A sequential, multiple-assignment, randomized trial of analgesic strategies for acute musculoskeletal Pain.

BACKGROUND: Most methodologically rigorous, ED-based, comparative effectiveness analgesic studies completed in the last two decades failed to find a clinically important difference between the comparators. We believe that many of these comparative effectiveness studies were biased towards the null hypothesis because some ED patients with intense pain will respond to relatively mild interventions. We hypothesized that including a run-in period would alter the results of an acute pain RCT. METHODS: We conducted a sequential, multiple-assignment, randomized study. Adults with acute moderate/severe musculoskeletal pain were randomized (3:1 ratio) to run-in period or no run-in. We administered 650 mg acetaminophen to run-in participants. Those run-in patients who reported insufficient relief one-hour later were randomized (1:1 ratio) to ibuprofen 800mg PO or ketorolac 20mg PO as were all participants randomized to no run-in. The primary outcome was achieving a clinically important improvement, defined as improvement ≥1.3 on a 0-10 scale. We built a logistic regression model including run-in/no run-in, ketorolac/ibuprofen, age and sex. RESULTS: Of 307 participants who received acetaminophen, 100 (32.6%) reported inadequate relief and were randomized to an NSAID. Of the 100 patients randomized to no run-in, 84/100 (84%) achieved the primary outcome versus 246/287 (86%) run-in participants (95% CI for difference = 2%:-7,10%). Among run-in participants who received an NSAID, 82/99(83%) achieved the primary outcome versus 84/100(84%) no run-in participants (p = 0.82). Among all ibuprofen participants, 44/49(90%) randomized to run-in and 42/50(84%) randomized to no run-in achieved the primary outcome. Among all ketorolac participants, 38/50(76%) randomized to run-in and 42/50 (84%) randomized to no run-in achieved the primary outcome. We observed the following results in a multivariable analysis: OR for ketorolac versus ibuprofen:0.60 (95% CI: 0.28, 1.28); OR for run-in versus no run-in:0.91(95% CI: 0.43, 1.93). CONCLUSIONS: Among patients with acute musculoskeletal pain, using an acetaminophen first strategy did not alter pain outcomes.

Use of clinical phenotypes to characterize emergency department patients administered intravenous opioids for acute pain.

OBJECTIVE: Individual experience with opioids is highly variable. Some patients with acute pain do not experience pain relief with opioids, and many report no euphoria or dysphoric reactions. In this study, we describe the clinical phenotypes of patients who receive intravenous opioids. METHODS: This was an emergency department-based study in which we enrolled patients who received an intravenous opioid. We collected 0 to 10 pain scores prior to opioid administration and 15 minutes after. We also used 0 to 10 instruments to determine how high and how much euphoria the patient felt after receipt of the opioid. Using a cutoff point of ≥50% improvement in pain and the median score on the high and euphoria scales, we assigned each participant to one of the following clinical phenotypes: pain relief with feeling high or euphoria, pain relief without feeling high or euphoria, inadequate relief with feeling high or euphoria, and inadequate relief without feeling high or euphoria. RESULTS: A total of 713 patients were enrolled, 409 (57%) of whom reported not feeling high, and 465 (65%) reported no feeling of euphoria. Median percent improvement in pain was 37.5% (interquartile range, 12.5%-60.0%). One hundred seventy-eight participants (25%) were classified as experiencing pain relief with euphoria or feeling high, 190 (27%) experienced inadequate relief with euphoria or feeling high, 101 (14%) experienced pain relief without euphoria or feeling high, and 244 (34%) reported inadequate relief without euphoria or feeling high. CONCLUSION: Among patients who receive intravenous opioids in the emergency department, the experiences of pain relief and euphoria are highly variable. For many, pain relief is independent of feeling high.

Oxycodone induced euphoria in ED patients with acute musculoskeletal pain. A secondary analysis of data from a randomized trial.

OBJECTIVES: Some opioid-naïve patients with acute musculoskeletal pain who are treated with opioids develop persistent opioid use. The impact of opioid-induced euphoria on this transition to persistent use has not been explored. We determined whether opioid-induced euphoria could be measured as a phenomenon distinct from relief of pain. METHODS: Patients with acute pain were randomized to receive oxycodone/acetaminophen (Oxy) or acetaminophen (APAP). We measured pain using a 0-10 verbal scale. To assess euphoria, participants provided a 0-10 response to each of these: 1) How good did the medication make you feel?; 2) How high did the medication make you feel?; 3) How blissful did the medication make you feel? We analyzed these data using successive multivariable linear regression models, in which each of these items was the dependent variable, and improvement in pain and medication were the independent variables, while controlling for age and sex. RESULTS: 75 were randomized to Oxy, 76 to APAP. Mean "how good" scores were 6.3 (SD 3.3) in the Oxy group and 4.8 (3.3) in the APAP group. Mean "how high" scores were 3.8 (3.7) in the Oxy group and 2.0 (3.0) in the APAP group. Mean "how blissful" scores were 4.9 (3.7) in the Oxy group and 3.1 (3.4) in the APAP group. After controlling for improvement in pain, age, and sex, the between-group difference in "how good" was 1.0 (95%CI: -0.1, 2.0), "how high" 1.5 (95% CI 0.4, 2.6), and "how blissful" 1.5 (95%CI: 0.4, 2.7). DISCUSSION: "How high" and "how blissful" but not "how good" were associated with opioid use after controlling for improvement in pain.

Diphenhydramine as Adjuvant Therapy for Acute Migraine: An Emergency Department-Based Randomized Clinical Trial.

STUDY OBJECTIVE: More than 1 million patients present to US emergency departments (EDs) annually seeking care for acute migraine. Parenteral antihistamines have long been used in combination with antidopaminergics such as metoclopramide to treat acute migraine in the ED. High-quality data supporting this practice do not exist. We determine whether administration of diphenhydramine 50 mg intravenously+metoclopramide 10 mg intravenously results in greater rates of sustained headache relief than placebo+metoclopramide 10 mg intravenously. METHODS: This was a randomized, double-blind, clinical trial comparing 2 active treatments for acute migraine in an ED. Eligible patients were adults younger than 65 years presenting with an acute moderate or severe headache meeting International Classification of Headache Disorders-2 migraine criteria. Patients were stratified according to presence or absence of allergic symptoms. The primary outcome was sustained headache relief, defined as achieving a headache level of mild or none within 2 hours of medication administration and maintaining this level of relief without use of any additional headache medication for 48 hours. Secondary efficacy outcomes included mean improvement on a 0 to 10 verbal scale between baseline and 1 hour, the frequency with which subjects indicated they would want the same medication the next time they present to the ED with migraine, and the ED throughput time. Sample size calculation using a 2-sided α of .05, a ß of .20, and a 15% difference between study arms determined the need for 374 patients. An interim analysis was conducted when data were available for 200 subjects. RESULTS: Four hundred twenty patients were approached for participation. Two hundred eight eligible patients consented to participate and were randomized. At the planned interim analysis, the data and safety monitoring board recommended that the study be halted for futility. Baseline characteristics were comparable between the groups. Fourteen percent (29/208) of the sample reported allergic symptoms. Of patients randomized to diphenhydramine, 40% (40/100) reported sustained relief at 48 hours, as did 37% (38/103) of patients randomized to placebo (95% confidence interval [CI] for difference of 3%: -10% to 16%). One hour after medication administration, patients randomized to diphenhydramine improved by a mean of 5.1 on the 0 to 10 scale versus 4.8 for those randomized to placebo (95% CI for difference of 0.3: -0.6 to 1.1). Eighty-five percent (84/99) of the patients in the diphenhydramine arm reported they would want the same medication combination during a subsequent ED visit, as did 76% (77/102) of those who received placebo (95% CI for difference of 9%: -2% to 20%). Median ED length of stay was 122 minutes (interquartile range 84 to 180 minutes) in the diphenhydramine group and 139 minutes (interquartile range 90 to 235 minutes) in the placebo arm. Rates of adverse effects, including akathisia, were comparable between the groups. CONCLUSION: Intravenous diphenhydramine, when administered as adjuvant therapy with metoclopramide, does not improve migraine outcomes.

A randomized trial of intravenous ketorolac versus intravenous metoclopramide plus diphenhydramine for tension-type and all nonmigraine, noncluster recurrent headaches.

STUDY OBJECTIVE: We compare metoclopramide 20 mg intravenously, combined with diphenhydramine 25 mg intravenously, with ketorolac 30 mg intravenously in adults with tension-type headache and all nonmigraine, noncluster recurrent headaches. METHODS: In this emergency department (ED)-based randomized, double-blind study, we enrolled adults with nonmigraine, noncluster recurrent headaches. Patients with tension-type headache were a subgroup of special interest. Our primary outcome was a comparison of the improvement in pain score between baseline and 1 hour later, assessed on a 0 to 10 verbal scale. We defined a between-group difference of 2.0 as the minimum clinically significant difference. Secondary endpoints included need for rescue medication in the ED, achieving headache freedom in the ED and sustaining it for 24 hours, and patient's desire to receive the same medication again. RESULTS: We included 120 patients in the analysis. The metoclopramide/diphenhydramine arm improved by a median of 5 (interquartile range 3, 7) scale units, whereas the ketorolac arm improved by a median of 3 (IQR 2, 6) (95% confidence interval [CI] for difference 0 to 3). Metoclopramide+diphenhydramine was superior to ketorolac for all 3 secondary outcomes: the number needed to treat for not requiring ED rescue medication was 3 (95% CI 2 to 6); for sustained headache freedom, 6 (95% CI 3 to 20); and for wish to receive the same medication again, 7 (95% CI 4 to 65). Tension-type headache subgroup results were similar. CONCLUSION: For adults who presented to an ED with tension-type headache or with nonmigraine, noncluster recurrent headache, intravenous metoclopramide+diphenhydramine provided more headache relief than intravenous ketorolac.