. Systemic opioids are used alone or in combination with other analgesics.47,48 Generally, higher doses of parenteral opioids are given during the first 24 to 48 hours after surgery when pain tends to be severe and patients are not able to tolerate oral medications. The intravenous (IV) route is the preferred parenteral route because most hospitalized patients already have IV catheters in place. Later, oral opioids, often in combination preparations such as Percocet (oxycodone with acetaminophen), replace the parenteral opioid. Side effects may limit opioid use, but there are few absolute contraindications, and true allergy to opioids is rare. Meperidine should not be used with monoamine oxidase inhibitors (MAOIs).
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Morphine is the main constituent of opium, it was the first opioid alkaloid to be identified, and it is the standard opioid to which other opioids are often compared. Codeine is the only other naturally occurring opioid in common use. The other familiar opioids are semisynthetic, derived from opium constituents (hydromorphone, hydrocodone, and oxycodone) or synthetic, synthesized de novo (meperidine, methadone, fentanyl, and fentanyl derivatives). These drugs are all opioid agonists, chiefly at the μ-opioid receptor. Other opioids are mixed agonists/antagonists or partial agonists (buprenorphine, butorphanol, pentazocine, nalbuphine) and are generally used for treating chronic rather than acute pain (or addiction), at least in the United States. They are not described in detail here. Naloxone is a pure opioid antagonist and can be useful to treat opioid overdose. The commonly used opioid-agonists are listed, with recommended doses, in Table 72-1. Opioid effects are summarized in Table 72-2. The opioids described next are μ-agonists with essentially similar effects. Choice of opioid depends as much on the familiarity and preference of the treating physician as on the generally subtle differences in pharmacology between these drugs.
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Morphine is the standard, most widely used of the opioids, and in some countries, it is the only available opioid. It is the least lipophilic opioid, which delays its peak effect (occurs at 20 min after IV injection) but makes it a good choice for epidural administration when a widespread effect is desirable. Morphine is highly metabolized and has at least 2 active metabolites (morphine-6-glucuronide and morphine-3-glucuronide), which can delay normalization after morphine administration, especially during renal compromise and continuous administration. (Morphine metabolites may also contribute to morphine toxicity and morphine-induced hyperalgesia in the special circumstance of sustained use.) Morphine induces histamine release, and rapid bolus injection may produce local erythema, hypotension, or rarely, bronchospasm. The normal duration of a standard dose (10 mg) is 3 to 4 hours. Morphine has poor oral bioavailability, and the oral dose is 3 times the parenteral dose. Morphine may cause biliary and urinary tract spasm, and a different opioid is often substituted (meperidine or fentanyl) during treatment for gallstones and renal stones or during biliary tract and urinary tract surgery, although recent studies suggest that the effect is an opioid effect, not specifically a morphine effect.49,50
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Codeine is less potent, although more constipating, than morphine. Constipation limits the recommended dose to 30 mg, which has only mild analgesic (and respiratory depressant) effects. Codeine is available for oral use only and is commonly found in combination analgesics such as Tylenol 3 (acetaminophen with codeine). In many countries, codeine is available over the counter because it is considered to have low abuse potential and a good safety record. Its main use is for pain of moderate severity, especially for children.
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Hydromorphone (Dilaudid) is a useful alternative to morphine. For ill-defined reasons, many patients seem to prefer hydromorphone and claim they feel more clear headed, less dizzy, and less nauseated. At present, these can only be considered anecdotal observations. There are no active metabolites; therefore hydromorphone is a good choice for continuous administration, especially in patients with renal compromise.
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Hydrocodone is used for mild to moderate pain, most commonly in the oral combination formulation Vicodin (hydrocodone with acetaminophen).
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Oxycodone is not available for parenteral use in the United States, although it is elsewhere. It is a familiar opioid in the United States in the form of Percocet (oxycodone with acetaminophen) and widely used for the treatment of moderately severe acute pain, including home treatment. More recently, oxycodone was formulated as a long-acting preparation (OxyContin), which has become a useful alternative to morphine and MS Contin (long-acting morphine) for the treatment of cancer and selected chronic pain. OxyContin and other long-acting oxycodone preparations have also been used for the treatment of acute pain, to aid sleep at night and function during the day. OxyContin availability has been limited by constraints associated with its popularity as a drug of abuse.
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Meperidine (Demerol) was widely used for sedation and analgesia during procedural treatments, particularly in the office setting, as well as for hospital treatment of intra- and postoperative pain, until in the early 1980s several problems with the drug became clear. The first was normeperidine toxicity. Normeperidine is a toxic metabolite capable of inducing central nervous system excitation and seizures, and liable to accumulate in the elderly and those with impaired renal function. The second was the propensity of meperidine to cause addiction, probably related to its lipophilicity and rapid onset of both analgesia and euphoria. Published guidelines began to state that meperidine should not be used routinely,7,8 and many hospitals withdrew it from their formularies. When it is available, meperidine remains a useful drug, and its ability to produce fast-onset analgesia and euphoria is its great advantage, especially during the treatment of postoperative pain. It also has an idiosyncratic and little understood advantage for treating postoperative shivering. It must, however, be used cautiously, being particularly mindful of normeperidine toxicity that can occur with repeated or continuous use. Meperidine has mild anticholinergic, antihistaminic, and local anesthetic effects. There may be a dangerous interaction (serotonin syndrome) with MAOIs producing seizures, coma, and possibly death, even after a single meperidine dose.
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Methadone is a complex drug, rarely used for acute pain, except in patients already treated with this drug. Important considerations are its multiple interactions with other drugs, especially with antibiotics and antifungals, and its propensity to prolong the QTc interval, especially at high doses.51,52 Refer to more detailed texts if you are faced with a patient requiring high-dose methadone or receiving methadone as part of a complex drug treatment regime.
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Fentanyl use in the postoperative setting is largely confined to PCA and epidurals, where its high lipophilicity and short duration can be used to advantage.
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Tramadol (Ultram) is an interesting drug with weak opioid activity and additional norepinephrine and serotonin reuptake inhibition. It has low abuse potential and is not a controlled substance. It is widely used in Europe to treat acute and postoperative pain but is less favored in the United States, where it is only available for oral use. Its use for severe pain is limited by the fact that it has a ceiling effect, but it may be useful for mild to moderate pain, particularly in patients who refuse opioids or tolerate them badly.
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Respiratory depression is the most feared of the opioid side effects, and rightly so, because this is a potentially fatal side effect. The possibility of respiratory depression produces a real conflict when trying to balance effective analgesia with safety. A key issue is to understand the likelihood of the event, and therefore the risk, and to provide adequate monitoring in high-risk situations. The immediate postoperative period is a period of high risk: The patient is often opioid naive, has been given multiple sedating drugs during surgery, may be weak, and may have a high analgesic requirement. Neonates and infants are always at high risk because of their immature nervous systems, propensity to apnea, and poor ability to metabolize opioid drugs. The elderly display similar risks. Patients established on a stable opioid regime are at lower risk. The level of monitoring required is a matter of judgment, whether this consists of frequent checks by a nurse or the application of a monitor such as an apnea monitor or pulse oximetry.
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Other side effects are less catastrophic but can significantly compromise the success of opioid therapy. Patients may prefer to be in pain than feel disorientated, dizzy, or nauseated; physicians may undertreat pain rather than delay hospital discharge because of ileus or nausea. Secondary treatments such as antiemetics may help, but it is the principles of opioid sparing that play a key role in minimizing opioid side effects and optimizing pain control.
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Tolerance, Dependence, and Addiction
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It is important to understand tolerance, dependence, and addiction, and the differences between these 3 phenomena. Drug tolerance arises when an increase in dose is required to achieve the effect of an initial dose. Opioid tolerance arises through a combination of receptor desensitization (nonassociative tolerance) and psychologic factors (associative tolerance).53,54 Apparent tolerance could also result from opioid-induced hyperalgesia (OIH).31,55,56 Patients receiving chronic opioid therapy could manifest either or both pharmacologic tolerance and OIH, and in fact, the 2 may be difficult to distinguish clinically because both are manifest as increased opioid dose requirement, and both result from biologic adaptations to continued opioid use.57,58 The phenomenon of OIH becomes increasingly important during acute and postoperative pain management as more and more patients present for surgery with opioid refractoriness caused by the neuroadaptations to it.59 The management of these patients is described in the section Special Populations. The development of tolerance and hyperalgesia during acute treatment is rare but can occur, especially when opioid infusions are used (eg, remifentanil during surgery or opioid infusions on an intensive care unit).60-62 NMDA antagonists such as ketamine may have an increasingly important role in the treatment of acute and postoperative pain because they seem to be effective for attenuating hyperalgesia, OIH, and opioid tolerance.63-65
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Dependence, also known as physical dependence, arises after chronic opioid use, is thought to reside in norepinephrine pathways of the locus ceruleus, and results in a typical withdrawal syndrome when an opioid-dependent patient is deprived of opioid. The typical opioid withdrawal syndrome comprises central neurologic arousal and sleeplessness, irritability, psychomotor agitation, diarrhea, rhinorrhea, and piloerection. In the management of acute pain, withdrawal may occur if habitual doses are not maintained during acute pain treatment. Patients who use opioids illicitly are not typically honest about their use, so physicians must be watchful for the signs of withdrawal when there is any suspicion of illicit use. Treatment consists of reestablishing previous opioid levels, before a gradual taper. Clonidine can be a useful adjunct and effectively treats many of the manifestations of opioid withdrawal.
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Addiction, a behavioral syndrome with a neurobiologic basis, virtually never arises out of hospital treatment of pain with opioids. Patients who are worried about the addiction risk can be assured of this.66 However, addicted patients present for surgery and with acute trauma-related pain, and they require skillful pain management. The management of these patients is described in the section Special Populations.
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Nonsteroidal Anti-Inflammatory Drugs and Acetaminophen
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The NSAIDs are a group of drugs that inhibit cyclooxygenase (COX) (an enzyme in the arachidonic acid pathway), thereby inhibiting prostaglandin and thromboxane production (Fig. 72-2). Prostaglandin and thromboxane actions are summarized in Table 72-3. Inhibition of prostaglandin and thromboxane accounts for the analgesic and anti-inflammatory effects of NSAIDs, as well as for their adverse effects. Acetaminophen is not strictly an anti-inflammatory drug but is included here because it shares many of the properties of the NSAIDs. In contrast to the true NSAIDs, which are polarized and therefore do not readily cross the blood-brain barrier, acetaminophen is nonacidic and crosses the blood-brain barrier. Its action resides mainly in the central nervous system where prostaglandin inhibition produces analgesia and antipyresis. Its peripheral and anti-inflammatory effects are weak. Commonly used NSAIDs and their doses are listed in Table 72-4.
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The NSAIDs and acetaminophen are commonly used over-the-counter analgesics, and have a long history of use for mild to moderate surgical pain, especially during home treatment. They are also used with opioids in oral combination formulations. The advent of ketorolac, the first injectable NSAID with Federal Drug Administration (FDA) approval for use in surgical patients, triggered a surge in interest in the use of NSAIDs as sole analgesics and as adjuncts for the treatment of moderate to severe acute and surgical pain. Ketorolac is a potent NSAID, unfortunately with a side-effect profile that reflects its potency, which can be used as a sole analgesic, even for severe pain. The NSAIDs and acetaminophen have emerged as useful adjuncts in multimodal analgesic regimes.
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A new subclass of NSAIDs was recently released for clinical use: the selective COX-2 inhibitors. COX-2 is an inducible isoenzyme and a source of prostaglandins during inflammatory processes. COX-1, in contrast, is a constitutive isoenzyme and has protective effects on the stomach where it mediates the production of cytoprotective prostaglandins (Fig. 72-3).67 The selective COX-2 inhibitors were developed in the hope of being able to reduce NSAID side effects, particularly the damaging gastrointestinal (GI) effects. Early clinical trials and clinical experience confirmed the analgesic efficacy and favorable side-effect profile of these drugs with regard to their effect on the gastric mucosa and their platelet effects, although some of the early trial results have now been brought into question. The great hope for these drugs was that they would replace standard NSAIDs and reduce complications, particularly NSAID-induced GI bleeding, which is thought to account for up to 100,000 hospitalizations and 20,000 deaths per year in the United States. However, these hopes have been crushed by the steady emergence of evidence that deleterious cardiovascular and thrombotic effects preclude the use of these drugs in many patients.68,69 In fact, most are now withdrawn, and the only selective COX-2 inhibitor on the market in the United States at the time of writing is celecoxib (Celebrex).
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Adverse Effects and Limitations on Perioperative Use
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Adverse effects of NSAIDs in surgical patients are listed in Table 72-5. Contraindications arise out of these adverse effects, listed in Table 72-6. Acetaminophen is relatively safe and not associated with the adverse effects listed for standard NSAIDs. The COX-2 inhibitors are less likely to cause bleeding (platelet effects), particularly GI bleeding (unprotected GI mucosa), but they carry the same risk as standard NSAIDs with the other listed adverse effects and additional cardiovascular and thrombotic risks. These drugs therefore have similar contraindications to the standard NSAIDs.
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Patients should be advised to stop taking NSAIDs before surgery, chiefly because of their platelet effects and their propensity to increase surgical bleeding. Aspirin, whose platelet effects are not reversible, should be stopped for up to 10 days before elective surgery. Other NSAIDs have rapidly reversible platelet effects, and 24-hour cessation is probably sufficient, although 2 to 3 days cessation is usual. Acetaminophen and COX-2 inhibitors can be continued because they do not have platelet effects.
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A factor that makes perioperative NSAID use relatively safe is the fact that they are used for a short period, and most adverse effect are associated with prolonged use. This is true of platelet, GI, and renal effects. Thus even in patients chronically treated with NSAIDs who have stopped the treatment to minimize surgical bleeding, short-term perioperative use may be appropriate. This brings into question the issue of timing of NSAID administration, which is linked to the drugs' liabilities. There are theoretical advantages to giving NSAIDs early in the surgical course, even preoperatively. These include the drugs' pharmacokinetics—for example, the peak effect of ketorolac may occur as late as 4 hours after administration—and the consideration that the drugs may have preemptive effects. However, for major surgery, where there is a likelihood of bleeding and/or hypotension with deleterious effects on clotting and renal function, it is probably better to wait until the extent of any derangement is clear. Surgical considerations are also important when deciding whether to use an NSAID. These include possible postoperative bleeding, especially into closed cavities such as the knee joint, as well as retardation of bone remodeling, a consideration after bone fusion especially of the spine.
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Use of NSAIDs and Acetaminophen for Postoperative and Acute Pain
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For mild postoperative or acute pain, NSAIDs or acetaminophen can be used as sole analgesics. In addition, even though they are considered weak analgesics, they have an important role as adjuncts and in multimodal analgesic regimes. Their mechanism of action (prostaglandin inhibition) means that they are synergistic with many other analgesic interventions, particularly with opioid analgesia. Multiple studies and meta-analyses confirm an average 30% to 50% opioid-sparing effect of NSAIDs.68,70-74 Whether this reduction in opioid dose with NSAIDs translates into improved recovery and morbidity is less clear. The most recent meta-analysis of 22 RCTs by Marret et al affirmed a reduction in nausea (30% reduction) and sedation (29% reduction), but effects on urinary retention and respiratory complications were inconclusive. Overall, studies assessing the effects on adjunctive NSAID use on recovery have had mixed results.70,71 The availability of the injectable NSAID ketorolac has extended perioperative use to the many patients who cannot tolerate oral medications after surgery. Initially, the side effects of this drug seemed unacceptable, but this was an effect of an initial recommendation to use a 60 mg first dose with 30 mg repeat doses. Now that the recommended dose has been halved (30 mg first dose, 15 mg repeat doses) and a 5-day limit has been placed on ketorolac use, the early problems of catastrophic bleeding (GI, surgical, and joint) seem to be resolved. Injectable acetaminophen is available and widely used perioperatively in Europe, but it is not available in the United States.
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Although the NSAIDs are the most widely used and useful systemic analgesic adjuncts in postoperative pain regimes, there has recently been interest in testing other possible adjuncts.
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NMDA receptor antagonists are known to reduce central sensitization, hyperalgesia, and opioid tolerance.27,31,55 This makes them theoretically an attractive option for treating acute pain: By reducing central sensitization they might reduce postoperative pain and possibly reduce the likelihood of developing chronic pain; they could also reduce opioid requirements and opioid tolerance. Ketamine is the most widely tested of currently available NMDA receptor antagonists (ketamine, dextromethorphan, and amantadine), but use has been limited by this drug's side effects (psychomimetic effects, including nightmares and hallucinations). These side effects can be reduced by concomitant use of benzodiazepines and by dose restriction; efforts to study the possible usefulness of ketamine as an adjunct analgesic for postoperative pain have centered on dose-finding and regime modeling. A recent detailed study suggests that although ketamine has demonstrable antihyperalgesic effects (as shown by skin measurements around the surgical incision), this may not translate into a useful opioid-sparing effect.35,75 A 2005 systematic review by Elia and Tramer incorporating 53 trials (2839 patients) found a small difference (<1 cm on a 0-10 cm visual analog scale) in postoperative pain level, a significant difference in opioid use during the first 24 hours after surgery, and no difference in opioid side effects.76 The highest risk of hallucinations occurred in awake or sedated patients receiving ketamine without a benzodiazepine. The role of ketamine and other NMDA receptor antagonists remains uncertain at present, although ketamine is being used increasingly as evidence is accumulating that it may have a useful adjunctive role in reversing hyperalgesia, OIH and opioid tolerance.63-65
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Neuropathic pain medications such as anticonvulsants and antidepressants, as their name suggests, have their chief pain indication for the treatment of chronic neuropathic pain. Gabapentin has long been a useful adjuvant medication for chronic neuropathic pain, and its use for perioperative and acute postoperative pain is increasing. A more recent addition to this class of agent, pregabalin, also has antiallodynic and antihyperalgesic properties useful for treating neuropathic pain, which appear to make them beneficial agents in acute postoperative pain.
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Gabapentin and pregabalin are inhibitors of the α2-Δ-subunit of the high-voltage-activated calcium channel. Their use reduces both neurotransmitter release as well as postsynaptic excitability. Data increasingly suggest that both of these agents have a role to play in the attenuation of postoperative pain. A systematic review of randomized controlled trials (RCTs) by Ho et al in 2006 demonstrated that a single preoperative dose of 1200 mg of gabapentin was associated with significantly decreased cumulative opioid consumption at 24 hours after surgery. Even when gabapentin was administered at doses less than 1200 mg, pain intensity was lower at both 6 and 24 hours, and 24-hour cumulative opioid consumption was less, although these findings did not reach statistical significance. In all cases, gabapentin was associated with an increased risk of sedation with less opioid-induced adverse effects such as pruritus and postoperative nausea and vomiting (PONV).77 A systematic review by Tiippana et al in 2007 supports that gabapentinoids effectively decrease acute postoperative opioid consumption and opioid-induced adverse events following surgery.78
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A more recent systematic review by Dauri et al in 2009 analyzed the evidence supporting gabapentin and pregabalin use for postoperative pain. When administered solely as a preemptive analgesic, gabapentin provided better postoperative analgesia and decreased opioid use postoperatively than placebo in 6 of 10 RCTs. However, gabapentin did not reduce PONV compared with placebo in 14 RCTs.79 Although studies support the role of gabapentin and pregabalin versus placebo in reducing pain and opioid consumption, comparisons with other postoperative regimens are lacking. More refined data delineating the optimal dose and duration of therapy, including when to begin, do not exist as yet.
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Patient-Controlled Analgesia
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Simple although it seems, PCA technology represents a huge advance in acute pain management. Computer-controlled pumps allow patients to control their own injections and to do this safely, and microchips have made controllable pumps easily portable. PCA satisfies the needs of patients to receive pain medication easily and quickly when needed. Nursing time spent obtaining, checking, documenting, drawing up, giving, and monitoring frequent doses is minimized. The hospital's need to comply with JCAHO's pain mandate is greatly aided. Most moderate to severe postoperative pain in hospitalized patients can be managed satisfactorily using routine IV opioid PCA for 24 to 48 hours after surgery, with or without adjuncts. A proviso is that pain in the immediate postoperative period is controlled by nurse bolus injections until it is under adequate control; patient-triggered boluses using standard settings may be inadequate for treating immediate postoperative pain, and early failed analgesia can prove difficult to overcome. Ideally, patients should be educated in the use of PCA before surgery.
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The Inherent Safety of PCA
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Because of the ease with which each PCA bolus dose can be given, PCA dosing regimes were devised using small frequent doses. For example, a standard regime for morphine is 1 mg every 6 minutes. A maximum hourly limit can be used, as can a background infusion if desired (the latter is particularly useful at night so that the patient can sleep). Part of the logic was to avoid the large swings between high peaks and low troughs associated with less frequent and larger doses (Fig. 72-4) but another was to improve safety. Small patient-controlled doses are inherently safe because a single dose is too small to produce overt sedation or respiratory depression, and an obtunded patient will stop pushing the button so there will be no further dosing beyond this early warning stage. The inherent safety of PCA also means there is less need for monitoring and no need to use the intramuscular route (with its slower absorption) for the sake of safety. Naturally, no method of delivery of opioids is completely safe, so a degree of vigilance is always required. The inherent safety of PCA is lost if persons other than the patient are permitted to push the button.
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Many studies have been conducted since PCA became popular in the 1980s to assess whether the use of PCA results in better analgesia, lower opioid requirements, fewer side effects, better surgical outcome, or superior patient satisfaction. Two meta-analyses of PCA versus "conventional analgesia" (intermittent large-dose opioid injection) have been published, the first in 199380 and the second in 2001.81 The second analysis added 17 new trials to the first, but its results were essentially similar to those of the first. There was slightly better analgesia associated with PCA use (difference 5.6 on a 0-100 scale, p = 0.006, debatably not a clinically important difference) and a large difference in patient satisfaction favoring PCA (42% improvement; p = 0.02). There was no difference in opioid usage, side effects, or surgical outcome. Thus the overriding benefit of PCA seems to be that patients like it. It has, in fact, become a standard of care in most US hospitals.
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The issue of cost of PCA is frequently analyzed and debated.82-84 It has proven difficult to come up with a global assessment of PCA costs and the cost savings associated with reduced nursing involvement, improved safety, and other factors. This is because all related costs, including the initial outlay or rental of the PCA systems and their hardware, and including nursing costs, vary from location to location. Overall, it seems that the literal costs to a hospital are slightly higher for PCA versus "conventional analgesia," but imponderables such as increased safety and greater patient satisfaction are hard to translate into cost benefits.
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Patient-Controlled Epidural Analgesia
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PCA technology can also be used for epidural analgesia. As with IV PCA, the main advantage is that patients like the sense of control offered by the patient-triggered pump.
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Novel PCA Technologies
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Using iontophoretic transdermal and intranasal delivery systems, new methods of providing PCA are now in development.85,86 The most advanced of these is the fentanyl patient-controlled transdermal system (PCTS), which is a noninvasive, needle-free, credit card size, self-contained drug delivery system. A small imperceptible electric current drives ionized drug across the normally impenetrable stratum corneum (outer layer of skin). The adhesive system can be placed on any patch of hairless skin, and for convenience, the upper arm is usually chosen. The system is preprogrammed to deliver 40 μg fentanyl per dose and can deliver up to 6 doses per hour for 24 hours, or 80 doses, whichever comes first. Each dose is triggered by the patient pushing a button on the system twice (twice so it is not triggered accidentally). Cost is likely to play a large part in whether this type of system is adopted for hospital versus home use, or acute versus cancer/chronic pain.
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The provision of epidural analgesia is probably the single most important contribution that anesthesiologists currently make to postoperative pain management for individual patients. There are 2 reasons for this: (1) after major surgical procedures, particularly abdominal and thoracic, epidural analgesia has proven analgesic superiority,87 an effective opioid-sparing effect, and probably a beneficial effect on surgical outcome,34,88,89 and (2) the ease with which the alternative (systemic opioid) can be provided using PCA has diminished the role of anesthesiologists in the provision of standard treatment. A perplexing thought, however, is how much we truly understand the risk versus benefit of epidural analgesia, especially in an era of potent thrombosis prophylaxis and seemingly increasing numbers of epidural hematomas. How do we weigh rare but catastrophic outcomes against common benefits of debatable value? This is one of the most important issues we face as we continue to teach and encourage the use of epidural analgesia.
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A review of indications for intraoperative epidural use is outside the scope of this chapter, but there are also independent indications for postoperative epidural analgesia. These include patients having thoracic or abdominal surgery, patients having lower limb surgery in whom early mobilization is important, patients having lower body vascular procedures in whom a sympathetic block is desirable, and patients with compromised cardiac or pulmonary function.
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Epidural placement is always contraindicated in patients who refuse this option. It is also contraindicated in patients with coagulopathy, concurrent or planned treatment with low-molecular-weight heparin or with potent antiplatelet agents, and in patients with bacteremia or local infection at the insertion site. The presence of spine pathology is a relative contraindication: The placement may be technically challenging and the treatment may fail if distorted anatomy prevents good distribution of the epidural medications. Neurologic disease is also considered a relative contraindication because if there is a change in neurologic status, which is not uncommon after the stress of surgery, diagnosis of the deterioration can be confused in the presence of an epidural.
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Drug Choices and Drug Effects
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Drugs injected or infused into the epidural space diffuse and spread according to their pharmacokinetics. The epidural space is complex because it contains arteries, veins, and lymphatics that are capable of absorbing drugs into the systemic circulation, nerve roots on which drugs can act directly, and fat in which drugs can form a reservoir (Fig. 72-5). The intrathecal space is a close neighbor of the epidural space, and diffusion into this space brings the epidural drugs across to more nerve roots, to the spinal cord, and, if spread is extensive enough, into the ventricular system of the brain (Fig. 72-6). When planning epidural infusion regimes, one has to consider not only local effects but also distant effects, as related to the individual drug's epidural pharmacokinetics.
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Local anesthetics act directly on nerve axons to block sodium channels and thus block saltatory conduction. They can block nerves in the epidural space itself, or more widely once they cross into the intrathecal space. Because of the arrangement of nerve fibers within the nerve roots, with small fibers lying outside larger fibers, small fibers are the first to be blocked and the most sensitive to local anesthetics. This characteristic of the spinal nerve roots means that differential blockade can be achieved using low-dose local anesthetics to block only small fibers (C-fibers: sympathetic, pain, and temperature fibers) and high-dose local anesthetics to achieve total sensory blockade, often accompanied by motor blockade (α and β fibers). To achieve analgesia without sensory decrement, a low-dose local anesthetic (eg, 0.1% bupivacaine) is chosen for postoperative use. Epidurals with low-dose local anesthetic infusion are sometimes termed walking epidurals, a useful term because it emphasizes that patients can and should be walking around to hasten recovery and minimize complications.
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Opioids have a completely different target: the opioid receptors in the dorsal horn of the spinal cord. Epidural opioid analgesia is also more likely to be complicated by systemic effects because, in contrast to the local anesthetics, which also undergo a degree of systemic absorption, there are clinically relevant systemic effects, especially when highly lipophilic opioids such as fentanyl are used. The degree to which opioids are absorbed systemically versus into cerebrospinal fluid (CSF) versus onto spinal cord receptors depends almost entirely on their lipophilicity (Table 72-7). As can be seen from Table 72-7, morphine is several times less lipophilic than all the other commonly used opioids. So it tends to be less readily absorbed into the systemic circulation and therefore provides a better selective spinal effect, and it also tends to spread more within the intrathecal space because it will favor staying in the watery medium of the CSF. This has advantages (more widespread spinal analgesia) and disadvantages (a higher risk that the drug will reach the ventricular system and cause respiratory depression; see Fig. 72-6). However, more lipophilic opioids such as fentanyl tend to have much greater systemic absorption (less selective spinal analgesia), and absorption onto spinal cord receptors tends to be localized, with poor spread. There is a great deal of experience using morphine and other opioids safely and effectively, and individual institutions must choose suitable regimes on the basis of the published experience and their ability to adequately follow and monitor patients receiving epidural analgesia.
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The addition of clonidine to the local anesthetic and opioid has been found to significantly improve the quality and duration of neuraxial analgesia.90 The effect is mediated by descending modulatory pathways to the spinal dorsal horn. Despite the low doses used for neuraxial administration, systemic side effects (hypotension, bradycardia, and sedation) can occur. Dose-finding studies are still underway, and the therapeutic window for useful analgesia without side effects seems to be narrow. A reasonable regime uses a 1 to 2 μg/kg bolus followed by 0.4 μg/kg per hour.
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Management Principles
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The management of epidural catheters should always be under the direct supervision of anesthesiologists. Patients should be seen daily to ensure that catheters and medications are working effectively and possible complications are recognized, and recognized early. Pain reports should be satisfactory, and side effects such as pruritus, sedation, and changes in sensation or motor function should be carefully evaluated. Medication charts should be checked, especially for unintentional anticoagulant administration. Catheters and their insertion sites should be inspected for migration, integrity of the dressing, and for inflammation or back tenderness. Anesthesia personnel should make changes to the analgesic regime and administer specific medication as necessary. At the end of treatment, the anesthesia team should be responsible for pulling the catheter and ensuring it is removed intact. Nurses should be properly educated before they care for patients with epidural catheters. Important teaching points include typical medication doses and concentrations, anticoagulation issues, assessment parameters, the normal appearance of the catheter and catheter site, operation of the infusion pumps, common medication side effects that can be treated by them, and side effects requiring a call to the physician in charge.
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If an epidural does not appear to be functioning well, it is first necessary to test whether the catheter is well positioned. The ideal way to do this is to attempt to produce a discernable level using a bolus dose of local anesthetic. However, the dose of local anesthetic needed to produce a sensory level may also induce hypotension, which would not be desirable in an unmonitored situation such as a regular floor, particularly if there are no means readily available to treat the hypotension. A surprisingly helpful test is to inject 5 to 7 mL of the analgesic infusion (low-dose local anesthetic), in which case no special monitoring is needed because the low-dose anesthetic is unlikely to produce extreme hypotension. If the catheter is well positioned, analgesia should be noticeably improved by the injection.
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Once good catheter function is established, several approaches to improve analgesia can be taken. Bolus injections can be continued until good analgesia is achieved. The infusion rate can be titrated upward as tolerated. Epidural medication can also usefully be administered through a patient controllable pump, termed patient-controlled epidural analgesia. Systemic analgesic can be added to the regime. NSAIDs are useful adjuncts to epidural analgesia, especially when the epidural level does not cover the entire area of surgical pain, for example when the incision is high or when pain is referred outside the epidural area as occurs when chest tubes irritate the diaphragm and produce shoulder pain via the phrenic nerve. Systemic opioids (including PCA) can also be added, in which case it is preferable to remove the opioid from the epidural infusate, if used.
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Managing Side Effects
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Hypotension, mild sensory and/or motor changes, and urinary retention are the most common side effects of epidural local anesthetics, whereas pruritus, sedation, dizziness, and urinary retention are the most common side effects of epidural opioids. Most side effects are alleviated by either lowering the infusion rate or changing the drug or dose. Hypotension can become a considerable nuisance during epidural analgesia, even though the sympathectomy from low-dose local anesthetics is theoretically minimal. Some patients are particularly sensitive to the local anesthetic and manifest hypotension that does not respond to the primary measure of fluid replacement. For these patients, the local anesthetic can be removed from the epidural mix, or the epidural treatment may have to be abandoned altogether. Pruritus is a common side effect and usually responds well to antihistamine treatment. The mixed agonist/antagonist nalbuphine (Nubain) (5-10 mg IV, 4-6 mg hourly) also works well, as does low-dose naloxone infusion. Contrary to popular belief, nausea rarely occurs because opioid doses are low. Gut mobility is in fact improved by epidural therapy because of opioid sparing and the favorable effects of neuraxial local anesthetic on bowel motility. Urinary retention is common, and it is common practice to keep a Foley catheter in place until epidural therapy is discontinued.
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Unilateral lower extremity numbness with occasional weakness or motor block occurs fairly frequently. It is often a result of the epidural catheter tip migrating along a nerve root so that the local anesthetic is concentrated in one area. Pulling the catheter back, or lowering the infusion rate, often rectifies the problem. However, one should always remain vigilant and continue to watch for more serious complications.
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The most common complications are failed block/analgesia and postdural puncture headache (PDPH). Both are considered benign, although they may be devastating to patients who have committed to an epidural to optimize their surgical recovery. The exact incidence of these common complications is difficult to establish because reports vary, and the occurrences likely vary according to reporting and practice habits. Recent reports suggest that failed analgesia occurs in as many as 15% of cases.91-93 PDPH may occur in up to 86% of patients after accidental dural puncture (rate: 0.16%-1.3%).94 The incidence of other self-limiting neurologic complications such as radicular pain and peripheral nerve lesions is difficult to determine because these occurrences are rarely reported.
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PDPH is thought to result from a small CSF leak secondary to accidental dural puncture. Typically, there is a delay in onset of the headache of up to 24 hours, so that the complication tends to manifest on the first postoperative day. Because PDPH tends to worsen on sitting up, and particularly on walking, it may not present itself until the patient gets out of bed for the first time after surgery. Other characteristics of the headache are that it tends to occur at the back of the head (occiput) and neck, and it produces a tight, pulling, and throbbing sensation. Conservative management consists of bed rest (up to bathroom only), plenty of fluids (IV or oral), and headache medication (NSAIDs, acetaminophen, Fioricet, caffeine, and theophylline all work well). If there is no resolution, or if conservative measures are contraindicated, a blood patch is recommended. This consists of an epidural injection of 20 mL of the patient's own blood (drawn under aseptic conditions). The exact mechanism by which an epidural blood patch works is uncertain but is probably either a pressure effect or a laying down of clot or fibrosis onto the puncture site.
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Epidural hematoma with consequent paraplegia is extremely rare but a catastrophic complication of epidural therapy. Permanent paraplegia can occur even when a hematoma is diagnosed and treated in a timely manner, although early intervention usually reverses the neurologic injury. Persistent lower extremity neurologic changes or cauda equina syndrome (loss of bowel and bladder control) should always be taken seriously, especially if there is accompanying back pain and tenderness, which are cardinal signs of epidural hematoma and abscess although not necessarily present. Neurology can be consulted, but early imaging, preferably with magnetic resonance imaging (second choice computed tomography), should always be instituted. The presence of a space-occupying intracanal spinal lesion should always herald immediate transfer to the operating room for surgical decompression.
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The incidence of epidural hematoma after neuraxial injection, catheter placement, or catheter removal has been estimated to be 1 in 190,000, with many of the reported cases associated with anticoagulant use.95-97 A rash of reports of epidural hematoma occurring after neuraxial interventions in patients receiving low-molecular-weight heparin alerted us to the dangers of epidural injections and catheters in patients receiving highly effective thrombosis prophylaxis. More problems followed when chronic treatment with potent and long-acting antiplatelet agents such as clopidogrel became more widespread.96 In view of the rapidity with which new agents are being introduced and the time lag before the extent of a problem can be assessed, we are left with a great deal of uncertainty about the safety of neuraxial procedures. Table 72-8 summarizes guidelines for managing epidurals in patients receiving anticoagulants. These recommendations are based on the consensus guidelines published by the American Society of Regional Anesthesia and Pain Medicine (ASRA). The guidelines are updated periodically and published on ASRA's Web site. Epidural bleeding is known to occur secondary to single-shot neuraxial techniques as well as neuraxial catheter insertion and removal, so recommendations are needed for the start and end of neuraxial therapy, as well as for starting anticoagulant therapy after neuraxial instrumentation or catheter removal.
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Epidural abscess occurs less often than epidural hematoma, but it can be equally catastrophic and may cause permanent and serious neurologic injury, even death.98 Fever is a likely accompaniment to epidural abscess; otherwise it presents much as epidural hematoma. In fact, it may not be clear whether the mass is blood or pus until it is exposed during surgery. The mortality of spinal abscess can be as high as 18% (from case report).99 The incidence of epidural abscess secondary to neuraxial blockade is estimated at 1 in 250,000 in healthy patients, but 1 in 2000 in diabetic or immunocompromised patients.100,101 Other serious complications such as anterior spinal artery syndrome, transverse myelitis, and meningitis have been reported but are extremely rare.
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Epidurals and Surgical Outcomes
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In terms of truly understanding the benefit versus the risk of epidural analgesia in any individual patient, it is important to understand whether or not the benefit extends beyond that of the simple provision of excellent analgesia. Is mortality improved? Is recovery hastened? Are high-risk patients such as those with serious cardiac disease less susceptible to cardiac morbidity? Do the bowels recover quicker? Do epidurals reduce thromboembolism? Is postoperative pulmonary function improved? These are all questions that have been asked in countless trials often with conflicting results.74,89 Perhaps the clearest result is that epidural analgesia (particularly that from thoracic epidurals) does improve bowel mobility and reduce the period of ileus, with consequent earlier hospital discharge.102 There is also considerable support for improved pulmonary function.103-107 But support for a beneficial effect on other outcomes, particularly catastrophic outcomes, seems to be elusive. Large multicenter studies published relatively recently found no advantage to epidural analgesia in terms of mortality or major morbidity.105,107 Yet earlier trials and meta-analyses had suggested significant improvements in mortality and serious morbidity.103,104,106,108,109 Has some of the earlier advantage of neuraxial anesthesia and analgesia dissipated because they no longer provide the benefit of reduced thromboembolism in this era of improved thromboprophylaxis? And could general improvements in perioperative care such as better preoperative optimization, shorter acting anesthetic drugs, improved standards of vigilance and monitoring, and accelerated recovery programs have diminished the role of neuraxial anesthesia and analgesia?89
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Despite all the blows against epidurals—incompatibility with modern thromboprophylaxis and dwindling returns in terms of improvements in mortality and major morbidity—they remain a beneficial and helpful intervention for selected patients undergoing invasive surgical procedures. For patients who accept the risks because of a promise of good postoperative pain relief, that promise is usually fulfilled. Patients with serious respiratory disease and those undergoing extensive lung resection benefit from opioid sparing and the favorable effects of epidural analgesia on pulmonary mechanics. Recovery can be hastened after bowel surgery because of favorable effects on bowel mobility. And patients with cardiac ischemia or failure can benefit from the moderate reductions in afterload and the negative inotropy and chronotropy of a well-managed thoracic epidural.
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The primary indication for nerve blocks is for the provision of surgical anesthesia. But there are secondary benefits in terms of pain relief in the postoperative period, and in some cases analgesic effects can be prolonged using plexus catheters. As nerve blocks wear off, there remains some degree of analgesia (probably from residual small fiber blockade), and surprisingly, these effects appear prolonged beyond the known half-life of the local anesthetic, especially in the case of distal peripheral blocks such as hand and ankle blocks. Certain nerves are accessible enough to be injected intermittently should the need arise: Femoral nerve blocks provide good but incomplete analgesia after knee surgery, and intercostal nerve blocks can be useful after thoracic surgery or chest trauma when epidural analgesia is contraindicated. The analgesia from single-shot neuraxial blocks can be prolonged by injecting an opioid at the time of placing the block. Injection or infiltration of local anesthetic into the wound by the surgeon can provide helpful analgesia during the early postoperative phase. These techniques are particularly useful for postoperative pain control: (1) prolongation of neural blockade using catheters, (2) neuraxial opioid injections, and (3) prolongation of neural blockade using catheters.
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With the increasing number of procedures being performed in the ambulatory setting in the United States and elsewhere, it becomes especially important to ensure adequate postoperative analgesia. In fact, ambulatory surgical procedures now account for at least 50% to 70% of all surgical procedures performed throughout the United States.110 Regional anesthesia has several benefits in the ambulatory setting, and has grown in popularity among physicians and patients alike.36 The ability to provide an alternative to general anesthesia with associated rapid recovery, early analgesia, decreases in consumption of postoperative opioids, nausea, and sedation as well as improved mobility of the operative extremity make regional techniques a welcome and attractive addition to our armamentarium. A recent meta-analysis by Liu et al confirms that peripheral nerve blocks are associated with reduced pain, decreased postanesthesia care unit time, less postoperative nausea, and a decreased analgesic requirement.111 Reduction of patients' overall time in the ambulatory surgery setting was not demonstrated, but patient satisfaction was improved.
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The type of regional technique chosen depends on the site and anticipated length of the surgery, any postoperative mobilization requirements, as well as a review of patients' comorbidities and possible contraindications to specific regional techniques (eg, peripheral techniques may be safer than neuraxial in patients with a coagulopathy).
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Brachial plexus blocks are commonly used for upper extremity surgery. In general, these blocks are well tolerated and have few contraindications. Interscalene blocks produce ipsilateral phrenic nerve paresis for the duration of the blockade and should be avoided in patients who cannot tolerate a modest (25%) decrease in pulmonary function. The supraclavicular approach carries with it the risk of pneumothorax, and the infraclavicular approach may be useful particularly in the ambulatory setting. Regional techniques have transformed both total elbow and total shoulder arthroplasties from procedures commonly requiring several days of hospitalization into ambulatory procedures with the further option of continued analgesia via a perineural catheter.112,113
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For the lower extremity, spinal anesthesia has largely been superseded by peripheral blocks in the ambulatory setting to minimize side effects such as urinary retention and inability to ambulate, all of which can delay discharge. Femoral, sciatic, and ankle blocks all provide excellent conditions for surgery as well as analgesia extended well into the postoperative period. As with the upper extremity blocks, plexus catheters can be placed at the time of block placement and used to prolong analgesia.
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Intercostal nerve blocks can be useful when in the case of chest trauma; regional anesthesia helps improve pulmonary mechanics but epidural is contraindicated. Intercostal bupivacaine has been used successfully in patients with severe chest pain following rib fractures to provide sustained analgesia and a significant increase in both pulse oximetry saturation and peak expiratory flow rates.114,115
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When a perineural catheter is placed, a PCA pump can be used to infuse via the catheter so that patients can control and adjust their own demand dosage of medication on the background of a preprogrammed continuous basal infusion. More recently, the development of new disposable pumps allows for patients to experience at home the type of analgesia that was recently available only as an inpatient. Recent data suggest that disposable pumps are as successful as battery-operated mechanical pumps, with fewer technical problems and higher patient satisfaction scores.116
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Whatever peripheral nerve block is used to control postoperative pain, it is important to realize that a plan for either supplemental coverage of noncovered surgical areas or provision of breakthrough pain coverage is necessary and should be provided in addition.
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Neuraxial Opioid Injections
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Neuraxial morphine is safe provided dosing is reasonable and patients are appropriately monitored. A single shot of morphine into the epidural space (1-4 mg) or intrathecal space (0.1-0.4 mg) can provide prolonged analgesia (up to 24 h), but it carries a risk of delayed respiratory depression. Morphine is poorly lipophilic, tends to stay in CSF once there, and is subject to CSF bulk flow with passage to higher centers including the respiratory center (see Fig. 72-6). At the same time, the fact that morphine tends to remain in CSF is the reason that it produces excellent selective spinal analgesia (ie, good spread to spinal cord receptors). Single-shot neuraxial morphine is an excellent means of providing analgesia when there is no epidural catheter. Patients should be monitored in the same way as those receiving epidural opioid infusions. PCA can be used to provide supplementary analgesia if necessary, but for safety, only demand doses should be used, and continuous background infusions should be avoided.