Emergency Medicine

Acute pain management in the Emergency Department: Use of multimodal and non-opioid analgesic treatment strategies

a b s t r a c t

Pain is a common complaint precipitating emergency department (ED) visit, occurring in more than half of pa- tient encounters. While opioids are effective for acute pain management in the Emergency Department (ED), the associated adverse effects, including respiratory and central nervous system depression, nausea, vomiting, and constipation, and physical manifestations of use, including tolerance, dependence and misuse leading to overdose and death, accentuate the need for Non-opioid alternatives and/or multi-modal pain control. This re- view will provide examples of non-opioid pain management strategies and multimodal regimens for treatment of acute pain in the ED.

(C) 2022

  1. Introduction

Pain is a common complaint precipitating emergency department (ED) visit, occurring in more than half of patient encounters [1]. Despite the frequency with which emergency medicine (EM) clinicians encoun- ter patients with pain, analgesia is often sub-optimally treated or re- assessed in a significant number of patients [1]. Numerous opportuni- ties exist to enhance pain management strategies, including the utiliza- tion of combination of non-pharmacologic and pharmacologic (opioid and non-opioid) analgesics modalities.

Opioids are effective analgesics that are commonly used for acute pain management in the ED. Acutely painful conditions such as traumas, fractures, renal colic, burns, and abdominal pain may warrant the use of opioids [2]. They exert their effects by binding to mu, delta and kappa

* Corresponding author at: Loyola University Chicago, Loyola University Medical Center, Stritch School of Medicine, Department of Emergency Medicine, S 1st Ave, Maywood, IL 60153, United States of America.

E-mail address: [email protected] (M.A. Rech).

Opioid receptors located in the central and peripheral nerve system, leading to positive and desirable effects, such as analgesia, anti- inflammatory properties, and euphoria [3]. Though very effective, opi- oids are associated with dose-dependent adverse effects like respiratory and central nervous system depression, and nausea, vomiting, dizziness and constipation [4-6]. Opioids may also cause physical manifestations of use, including tolerance, dependence and misuse [3]. Opioid misuse poses a huge burden to society, including an estimated 75,673 deaths in the year preceding April 2021, averaging 207 overdose deaths nation- ally every day [7]. Furthermore, of more than two million individuals with an Opioid use disorder (OUD), a substantial proportion were first exposed to Prescription opioids [8]. Some individuals who developed OUD by misusing prescription opioids will progress to more dangerous substances like heroin and fentanyl, which have fueled mortality in the ongoing opioid crisis [8].

The high prevalence of patients with pain presenting to the ED puts EM providers on the front lines of the opioid epidemic. Indeed, studies estimate 12-21% of opioid-naive ED patients prescribed opioids for

https://doi.org/10.1016/j.ajem.2022.05.022

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pharmacologic treatment“>acute pain at discharge filled additional Opioid prescriptions at up to one year after visit [9,10]. As such, it is imperative that EM clinicians have an understanding of the wide availability of pharmacological and non- pharmacological agents available to treat patients with acute pain [11]. In constructing a patient-specific, pain syndrome-targeted analge- sic regimen, it is important to consider the type and location of pain, pharmacokinetics (e.g. onset and duration) of medications and their ad- verse effects, and the use of a multi-modal approach to pain manage- ment. The purpose of this review is to summarize the available literature supporting the use of non-opioid analgesics for the treatment of acute pain in the ED.

  1. Methods

A literature search was performed using PubMed that included clinical trials, prospective observational studies, retrospective cohort studies, and case reports. We included key words in our search including emergency department, acute pain, pain, multimodal pain control, opioids, non-pharmacologic, Non-steroidal anti-inflammatory drugs, acetaminophen, lidocaine, ketamine, dopamine receptor an- tagonists, prochlorperazine, chlorpromazine, haloperidol, droperidol, metoclopramide, gabapentin, and pregabalin. Search terms and included non-opioid analgesics and pain management strategies were decided based on author consensus. Specific painful Disease states were not included in the search strategy.

    1. Multimodal pain control

Multimodal pain control involves simultaneously using multiple agents from different classes acting on different target sites for the treat- ment of pain, in order to work synergistically to improve analgesic effi- cacy and reduce the dose of any individual agent [12]. This should in turn reduce the risk of adverse effects from any given pharmacotherapy (though drug-Drug interactions from multiple interventions must be

considered) and limit or obviate the need for opioids. This approach is recommended in the American Academy of Emergency Medicine evidence-based Consensus guidelines for the management of acute pain in the ED. [11] In order to use this method successfully, a thorough evaluation of the type of pain, targeting the Underlying etiology, should be performed.

Channels-Enzymes-Receptors TargetED analgesia, also known as “CERTA”, is a multimodal analgesic strategy that promotes a mechanis- tic view of pain signaling transmission in order to target the physiologic pathway that is the stimulus for pain [13]. This approach is a departure from the system-based assessment. Table 1 provides specific examples of multimodal pain regimens by disease state. Understanding the pain signal pathway allows for selection of optimal, multimodal analgesic and non-pharmacological agents that minimize opioid use [13]. This re- view will provide examples of non-opioid pain management strategies and multimodal regimens for treatment of acute pain in the ED.

    1. Non-pharmacologic treatment

Non-pharmacologic interventions have been a mainstay of EM pain management. The goals of non-pharmacological interventions include a reduction in Inflammatory mediators that cause pain, distraction of the nervous system to decrease the painful experience, and promotion of healing that leads to improved function. The ED is an ideal environment for such interventions, including cryotherapy (ice and cold pack), heat therapy, physical manipulation, and electrical stimulation. As many types of acute pain are self-resolving and these therapies have few side effects, choosing non-pharmacologic treatment as part of a multi- modal strategy spares the risk associated with pharmacological treat- ment and can reduce pain during recovery.

Ice therapy, also called cryotherapy, has been used in medicine for centuries. It works by decreasing swelling and inflammation through vasoconstriction and reduction in enzymatic activity [14]. Furthermore, it decreases motor and sensory nerve conduction, resulting in reduction

Table 1

Multimodal Pain Regimens by Common Acutely Painful Conditions in the ED [10,11,13,23,39,51,72,92,101,105].

Agent

Type of Pain

Abdominal

Arthritis

Cancer

CHS

Dysmenorrhea

Gout

Headache

Neuropathic

Migraine

Musculoskeletal

SCD

VOC

Soft

Tissue

Visceral

Non-pharmacologic

Ice

Cryotherapy

Pharmacologic

Acetaminophen

NSAIDs

Lidocaine

Ketamine

Dopamine

receptor antagonists

Gabapentinoids

Nitrous oxide

Propofol

Capsaicin

Opioids

CHS = Cannabinoid hyperemesis syndrome; SCD = Sickle cell disease; VOC = vasoocclusive crisis.

of pain sensation [15]. Cryotherapy has demonstrated particular benefit in patients with Ankle sprains and in orthopedic post-surgical popula- tions [14]. Additionally, both cryotherapy and heat therapy show bene- fit in outpatient treatment of Acute back pain [16]. Alternatively, heat therapy works by increasing blood flow to the affected tissue, which in- creases healing and tissue elasticity. It changes nerve signaling, amelio- rating the sensation of pain [17]. Heat therapy is also effective for neck pain when compared to placebo; effectiveness improves when ibupro- fen is added to regimen [18]. While the ED literature remains limited for cryotherapy and heat therapy, these low-risk adjunctive therapies should be considered part of the multimodal treatment of musculoskel- etal pain.

Physical interventions, such as osteopathic manipulation techniques (OMT), Physical therapy, and early mobilization, effectively reduce pain in the ED, particularly for musculoskeletal injuries. OMT demonstrated particular effectiveness in ED patients with ankle sprain [19]. In acute low back pain, the American College of Physicians recommend non- pharmacologic physical interventions, such spinal manipulation and massage, as first line therapy [20]. In addition, early physical therapy fol- low up after an ED visit for back pain demonstrates cost savings and re- duced healthcare savings [21].

Other direct physical interventions including acupuncture, massage, and transcutaneous electrical nerve stimulation (TENS) might have a role in acute pain management in ED patients, though less data are available and cost must be a consideration. In a small pilot study in the ED, the TENS unit was noted to be effective in relieving pain in 99% of cases [22]. Acupuncture has demonstrated efficacy for multiple complaints, including headaches, migraine, neck pain, back pain, and osteoarthritis [23]. A systematic review of non-pharmacologic interven- tions in the ED found four randomized controlled trials and several smaller reports demonstrating a reduction in pain during ED visit [23]. A feasibility study of 30 patients with low back pain found that battle- field Ear acupuncture performed by EM physicians who were super- vised by an acupuncturist demonstrated effectiveness [24]. Further research is needed on OMT, massage, TENS units, and acupuncture in the ED setting. Presently, these agents may be considered as adjunctive pain therapies on case-by-case basis as part of a multimodal strategy.

    1. Pharmacological treatment
      1. Acetaminophen

Acetaminophen is an over-the-counter analgesic and antipyretic fre- quently used in multimodal pain therapy in the ED. It works through several pathways, acting on transient receptor potential cation channel subfamily V member 1 (TRPV1) receptors, peripheral and central cyclo- oxygenase (COX) inhibition, central descending serotonin pathways, Endocannabinoid system, and L-arginine and nitric oxide pathways (see Table 2) [25]. It demonstrates modest efficacy across a wide range of painful conditions. Though hepatotoxic when taken in excess, it otherwise has fewer adverse effects compared to non-steroidal anti- inflammatory drugs (NSAIDs) or opioids [25]. The combination of NSAIDs and acetaminophen together has may have additive efficacy in treating some painful conditions, though studies to date have heteroge- neous findings [26]. One randomized open-label study found analgesia was improved when acetaminophen was added to NSAIDs more than when NSAIDs were used as monotherapy for three days [27]. However, two other randomized, double-blinded trials set in the ED did not find a benefit with the acetaminophen combined with NSAIDs compared to either NSAIDs alone or acetaminophen alone [28,29]. Whether the dura- tion of treatment (three days versus a single dose) in these studies let to discrepant findings in unclear.

There has been much discussion concerning Analgesic efficacy and cost-effectiveness of intravenous (IV) acetaminophen in the acute care and perioperative care setting. Current evidence does not support IV acetaminophen as a primary analgesic in the ED. [30] One small study- ing including ED patients did not find a benefit for using the IV

formulation over oral acetaminophen [31]. In a randomized controlled trial of 103 patients, IV acetaminophen failed to decrease severe pain as much as IV hydromorphone in the ED setting, as would be expected [32]. Outside of the ED, a randomized trial of 486 patients undergoing hip or knee arthroplasty found similar rates of pain control and Opioid requirements between IV and oral APAP [33]. The most compelling ar- gument for the use of IV acetaminophen is in patients with acute pain that are unable to take oral acetaminophen in the ED; however, rectal administration of acetaminophen may also be indicated in this setting.

      1. Non-steroidal anti-inflammatory drugs

NSAIDs are a highly effective class of medications that are frequently used for both acute and chronic pain [34]. In the ED, NSAIDS are indi- cated for a variety of conditions, ranging from Musculoskeletal pain, headache, inflammatory abdominal pain, renal colic, gout flairs and pain related to other Inflammatory conditions. Their mechanism of ac- tion is via the inhibition of the enzyme COX (see Table 2). Non- selective COX inhibitors that inhibit both COX-1, expressed constitu- tively, and COX-2, expressed during times of stress and inflammation, while selective inhibitors target only COX-2 [34]. Non-selective NSAIDs include ibuprofen, ketorolac, diclofenac, and naproxen, among others. The COX-2 inhibitor celecoxib is less frequently used in the ED. NSAIDs are available through a variety of routes, including IV (e.g. ketorolac), oral (e.g. ibuprofen) and topical (e.g. diclofenac).

Adverse effects include gastrointestinal (GI) bleeding, renal dysfunc- tion, platelet aggregation, and cardiovascular sequelae. These effects are typically seen with long-term use, though caution should be used in pa- tients with renal insufficiency or at high risk of bleeding. Selective inhib- itors like celecoxib have less gastrointestinal side effects than the non- selective NSAIDS; however, significant GI side effects remain when compared to placebo [35]. A secondary analysis from the PRECISION trial suggested celecoxib has less cardiovascular, gastrointestinal, and renal side effects compared to naproxen or ibuprofen [36]. While naproxen may have less cardiovascular side effects than ibuprofen, it produces similar efficacy across a wide range of painful conditions com- pared to ibuprofen [37]. Ibuprofen is also a good choice due to its wide availability and low cost, but may have slightly higher cardiovascular risk compared to naproxen and celecoxib. Particular caution should be taken in patients taking Angiotensin converting enzyme inhibitors or angiotensin receptor blockers with diuretics, since the concomitant use of NSAIDs with patients on dual therapy may result in acute renal failure [38].

The comparative effectiveness to oral opioids is notable. In a recent ED study of extremity pain in over 400 patients, there was no difference in pain scores between NSAIDs combined with acetaminophen com- pared to three different opioid regimens combined with acetaminophen [39]. Determining the efficacy of one NSAID over another across all pain conditions is difficult due to the heterogeneous literature [34]. Com- monly prescribed NSAIDs in the ED include ketorolac, ibuprofen, and naproxen. Choosing the lowest effective dose for the shortest duration to adequately manage pain is important to mitigate adverse effects Pre- vious studies in the ED support this approach, demonstrating that keto- rolac has an analgesic ceiling at 10 mg and ibuprofen at 400 mg [40,41]. When prescribing NSAIDs for acute pain, patients should be instructed to take the lowest effective dose for a three to five day period should be warned of the side effects of long-term use.

Topical NSAIDs are also an effective treatment for acute and chronic musculoskeletal pain that spare adverse effects from systemic exposure and can be used longer term [42]. A Cochrane review including 206 studies of 30,000 patients found that, topical NSAIDs were effective in treating acute sprains and strain [42]. Topical diclofenac has been used safely in elderly patients [43]. In a large retrospective cohort, EM clini- cians were much less likely to use topical NSAIDs for sprains, strains and contusions compared to primary care providers. [44] Though there is limited research pertaining to topical NSAIDs use in the ED

Table 2

M.A. Rech, C. Griggs, S. Lovett et al.

American Journal of Emergency Medicine 58 (2022) 5765

60

Pharmacologic Interventions for Acute Pain in the ED [21,27,38,52,88]

Agent

Uses

Mechanism

Usual Dose

Pharmacokinetics

Adverse Effects

Onset Duration

Acetaminophen

Ibuprofen

Broad implications for acute pain

Broad implications for acute pain

TRPV1 receptors, peripheral and central COX inhibition, central descending serotonin pathways, endocannabinoid system, and L-arginine and nitric oxide pathways

Non-selective COX inihibition

500-1000 mg PO, PR, IV

every 4-6 h a

200-800 mg PO every

PO/PR: <60 4-6 h

min

IV: 5-10

min

30-60 min 6-8 h

Gastrointestinal

Gastrointestinal, bleeding, renal

Diclofenac

6-8 h

50 mg PO every 8 h;

<60 min 6-12 h, depending

dysfunction, delayed wound healing,

bronchospasm, and cardiovascular

Naproxen Ketorolac

topically up to 4 times daily

250-500 mg PO every 8-12 h

10-30 mg IV; 30-60 mg

IM every 6 h

on formulation 30-60 min <12 h

30 min 4-6h

events

Lidocaine

Ketamine

Renal colic, abdominal pain, Limb ischemia, radicular back pain, migraine; of post-herpetic neuralgia (topical)

Acute pain

Sodium channels antagonist in the peripheral and central nervous system

NMDA receptor antagonism; mu opioid receptor agonist

1-1.5 mg/kg IV; 4.5 mg/kg subQ; topical 1-2 patches

0.1-0.5 mg/kg IV push

IV: 45-90 s IV: 1-2 h

IV: 30-60 s Variable, depending

Cardiovascular (arrhythmias), dizziness, altered mental status, nausea, vomiting, hepatic

Dizziness, agitation, feeling of ‘unreality’,

Prochlorperazine

Migraine

D2-dopamine receptor antagonist; anti-muscarinic (M1);

over 2-5 min or IVPB over 15 min; 1 mg/kg IN

10 mg IV over 10-15

IM/IN: <10 on dose, route and rate min of administration

IV: <10 min 3-4 h

nausea/vomiting

ESPs, drowsiness, QT prolongation

Chlorpromazine

Migraine

anti-histamine (H1)

min; 10 mg IM/PO; 25 mg PR

IV/IM/PO: 10-25 mg

IM: 10-20

min

PO: 30-40

min

PR: 60 min

15-60 min 4-6h

Metoclopramide

Haloperidol

Migraine

Migraines, cyclic vomiting,

Dopamine D2 receptor antagonist at low doses; serotonin receptor antagonist at high doses

D2-dopamine receptor antagonist

10 mg IV, PO

2-5 mg IV, 2-10 mg IM,

IV:1-3 min 1-2h PO: 30-60

min

IV: <60 s 2-4 h

ESPs, drowsiness, long QT, torsades de

Droperidol

Gabapentin

gastroparesis, cannabinoid hyperemesis syndrome

Migraines, acute pain

Neuropathic pain (post herpetic

Calcium channel antagonist

PO

2.5 mg IV or 5 mg IM

100-300 mg PO (titrate

IM: 20-30

min

IV: <30 s 2-4h

IM: 3-10

min

PO: within 1 5-7 h; dependent on

pointes

Dizziness, fatigue, nystagmus, weight

Pregabalin

neuralgia, diabetic neuropathy) Neuropathic pain (post herpetic neuralgia, diabetic neuropathy),

fibromyalgia

up to 1200 mg max dose) 50-75 mg PO (titrate up to 150 mg max dose)

h renal function PO: 1.5-3 h; 8-12 h

prolonged with food

gain, ataxia

COX = cyclooxygenase; ESP = Extrapyramidal symptoms; TRPV1 = transient receptor potential cation channel subfamily V member 1.

setting, we recommend use for localized painful conditions, especially for those who may experience adverse effects to systemic NSAID exposure.

      1. Lidocaine

Lidocaine is commonly used in the ED for its analgesic, anti- inflammatory, and opioid-sparing properties [45]. It works by blocking voltage dependent sodium channels both in the peripheral and central nervous system, blunting pain signal transmission (Table 2) [46]. A 2012 study including 240 ED patients with renal colic demonstrated that IV lidocaine decreased pain scores more than morphine [47]. It was also comparable to IV ketorolac in ED patients with radicular back pain [48]. Furthermore, a randomized study of 50 patients traumatic limb pain demonstrated that lidocaine reduced pain scores to a similar degree as morphine [49]. A review of the IV lidocaine literature, al- though limited, demonstrates superior efficacy to morphine for renal colic and limb ischemia, equivalent efficacy to ketorolac for acute radic- ular lower back pain, and is more efficacious than dihydroergotamine for acute migraine, but less efficacious than IV chlorpromazine [45]. Fi- nally, a recent systematic review and meta-analysis of 1351 patients with a variety of painful conditions found that IV lidocaine was an alter- native analgesic for pain control in the ED, but did not demonstrate im- proved efficacy for treatment of any given disease state or against any comparator group [50]. Studies are heterogeneous in terms of dosing and length of administration, and the safety of IV lidocaine across all acute pain conditions has yet to be determined.

Lidocaine can also be administered a number of other routes, includ- ing topically, nebulized, and subcutaneously. Topical lidocaine patches are available by prescription in 5% concentration or over the counter in 4% concentration. The FDA has approved 5% lidocaine patches for the treatment of post-herpetic neuralgia; other indications including di- abetic neuropathy, osteoarthritis, and lower back pain. [46,51] Two small open label non-randomized studies outside of the ED showed im- provements in pain and increased quality of life in patients with acute and Chronic back pain [52,53]. Future research should explore the utility of lidocaine patches in back pain. The minimal adverse effects and the low cost of 4% over the counter lidocaine patches provide a reasonable adjunct in the treatment of low back pain.

      1. Ketamine

Ketamine, a phencyclidine derivative, blocks the N-methyl-D- aspartate (NMDA) glutamate receptor complex and is frequently used as an anesthetic at dissociative doses. It can be used of indications in- cluding depression, acute agitation, post-operative pain, chronic pain, and, most notably, acute pain in the ED. [54] Low dose ketamine (fre- quently referred to as “sub-dissociative”) results in analgesia in part due to NMDA receptor antagonism in the brain and spinal cord, but also through direct action on the mu opioid receptor, enhancing opioid-induced analgesia while preventing hyperalgesia (Table 2) [55].

Multiple studies have demonstrated that sub-dissociative ketamine is an effective opioid-sparing analgesic for broad-spectrum short term pain relief in the ED. [4,5,56-58] It has been most frequently studied when administered as IV push dose over 2-5 min, IV piggyback over 10-15 min, at doses ranging from 0.1 mg/kg to 0.3 mg/kg [59]. When administered at these doses, the most common side effects are nausea, vomiting, dizziness, and ‘feeling of unreality’, which are all typically mild to moderate and resolve without intervention [60]. One study demonstrated reduced psychoperceptual side effects and similar anal- gesic efficacy as an IV piggyback over 15 min compared to IV push, and this modality been demonstrated to also be safe in Geriatric patients over 65 years of age [61,62]. A recent randomized controlled trial of 98 patients found that a dose of 0.15 mg/kg was non-inferior to 0.3 mg/kg, suggesting that low doses can produce adequate analgesia [59]. A retro- spective cohort of 104 patients on a mean of ketamine 11 mg/h for mean duration of 136 min demonstrated a significant decrease in numeric pain score [54]. Another study prospectively evaluated an hour long

ketamine infusion at 20 mg/h following a 15 mg bolus [63]. Another re- cent study including 278 evaluated ketamine in adults with Sickle cell disease who presented with acute sickle vasoocclusive crisis (VOC) found that ketamine produced similar decrease in pain scores compared to morphine and also significantly reduced opioid exposure [64]. There is a need for randomized controlled trials studying pro- longed infusions and pain control for longer than 1-2 h in ED patients. In the event that parenteral access is unavailable or unnecessary, ke- tamine can be administered via intranasal (IN), nebulization, and sub- cutaneous (subQ) routes. It is used for agitation via intramuscular injection, reduced bioavailability and delayed onset make it chal- lenging to predict an efficacious and safe dose to administer for acute pain [65]. IN ketamine has gained recent attention in both pre- hospital and ED settings due to rapid administration without the delay or discomfort of IV or IM routes, especially in the pediatric population [66]. One trial randomized 90 patients to either 1 mg/kg IN ketamine,

0.1 mg/kg IV morphine, or 0.15 mg/kg IM morphine for acute traumatic pain. Similar analgesic efficacy and safety was observed among the three groups [67]. Two randomized, controlled trial compared 1 mg/kg IN ketamine to 1.5 ug/kg IN fentanyl in pediatric patients with acute extremity pain. Both demonstrated similar analgesic efficacy but more mild side effects with the ketamine group [68,69]. The more re- cent pain reduction With Intranasal Medications for extremity injuries (PRIME) trial randomized 90 pediatric patients with extremity injuries to 1.5 mg/kg IN ketamine or 2 ug/kg IN fentanyl, demonstrated that ke- tamine was non-inferior to fentanyl but with more minor, transient ad- verse effects [70]. These studies demonstrate that ketamine may be a reasonable IN alternative to fentanyl, though more data are needed in adult patients as dosing is limited by volume. Of note, Intranasal dosing of ketamine might require a highly concentrated formulary that is not readily available in many EDs.

While the data supporting the efficacy of ketamine via nebulization and subQ routes are less robust, a case series of five patients receiving doses of nebulized ketamine between 0.75 mg/kg and 1.5 mg/kg, re- sulted in decreased pain from baseline to 120 min, with minimal, self- limited adverse effects [71]. Alternatively, 40 patients with acute trau- matic musculoskeletal pain received 0.1 mg/kg/h subQ ketamine com- pared to 0.1 mg/kg of IV morphine. Ketamine resulted in less drowsiness, nausea, and vomiting, and better pain relief than the mor- phine group, although subQ continuous infusions may require special- ized training for nursing staff [72].

The favorable safety and efficacy profile of ketamine has led the American College of Emergency Physicians (ACEP) to recommend it as a first line analgesic, specifically in patients whom opioids and/or other non-opioid analgesics are absolutely or relatively contraindicated [73]. Additionally, when administered in sub-dissociative doses, keta- mine may be safely administered by nursing staff under similar proto- cols to opioid analgesics, though some institutional restrictions may limit use.

      1. Dopamine receptor antagonists

There are a number of dopamine receptor antagonists used in the ED, including prochlorperazine, chlorpromazine, haloperidol, droperidol, and metoclopramide. Prochlorperazine and chlorpromazine are pheno- thiazine class anti-dopaminergic agents that act predominantly on D2- dopamine receptors, producing primarily an anti-emetic effect, with minimal anti-muscarinic (M1) and anti-histamine (H1) effect [74]. Haloperidol and droperidol are butyrophenones, with more sedative effects as well as anti-emetic efficacy [75]. Finally, metoclopramide blocks both central and peripheral dopamine D2 receptors in low doses, with some anti-serotonin effects at higher doses. It also stimulates cholinergic receptors on gastric smooth muscle cells, and thus useful as a pro-motility agent (Table 2).

The primary indication for both prochlorperazine and chlorproma- zine is nausea and vomiting; however, in the ED, prochlorperazine is frequently used for treatment of headaches. It has been extensively

Muscle relaxants“>studied in the ED for migraines and demonstrated to be similar or better than metoclopramide, and more effective than magnesium, ketorolac, sumatriptan, octreotide, ketamine and hydromorophone [76-79]. In a double blinded, randomized controlled trial of ED patients with mi- graine, prochlorperazine 10 mg IV over 5 min with diphenhydramine 25 mg IV was compared to hydromorphone 1 mg IV over 5 min. The prochlorperazine plus diphenhydramine group resulted in sustained headache relief in 60% of patients at 48 h, compared to 31% of patients after one study dose of hydromorphone [76]. As bolus dosing may carry higher risk of extra-pyramidal effects (e.g. dystonia and tardive dyskinesia), 25 mg of diphenhydramine can be co-administered; however, this is not necessary if given as a 15 min infusion [80]. Prochlorperazine is also efficacious when administered intramuscularly and available per rectum; these alternatives may be useful for treatment of nausea and vomiting.

Similar to prochlorperazine, metoclopramide is a First-line treatment for migraines in the ED over opioids [81]. Administration over 10-15 min is ideal to prevent extrapyramidal adverse effects. The recom- mended dose of 10 mg IV was non-inferior to 20 mg IV or 40 mg IV [81]. Data supporting chlorpromazine less robust.

Haloperidol and droperidol also have demonstrated efficacy in the treatment of acute migraine in the ED. [82,83] Recently, haloperidol has gained attention for the treatment of gastroparesis, cyclic vomiting, and cannabinoid hyperemesis syndrome [84,85]. The use of droperidol in ED decreased significantly as a result of a black box warning pertaining to risk of Torsades de pointes induced by QT prolongation, however, this effect appears to be rare [86,87]. In fact, when used for se- dation in ED patients with acute behavioral disturbances, a large obser- vational study found no cases of torsades de pointes in the 1009 patients receiving a median dose of 10 mg IM or IV [88]. The recommended dose for migraines is 2.5 mg IV or 5 mg IM; doses up to 10 mg IM are also sup- ported by the American Academy of Emergency Physicians in a position statement regarding the safety of droperidol in the ED. [87,89] An obser- vational study of 6881 ED visits demonstrated efficacy and safety of droperidol for both migraines and acute pain. The need for rescue anal- gesia after administration of droperidol occurred in only 5.2% of patients with migraine and 7.4% patients with pain, and no patients had fatal ar- rhythmias. The most common side effect of droperidol, consistent with other studies, was akathisia (2.9%) [90].

      1. Calcium channel blocking anticonvulsants: Gabapentinoids

Gabapentin and pregabalin are primarily used for the treatment of neuropathic pain. While data are limited in an ED setting, both medica- tions block Calcium channels in the peripheral and central nervous sys- tems, preventing voltage-gated postsynaptic neurotransmitter release to cause reduced central pain sensitization (Table 2) [91]. While gaba- pentin and pregabalin have an onset of effect within an hour when ad- ministered orally, a low dose should be initiated and titrated up daily, which may limit utility in the ED. Additionally, adverse effects include dizziness and somnolence, necessitating a driver for patients who are initiated on these agents and discharged from the ED. [92]

Both gabapentin and pregabalin are recommended for the treatment of post-herpetic neuralgia and diabetic neuropathy; pregabalin has also demonstrated efficacy in fibromyalgia-related pain [92]. In one study in- cluding patients with postherpetic neuralgia and chronic neuropathic pain, oral gabapentin was associated with at least 50% pain reduction, although patients experienced more dizziness [92]. In a systematic review of patients with painful diabetic neuropathy, 300 or 600 mg of pregabalin was associated a greater reduction in pain compared to placebo [92]. In a meta-analysis of nine randomized trials, both medications were not effective for low back pain with or without radiculopathy, and were associated with increased risk for adverse events [93]. EM prescribers should be aware of both the danger of respi- ratory depression, especially when combining gabapentinoids with opioids, and potential for misuse [94].

Skeletal muscle relaxants, though often used to treat painful condi- tions like low back pain, have not been found to be useful for acute pain in ED patients. A study of over 2.6 million ED visits showed that skeletal muscle relaxants were given to 43% of patient [95]. Since that time, multiple well-done, randomized controlled trials of ED patients with low back pain have demonstrated no benefit compared to or in ad- dition to NSAIDs [96-99]. Therefore, we recommend avoiding the use of skeletal muscle relaxants for treatment of acute pain.

    1. Alternative analgesic strategies

Several other agents have been studied treatment of acute pain in the ED. Regional blocks using local anesthetics (e.g. lidocaine, bupiva- caine) with or without epinephrine, can be used for a variety of indica- tions in the ED. While regional block techniques are not new, use is increasing in the ED in recent years. Data demonstrate a benefit in hip and femoral head fractures, rib fractures, Humerus fracture and Shoulder dislocation reduction, and facial, wrist and hand wounds, among other indications [100-103]. Local anesthetics have also been used for Trigger points to treat focal, hyper-irritated Muscle spasm [104]. Regional blocks offer effective pain relief and reduce opioid requirements, but re- quire specialized training to perform. Adverse effects include central nervous system effects like dizziness, drowsiness, and seizures, and cardiotoxic effects like arrhythmias [105].

Methoxyflurane and nitrous oxide are both self-administered, self-titrated, rapid-acting, and noninvasive inhalational agents. While both have been available for a number of years, limited data is available in the ED setting and methoxyflurane is currently unavailable in the United States. A systematic review found one randomized, placebo controlled trial for each agent, both demon- strating rapid pain control compared to placebo [106]. In 120 ED patient with renal colic, nitrous oxide/oxygen (“entonox”) was compared placebo. All patients received 50 ug of IV fentanyl. A significant and sustained reduction in pain scores were found in the entonox group. It has also been used to facilitate minor procedures, peripheral intravenous cannulation, in pediatric patients [107].

Propofol and dexmedetomidine are typically used as Sedative agents in the ED. Propofol is a gamma-aminobutyric acid (GABA) receptor ag- onist that has been used successfully to treat refractory migraine. In study of 77 patients presenting to a headache clinic with refractory migraine, 63 patients (82%) reported complete resolution of their symptoms [108]. Patients received 20-30 mg IV every 3-5 min. The average total dose was 110 mg over about an hour. Another randomized study of 90 ED patients found IV propofol was more effective and faster than dexamethasone. Not all studies demonstrated positive results. A double-blind randomized trial of 40 patients found similar rates of headache resolution compared to an intralipid placebo [109,110]. At present it is unclear what predicts a response to propofol. Dexmede- tomidine is and ?2 agonist that is used continuously as a sedative analgesic, but also has analgesic properties. While it plays a limited role in the ED for acute pain management, it may be considered when a patient requires continuous analgosedation and there is concern for respiratory depression [88].

Finally, capsaicin has been used recently for the treatment of painful conditions, such as cannabinoid hyperemesis syndrome (CHS), postherpetic neuralgia and diabetic neuropathy [13] It is ap- plied topically to the abdomen. Similar to acetaminophen, capsaicin agonizes TRPV1, which is expressed on nociceptive nerve fibers in the skin. In a recent RCT it demonstrated significant reduction in nausea associated with CHS [111]. Given the limited treatment option for CHS and low risk of adverse effects from this topical intervention, we recommend consideration of capsaicin for pain associated with CHS.

    1. When opioids are unavoidable

There are situations in the ED that necessitate the use of an opioid analgesic. The American Academy of Emergency Medicine white paper and the American College of Emergency Physicians policy statement recommends maximizing non-opioid and non-pharmacologic analge- sics and assessing the risk benefit ratio before resorting to initiating opi- oid [11,112]. shared decision-making and setting expectations about a natural trajectory of painful syndromes are recommended. Opioids should generally be started at the lowest possible dose and titrated to reasonable pain management goals while monitoring for adverse effects [11,112]. Though oral opioids are preferable in most situations, in ED pa- tients with acutely painful conditions (e.g. vasoocclusive crisis in sickle cell disease, aortic dissection, Mesenteric ischemia, severe burn or trauma injury, etc.), EM clinicians should move expeditiously to control pain with liberal use of IV opioids. Finally, in the event that the patient is on chronic opioids, all dosage forms should be converted into morphine milligram equivalents (MME) in order to inform providers of risk of opioid-related adverse effects and trend over time. A daily MME of

<=49 mg should be targeted to avoid opioid-related mortality.

Upon discharge from the ED, providers should prescribe the shortest course of opioids possible (2-3 days are sufficient for most types of acute pain) after a detailed review of the patient’s history, including co- morbid conditions, Substance abuse history, and prescription history utilizing a prescription database. In addition to a Short duration, EM cli- nicians should address the euphorigenic potential (or “likeability”) of opioids and consider prescribing opioids with lowest potential to cause euphoria [113,114]. Oxycodone has pharmacologic properties that render it highly “likeable” and therefore should be avoided if possi- ble in lieu of opioids like morphine immediate release [ 114,115].Finally, patients should be counseled on the risk of adverse effects beyond toler- ance and dependence, including nausea and vomiting, dizziness, consti- pation and drowsiness, which combined occurred in 79% of patients in one study [6].

  1. Conclusion

In conclusion, pain is a common occurrence in ED patients. There are many pharmacologic and non-Pharmacologic options available for treatment of pain in the ED. Utilizing a multimodal approach to pain control will help to minimize adverse effects, effectively control pain and appropriately steward the use of opioids.

CRediT authorship contribution statement Megan A. Rech: Writing – review & editing, Writing – original draft,

Software, Project administration, Methodology, Conceptualization.

Christopher Griggs: Writing – review & editing, Writing – original draft. Shannon Lovett: Writing – review & editing, Writing – original draft. Sergey Motov: Writing – review & editing, Writing – original draft.

Declaration of Competing Interest

The authors have no conflicts of interest directly pertaining to this work. Megan Rech, PharmD has investigator-initiated research funding from Spero Pharmaceuticals unrelated to this subject.

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