Analgesia in the emergency department: a GRADE-based evaluation of research evidence and recommendations for practice

Emergency physicians care for patients with pain on an extremely frequent basis [1–20]. The prevalence of pain as the presenting complaint of patients seeking emergency department (ED) care ranges from 38 % [3] to as high as 78 % [1]. As a result, evidence-based use of analgesics should be a foundational skill of emergency physicians. However, the literature consistently reports that emergency physicians are often poor at treating pain [1, 2, 8, 13, 14, 16, 19, 20]. Notwithstanding the prevalence of pain in the ED, many patients often report that their pain was not properly treated [3, 7, 20]. In addition to a compromised patient experience, sub-optimal treatment of pain will result in decreased department flow, increased wait times, more return visits to the ED, and increased hospitalization rates.

Very few evidence-based resources and guideli nes exis t to inform emergency physicians on how to treat pain. One recent guideline on acute pain management compiled by the college of Anaesthetists of Australia and New Zealand [21] was focused primarily on treating pain perioperatively and did not include stratifi ed or graded recommendations based on the literature, highlighting the paucity of emergency medicine-specifi c guidance. Emergency physicia ns need an eff ective, evidenced-based approach to analyze and apply the options available for acute pain management.
Th e objective of this article is to synthesize and evaluate the quality of medical literature surrounding analgesia delivery in the adult ED using the Grading Assessment, Development and Evaluation (GRADE) framework. We further strived to provide emergency physicians with graded recommendations upon which analgesics should be used to treat adults with acute pain in the ED.

Question formulation
Prior to searching the literature we developed seven clinically-oriented questions based on a scoping of the literature and a review of locally utilized ED analgesic order sets. Th is initial surveying of medical literature and our local practice environment allowed us to identify the most commonly prescribed intravenous and oral analgesics used in adult EDs in our health care region.
We then used the patient-intervention-comparisonoutcome (PICO) approach to develop our seven research questions (Table 1). Th is approach has been adopted by many authors of systematic reviews and guideline panels, including the Internati onal Liaison Committee on Resuscitation (ILCOR) and the American College of Chest Physicians (ACCP) [22][23][24]. It involves identifying a specifi c population or setting to which recommen dations may be applied. Subseq uently each question compares two specifi c management strategies (intervention and comparison). Fi nally, we defi ned important patient oriented outcomes (e. g., change in pain) as well as any adverse eff ects of the medication or other safety concerns.
All seven draft questions were reviewed and revised through an iterative process involving all authors. Th ese seven clinically-based PICO questions compared analgesics (morphine, fentanyl, hydromorphone, nonsteroidal anti-infl ammatory drugs [NSAIDs], codeine, oxycodone) commonly used in the management of adult acute pain in the ED. Th e primary critical outcome across all PICO questions was a clinically signifi cant change in pain using validated instruments, such as a visual analog (VAS) or numeric rating scale (NRS). Th e time frame used to assess change in pain varied from 30 minutes to two hours, depending on the medication route of adminis tration. Secondary patient-oriented outcomes included serious adverse events, patient satisfaction, and side eff ects. Serious adverse events were defi ned as respiratory depression (less than 12 breaths per minute), decline in pulse oximetry oxygen saturation to less than 92 %, decline in systolic blood pressure below 90 mmHg, or the need for administration of naloxone after opioid administration.

Search strategy
After developing the seven PICO questions we conducted searches for each question using PubMed, Ovid MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and the TRIPdatabase. Th ese databases were systematically searched following consultation with a professional health sciences librarian who assisted us in our search methodology and use of specifi c keywords including Medical Subject Headings (MeSH) terms (Table 2). Our search took place over a six-month period of time, from January to June 2011. We conducted seven unique searches using the same search keywords as well as the various names of the intervention and c omparison drugs in each question. When possible, we used MeSH terms for searching the U.S. National Library of Medicine. Prior to searching the databases we also developed inclusion and exclusion criteria ( Table 2) to assist us in focusing each literature search.
Th e results of each literature search were saved and a single reviewer screened titles, fl agging articles that met the inclusion criteria based on the search keywords and terms.
A rticles fl agged as relevant in the initial screen were selected for abstract review. Abstracts for each PICO question were screened by the same reviewer and when abstracts met the inclusion criteria, a full text copy of the article was retrieved.

Use of GRADE
In our analysis of the situation we decided to use the GRADE framework, which is becoming the benchmark for communicating evidence-based medicine throughout the world [25]. Numerous prominent health organizations, including the World Health Organization (WHO), the ACCP, the Society of Critical Care Medicine (SCCM), the National Institute fo r Clinical Excellence (NICE, UK), and the European Respiratory Society (ERS) have endorsed or adopted the GRADE approach as a means of analyzing medical evidence and developing guidelines.
We used the GRADE system and its quality of evidence criteria as well as GRADE-Pro software to analyze the articles for each PICO question. Th is software-supported approach is used in the GRADE methodology and enables clinician-researchers to succinctly analyze structured clinical questions using the GRADE methodology [26,27]. GRADE classifi es evidence into four categories (high, moderate, low and very low) based on a bod y of e vidence related to a specifi c outcome. Th is classifi cation is based on an assessment of the research studies in question, including assessing for bias, indirectness, im precision, For adults accessing the emergency department with acute pain, should parenteral hydromorphone or morphine be used to manage acute severe pain based on reported change in pain using the visual analog scale?
For adults accessing the emergency department with acute pain, should a parenteral hydromorphone 1 + 1 mg patient-driven protocol or other intravenous opioids at any dose (physician-driven protocol) be used to manage acute pain based on reported change in pain using the visual analog scale?

4.
For adults accessing the emergency department with acute pain who do not need parenteral analgesia but request an analgesic for outpatient pain management, should oral hydromorphone or oxycodone be used to treat acute pain based on patient reported effi cacy (change in pain) and adverse side eff ects?
For adults accessing the emergency department with acute pain who do not need parenteral analgesia but request an analgesic for outpatient pain management, should non-specifi c NSAIDs (e. g., ibuprofen) or codeine-acetaminophen be used for mild-moderate acute pain based on patient reported effi cacy (change in pain) and adverse side eff ects?
For adults accessing the emergency department with acute pain who do not need parenteral analgesia but request an analgesic for outpatient pain management, should COX-2 specifi c NSAIDs (e. g., celecoxib) or codeine-acetaminophen be used for mild-moderate acute pain based on patient reported effi cacy (change in pain) and adverse side eff ects?
For adults accessing the emergency department with acute pain who do not need parenteral analgesia but request an analgesic for outpatient pain management, should oxycodone-acetaminophen or codeine-acetaminophen be given to patients with acute pain based on patient reported effi cacy (change in pain) and adverse side eff ects?
Oral NSAID: non-steroidal anti-infl ammatory drug; COX: cyclooxygenase inconsistency, and publication bias. Subse quently, the software assists the researcher through a multifactorial process of compiling the results of each study for the outcomes studied in the research question. Th e software then summarizes all the pertinent details of the research question and each outcome in a summary of fi ndings (SoF)   We recommend fentanyl (1 mcg/kg, then ~30 mcg q 5 min) over morphine (weak recommendation, low quality evidence) If morphine is used to treat acute pain, we sug gest giving 0.1 mg/kg, then 0.05 mg/kg at 30 min, with the maximum suggested dose of 10 mg Rationale [28][29][30] • People with morphine allergies do not have allergies to fentanyl • Fentanyl has a shor ter onset of action as well as being 100 times more potent than morphi ne, and thus is better suited to treat acute mo derate to severe pain. (Fentany l is more lipid soluble and thus has higher bioavailability) • There is no substantial cost diff erence between the two medications • Fentanyl is reported to be less pro-emetic than morphine and does not produce a histamine release like morphine does. This leads to less hypotension and less pruritus, facial fl ushing, or urticaria • Fentanyl with its 2-3 min onset and 30-60 min duration is less likely to cause prolonged sedation, and may encourage more frequent reassessment of ill patients • Fentanyl has less of a dose stacking risk than morphine. This is especially relevant in patients with renal failure in whom morphine's meta bolite accumulates, whereas fentanyl does not.
Currently the order sets have general doses of morphine at 2.5 mg or 5 mg, and fentanyl at 50 mcg. Because adults vary in weight, ED physicians may be well served to estimate th e patient's weight and dose based on that For example a 70 kg patient should be given 7 mg of morphine or 70 mcg of fentanyl as an initial loading dose (assuming there is no contraindication to a high loading dose)

Should hydromorphone or morphine be used for acute severe pain in the emergency department?
We recommend hydromorphone (0.015 mg/kg i.v.) as a comparable, potentially superior, analgesic to morphine (0.1 mg/kg i.v.) (strong recommendation, moderate quality evidence) Rationale [28,31,32] • Hydromorphone has a quicker onset of action, when compared with morphine • Hydromorphone is comparable in cost to morphine • Morphine, with a longer onset of action and greater risk for dose stacking, places patients at a higher risk for toxicity (in the context of renal failure) and hypoventilation or, on the ot her hand oligoanalgesia • Because hydromorphone is more potent, at a much smaller milligram dose, physicians may be more likely to adequately treat pain by gi ving a dose of 1.5 mg of hydromorphone vs. 10 mg of morphine • Hydromorphone causes little or no histamine rele ase, and may be safely administered to patients who report a type 2 allergy to morphine (urticaria, pruritis, and facial fl ushing)

Should hydromorphone 1 + 1 mg patient-driven protocol or other intravenous opioids at any dose (physician-driven protocol) be used for acute pain management?
We recommend a 1 mg + 1 mg patient-driven protocol over other intravenous opioids in the emergency department (weak recommendation, low quality evidence) This may be especially helpful for patients who are unable to clearly communicate their level of pain (acute mental status change, non-English speaking patients) Rationale [28,[31][32][33] • Hydromorphone has a quicker onset of action compared wi th morph ine • Hydromorphone is comparable in cost to morphine • Morphine, with a longer onset of action and greater risk for dose stacking, places patients at a higher risk for toxicity (in the context of renal failure) and hypoventilation or, on the other hand, oligoanalgesia

Should hydromorphone or oxycodone be used for acute pain?
We are unable to comment on the superiority/inferiority of either of these drugs in treating acute pain The only studies we identifi ed that compared these drugs assessed the extended release forms of hydromorphone (Exalgo®) and oxycodone Further research is needed to assess the immediate release forms of hydromorphone (e. g., Dilaudid®) and oxycodone, and whether they have a role in treating acute pain in the emergency department Rationale [34,35] • We only identifi ed two studies comparing hydromorphone and oxycodone. They assessed the extende d releas e forms. Both studies suggested no diff erence between the drugs in either pain relief or adverse eff ects • We are unable to make recommendation about hydromorphone (PO) and oxycodone (PO) in treating acute pain. Extended release forms appear to be equal in terms of pain re lief and side eff ect profi le (when dosed in an equal analgesic way 2:5) based on two RCTs (strong recommendation, very low quality evidence).

Should non-specifi c NSAIDs (e. g., ibuprofen) or codeineacetaminophen be used for mild-moderate acute pain?
We recommend non-COX specifi c NSAIDs over codeine-acetaminophen combinations (weak recommendation, moderate quality evidence) Rationale [36][37][38] • The reported numbers needed to treat for naproxen and ibuprofen are 2.7 vs. 4.4 for codeine-acetaminophen • NSAIDs have been shown to have a longer time t o re-medication with a safer side eff ect profi le. The number needed to treat for codeineacetaminophen was 6 • NSAIDs do not have the CNS depressing eff ects of codeine • Certain genotypes may not metabolize or may hyper-metabolize codeine into morphine (due to a CYP2D6 polymorphism)

Should COX-2 specifi c NSAIDs (e. g., celecoxib) or codeineacetaminophen be used for mild-moderate acute pain?
We recommend COX-specifi c NSAIDs over codeine acetaminophen combin ations (weak recommendation, moderate quality evidence) Rationale [36] • This is based on a Cochrane systematic review that compared NSAIDs and codeine-acetamino phen combinations with placebo in treating acute postoperative pain • The number needed to treat for 400 mg of celecoxib was 2.5 whereas that for 600 mg/ 60 mg of acetaminophen/codeine was 3.9 • The average time to re-medication with cele coxib was 8.4 h, whereas patients who used acetaminophen/codeine re-medicated in 4.1 h • The relative risk between these two drugs is 1

Should oxycodone-a cetaminophen or codeine-ac etaminophen be given to patients with acute pain in the ED?
We recommend oxycodone-acetaminophen as marginally superior to codeineacetaminophen (weak recommendation, low quality evidence) Rationale [39][40][41] • This recommendation is based on two Cochrane reviews that compared each of these drugs with placebo • There are few studies that directly compare these two drugs, especially in an adult emergency department setting • However, the Cochrane reviews and single studies consistently show that oxycodone with acetaminophen is slightly better at relieving pain than acetaminophen-codeine developed by the fi rst author using the GRADE-Pro soft ware. Subsequently the fi rst author drafted recommen dations for each of the seven PICO question using the data in the SoF tables. Once these drafts were complete, the second and third authors reviewed the SoF tables and reviewed the recommendations in an iterative process. Th ese recommendations were then compiled into a succinct table.
Th e 14 articles evaluated using th e GRADE ap proach included eight randomized clinical trials, four systematic reviews, one retrospec tive coh ort study, and one prospective clinical trial. An example of a SoF tab le developed for PICO number two is included (Table 3). Similar SoF tables were developed for each PICO question. Overall, the grading process supported the use of intravenous hydromorphone and fentanyl as superior to intravenous morphine for rapid and eff ective pain relief (weak recommendation, moderate quality eviden ce).
Oral NSAIDs, oxycodone, and hydromorphone are generally superior to codeine-aceta minophen combinations (weak recommendations, very-low quality evidence; due to bias, indirectness, and imprecision).

Discus sion
Using the GRADE framework, we have synthesized and evaluated the medical literature surrounding analgesia delivery in the adult ED and developed clear and actionable recommendations for analgesic use based on graded recommendations. Despite using a thorough, systematic approach to reviewing the literature on each PICO question we identifi ed only 14 articles that met our inclusion criteria. However, although the number of studies used to make our recommendations may seem low, our re commendations take into consideration the quality of evidence of the studies. Pragmatic derivations of the seven PICO questions, their recommendations, and the rationale for these recommendations are listed in Table 4 [28][29][30][31][32][33][34][35][36][37][38][39][40][41]. Furthermore, we also developed a fl owchart as a suggested approach to analges ia in the ED (Fig. 1).
Despite the synthesis of information in this study there are also some limitations to consider. First, there is a limited body of literature analyzing the use and effi cacy of analgesi cs in the ED setting. Even after searching multiple databases there were few studies conducted in the ED setting that compared one oral analgesic with another oral analgesic. As a result, many of our recommendations were limited by the fact that some studies were conducted in postoperative settings and subsequently downgraded due to indirectness. Second, there were diffi culties making comparisons between diff erent studies that compared the various oral agents. In particular, it was diffi cult to properly compare studies in which codeine-acetaminophen combinations were used as there is a signifi cant amount of variability in the codeine to acetaminophen ratio in the various combinations of this oral analgesic. As a result, we were unable to clearly compare two studies if they diff ered in their codeine to acetaminophen ratios. Th ird, while the Table 4. Continued

Intravenous analgesics Oral analgesics
• Because hydromorphone is more potent, at a much smaller milligram dose, physicians may be more likely to adequately treat pain by giving a dose of 1.5 mg of hydromorphone vs. 10 mg of morphine • Hydromorphone causes little or no histamine release, and may be safely administered to patients who report a type 2 allergy to morphine (urt icaria, pruritis, and facial fl ushing) • This is superior to standard morphine and fentanyl dosing for a few reasons: Physicians tend to be concerned about giving patients more morphine than 5 mg and often give small doses, e. g., 2.5 mg. A 1 + 1 approach not only allows physicians to appropriately treat pain, but also requires fewer repea t orders authors collaborated extensively throughout this project, only one author was responsible for analyzing the article titles and ab stracts. Finally, this review did not include the pediatric population in the literature search, and our recommendations do not extend to treating acute pain in children.
Despite these limitations this study also has a number of strengths. First, this study is extremely relevant to emergency physicians and health care workers who must treat acute pain, and to our knowledge it is the fi rst GRADE-based evaluation of ED analgesia. Furthermore, this study serves as a model for cli nician-researchers and administrators who want to promote evidence-based medicine in their clinical context. By conducting similar PICO question based analyses, successful knowledge translation from medical literature into clinical practice may be accomplished and, thereby, insure that treatments at the bedside remain current.

Conclusion
Despite the frequent occurrence of pain in ED patients, there are no ED-based syntheses and guidelines that compare analgesics commonly used in the ED. We have developed the fi rst GRADE based recommendations for improving analgesia in the ED. Going forward, these fi ndings can be used by ED clinicians and guideline panels to evaluate and develop analgesic order sets based on specifi c clinical presentations as well as drive the research agenda in ED analgesia.
Th ese evidence-based guidelines have the potential to not only impact on patient morbidity, but also on health care costs and ED effi ciency. As health care professionals with the role of treating emergent health problems, it is crucial that all emergency physicians have up-to-date, evidence-based knowledge to adequately treat acute pain.