When possible, treatment should be directed at the source of injury rather than more centrally, where the mechanism becomes more comminuted. Generalized agents (such as opioids) may decrease the sensation of pain, but they may also blunt other elements of the sensorium and are associated with an increased incidence of unwanted effects (eg, vital sign derangements, mental status changes, and constipation). Various agents and techniques work on different parts of the pain pathway (See Figure 1.) and may provide more targeted treatments with fewer adverse events.
Agents For Systemic Analgesia
An opiate is a chemical structure derived from the opium plant, which has been used for centuries for its analgesic effects. Opioid refers to a structurally similar synthetic compound. Examples of popular opioid medications include morphine, hydromorphone, fentanyl, hydrocodone, and oxycodone. This class of medication is very effective for the management of moderate to severe acute pain, but these agents possess concerning side effects and abuse potential.
The analgesic effect of different opioids is based on their relative affinity for different types of opioid receptors. The most physiologically relevant receptor types are: (1) mu1, which mediates supraspinal analgesia, euphoria, miosis, and urinary retention; (2) mu2, which is responsible for respiratory depression, depressed gastrointestinal motility, and cardiovascular depression as well as addictive behavior; and (3) kappa, which modulates dysphoria and spinal-level analgesia.
There is a great deal of heterogeneity in patients’ responses to these medications. Not only must the practitioner account for physical variables (eg, size, age), opioid type, and type of injury, but history of use must be considered when determining an optimal regimen, as this may suggest opioid tolerance. Different agents have different potencies, and their relative receptor affinities present a wide range of treatment options. (See Table 1.) In addition to selecting different agents, different routes of administration, which are discussed later in this review, may also create variable effects. There is no compelling evidence to suggest that, at equivalent doses, any opioid is more effective than another in providing pain relief.
In addition to the abuse potential, the major factor limiting the use of opioids is their side-effect profile. As the practiced emergency clinician is aware, this class of medication may cause profound sedation and respiratory depression. In addition, patients may experience nausea, vomiting, flushing, or hypotension, particularly with agents (most notably morphine) that increase the release of histamine. Continued use may cause urinary retention and constipation.
Partial opioid agonists (agonists-antagonists), such as buprenorphine, are a newer class of analgesic medications. These have the advantage of a “ceiling” effect on respiratory depression, but they may also have a therapeutic ceiling. Attention must be paid in a patient with chronic opioid dependence, as these agents may displace more complete agonists (eg, methadone) and precipitate a withdrawal syndrome.
Meperidine (pethidine or Demerol®) deserves special mention with regard to side effects. It was once a commonly used synthetic opioid, noted for its reported decreased biliary spasm compared to other opioids (although the clinical significance of this effect has been questioned). It also causes increased euphoric effects, compared to morphine.66 Its use has declined because of its potential for toxicity, largely as a result of its metabolite, normeperidine, which causes central nervous system stimulation (eg, anxiety, tremor, hallucinations, and seizure). This effect may be exacerbated by attempted reversal with naloxone. Meperidine also stimulates serotonin receptors, which may precipitate serotonin syndrome, particularly in patients on other serotoninergic medications such as monoamine oxidase inhibitors.67
It is prudent to become familiar with several different opioid medications in order to facilitate treatment when particular agents are not available or not tolerated by a patient. Nonetheless, when possible, a single agent should be used and titrated to provide the best analgesic effect; mixing agents may complicate the adverse side-effect profile and should be avoided.
Popular nonsteroidal anti-inflammatory drugs (NSAIDs) include aspirin, ibuprofen, indomethacin, ketorolac, and naproxen. (See Table 2.) Their analgesic effect is achieved through binding to cyclooxygenase (COX) receptors in the spinal cord without causing mental status changes or respiratory depression. Peripherally, they inhibit COX isoforms 1 and 2, limiting the production of prostaglandin and thromboxane inflammatory mediators. This inhibition of prostaglandin synthesis has the unintended consequence of disrupting their protective effects in the stomach, thus contributing to the development of ulcers. The other major limiting side effect of NSAIDs is impedance of dilation of the afferent glomerular arteriole and a consequent decrease in glomerular filtration rate and decreased renal perfusion pressure. This may contribute to renal failure, especially in patients with advanced age, with underlying renal insufficiency, with hypovolemia, or in those taking an angiotensin-converting-enzyme (ACE) inhibitor.
Prostaglandins (especially PGE-2 and PGF-2-alpha) stimulate bone formation. Inhibition of prostaglandin formation with NSAIDs is suggested to disrupt bone healing. This was demonstrated with various agents in several animal models, although the clinical significance of these findings is unknown.68 Giannoudis et al found an association between NSAID use and nonunion of femoral fractures treated with intramedullary nailing in 377 patients.69
Bhattacharyya et al found a similar association with distal radius fractures, retrospectively, in 9995 Medicare patients. This association, however, only existed in the 61- to 90-day cohort, and they found a similar association with opioids during the same time frame.70 There are no large prospective randomized trials to support this theoretical concern; thus, while some providers avoid NSAID use for fractures, they remain a reasonable treatment option.
Acetaminophen (N-acetyl-p-aminophenol [APAP], or paracetamol) is sold under the brand name Tylenol® and remains the most popular over-the-counter analgesic. The exact mechanism of action is incompletely understood, but inhibition of cyclooxygenase isoforms plays a key role. The resulting decreased production of PGE-2 explains its antipyretic effect. It has limited peripheral anti-inflammatory effects and is, therefore, generally classified differently from other NSAIDs. It does not inhibit proclotting thromboxanes and, thus, does not prevent platelet aggregation. Acetaminophen also acts upon the endogenous cannabinoid system, resulting in its antinociceptive effects.71
Ketamine is a phencyclidine (PCP) derivative that has analgesic and dissociative properties. It has been used extensively for pain control and procedural sedation anesthesia in children and animals, and it is gaining popularity for use in adults. It is effective for analgesia,72 does not cause respiratory depression, promotes bronchodilation, maintains hemodynamic stability relative to other agents, and has been associated with few serious adverse outcomes.73 This makes it particularly attractive in austere environments74 or areas with limited monitoring capabilities.29 Dosing for adults is 1 to 4.5 mg/kg IV or 6.5 to 13 mg/kg intramuscular (IM), and maintenance infusion of 0.1 to 0.5 mg/min IV or intermittent boluses of 0.5 to 4.5 mg/kg IV, as needed. Pediatric dosing is 1.5 mg/kg IV or 4 to 5 mg/kg IM. Administration may be associated with nausea/vomiting, hypersalivation, and emergence phenomena that are easily treated with an adjunctive antiemetic, antisialogogue, or benzodiazepine, respectively. Concern has existed for ketamine causing an increase in intracranial pressure in patients with head injury through its stimulation of endogenous catecholamines, but there is a great deal of evidence from prospective trials to refute this concern and even to suggest that it may lower intracranial pressure.75-81
Clonidine has been used for years as an antihypertensive agent, and it is noted to have analgesic properties as well. Stimulation of alpha-2 receptors in the central nervous system (particularly the locus ceruleus) produces sedation and analgesia without causing respiratory depression. More recently, dexmedetomidine has been developed, which has increased alpha-2 selectivity.82 It also modulates the release of norepinephrine, which may result in bradycardia or hypotension, potentially limiting its use. There are relatively little data on its routine use in the ED, but this represents an area for future research.
Droperidol is the most widely studied butyrophenone used for analgesia. It has many chemical effects, accounting for its wide range of applications.83 It is primarily a dopamine D2 antagonist, but it also antagonizes serotonin and histamine receptors, potentiates mu opioid receptors, and, among its other properties, has a dose-dependent agonist/antagonist effect on type A gamma-aminobutyric acid (GABA) receptors. It has been useful for treatment of psychosis, nausea and vomiting, agitation, vertigo, and headaches. An opioid-sparing effect of adjuvant droperidol has been demonstrated in several trials of surgical patients. In addition, its antiemetic properties make it particularly attractive. Akathisia and dystonia are the most commonly reported adverse effects of droperidol, but they usually resolve after treatment with anticholinergics such as diphenhydramine or benztropine. Refractory cases may warrant a beta-blocker or benzodiazepine.
Sharma and Davies randomized 50 patients after hysterectomy to patient-controlled analgesia with morphine or morphine plus droperidol and found that the addition of droperidol provided significantly decreased nausea and improved patient-reported pain control.84 Lo et al reported similar results with patient-controlled analgesia in 179 posthysterectomy patients.85 Freedman et al randomized 40 patients after orthopedic surgery in a similar fashion and reported significantly reduced nausea, vomiting, and morphine dosing with the addition of droperidol.86 Yamamoto et al also demonstrated improved pain scores and an opioid-sparing effect with preoperative doses of droperidol in a randomized trial of 84 orthopedic surgery patients.87 No adverse effects (extrapyramidal symptoms) from droperidol were found in any of these 4 trials.
The use of droperidol declined after 2001, when the United States Food and Drug Administration (FDA) issued a black box warning regarding its association with QT prolongation and torsades de pointes. This was based on a small case series, and its validity has been called into question.88 One review estimates that of 16,791 cases using droperidol, there were no dysrhythmias due to QT prolongation.89 Nonetheless, because the concern still exists, a screening electrocardiogram is recommended to measure the QT interval.
Route Of Administration
Systemic analgesia may be administered through a variety of routes, each with relative advantages and disadvantages. (See Table 3.) There is evidence that the route of administration alone does not account for a significant difference in analgesic effect, despite many patients’ and providers’ belief to the contrary.90 The clinician should determine the most appropriate route based on the potency and pharmacokinetics of the agent, resource availability, and patient factors.
Frequency Of Dosing
Frequency of dosing and reassessment of pain is a consideration based on the pharmacokinetics of the analgesic and route prescribed. Certain agents and routes of administration may have a shorter time to onset but may also require more frequent reassessment or redosing. Care must be taken to avoid premature readministration and consequent dose “stacking,” which may cause unintended deleterious effects.
Topical application of a local anesthetic is the simplest and least resource-intensive form of regional anesthesia. It averts much of the pain and apprehension from using a needle for injection, which may be particularly useful in children. It may also prove a useful adjunct in distinguishing cutaneous pain from a deeper musculoskeletal injury (eg, evaluation of pain while ranging a joint may be differentiated from the pain from an overlying abrasion, as the topical anesthetic is unlikely to affect deeper structures). Various combinations of local anesthetics and vasoconstrictors are used for injuries that disrupt the dermis. Among the most common is a mixture of 4% lidocaine, 0.1% epinephrine (adrenaline), and 0.5% tetracaine (abbreviated LET or TAL). These are often formulated locally in the hospital pharmacy.
Intact skin may be anesthetized with an alkaline mixture of lidocaine and prilocaine (eutectic mixture of local anesthetic, or EMLA®), which is often useful for IV insertion or lumbar puncture but requires application for at least 60 minutes for full effect.91
Topical application of NSAIDs for acute musculoskeletal conditions was evaluated in a Cochrane review of 47 trials totaling 3455 patients. It demonstrated a significant reduction in pain compared to placebo with treatment periods of 6 to 14 days for topical diclofenac, ibuprofen, ketoprofen, and piroxicam. Adverse effects did not differ from placebo.92 These results suggest that topical administration of NSAIDs is a useful method of administration.
Corneal abrasions represent a painful scenario that may be frustrating to both the patient and the provider. Local anesthetics provide good relief, but prolonged use is associated with corneal infiltrates, ulcer formation, and perforation.93 Topical application of NSAIDs may safely provide effective localized analgesia when used for a longer period of time. A meta-analysis by Calder et al, including data from 3 high-quality randomized controlled trials totaling 459 patients, demonstrated significantly improved pain with the use of topical NSAIDs.94 Adverse outcomes were rare and generally consisted of stinging with instillation of the drops. Topical NSAIDs for corneal abrasions provide a safe, effective method of analgesia, sparing the side effects of systemic agents.
Regional anesthesia is a method for providing anesthesia and/or analgesia to a specific area of the body, potentially sparing many of the risks of systemic analgesia or procedural sedation. Serious complications from regional anesthesia are exceedingly rare,95 and many techniques can be safely and effectively performed by emergency clinicians, with proper instruction.96 Regional anesthesia incorporates a range of approaches, from central neuraxial blocks (spinal and epidural anesthesia) to local infiltration, which may be considered a nerve block at its most distal aspect. There are many potential applications for regional anesthesia with traumatic injuries; some of the most popular and well-investigated are reviewed here.
Agents For Regional Anesthesia
Cocaine belongs to a class of nitrogen-containing chemicals known as alkaloids. It is an amino ester derived from the coca plant, and it was first used therapeutically as a local anesthetic in 1884. Twenty years later, Alfred Einhorn synthesized the structurally related amino ester, procaine (Novocain®), which does not have the addictive and euphoric qualities that led to cocaine’s abuse potential. Procaine has since been largely replaced by an amino amide, lidocaine, due to its longer duration of action and lower incidence of allergic reaction.91 Benzocaine is an ester with high mucosal absorption and is often used as an anesthetic in the ear and throat. Tetracaine is another amino ester that has improved mucosal absorption and longer duration, but it has been associated with increased toxicity.97,98
Other amino amide agents have been developed subsequently for their additional advantages. (See Table 4.) Bupivacaine and ropivacaine have a longer duration of action than lidocaine. Ropivacaine and prilocaine have decreased cardiac toxicity, which supports their use intravenously.
There is potential for cartilage toxicity from intra-articular injection of amino amides. This was first suggested by Nole et al in a porcine and canine model in 1985.99 They found that bupivacaine decreased proteoglycan synthesis both in vitro and in vivo, which returned to normal at 72 hours. Subsequently, Chu et al found a dose- and time-dependent relationship in vitro with human chondrocytes.100 Dragoo et al showed similar effects from lidocaine in vitro with human chondrocytes.101 The clinical consequences of these findings are still unclear due to a lack of supporting evidence. Chondrolysis can be a devastating condition requiring joint replacement, particularly in the glenohumeral joint. Postarthroscopic glenohumeral chondrolysis has been described in several case series, most often associated with prolonged, continuous infusion of bupivacaine. Causality has not been established, as there are almost no prospective data available. One randomized trial by Järvelä showed no difference in outcome at 2 years with 24-hour infusion of ropivacaine, but it was based on only 25 patients in each group.102
The significance of a single intra-articular injection is even less well-studied. There are insufficient data to suggest that this is a harmful technique, but this potential should be considered if this approach is used.
Additives For Regional Anesthesia
Epinephrine may be added to a short-acting local anesthetic (eg, lidocaine) to promote vasoconstriction, thus decreasing diffusion of the anesthetic and consequently prolonging its action. It does not appear to confer this benefit when used with longer-acting agents, likely because the anesthetic duration outlasts the epinephrine. It may, however, provide additional benefit, including assistance with hemostasis.
Sodium bicarbonate may be added to local anesthetic preparations to increase its pH, theoretically hastening the time to sensory blockade, although evidence for this effect in vivo is conflicting.103,104 Additionally, it is suggested that increasing the pH results in less-painful infiltration.105,106
Clonidine has been added to local anesthetic preparations and has been shown to increase the duration of anesthesia, but it has been associated with hypotension, which may limit its use.107 The addition of other agents (eg, tramadol, midazolam, dexamethasone, dexmedetomidine) to local anesthetic preparations have been studied,108 but their mainstream use is not yet supported.
Perhaps the most commonly employed method of local anesthesia is injection of a local anesthetic directly into the injured area, anesthetizing nerve endings directly at the site of injury. This has the benefit of easy identification and procedural simplicity but may cause distortion of the tissues and variable efficacy.
A hematoma block is a version of local infiltration in which an anesthetic is injected into the hematoma created by a fractured bone. (See Figure 2.) This allows diffusion of the anesthetic into surrounding sensory nerves, particularly in the sensitive periosteum. Aspiration of the hematoma prior to injection may facilitate this process. A prospective randomized trial of 96 patients by Myderrizi and Mema compared a hematoma block to sedation with propofol. They demonstrated faster time to reduction, no significant difference in pain control, and similar rates of reduction displacement at 1 week.109 The safety and simplicity of this technique make it a desirable option for fracture reduction in the ED.
Intravenous Regional Anesthesia (Bier Block)
IV regional anesthesia is a simple and effective means of achieving regional anesthesia in the extremities. It was first described by August Bier in 1908 as a technique of introducing local anesthetic between (or distal to) tourniquets to achieve localized concentrations. (See Figure 3.) It remained an obscure technique, however, until the 1960s.110
The procedure is performed by first exsanguinating the extremity with a compression wrap and/or gravity. A small IV catheter is placed in the distal part of the extremity, and a double pneumatic cuff is placed proximally. Local anesthetic (1.5-3 mg/kg of 0.5% lidocaine) is infused through the catheter, which diffuses into the surrounding tissues. After 30 minutes, the cuff is intermittently deflated to slowly release the anesthetic into the circulation (there should be very little anesthetic left intravascularly at this point). A complete description of the technique is available at: http://www.nysora.com/peripheral_nerve_blocks/intravenous_regional_blocks/3009-bier_block.html
A Cochrane review of anesthetic options for treating distal radius fractures found evidence from 5 trials comparing intravenous regional anesthesia (IVRA) with hematoma block.111 IVRA provided superior analgesia during manipulation as well as better and easier fracture reduction. The procedure is not without its own risks, however. Most notably, deaths from leakage of regional anesthetic, although rare, have been reported.112 More common (though likely less concerning) are untoward effects from the tourniquet,113 particularly neural or vascular injury, edema, hematoma development, and tissue necrosis. To decrease the likelihood of these complications, IVRA should be performed with a specialized double-pneumatic tourniquet.94,114 This technique is more time-intensive than a hematoma block, and the requirement for specialized equipment may preclude this technique for some EDs.
Regional Nerve Blocks
Application of a local anesthetic on or near peripheral nerves or plexi produces anesthesia restricted to the distribution of specific sensory nerves. This may provide the benefit of analgesia without the unwanted effects of systemic analgesia. Nerve stimulators have historically been used to assist with the identification of nerves and appropriate placement of the anesthetic.115 More recently, a Cochrane review demonstrated that ultrasound use reduces complication rates and improves quality, performance time, and time to onset of blocks.116
Any specific nerve that can be identified and that provides appropriate access may be anesthetized in this fashion. (See Table 5.) Common applications include central neuraxial blocks (eg, epidural or spinal anesthesia), nerve plexus blocks (eg, brachial plexus block), and peripheral nerve blocks (eg, femoral nerve block). Some of the methods most commonly used in the ED are reviewed here.
A digital block is a simple method for providing a ring of anesthetic to the proximal aspect of a finger or toe. (See Figure 4.) Any sensory nerves to the digit should penetrate this ring and become insensate via the anesthetic. The addition of epinephrine to this technique has long been touted to promote ischemia of distal structures, but evidence for this claim is lacking. Wilhelmi et al showed improved hemostasis and a trend toward improved anesthesia and decreased complications with the addition of epinephrine in a randomized trial of 60 patients.117 Chowdhry et al reported 611 patients with epinephrine injection in the hand or fingers with no cases of ischemia.118
A potentially less familiar approach to providing digital anesthesia is the transthecal (flexor tendon sheath) nerve block. Injection of anesthetic into the flexor tendon sheath disseminates along its course, providing anesthesia to the entire finger. A single injection is performed at the palmar crease at the base of the digit. (See Figure 5.) This method provides similar anesthesia, though it may have delayed onset and increased pain compared with the traditional digital block, as demonstrated in 3 randomized trials totaling 106 patients.119-121 Both of these techniques are described and demonstrated at the following website: http://www.mainehealth.org/em_body.cfm?id=3241
Femoral Nerve Block
Femoral nerve blocks have been investigated for pain relief in hip fractures. (See Figure 6.) A Cochrane review concluded that, over the 9 presurgical trials reviewed (525 patients), there was improvement in pain and decreased need for systemic analgesia, with few adverse outcomes.122
A femoral nerve block can be performed with sterile technique, by injection of 20 mL of 0.5% bupivacaine into the area immediately surrounding the femoral nerve (lateral to the femoral artery, below the fascia iliaca). These structures can be visualized with ultrasound, which has been shown to improve performance time and decrease complication rate.116 A tutorial of the femoral nerve block technique is available online: http://www.neuraxiom.com/html/newfemoral.html. A video demonstration of the technique (used for a thigh laceration) is available at this website: http://ulscourse.com/video/ultrasound-guided-femoral-nerve-block-large-thigh-laceration
The proximal femur often shares partial sensory innervation with the obturator and lateral femoral cutaneous nerves, which may result in incomplete anesthesia from a femoral nerve block alone. Applying constant pressure to the fascia distal to the site of the injection for several minutes allows the injected anesthetic to distribute to these nerves as well, giving this technique the moniker “3-in-1” block.123
Upper Extremity Anesthesia
Upper extremity nerve blocks may be clinically useful as well. Ulnar, radial, and median nerve blocks may be used for anesthesia of the hand. These nerves may be identified by anatomical landmarks or ultrasound. A detailed tutorial of these techniques is available online: http://www.mainehealth.org/em_body.cfm?id=3242. The ulnar nerve block may be particularly useful for fifth metacarpal fractures, as demonstrated at this video: http://ulscourse.com/video/ultrasound-guided-ulnar-block-boxers-fracture.
Interscalene Brachial Plexus Block
An interscalene brachial plexus block has demonstrated utility in the ED for analgesia during reduction of shoulder dislocation. (See Figure 7.) Blaivas et al reported a series of 4 patients treated in this fashion with good results in the ED.124 This was followed by a prospective randomized comparison of the technique with etomidate in 42 patients. The interscalene block showed decreased length of ED stay as well as less need for one-on-one provider time.125 An explanation and video demonstration of the technique is available at the following website: http://pointofcare.blogspot.com/2010/12/interscalene-block-for-deltoid-abscess.html
Intercostal Nerve Block
The use of regional nerve blocks is not restricted to the extremities. An intercostal nerve block may effectively decrease traumatic chest pain, especially with associated rib fractures.126,127 (See Figure 8.) Truitt et al showed improved pain scoring and decreased length of stay with continuous infusion of intercostal nerve blockade in 102 patients with rib fractures.126 While insertion of a continuous infusion catheter may not be practical for some emergency practitioners, a single injection of anesthetic can provide relief for many hours. The technique is described online here: http://www.nysora.com/peripheral_nerve_blocks/nerve_stimulator_techniques/3098-intercostal-nerve-block.html
Dental trauma is notably painful and difficult to control with systemic analgesia. Apical periosteal blocks and inferior alveolar nerve blocks can be used to provide anesthesia to the upper and lower teeth, respectively.128,129 (See Figures 9 and 10.) In addition, anesthesia of the inferior alveolar nerve may provide relief from the pain of a mandibular fracture or superficial injury. These techniques are described at the following website: http://www.nysora.com/peripheral_nerve_blocks/head_and_neck_block/3062-oral_maxillofacial_regional_anesthesia.html. A video demonstration of an inferior alveolar nerve block is available here: http://www.mainehealth.org/em_body.cfm?id=3244#inferior.