Pain management in the orthopaedic trauma patient: Non-opioid solutions

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Pain management in the orthopaedic trauma patient: Non-opioid solutions Daniel M. Gessnera , Jean-Louis Horna , David W. Lowenbergb,* a b

Department of Anesthesiology, Stanford University School of Medicine, USA Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway St., Mailcode 6342, Redwood City, CA, 94063, USA

A R T I C L E I N F O

A B S T R A C T

Article history: Received 6 April 2019 Accepted 18 April 2019

When treating pain in the orthopaedic trauma patient opioids have classically represented the mainstay of treatment. They are relatively inexpensive and modestly effective for basic pain management. However, they are fraught with considerable side effects as well as the very high risk of addiction. Their use in pain management has been implicated in the opioid epidemic. For this reason, as well as their only moderate efficacy, alternative modes of treatment have been sought for both the patient with isolated limb trauma and the patient with poly trauma. We review alternative treatment methods in pain management for those with isolated limb trauma and poly trauma. These methods include topical agents, as well as non steroidal anti-inflammatory medications, acetaminophen, gabapetoids, intravenous agents, varying degrees of local anesthetic infiltration and peripheral nerve blocks, and the newer modality of fascial plane blocks. Often, it is a combination of these analgesic modalities that gives the most optimum treatment for the trauma patient. This also, more frequently than not, must be individually tailored to the patient, as no two patients act the same in this regard. It is therefore of importance that the physician managing such patients's pain be experienced and well-versed in all these treatment modalities. We also provide a basic stepwise algorithm we have found useful in treating those with single extremity or single site trauma versus those patients with poly trauma and resultant multiple sources as pain generators. It is hoped that this breakdown of the different modalities along with a better understanding of each modality's potential benefits and indications will aid the surgeon in providing better care to patients following orthopedic trauma. © 2019 Elsevier Ltd. All rights reserved.

Keywords: Pain management Orthopaedic trauma patient Fascial plane blocks Multimodal analgesia

Introduction Opioids are ubiquitous on the trauma ward, and a majority of adult trauma patients in the United States receive a prescription for opioids on discharge from the hospital [1]. Unfortunately, injured patients are more likely than uninjured patients to become persistent opioid users, and a traumatic injury is an independent risk factor for developing persistent opioid use [2]. Since 2000, most recent illicit opioid users began their addiction by abusing prescription opioids [3]. Opioids are obviously effective analgesics, and there is good evidence that opioids, when compared to placebo, can provide effective analgesia for at least months [4]. But opioids are also associated with significant rates of serious adverse events for both inpatients [5] and outpatients [6]. For inpatients, these serious

* Corresponding author. E-mail address: [email protected] (D.W. Lowenberg).

adverse events lead to longer hospital stays, higher costs, and increased mortality [5]. Furthermore, the superiority of opioids is unclear when compared to other analgesics. Head-to-head comparative trials have demonstrated that opioid and nonopioid analgesics provide equivalent pain relief as a single dose for extremity trauma [7], over a week after outpatient general surgery [8], and over one to two weeks for nonoperative acute pain [9]. Multimodal analgesia, typically defined as the simultaneous use of different analgesic drug classes, may provide superior analgesia with fewer side effects as compared to opioids alone. The use of multimodal analgesia is recommended by national societies in anesthesiology, pain medicine [10], trauma [11], and “enhanced recovery” (ERAS) colorectal surgery [12] and is beginning to be incorporated into national quality measures [13]. There are multiple recent reviews of multimodal nonopioid methods and medications for perioperative and surgical analgesia in the anesthesia [14], surgical [15], and nursing [16] literature. Here we will focus on the utility of multimodal non-opioid analgesics for the trauma patient. We will differentiate between

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simple trauma (i.e. single limb, uncomplicated fracture) and complex trauma (i.e. multisystem injuries, complicated fracture) and the utility of these analgesics in these diverse patient populations, focusing on ease of administration, effects on bone healing, effects on bleeding and anticoagulation, and effects on mobility and rehabilitation, as well as notable contraindications.

dramatically in critically ill poly-trauma patients, with one pharmacokinetic study projecting doses of up to 12 g per day as necessary to achieve therapeutic levels [28]. A reasonable safe maximum dose is 4 g per day while under healthcare provider supervision for all but cirrhotic patients, who should receive 2 g per day.

Topicals

Non-selective NSAIDs

It is worth considering the use of topical analgesics for any patient that has intact skin. There are multiple options, and while they have variable efficacy in prospective trials, they are largely inexpensive and safe, ease to administer, and have minimal negative side effects on healing, bleeding, or rehabilitation. Topical NSAIDs are safe and mildly effective analgesics in simple trauma. There is evidence that highly absorbable formulations of diclofenac and ketoprofen, compared to placebo, provide >50% pain relief for simple closed orthopedic injuries (e.g. sprains and strains) when administered over one week while producing very low (< 5% as compared to oral administration) plasma levels and thus minimal systemic side effects. [17] Topical lidocaine is safe to use on intact skin with minimal systemic uptake (at up to 4 patches/day) and is effective analgesia for specific traumatic injuries associated with cutaneous allodynia, or painful sensations from a nonpainful stimulus. This may include intercostal neuralgias or post-amputation pain. It is also be effective for pre-existing chronic neuropathic pain like that of post-herpetic syndromes or diabetic neuropathy [18]. There is no evidence of effectiveness for other types of traumatic or postsurgical pain [19]. Cryotherapy with ice or cold-water recirculation is a mainstay of outpatient knee arthroscopic ligament repair and can effectively reduce reported pain without increased risk of adverse events [20], however it is not effective after elective total knee arthroplasty [21] so it may be less useful in general orthopedic trauma. There is a single trial demonstrating decreased pain and opioid consumption by applying ice packs to midline abdominal incisions [22] so there may be utility in complex trauma patients after laparotomy. TENS (Transcutaneous Electrical Nerve Stimulation) units administer mild electric current to the skin to stimulate peripheral nerves. This is distinct from spinal cord stimulators and other more centrally-acting devices. Multiple trials in acute pain have demonstrated that TENS can reduce pain sensations as compared to placebo, however evidence in trauma specifically is limited, and skin irritation and other mild adverse effects have been reported [23].

The NSAIDs are the single most effective analgesics for acute pain (Fig. 1). NSAIDs, both with [7,8] and without [9] acetaminophen, provide at least equivalent analgesia to opioids. Combination therapy with an NSAID and acetaminophen together approximately doubles their opioid-sparing analgesic effect [24] and provides better pain relief than either single agent [29]. NSAIDs have notable contraindications, some of which are specifically relevant to trauma care. NSAIDs cause edema and fluid retention and are associated with worsening mortality in heart failure patients [30], and since 2015 there is a boxed warning on all NSAIDs highlighting their relationship with an increased risk of heart attack or stroke regardless of patient risk factors within “weeks” of starting chronic NSAID therapy [31], however there is minimal evidence of risk in shorter term acute therapy. Chronic kidney disease is a relative contraindication, and many NSAIDs package inserts include recommended dose reductions in stable kidney insufficiency. NSAIDs do reduce renal blood flow and can cause or exacerbate acute kidney injury, particularly in patients already at risk due to pre-existing renal insufficiency or volume depletion. Since acute kidney injury (AKI) is a significant predictor of mortality in the complex critically-ill trauma patient [32], it is reasonable to avoid NSAIDs when patients have objective concern for developing AKI. Through inhibition of COX-1, nonselective NSAIDs can cause gastrointestinal bleeding and can interfere with platelet aggregation, which can theoretically cause or worsen surgical bleeding. In retrospective studies NSAIDs are associated with an increased risk of surgical bleeding [33], but prospective data does not confirm the association. For example, a meta-analysis of trials of perioperative ketorolac for up to 4 days at all doses is not associated with increased risk of bleeding or other adverse events [34]. Notably aspirin, particularly at a low dose (81mg-325 mg) will produce similar platelet inhibition to other NSAIDs [35], so if a surgical cohort seems to tolerate aspirin for thromboprophylaxis, they may also tolerate NSAIDs for analgesia. In mice, COX-2 seems essential for healing of both bone fractures [36] and bowel anastomoses [37]. Retrospective human data has associated NSAID exposure with doubling the odds of nonunion/malunion after long bone fracture [38] and increasing risk of stress fracture in soldiers [39], but nonunion is a painful condition and itself likely increases the risk of receiving additional analgesics including NSAIDs. Prospective trials avoid this confounding, and do not confirm a risk of nonunion after short term NSAID usage, demonstrating an increased risk only in trials where patients receive prolonged (~6 weeks) indomethacin for heterotopic ossification prophylaxis [40]. Retrospective human data has also associated NSIADs with bowel anastomic leaks, though prospective trials have not confirmed a risk of leak after NSAID use [41], and the most recent clinical practice guidelines from relevant American colorectal and gastrointestinal surgical societies emphasize the strong analgesic value of NSAIDs despite their unclear risk profile [42].

Systemics available as oral formulations Acetaminophen Acetaminophen is safe and synergistic with opioids for acute pain. It is substantially opioid sparing (>20 mg morphine per day) when combined with other non-opioid analgesics but does not tend to reduce actual reported pain [24], so is likely best given as a scheduled medication rather than as needed. Intravenous acetaminophen has theoretical advantages in bioavailability and onset speed, but in patients who can tolerate an oral formulation there is no clinically significant difference in efficacy versus the intravenous formulation [25]. High dosages of acetaminophen are associated with liver injury, but the specific toxic dose for a given patient appears idiosyncratic; it is not infrequent for hospitalized inpatients to inadvertently receive doses higher than 4 g per day without obvious adverse laboratory or clinical effect [26], and newly abstinent alcoholics have been prospectively given doses of 4 g per day [27] without evidence of liver injury. Clearance also seems to increase

Selective NSAIDs/COX-2 inhibitors The selective COX-2 inhibitor celecoxib provides analgesia similar to that of the non-selective NSAIDs [24,43] without

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Fig. 1. Selected NNTs from the 2007 Oxford league table of analgesic efficacy, modified from [86].

effecting platelet function [44] and is an appropriate analgesic even after high-bleeding-risk surgical procedures like craniotomy [45]. Diclofenac is also relatively selective for COX-2 and has an adverse effect profile similar to celecoxib [43]. After the marketing withdrawal of rofecoxib because of adverse cardiac effects, the FDA required a large prospective trial to evaluate the safety of celecoxib, which demonstrated that celecoxib is at least as safe from a cardiovascular perspective as naproxen and ibuprofen, and less likely to cause renal or gastrointestinal adverse events [46]. Celecoxib, like the nonselective NSAIDs, have a theoretical risk of inhibiting bone and bowel healing, but prospective human trials have not demonstrated an actual risk [40–42].

gabapentin increased the rate of postoperative opioid cessation in a mixed surgical cohort [52]. Muscle relaxants The “muscle relaxants” are a diverse class of medications that are primarily central nervous system depressants. They include methocarbamol, tizanidine, baclofen, cyclobenzaprine, and carisoprodol. An older but high-quality meta-analysis demonstrated analgesic efficacy in nonspecific low back pain that was equivalent across the entire class of medication, but with a significant risk of adverse effects including drowsiness and dizziness [53]. There is no significant evidence of efficacy in other acute pain, and except when sedation is a goal, there is probably little role for this class of medications.

Gabapentoids Systemics available as intravenous formulations Gabapentin and pregabalin block voltage-dependent Ca++ channels and can provide analgesia though with prominent side effects including sedation. Gabapentin bioavailabity exhibits high variability between different patients and at different dosages, peak absorption can be unpredictably delayed, and the dose-response curve for its analgesic effects is non-linear, so pregabalin may be preferred when it is available because it is predictably and rapidly absorbed and has a more consistent dose-response curve [47]. Peri-operative pregabalin, in most but not all types of surgery, decreases opioid consumption and pain during the first 24 postoperative hours, but with an increase in sedation [48] which may impair mobility and rehabilitation. Gabapentin similarly modestly decreases opioid usage but does not decrease pain scores [49]. Gabapentinoids seem primarily effective in painful surgeries known to be pronociceptive, like amputations, joint replacements, and spine surgery [50]. More promising, 14 days of prebagalin reduced the incidence of chronic pain after TKA [51] and 3 days of

Intravenous lidocaine Lidocaine given via intravenous infusion is a mild analgesic and safe to administer, with no significant adverse events seen in a meta-analysis of 50 trials [54]. It is as effective as morphine as a single dose after acute limb trauma [55]. In general, periprocedural lidocaine has a short-lived (i.e. 4 h postoperatively) analgesic effect, but has multiple other positive effects including a reduction in the time to first flatus, decreased length of hospital stay, reduced nausea in the PACU, and reduced intraoperative opioid consumption [54]. Ketamine Ketamine is a potent analgesic and anesthetic with clear opioidsparing effects. Recent guidelines suggest that it is most effective

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for patients in at least moderate pain (i.e. VAS score of 7 or more of 10) and in patients who are opioid-dependent, and there is limited but compelling evidence that ketamine can reduce both shortterm (i.e. 48 h postoperatively) and long-term (i.e. six weeks postoperatively) opioid consumption after painful surgery [56]. In the complex trauma patient with head injury, ketamine is safe, with multiple neuro-intensive care studies since the 1990s demonstrating that ketamine does not reduce cerebral perfusion pressure [57]. Ketamine infusion is generally well tolerated, but occasionally associated with adverse effects including nausea, vomiting, and vivid dreams, but dissociative effects are rare and psychosis is not an absolute contraindication to ketamine infusion [56]. Alpha 2 agonists Infusion of an alpha-2 agonist, particularly dexmedetomidine, is an effective opioid-sparing postoperative analgesic. There is good-quality meta-analysis evidence that dexmedetomidine reduces pain intensity, opioid doses, and nausea for at least 24 h post-operatively [58]. Bradycardia is a common side-effect of dexmedetomidine, as well as hypotension, which may inhibit mobility and rehabilitation in the trauma patient. Neuraxial Non-opioid neuraxial analgesia, typically via the epidural route, has the best evidence in the anesthesia literature for a pre-emptive decrease in postoperative pain scores and analgesic requirements [59]. There is also moderate-quality evidence that epidural analgesia may prevent persistent postoperative pain after thoracotomy [60]. Thoracic epidurals are a well-studied option for rib fracture and are likely the best single analgesic but are contraindicated or limited by many anticoagulants, can cause hypotension, do not improve outcomes other than analgesia, and were recently downgraded to “conditionally” recommended by consensus guidelines for thoracic trauma pain management [11]. Epidurals remain an excellent option in specific circumstances, but the fascial plane nerve blocks will likely become the preferred option for complex trauma patients due to a better side effect profile and higher safety margin, especially in anticoagulated patients. Infiltration of local anesthetics and adjuvants Superficial infiltration of local anesthetics at surgical incisions is common practice prior to skin incision and/or closure. Generally, there is a mild pre-emptive benefit in infiltration prior to incision, which results in decreased postoperative analgesic requirements as compared to infiltration after incision [59]. There are diverse techniques for superficial infiltration, including continuous wound infiltration catheters, but demonstrated analgesic efficacy is inconsistent [61]. For example, simple wound infiltration is modestly effective for breast surgery [62] but does not provide significant analgesia after spine surgery [63]; continuous wound infiltration is modestly effective in abdominal surgery [64] but ineffective in percutaneous femur fixation [65]. Superficial liposomal bupivacaine infiltration effectively reduces skin sensation in healthy volunteers for up to 48 h [66] but is clinically indistinguishable from plain bupivacaine infiltration when compared in surgical trials [67]. Liposomal bupivacaine is also significantly more expensive than plan bupivacaine, and the package insert for the most popular formulation specifically prohibits additional use of local anesthetic for 96 h following injection, a limitation which may be both counterproductive and

difficult to enforce in a complex trauma patient returning frequently to the OR [68]. Deeper peri-articular local anesthetic infiltration analgesia was first described in 2008. It is effective in primary hip and knee arthroplasty and when both administered meticulously and supplemented postoperatively via an intraarticular catheter, it can be entirely opioid-sparing in some patients [69]. Trials of similar deep infiltration techniques after femoral fracture repair have had mixed results [65,70,71]. All local anesthetics exhibit experimental concentrationdependent myotoxicity in non-human animal studies, but clinical myotoxic effects have not been conclusively demonstrated in humans, and in any case are likely either very rare or subclinical [72]. Local anesthetics have also been associated with delayed chondrolysis, a rare but devastating complication that can be seen even with a single intraarticular dose of any local anesthetic [73]. Despite theoretical concerns about bone healing, periarticular NSAIDs do not seem to cause prosthetic loosening [74], and deep infiltration of local anesthetic does not seem to worsen bleeding in hip arthroplasty [75]. In trauma, superficial infiltration may be particularly useful after abdominal exploration in complex trauma, and deeper infiltration in hip fracture deserves further study. Wound infiltration of plain local anesthetic in simple orthopedic trauma may not be particularly efficacious but is safe and does not preclude additional regional anesthesia techniques. Peripheral nerve blocks Single injection nerve blocks provide both excellent analgesia and can serve as the primary anesthetic for limb debridement and fixation. As a sole agent peripheral nerve blocks provide equivalent or better analgesia than systemic medications and may help critically-ill trauma patients avoid general anesthesia and mechanical ventilation for surgical procedures. Avoiding general anesthesia can be particularly important for trauma patients with head or airway injuries. There is some evidence that peripheral nerve blocks improve blood flow to traumatically injured limbs via sympathectomy and may reduce the incidence of chronic pain after traumatic injury. [76] Continuous peripheral nerve blocks are demonstrably effective for a wide array of limb surgeries. Continuous blocks generally reduce pain scores and opioid requirements, decrease postoperative nausea and vomiting, increase patient satisfaction, and in some situations enable better postoperative mobilization and rehabilitation [77]. They have a variable failure rate that is likely technique and operator dependent but are typically effective for several days with very low rates of infection, bleeding, toxicity, or catheter-related (e.g. retention) complications. In centers with the proper support systems, patients can be discharged home with certain continuous blocks [78]. Continuous block catheters can also be placed pre-operatively without administering any local anesthetic, enabling clear postoperative neurological examination followed by rapid analgesia on demand. Anticoagulation, particularly therapeutic anticoagulation, can preclude peripheral nerve blockade in certain situations. The risk is primarily related to hemorrhage and the resulting effects of blood loss, though perineural bleeding may promote neural inflammation and contribute to nerve injury. Deeper nerve blocks in uncompressible locations are the most concerning for uncontrollable hemorrhage, however bleeding in any case is a rare complication and there is little data to demonstrate either safety or risk. Consensus guidelines suggest individualized decision making as to whether to perform any given block, so thresholds will likely be operator- and/or institution-dependent [35].

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The risk of nerve damage from a nerve block is real but the incidence rate is low and not distinguishable from the risk of nerve damage from surgery itself. Transient persistent sensory changes, typically numbness, are relatively common after nerve blocks, with an incidence up to 2.2% at 3 months and 0.2% at 1 year, however most patients who receive a nerve block also receive surgery, clouding the cause and effect relationship. A large retrospective study of risk factors for perioperative nerve injury indicated that the presence of a nerve block was not an independent risk factor for nerve injury and did not increase the risk of postoperative neurological injury as compared to general anesthesia alone [79]. Regardless of the presence or absence of a nerve block, transient neurological symptoms possibly secondary to nerve injury are relatively common after both elective surgery and traumatic injury. The incidence of nerve injury is approximately 1% after total hip, 1.3% after total ankle, and up to 9.5% of total knee arthroplasties [79], and a retrospective study found a nerve injury diagnosis rate of 1.64% at 90 days post-trauma in a large cohort of upper and lower limb traumas [80]. Historical teaching says that nerve blocks will prevent the diagnosis of compartment syndrome, leading to catastrophic results, but that is not consistent with recent practice or literature. No prospective studies have demonstrated this risk, and evidence is entirely limited to case reports. Most recent case reports of compartment syndrome diagnosed in the presence of regional nerve block demonstrate that patients have breakthrough pain despite the block and conclude that the nerve block did not delay the diagnosis of compartment syndrome [81]. Ischemic pain is likely transmitted through pathways that are less or not susceptible to nerve block, and modern continuous nerve block techniques can reasonably be expected to produce, when required, titratable analgesia that maintains some limb sensation and permits serial functional examinations [82]. Fascial plane blocks A promising recent development are the fascial plane nerve blocks, where local anesthetic is directed towards a potential space between fascial layers rather than a specific nerve or plexus. First

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described in 2001 was the transversus abdomins plain block (TAP, Fig. 2), targeted at the cutaneous nerves passing through the fascial plane just superficial to the transversus abdominis muscle. As ultrasound guidance has become more available, approaches to achieve better craniocaudal coverage of those same nerves have been described, including the more medial rectus sheath block and the more lateral/posterior quadratus lumborum block (QL or QLB, Fig. 3). All of these blocks are amenable to continuous catheterbased techniques, are safe and relatively simple to perform, and are excellent alternatives to epidural analgesia [83]. Most recently described is the erector spinae plane block (ESP or ESPB, Fig. 4), placed posteriorly in the fascial plane just superficial to the spine’s transverse processes. The mechanism of analgesia is uncertain, and likely involves either spread towards thoracic spinal nerves and/or sympathetic nerve fibers [84]. Originally intended to treat thoracic cutaneous pain [85], the ESPB has since been used for analgesia after sternotomy, thoracotomy, laparotomy, hip arthroplasty, shoulder surgery, and rib fracture, and it appears safe in anticoagulated patients, including those requiring cardiopulmonary bypass [84]. Algorithms First-line non-opioid analgesics (Fig. 5) after traumatic injury include local anesthetics, acetaminophen, and topical medications. For many patients, NSAIDs should also be a first line choice. Second-line analgesics are either less efficacious or are highly efficacious but have notable limitations. These include the gabapentinoiods, the “muscle relaxants”, neuraxial epidural analgesia, and intravenous infusions of ketamine, dexmedetomidine, and lidocaine. For simple isolated limb trauma, our preferred analgesic approach is to maximize the usage of all first-line analgesics. Topical analgesics are safe and can be very effective in selected patients. Oral medications are easier to administer and longer acting than IV bolus medications, which require infusion equipment and can hamper patient mobility. All patients should receive scheduled acetaminophen at the maximum dose, unless they have liver failure or allergy. Most patients should receive

Fig. 2. Transversus abdomins plane block, modified from [83]. Green highlights added here to indicate local anesthetic injection plane (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).

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Fig. 3. Quadratus lumborum block, modified from [83]. Green highlights added here to indicate local anesthetic injection plane (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).

Fig. 4. Erector spinae plane block, modified from [85]. Green highlights added here to indicate local anesthetic injection plane (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).

scheduled NSAIDs for at least several days, preferably a COX-2 specific NSAID, which is less likely to cause bleeding. Possible contraindications to an NSAID include acute kidney injury, heart failure, or recent myocardial infarction. Despite the lack of evidence, it may be reasonable to avoid NSAIDs in long bone fractures when patients have other risk factors for nonunion, so long as patients are able to achieve otherwise adequate analgesia. We add a continuous peripheral nerve block except when contraindicated by anticoagulation status, significant infection, an unstable neurological exam, or a very high risk of compartment

syndrome. In opioid tolerant patients and in patients not achieving adequate analgesia, we will add a gabapentinoid or a “muscle relaxant”, monitoring for sedation. In complex trauma patients with multi-system injuries, a more comprehensive approach is required, with some of the limitations of the second-line analgesics less relevant to the more critically ill patient. Neuraxial and peripheral nerve blocks may be contraindicated in the anticoagulated patient, but the fascial plane nerve blocks seem to provide good truncal analgesia, some limb analgesia, and appear safe in anticoagulated patients. If the fascial

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Fig. 5. First and Second Line Analgesics in Orthopaedic Trauma.

plane blocks are inappropriate or unavailable, continuous intravenous lidocaine infusion is safe, has been used successfully in multiply-injured patients [50], and may be the most straightforward way to enable a complex trauma patient to access the analgesic benefits available from the family of local anesthetics. Topical analgesics are less potent, but can be highly effective for selected patients, and most importantly seem generally safe. Scheduled acetaminophen at the maximum dose, either oral or intravenous, is also safe and moderately efficacious. Contraindications to NSAIDs may be more common, particularly acute kidney injury, but bleeding risk alone should not preclude the use of celecoxib. Complex trauma patients are more likely to require intravenous infusions and be in intensive care units, so the intravenous infusions of ketamine and dexmedetomidine are likely to be more available and are both effective analgesics with few contraindications. References [1] Chaudhary MA, Schoenfeld AJ, Harlow AF, Ranjit A, Scully R, Chowdhury R, et al. Incidence and predictors of opioid prescription at discharge after traumatic injury. JAMA Surg 2017;152(October (10)):930–6. [2] Alghnam S, Castillo R. Traumatic injuries and persistent opioid use in the USA: findings from a nationally representative survey. Inj Prev 2017;23(April (2)):87–92. [3] Cicero TJ, Ellis MS, Surratt HL, Kurtz SP. The changing face of heroin use in the United States: a retrospective analysis of the past 50 years. JAMA Psychiatry 2014;71(July (7)):821. [4] Meske DS, Lawal O, Elder H, Langberg V, Paillard F, Katz N. Efficacy of opioids versus placebo in chronic pain: a systematic review and meta-analysis of enriched enrollment randomized withdrawal trials. J Pain Res 2018;11 (May):923–34. [5] Kessler ER, Shah M, Gruschkus S K, Raju A. Cost and quality implications of opioid-based postsurgical pain control using administrative claims data from a large health system: opioid-related adverse events and their impact on clinical and economic outcomes. Pharmacother J Hum Pharmacol Drug Ther. 2013;33 (April (4)):383–91. [6] Els C, Jackson TD, Kunyk D, Lappi VG, Sonnenberg B, Hagtvedt R, et al. Adverse events associated with medium- and long-term use of opioids for chronic noncancer pain: an overview of Cochrane Reviews. Cochrane Database Syst Rev 2017;30(10)CD012509.

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