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The administration of pharmacologic agents is the mainstay of acute pain management. The key to effective pharmacologic pain management in the ED is selection of an agent appropriate for the intensity of pain and it's time to onset of analgesic activity, ease of administration, safety, and efficacy.29 Acute pain is usually accompanied by anxiety and feelings of loss of control. If verbal reassurance combined with an analgesic does not suffice, an anxiolytic may be useful.
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The "tiered approach" to pain management starts with an agent of low potency regardless of pain intensity, assesses the response after a clinically relevant period, and sequentially changes to agents of higher potency if pain persists. The tiered approach for acute pain management unnecessarily subjects the patient to more prolonged suffering. It is preferable to select initial analgesics that are appropriate to treat the intensity (mild, moderate, or severe) of the patient's pain. Agents such as nonsteroidal anti-inflammatory drugs should be considered for mild to moderate pain, and systemic opioids for moderate to severe pain (Table 35-3). In specific instances such as renal and biliary colic, a parenteral nonsteroidal anti-inflammatory drug may control severe pain, although combination therapy with an opioid is usually superior.
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When possible, local anesthesia is a useful adjunct (Table 35-4). Peripheral nerve blockade for pain control and for procedures is a useful option, especially if guided by US (see chapter 36, Local and Regional Anesthesia).30,31
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Opioid analgesics are the cornerstone of pharmacologic management of moderate to severe acute pain (Table 35-5). The term opiate refers to agents that are structurally related to natural alkaloids found in opium, the dried resin of the opium poppy. The term opioid describes any compound with pharmacologic activity similar to an opiate, regardless of chemical structure. Opioid use in the ED is often affected by concern for the precipitation of adverse events, such as respiratory depression or hypotension, or for facilitating drug-seeking behavior. As noted, a greater concern is oligoanalgesia and inadequate dosing of opioids when used. Considerations for use of opioids include (1) desired onset of action, (2) available routes of administration, (3) achievable frequency of administration, (4) concurrent use of nonopioid analgesics and adjunctive agents, (5) possible incidence and severity of side effects, and (6) continuation of the agent in an inpatient or ambulatory setting
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Opioids need to be titrated to effect; patients differ greatly in their response to opioid analgesics.32,33,34 Variation in pain reduction is related to age, initial pain severity, and previous or chronic exposure to opioids, but not body mass35,36 or gender.37 Relative potency estimates provide a rational basis for selecting the appropriate starting dose to initiate analgesic therapy,38 changing the route of administration (e.g., from parenteral to PO), or switching to another opioid (Table 35-6), but undue reliance on these ratios is an oversimplification with potential for over- or underdosing.39
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Opioid hypersensitivity is uncommon, and true allergic reactions are extremely rare. There is minimal evidence of clinical cross-sensitivity within opioid classes, with the possible exception that cross-sensitivity has been suggested among the piperidines (fentanyl, alfentanil, sufentanil, and meperidine). Until more is known, it would be prudent to switch to a drug from a different opioid class if a patient develops a hypersensitivity reaction. When used in equianalgesic doses, there is no compelling evidence to recommend one opioid over another. As much as possible, avoid using multiple agents, and titrate a single drug to the desired effect.
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The use of meperidine is discouraged for several reasons: it is often underdosed; meperidine can interact with many drugs to precipitate a serotonin syndrome; and the parent drug is metabolized to normeperidine, which has neuroexcitatory properties and a long elimination half-life (24 to 48 hours).40 Normeperidine can accumulate and produce toxicity in the elderly and those with renal failure, although this is a rare event.
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Codeine is not a reliable analgesic, and it produces more nausea, vomiting, and dysphoria than other opioids. The analgesic effect of codeine is highly dependent on the metabolic conversion to the active metabolites codeine-6-glucuronide and morphine. Up to 10% of the U.S. population is deficient in the relevant enzymes for this conversion and, therefore, has an inadequate analgesic response to codeine. Conversely, there are case reports of neonatal deaths as a result of breastfeeding from mothers who were hypermetabolizers of codeine. In addition, the standard PO dose of 30 to 60 milligrams produces little analgesic effect above that of acetaminophen or nonsteroidal anti-inflammatory drugs.41
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Tramadol binds to mu-receptors and weakly inhibits the reuptake of norepinephrine and serotonin producing a central opioid analgesic effect. Common side effects include dizziness, nausea, constipation and headache. Tramadol can induce the serotonin syndrome. Severe toxicity can include agitation and seizures. It is one of the many substances that can produce a false-positive result on the urine phencyclidine screen.42
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Adverse effects of opioids include nausea, vomiting, constipation, pruritus, urinary retention, confusion, and respiratory depression. Pruritus, urinary retention, confusion, and respiratory depression are more common with IV, transmucosal, and epidural administrations as opposed to PO administration.
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Adjuncts are sometimes used to enhance the analgesic effect, reduce the amount of opioid required, and prevent side effects (Table 35-7). Depending on the agent, amount, route, and setting, a beneficial effect can be seen. However, appropriate titration with opioids in the ED is highly effective, and there are few data to support the routine use of adjuncts with opioids in the ED.43 Pretreatment with antiemetics is not necessary given the low risk of emesis,44 but symptom-targeted therapy is sometimes necessary.
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Transdermal formulations are not useful for acute pain treatment because of delayed onset and prolonged duration of action. Transdermal fentanyl and transdermal buprenorphine preparations are used for chronic pain, particularly in cancer patients. When such patients are treated for acute pain in the ED, it is best to remove the delayed-release transdermal opioid patches to better titrate the acute opioid dose and to minimize adverse reactions from the combination of agents.
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OPIOID AGONISTS-ANTAGONISTS
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Opioid agonists-antagonists are used to minimize some of the adverse effects of pure opioid agonists (Table 35-8). The major benefit claimed is a ceiling on respiratory depression (no further reduction in respiration with increasing doses past a set amount). It is not clear if there is a ceiling effect for analgesia. The variability in efficacy relates to each particular agent's affinity for the various central opioid receptors. Because of the antagonistic effects, these agents should be used with extreme caution in patients with opioid addiction as they may precipitate withdrawal symptoms.
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Acetaminophen (paracetamol) is an effective analgesic for mild to moderate pain (Table 35-9).45 Acetaminophen does not affect platelet aggregation and does not have anti-inflammatory properties. No change is required for renal or mild hepatic impairment (see chapter 190, Acetaminophen).
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Aspirin and the nonsteroidal anti-inflammatory drugs are both anti-inflammatory agents and analgesics. As anti-inflammatory agents, aspirin and nonsteroidal anti-inflammatory drugs decrease the production of prostanoids and arachidonic acid–mediated inflammatory peptides generated at the site of tissue injury, diminishing the inflammatory response seen with some noxious stimuli. As analgesics, inhibition of the cyclooxygenase-2 enzyme in the spinal cord decreases the excitability of dorsal horn neurons that produce hyperalgesia and allodynia. These agents do not cause sedation or respiratory depression or interfere with bowel or bladder function. Nonsteroidal anti-inflammatory drugs have significant opioid dose-sparing effects.
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Adverse effects of nonsteroidal anti-inflammatory drugs include platelet dysfunction, GI irritation and mucosal bleeding, nephropathy, headaches, and dizziness. All nonsteroidal anti-inflammatory drugs increase the risk of cardiac death in patients with ischemic heart disease,46,47 although the cyclooxygenase-2–specific agents appear to carry higher risk than the nonselective agents.48,49 Nonsteroidal anti-inflammatory drug–induced acute renal failure is more common in elderly patients and in those who are volume depleted, have preexisting renal or cardiac disease, or are taking loop diuretics.
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OTHER PHARMACOLOGIC AGENTS
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A phencyclidine derivative, ketamine produces analgesia and/or dissociative anesthesia with the advantage of causing minimal respiratory depression with usual doses (see chapter 37, Procedural Sedation). Low-dose (subdissociative) infusions of ketamine are effective in combination with opioids for patients in severe pain.50,51,52 Ketamine dosing for analgesia is typically a loading dose of 0.15 to 0.4 milligrams/kg IV over 10 minutes followed by an infusion if desired. Ketamine can be used in trauma patients, resulting in a lower opioid requirement for pain control, and is also effective in controlling acute flare-ups of neuropathic pain. Ketamine is also useful as an SC infusion in palliative care patients. Adverse effects include hypersalivation and reemergence phenomena (disagreeable dreams or hallucinations upon awakening), especially when larger induction doses are used (1.5 milligrams/kg IV).
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Nitrous oxide is a fast-onset, short-acting analgesic and sedative inhalational agent useful for brief, minor procedures (see chapter 37) and for prehospital analgesia.53 The primary adverse effects are nausea and vomiting. Nitrous oxide is usually supplied as a preblended 50% mixture with oxygen and administered to the patient by face mask, but if available, the 70/30 nitrous oxide/oxygen mixture is more effective. Barriers to ED use of nitrous oxide include the need for patient cooperation and an effective scavenging system. In addition, nitrous oxide is contraindicated in patients with altered mental status, head injury, suspected pneumothorax, or perforated abdominal viscus. Severe pulmonary disease also may alter the respiratory elimination of nitrous oxide.
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Cyclic Antidepressants and Anticonvulsants
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Patients with acute-onset neuropathic pain, such as postherpetic or trigeminal neuralgia, are difficult to treat with short-acting opioid analgesics. It may be difficult to identify neuropathic causes of pain in ED patients, but if suspected, more specific therapy and follow-up instructions are needed. Long-acting opioids, cyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and anticonvulsants are effective for neuropathic pain (Table 35-10). When initiating an agent for patients with new-onset neuropathic pain, close follow-up with the primary care physician is important so that titration to effect may continue.54,55 Patients already taking one of these agents for chronic neuropathic pain may require either titration upward of their medication or addition of a second agent; this should be discussed with the patient's regular physician.
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Topical administration of medications at the site of injury or inflammation can provide pain relief with reduced systemic drug absorption and a lower risk of adverse drug reactions (Table 35-11).56 This approach differs from the transdermal drug administration to achieve systemic effects, typically with opioids (see Route of Administration). Topical nonsteroidal anti-inflammatory drugs are effective for treating acute soft tissue injuries such as sprains and strains and also for chronic joint pain from osteoarthritis. Topical lidocaine therapy is effective for patients with postherpetic neuralgia and diabetic neuropathy. Topical capsaicin has produced variable results depending on the treatment population and dose applied; regular use appears necessary for prolonged pain relief. A single 60-minute application of a high-dose preparation (8% capsaicin topical patch) is effective for postherpetic neuralgia but requires professional application and removal to minimize side effects.
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The primary adverse reaction of topical medications is local burning, particularly seen with capsaicin, which is derived from chili peppers. Rare cases of localized burns have been reported with topical muscle and joint pain relievers.57 Most of the serious burns were associated with agents containing menthol (>3% concentration) and/or methyl salicylate (>10% concentration).
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ROUTE OF ADMINISTRATION
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Systemic pain medications can be given by multiple routes (Table 35-12). Oral administration is convenient, inexpensive, and appropriate once the patient can tolerate oral intake; it is a mainstay of pain management in the ambulatory ED population.
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IV opioids are suitable for bolus administration or continuous infusion and are preferred to intermittent IM injections. IM injections are painful, do not allow for easy titration, and have no clinically relevant advantage over PO medications. Absorption can be variable, especially in sickle cell patients (due to scarring) and hypotensive or volume-depleted patients. Patient-controlled IV analgesic systems are particularly effective for ED patients with acute abdominal pain and in addicts with pain when compared with the usual approach of intermittent nurse-administered parenteral medications.58,59,60 Intra-articular analgesia using opioids or bupivacaine can provide sustained relief during the immediate postoperative period following hip and knee surgery.61,62,63 Nasal and buccal preparations of fentanyl are available primarily for breakthrough pain in opioid-tolerant cancer patients, and these routes may have a role in prehospital and ED acute pain management.64 Sublingual buprenorphine is described as effective for ED management of acute pain from fractures.65
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DOSAGE AND PRECAUTIONS
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Safe and effective use of opioids is facilitated by choosing an appropriate initial dose66 and subsequently titrating additional doses toward the desired effect, thus avoiding overmedication and minimizing unwanted effects. In unmonitored opioid-naïve patients, excessive doses of opioids can result in respiratory depression and decreased levels of consciousness. Hypotension is infrequent, is almost always due to histamine release with the first dose of medication, and is usually of short duration. With comorbidities, such as altered mental status, hemodynamic instability, respiratory dysfunction, or multisystem trauma, initial dosing should be decreased, and dose titration is important for achieving satisfactory pain relief.
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Acute pain management for the elderly can be a challenge; these patients may have more than one source of pain and/or multiple comorbidities and are at increased risk for drug–drug and drug–disease interactions.67 Opioid-naïve elderly patients are more sensitive to the analgesic effects of opioid drugs, because they experience a higher peak and longer duration of pain relief. Moreover, they are more sensitive to sedation, respiratory depression, and cognitive and neuropsychiatric dysfunction. Initial IV opioid doses in the elderly are typically half those used in younger adults (e.g., morphine 0.05 milligram/kg and hydromorphone 0.0075 milligram/kg), although single doses may not achieve adequate pain control for elderly patients with acute severe pain.68
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Addiction and Dependence
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Addiction is the misuse of a medication or drug to the detriment of the patient's well-being. Dependence infers that abrupt cessation of a medication will result in acute withdrawal symptoms. Dependence on opioids requires regular daily usage for 4 to 6 weeks in most patients, whereas addiction may occur after one use of heroin. Care should be taken to assess a patient's risk for addiction or diversion of prescription medications, but when uncertainty exists, the general approach is to err on the side of acute pain control, although management in opioid-tolerant patients can be a challenge.69 Contemporary and rigorous evidence is that dependence and addiction occur in up to one-third of patients on chronic opioid therapy,70 but there is little knowledge regarding the risk of short-term (<2 weeks) opioid therapy following an ED visit for an acute injury or temporary illness. Although EDs are not where most cases of opioid abuse originate, they are perceived as a potential perpetuator of misuse.71 Distinguishing patient requests for medications because of oligoanalgesia from addiction often requires multiple patient assessments over time; subjective assessment in the ED during a single visit is usually inaccurate for identifying addiction versus aberrant behavior due to oligoanalgesia.72 Use of an assessment tool such as the Drug Abuse Screening Test may provide a more objective means of screening for addiction.73
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Renal and Hepatic Dysfunction
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Because most analgesics are metabolized by the liver or kidney, take care when using opioids in patients with impaired hepatic or renal function. Renal excretion is a major route of elimination for such pharmacologically active opioid metabolites such as norpropoxyphene, normeperidine, morphine-6-glucuronide, and dihydrocodeine. Mild renal failure can impede excretion of the metabolites of many opioids, resulting in clinically significant narcosis and respiratory depression. In patients with renal failure, hydromorphone and fentanyl are the preferred opioids. Mild hepatic dysfunction has little effect on opioid metabolism. In patients with severe hepatic dysfunction, titration with low doses of analgesics will minimize the risk of overdose.
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Respiratory Insufficiency
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Patients with respiratory insufficiency and those with chronic obstructive pulmonary disease, cystic fibrosis, and neuromuscular disorders affecting respiratory effort (e.g., muscular dystrophy and myasthenia gravis) are particularly vulnerable to the respiratory depressant effects of opioids and nitrous oxide. Careful dose titration and monitoring of oxygenation and ventilation are necessary. Ketamine may be a useful alternative agent in such cases.
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Opioids may have adverse synergistic sedative effects in patients with psychiatric illnesses taking anxiolytics or other psychoactive drugs. The use of monoamine oxidase inhibitors with meperidine is associated with severe adverse reactions, including death as the result of precipitating a serotonin syndrome (see chapter 178, Atypical and Serotonergic Antidepressants). The cyclic antidepressants clomipramine and amitriptyline may increase morphine levels and potentiate the opioid effects.