WEB EXCLUSIVE R E S E A R C H
Editor’s key points
} Despite pain being the most common reason older adults seek care from the emergency department, and despite opioids being one of the most common interventions used for managing this pain, specifically when nonpharmacologic and nonopioid options are insufficient or contraindicated, emergency department physicians have little guidance for selecting the best opioid analgesic to treat older patients presenting with acute pain.
} Given that age-related pharmacodynamic and
pharmacokinetic changes occur, it might not be reasonable to simply extrapolate evidence for treatment based on younger populations and assume it holds true among an older population. In addition to potential differences in the efficacy of opioids for reducing severe, acute pain in older adults compared with younger adults, there might be differences in the comparative safety of opioids specific to the older adult population.
} Overall, there is little clinical evidence to support the systematic choice of one opioid over another in older patients, in terms of either efficacy or tolerability. Although the authors in the only study that met the inclusion criteria for this review did not find a statistically significant difference in mean decrease in pain between 2 opioids (morphine and hydromorphone) in older adults, they speculate that this might have been because the initial dose of both drugs was too low.
Comparative efficacy of opioids for older adults
presenting to the emergency department with acute pain
Systematic review
Maaike de Vries MSc Jonathan Gravel MD MSc Daphne Horn MI Shelley McLeod MSc Catherine Varner MD CCFP(EM) MSc
Abstract
Objective To systematically review the literature for studies comparing the efficacy of opioid analgesics for older adults (≥ 65 years) presenting to the emergency department (ED) with acute pain.
Data sources The Cochrane Library, MEDLINE, EMBASE, Web of Science, and CINAHL were searched up to August or September 2017. Reference lists were searched for potential articles and ClinicalTrials.gov was searched for unpublished trials.
Study selection Randomized controlled trials (RCTs) were sought that compared the efficacy of 2 or more opioid analgesics for acute pain in older patients (≥ 65 years) in the ED. Two reviewers independently screened abstracts, assessed study quality, and extracted data.
Synthesis After screening titles and abstracts of 1315 citations, the full texts of 63 studies were reviewed and 1 RCT met the inclusion criteria. This study randomized older adult patients presenting to an urban academic ED with acute, severe pain to receive a single dose of either 0.0075 mg/kg intravenous hydromorphone or 0.05 mg/kg intravenous morphine. This study found no clinical or statistical difference between the 2 treatments.
Conclusion The lack of published research in this area demonstrates a
considerable gap in knowledge of the comparative efficacy of opioid analgesics in the growing older adult patient population. Physicians are often uncertain in their choice of analgesia, potentially contributing to the undertreatment of pain. It is clear that well designed RCTs are urgently needed.
Résumé
Objectif Effectuer une revue systématique de la littérature scientifique pour recenser des études comparant l’efficacité des analgésiques opioïdes chez les adultes plus âgés (≥ 65 ans) qui se présentent à l’urgence souffrant de douleur aiguë.
Sources des données Une recherche documentaire a été effectuée dans la Bibliothèque Cochrane, MEDLINE, EMBASE, Web of Science et CINAHL pour recenser des articles publiés jusqu’en août ou septembre 2017. Les listes de références ont été dépouillées en quête d’éventuels articles, et une recherche a été réalisée dans ClinicalTrials.gov pour trouver des études non publiées.
Sélection des études Nous recherchions des études randomisées contrôlées (ERC) qui comparaient l’efficacité de 2 analgésiques opioïdes ou plus chez les patients plus âgés (≥ 65 ans) souffrant de douleur aiguë et se présentant à l’urgence. Deux examinateurs ont trié les résumés, évalué la qualité des études et extrait les données de manière indépendante.
Synthèse Après avoir trié les titres et les résumés de 1315 citations, les textes intégraux de 63 études ont fait l’objet d’une revue, et 1 ERC répondait aux critères d’inclusion. Dans cette étude, on choisissait au hasard des patients adultes plus âgés qui se présentaient, souffrant de douleur sévère, aux services d’urgence d’un établissement universitaire urbain pour recevoir une dose unique, soit de 0,0075 mg/kg d’hydromorphone par intraveineuse ou encore de 0,05 mg/kg de morphine par intraveineuse. L’étude n’a constaté aucune différence clinique ou statistique entre les 2 traitements.
Conclusion La rareté des études de recherche publiées dans ce domaine démontre des lacunes considérables dans les connaissances concernant l’efficacité des analgésiques opioïdes dans la population grandissante de patients adultes plus âgés. Les médecins hésitent souvent dans leur choix d’analgésiques, ce qui pourrait contribuer à un traitement insuffisant de la douleur. Il est évident qu’il est urgent d’effectuer des ERC bien conçues à ce sujet.
Points de repère du rédacteur
} Même si la douleur est la raison la plus fréquente pour laquelle les adultes plus âgés se présentent à l’urgence, et bien que les opioïdes soient l’une des interventions les plus courantes utilisées pour contrôler la douleur, surtout lorsque les options non pharmacologiques ou sans opioïdes sont insuffisantes ou contre-indiquées, les médecins des services d’urgence ont peu de sources d’information pour les guider dans le choix du meilleur analgésique opioïde pour traiter les patients plus âgés souffrant de douleur aiguë.
} Étant donné qu’il se produit des changements pharmacodynamiques et pharmacocinétiques avec le vieillissement, il pourrait ne pas être avisé de simplement extrapoler les données probantes en faveur des traitements pour les populations plus jeunes et présumer qu’ils conviennent à la population plus âgée. En plus des différences possibles dans l’efficacité des opioïdes pour soulager la douleur sévère aiguë chez les adultes plus âgés par rapport aux adultes plus jeunes, il pourrait y avoir des distinctions dans l’innocuité comparative s’appliquant spécifiquement à la population adulte plus âgée.
} Dans l’ensemble, très peu de données cliniques appuient systématiquement le choix d’un opioïde plutôt qu’un autre pour les patients plus âgés, que ce soit sur le plan de l’efficacité ou de la tolérabilité. Même si les auteurs de la seule étude qui répondait aux critères d’inclusion dans cette revue n’ont cerné aucune différence statistiquement significative dans la diminution moyenne de la douleur entre 2 opioïdes (morphine et hydromorphone) chez les adultes plus âgés, ils se sont demandé si cette constatation pourrait plutôt être attribuable à une dose initiale trop faible des 2 médicaments.
Comparaison de l’efficacité des opioïdes chez les adultes plus âgés se présentant à l’urgence avec une douleur aiguë
Revue systématique
Maaike de Vries MSc Jonathan Gravel MD MSc Daphne Horn MI Shelley McLeod MSc Catherine Varner MD CCFP(EM) MSc
RESEARCH
Comparative efficacy of opioids for older adults presenting to the emergency department with acute painC
urrently, more than 20% of emergency department (ED) visits are made by adults 65 years of age and older.1 This proportion, as well as the absolute num- ber of ED visits by older adults, will continue to increase as Canadians aged 65 and older make up a growing propor- tion of our population. The most common reason to seek care from the ED is for acute pain or acute exacerbations of chronic pain resulting from illness and injuries.2 Even though emergency care providers frequently treat pain in older adults, physicians often find choosing the best pain management approach challenging.Mild-to-moderate acute pain is generally treated with acetaminophen and nonsteroidal anti-inflammatory drugs, with a short duration of immediate-release opi- oids prescribed if needed. Immediate-release opioids, such as hydromorphone, morphine, and oxycodone, are used to treat moderate-to-severe, acute pain in the ED, and patients might be given a prescription for opioids to manage their pain following discharge from hospital.
Current guidance suggests use of multimodal pain con- trol methods, which include nonpharmacologic treat- ments (eg, ice, heat, physical or massage therapy)3-5; however, there is very little evidence showing the effi- cacy of nonpharmacologic approaches to treating pain in the ED.3,4,6 Recommendations suggest that when opi- oids are prescribed for people with acute pain, the low- est effective dose of the least potent immediate-release opioid should be used.5,7,8
In the wake of the current North American opioid crisis, ED physicians might hesitate to prescribe opi- oids, even when other analgesics are contraindicated or insufficient, because of the increased awareness and attention around the overprescribing of opioids and the risks of dependence and addiction.9-12
Treatment of acute pain in older adults is also com- plicated by difficulties assessing pain owing to under- reporting by patients and atypical manifestations of pain;
age-associated pharmacokinetic changes and enhanced pharmacodynamic sensitivity; potential differences in pain thresholds among older adults; and increased prev- alence of persistent pain and pain-associated conditions such as osteoarthritis.13
Studies have shown older adults receive less analge- sia than younger patients do,14-17 which has been inter- preted as the undertreatment of pain in older adults by emergency care providers. However, other studies have demonstrated no difference in pain treatment by age.18,19 Regardless of whether there is an overall difference in pain treatment for older adults, older adults are particu- larly vulnerable to the adverse effects of undertreated acute pain. In the hospital setting, inadequate pain con- trol in older adults has been associated with increased risk of delirium20 and longer hospital stays.21
No guidelines or best practices currently exist for
and addiction, ED physicians often report uncertainty regarding the ideal choice of opioid analgesic in older adults.22 The objective of this systematic review was to summarize the findings from studies comparing the effi- cacy of opioids for treating acute pain in older adults in the ED.
—— Methods ——
Data sources
A medical librarian (D.H.) implemented a systematic literature search to identify articles studying the effi- cacy of opioid analgesics for acute pain in older patients in the ED. Published studies were identified through searches in Ovid MEDLINE (1946 to September 2017), Ovid EMBASE (1947 to September 2017), Ovid Cochrane Central Register of Controlled Trials (to August 2017), Ovid Cochrane Database of Systematic Reviews (2005 to September 2017), Web of Science (1990 to September 2017), CINAHL (to September 2017), and the PubMed status subsets inprocess and pubmednotmedline (to September 2017). A combination of key words and sub- ject headings was used to create search terms for opi- oids, older adults, emergency department, and pain. A full description of the search strategy is available on request from the corresponding author. Reference lists of relevant retrieved articles and reviews were also hand searched for other relevant citations, and the regu- latory website ClinicalTrials.gov was searched to identify any unpublished trials. The searches were restricted to studies published in English.
Study selection
Two reviewers (J.G., M.D.) independently screened titles and abstracts to identify potential articles using Covidence systematic review software. The reviewers obtained full-text articles for studies they identified as potentially eligible and independently evaluated the arti- cles against the inclusion criteria. Articles were eligible for inclusion if they described randomized controlled trials (RCTs) comparing the efficacy of 2 or more opioid analgesics for acute pain (onset of pain within 7 days) in older patients (≥ 65 years) in the ED. The main efficacy measures of interest for the systematic review were changes in pain intensity or in function. Studies that compared opioid analgesics to placebo or nonsteroidal anti-inflammatory drugs were excluded from this review.
The 2 reviewers discussed and resolved any discrepan- cies. Reviewers were not blinded to author names, insti- tutions, journals of publication, or results.
Data extraction and risk-of-bias assessment
Using a standardized data collection form, 2 reviewers (J.G., M.D.) independently extracted data on patient popu-
sample size, opioid treatment protocol, outcome meas- ures, side effects and adverse events, and study design.
Risk of bias was independently assessed using the Cochrane Collaboration’s tool23 and discrepancies in quality assessment scores were resolved by discussion.
—— Synthesis ——
The search strategy yielded 1315 citations after dupli- cates were removed using the Covidence screening tool.
Following the screening of titles and abstracts, 63 arti- cles were identified for full-text review (Figure 1)24 and only 1 article met the inclusion criteria.
The included article by Chang et al presents the results of a prospective, randomized, double-blind clini- cal trial comparing the efficacy of weight-based intra- venous (IV) hydromorphone and IV morphine in adults 65 years and older presenting with acute, severe pain to an urban academic ED in the Bronx, NY.25 Patients were excluded if they had taken opioids within the past 7 days or had chronic pain syndromes (eg, sickle cell disease, fibromyalgia). In this study, 194 eligible patients (70% female; mean age 75 years) were ran- domized to receive a single 0.0075 mg/kg dose of IV hydromorphone or a single 0.05 mg/kg dose of IV mor- phine. The primary outcome of this study was the dif- ference between groups in mean decrease in pain measured using an 11-point numeric pain rating scale
(NRS; where 0 = no pain and 10 = worst pain possible) at baseline and 30 minutes after medications were infused.
The mean decrease in pain from baseline to 30 min- utes was 3.8 NRS units among patients who received hydromorphone and 3.3 NRS units among patients who received morphine. This difference of 0.5 NRS units was not statistically significant (95% CI -0.2 to 1.3 NRS units) and was further attenuated after multivariable adjust- ment was performed that took into consideration age, weight, analgesics taken at home, and pain location.
Furthermore, this difference was not considered clini- cally important based on a previous study by the same group, which defined a clinically significant difference as at least 1.3 NRS units.26,27 The mean decreases in NRS units at 10 minutes and at 2 hours were also not significantly different, and there was no difference in the incidence of adverse events (nausea, vomiting, sys- tolic blood pressure < 90 mm Hg, pruritus, respiratory rate < 12 breaths/min, oxygen saturation < 95%). Neither hydromorphone nor morphine provided more than 50%
pain relief to most of the included patients. Fourteen (15.1%) patients randomized to hydromorphone and 22 (24.4%) patients randomized to morphine were given additional analgesics over the study period (difference of -9.3%; 95% CI -20.8% to 2.2%).
Risk-of-bias assessment
The included RCT was judged to be at low risk of bias.
The risk of selection bias was mitigated by randomiza- tion and allocation concealment, and risk of performance bias was mitigated by blinding participants, investiga- tors, and physicians to the type of drug administered.
Randomization was conducted using a computer- generated randomization list, and the encoded list was kept hidden from all study investigators, physicians, and research assistants. There was minimal risk of attrition bias in this study owing to the short study period, and the authors addressed incomplete outcome data by report- ing the number and reason 11 randomized patients (4 patients in the hydromorphone group and 7 patients in the morphine group) were excluded from analysis.
—— Discussion ——
The near-zero findings from this systematic review of studies comparing the efficacy of opioid analgesics in older adults in the ED demonstrates a persistent gap in knowledge that others have previously reported.14,28
It is widely recognized that metabolic pathways and pharmacologic properties vary among opioids.29 Comparative efficacy of immediate-release opioids has been studied in RCTs for several types of acute pain, including moderate-to-severe postoperative pain and pain associated with fractures.30-34 However, as demon- strated by this review, there is little evidence compar- ing opioids specifically in older adults. Therefore, health Figure 1. Flow diagram of inclusion process according to the
2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines24
*More than 1 exclusion criterion applied to some articles.
Records identified through database searching (N = 1964)
Records after duplicates removed
(n = 1315)
Records screened (n = 1315)
Full-text articles assessed for eligibility (n = 63)
Records excluded (n = 1252)
Full-text articles excluded* (n = 62)
• Ineligible study design (n = 43)
• Ineligible study population (n = 17)
• Ineligible intervention (n = 9)
• Not found (n = 1) 1 study included
RESEARCH
Comparative efficacy of opioids for older adults presenting to the emergency department with acute paincare providers often base care decisions on evidence from studies of younger adults, and simply use a smaller dose than what would be given to younger adults to account for age-related decline in the systemic clear- ance of analgesics, greater pharmacodynamic sensitivity to analgesic nervous system effects, and possible inter- actions with other drugs.8,13,35
Given that age-related pharmacodynamic and phar- macokinetic changes occur, it might not be reasonable to simply extrapolate evidence for treatment based on younger populations and assume it holds true in an older population. For instance, the authors of the one study included in this review found in an earlier study that in adults aged 18 to 64 years, there was a statisti- cally and clinically significant decrease in pain among patients who received IV hydromorphone compared with those who received IV morphine.26 Their finding was not replicated in the study of older adults included in this review.25
In addition to potential differences in the efficacy of opioids for reducing severe, acute pain in older adults compared with younger adults, there might be differ- ences in the comparative safety of opioids specific to the older adult population, given their overall increased vul- nerability to adverse effects such as low blood pressure and low oxygen saturation.13,36
Although the authors in the included study did not find a statistically significant difference in mean decrease in pain between the 2 opioids (morphine and hydromor- phone) in older adults, they speculate that this might have been because the initial dose of both drugs was too low.25 In both groups, approximately 60% of patients experienced a less than 50% decrease in pain after 30 minutes. Similarly, but among a younger adult population (21 to 65 years), researchers found 60% of patients who received IV morphine at 0.1 mg/kg (twice the amount given in the Chang et al study25) reported a less than 50%
decrease in their severe, acute pain after 30 minutes.37 This systematic review did not find any studies com- paring outcomes associated with opioids prescribed to older adults at discharge from the ED. The one study included in the review had a study period that lasted 2 hours during an ED visit. The consequences of inad- equately treating acute pain reach beyond the hospital setting. Studies have shown pain to be associated with a decreased ability to conduct activities of daily living, poor self-rated health, depression, diminished quality of life, decreased cognition, and reduced mobility.38-42 Studies with longer follow-up time are needed to under- stand the effectiveness of opioids for controlling acute pain in older adults discharged from the ED.
Limitations
There are limitations to the systematic review that
search strategy did not include a term for study design and we made note of any potentially relevant articles during the screening process. We did not come across any observational studies that compared treatment of acute pain with opioid analgesics among older adults.
Also, the inclusion criteria required studies to have com- pared the effect of at least 2 opioids for the treatment of acute pain, so studies comparing opioids to other phar- macologic or nonpharmacologic treatments were not included in this review.
Conclusion
Despite pain being the most common reason older adults seek care from the ED and opioids being one of the most common interventions used for managing this pain, specifically when nonpharmacologic and nonopi- oid options are insufficient or contraindicated, ED phy- sicians have little guidance for selecting the best opioid analgesic to treat older patients presenting with acute pain. Overall, there is little clinical evidence to sup- port the systematic choice of one opioid over another, in terms of either efficacy or tolerability. The lack of evidence in this area highlights the need for research comparing the efficacy, side effects, and adverse events among types of opioid analgesics in older adults treated
in the ED for acute pain.
Ms de Vries is a doctoral student at the Institute of Health Policy, Management and Evaluation at the University of Toronto in Ontario. Dr Gravel is an emergency medicine resident in the Department of Medicine and the Department of Family Medicine at McMaster University in Hamilton, Ont. Ms Horn is Lead, Library Services, at Scarborough Health Network in Ontario. Ms McLeod is Research Director at the Schwartz/Reisman Emergency Medicine Institute at Sinai Health Systems and Assistant Professor in the Department of Family and Community Medicine at the University of Toronto. Dr Varner is an emergency physician at Mount Sinai Hospital, Clinician Investigator at the Schwartz/Reisman Emergency Medicine Institute at Sinai Health Systems, and Assistant Professor in the Department of Family and Community Medicine at the University of Toronto.
Contributors
All authors contributed to the concept and design of the study; data gathering, analy- sis, and interpretation; and preparing the manuscript for submission.
Competing interests None declared Correspondence
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This article has been peer reviewed.
Cet article a fait l’objet d’une révision par des pairs.
Can Fam Physician 2019;65:e538-43
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