Randomized Trial Comparing Low- vs High-Dose IV Dexamethasone for Patients With Moderate to Severe Migraine.

BACKGROUND AND OBJECTIVES: Dexamethasone decreases the frequency of migraine recurrence after emergency department (ED) discharge. However, the optimal dose of dexamethasone is unknown. We hypothesized that dexamethasone 16 mg IV would allow greater rates of sustained headache relief than 4 mg when coadministered with metoclopramide 10 mg IV. METHODS: This was a randomized double-blind study. Adults who presented with a headache meeting International Classification of Headache Disorders, 3rd edition, migraine criteria were eligible if they rated the headache as moderate or severe in intensity. Pain intensity was assessed for up to 2 hours in the ED and through telephone 48 hours and 7 days later. The primary outcome was sustained headache relief. Secondary outcomes included headache relief within 2 hours and the number of headache days during the subsequent week. Relying on a priori criteria, the data safety monitoring committee recommended halting the study early for futility. RESULTS: A total of 1,823 patients were screened, and 209 patients were randomized. The mean age was 38 years (SD 11). One hundred seventy-nine of 209 (86%) identified as women. One hundred fifty-one of 209 (72%) of the population reported severe intensity; the rest reported moderate. Thirty-five of 102 (34%) participants in the metoclopramide +4 mg arm achieved sustained headache relief as did 42/102 (41%) participants in the metoclopramide +16 mg arm (absolute difference 7%, 95% CI -6% to 20%). Headache relief within 2 hours occurred in 77/104 (74%) low-dose and 82/105 (78%) high-dose participants (absolute difference 4%, 95% CI -8% to 16%). During the week after ED discharge, low-dose participants reported a median of 2 headache days (25th, 75th percentile 1, 5); in the high-dose arm, this was also 2 (25th, 75th percentile 0, 4) (mean difference 0.4, 95% CI -0.3 to 1.2). DISCUSSION: When added to 10 mg IV metoclopramide, doses of dexamethasone greater than 4 mg are unlikely to benefit patients in the ED with migraine. TRIAL REGISTRATION INFORMATION: This study was registered at ClinicalTrials.gov on October 2, 2019 (NCT04112823). The first patient was enrolled on December 22, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 16 mg of IV dexamethasone is unlikely to provide greater rates of sustained headache relief than 4 mg of IV dexamethasone among patients in the ED with migraine treated concurrently with IV metoclopramide.

Randomized Study of Metoclopramide Plus Diphenhydramine for Acute Posttraumatic Headache.

OBJECTIVE: To determine whether IV metoclopramide 20 mg + diphenhydramine 25 mg (M + D) was more efficacious than IV placebo for acute moderate or severe posttraumatic headache in the emergency room. METHODS: We conducted this randomized, double-blind, placebo-controlled, parallel-group study in 2 urban emergency departments (EDs). Participants who experienced head trauma and presented to our EDs within 10 days with a headache fulfilling criteria for acute posttraumatic headache were included. We randomized participants in a 1:1 ratio to M + D or placebo. Participants, caregivers, and outcome assessors were blinded to assignment. The primary outcome was improvement in pain on a scale of 0 to 10 between baseline and 1 hour after treatment. RESULTS: This study was completed between August 2017 and March 2020. We screened 414 patients for participation and randomized 160: 81 to M + D and 79 to placebo. Baseline characteristics were comparable between the groups. All enrolled participants provided primary outcome data. Patients receiving placebo reported mean improvement of 3.8 (SD 2.6), while those receiving M + D improved by 5.2 (SD 2.3), for a difference favoring metoclopramide of 1.4 (95% confidence interval [CI] 0.7-2.2, p < 0.01). Adverse events were reported by 35 of 81 (43%) patients who received metoclopramide and 22 of 79 (28%) of patients who received placebo (95% CI 1-30 for difference of 15%, p = 0.04). CONCLUSION: M + D was more efficacious than placebo with regard to relief of posttraumatic headache in the ED. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03220958. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with acute moderate or severe posttraumatic headache, IV M + D significantly improved pain compared to placebo.

A Randomized, Double-Dummy, Emergency Department-Based Study of Greater Occipital Nerve Block With Bupivacaine vs Intravenous Metoclopramide for Treatment of Migraine.

BACKGROUND: Greater occipital nerve blocks (GONB) are used increasingly to treat acute migraine. OBJECTIVE: We conducted a randomized controlled trial to determine whether GONB was as effective as intravenous metoclopramide for migraine. METHODS: This was a double-dummy, double-blind, parallel-arm, non-inferiority study conducted in 2 emergency departments (EDs). Patients with migraine of moderate or severe intensity were randomized to receive bilateral GONB with each side administered 3 mL of bupivacaine 0.5% or metoclopramide 10 mg IV, the putative standard of care. The primary outcome was improvement in pain on a 0-10 scale between time 0 and 1 hour later. To reject the null hypothesis that metoclopramide would be more efficacious in relieving pain, we required that the lower limit of the 95% CI for the difference in pain improvement between those randomized to GONB vs those randomized to metoclopramide be >-1.3, a validated minimum clinically important difference. Secondary outcomes included sustained headache relief, defined as achieving and maintaining for 48 hours a headache level of mild or none without the use of additional analgesic medication, and the use of rescue medication in the ED. RESULTS: Over a 2.5-year study period, 1358 patients were screened for participation and 99 were randomized, 51 to GONB and 48 to metoclopramide. All of these patients were included in the primary analysis. Patients who received the GONB reported mean improvement of 5.0 (95% CI: 4.1, 5.8) while those who received metoclopramide reported a larger mean improvement of 6.1 (95% CI: 5.2, 6.9). The 95% CI for the between group difference of -1.1 was -2.3, 0.1. Sustained headache relief was reported by 11/51 (22%) GONB and 18/47 (38%) metoclopramide patients (95% CI for rounded difference of 17%: -1, 35%). Of the 51 GONB patients, 17 (33%) required rescue medication in the ED vs 8/48 (17%) metoclopramide patients (95% CI for rounded difference of 17%: 0, 33%). An adverse event was reported by 16/51 (31%) GONB patients and 18/48 (38%) metoclopramide patients (95% CI for (rounded) difference of 6%: -13, 25%). CONCLUSION: GONB with bupivacaine was not as efficacious as IV metoclopramide for the first-line treatment of migraine in the ED.

Ibuprofen Plus Acetaminophen Versus Ibuprofen Alone for Acute Low Back Pain: An Emergency Department-based Randomized Study.

OBJECTIVES: Patients with low back pain (LBP) are often treated with nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are modestly effective for LBP, but many patients with LBP continue to suffer despite treatment with these medications. We compared pain and functional outcomes 1 week after emergency department (ED) discharge among patients randomized to a 1-week course of ibuprofen plus acetaminophen versus ibuprofen plus placebo. METHODS: This was a randomized, double-blind study conducted in two urban EDs. Patients presenting with acute, nontraumatic, nonradicular LBP of no more than 2 weeks' duration were eligible for enrollment immediately prior to discharge from an ED if they had a score > 5 on the Roland Morris Disability Questionnaire (RMDQ), a 24-item validated instrument, indicating more than minimal functional impairment. All patients were given a standardized 10-minute LBP educational session prior to discharge. The primary outcome was improvement on the RMDQ between ED discharge and 1 week later. One secondary outcome was pain intensity, as measured on a 4-point descriptive scale (severe, moderate, mild, none) at 1 week. RESULTS: Enrollment began in October 2018. A total of 120 patients met selection criteria and were randomized. Baseline demographic characteristics were comparable between the two groups. By 1 week after the ED visit, patients randomized to ibuprofen plus placebo reported a mean (±SD) improvement in the RMDQ of 11.9 (±9.7), while those randomized to ibuprofen plus acetaminophen reported a mean (±SD) improvement of 11.1 (±10.7). The 95% CI for the between-group difference of 0.8 was -3.0 to 4.7. At 1 week, moderate or severe pain was reported by 15 of 53 (28%) patients in the ibuprofen plus placebo group and 16 of 57 (28%) patients in the ibuprofen plus acetaminophen group (95% CI for between-group difference of 0% = -17% to 17%). CONCLUSION: Among ED patients with acute, nontraumatic, nonradicular LBP, adding acetaminophen to ibuprofen does not improve outcomes within 1 week.

A Randomized, Placebo-Controlled Trial of Ibuprofen Plus Metaxalone, Tizanidine, or Baclofen for Acute Low Back Pain.

STUDY OBJECTIVE: Patients with low back pain are often treated with nonsteroidal anti-inflammatory drugs and skeletal muscle relaxants. We compare functional outcomes and pain among patients with acute low back pain who were randomized to a 1-week course of ibuprofen plus placebo versus ibuprofen plus 1 of 3 skeletal muscle relaxants: baclofen, metaxalone, and tizanidine. METHODS: This was a randomized, double-blind, parallel-group, 4-arm study conducted in 2 urban emergency departments (EDs). Patients with nonradicular low back pain for less than or equal to 2 weeks were eligible if they had a score greater than 5 on the Roland-Morris Disability Questionnaire, a 24-item inventory of functional impairment caused by low back pain. All participants received 21 tablets of ibuprofen 600 mg, to be taken 3 times a day as needed. Additionally, they were randomized to baclofen 10 mg, metaxalone 400 mg, tizanidine 2 mg, or placebo. Participants were instructed to take 1 or 2 of these capsules 3 times a day as needed. All participants received a 10-minute educational session. The primary outcome was improvement on the Roland-Morris Disability Questionnaire between ED discharge and 1week later. Secondary outcomes included pain intensity 1 week after ED discharge (severe, moderate, mild, or none). RESULTS: Three hundred twenty patients were randomized. One week later, the mean Roland-Morris Disability Questionnaire score of patients randomized to placebo improved by 11.1 points (95% confidence interval [CI] 9.0 to 13.3), baclofen by 10.6 points (95% CI 8.6 to 12.7), metaxalone by 10.1 points (95% CI 8.0 to 12.3), and tizanidine by 11.2 points (95% CI 9.2 to 13.2). At 1-week follow-up, 30% of placebo patients (95% CI 21% to 41%) reported moderate to severe low back pain versus 33% of baclofen patients (95% CI 24% to 44%), 37% of metaxalone patients (95% CI 27% to 48%), and 33% of tizanidine patients (95% CI 23% to 44%). CONCLUSION: Adding baclofen, metaxalone, or tizanidine to ibuprofen does not appear to improve functioning or pain any more than placebo plus ibuprofen by 1 week after an ED visit for acute low back pain.

A Randomized Trial of a Long-Acting Depot Corticosteroid Versus Dexamethasone to Prevent Headache Recurrence Among Patients With Acute Migraine Who Are Discharged From an Emergency Department.

STUDY OBJECTIVE: Migraine patients continue to report headache during the days and weeks after emergency department (ED) discharge. Dexamethasone is an evidence-based treatment of acute migraine that decreases the frequency of moderate or severe headache within 72 hours of ED discharge. We hypothesize that intramuscular methylprednisolone acetate, a long-acting steroid that remains biologically active for 14 days, will decrease the number of days with headache during the week after ED discharge by at least 1 day compared with intramuscular dexamethasone. METHODS: We conducted a randomized, blinded clinical trial comparing intravenous metoclopramide at 10 mg+intramuscular dexamethasone at 10 mg with intravenous metoclopramide at 10 mg+intramuscular methylprednisolone acetate at a dose of 160 mg for patients presenting to 2 different EDs with moderate or severe migraine. Outcomes were assessed by telephone with a standardized instrument. The primary outcome was number of days with headache during the week after ED discharge. Secondary outcomes were complete freedom from headache, without the necessity of additional headache medication for the entire week after ED discharge, and medication preference, as determined by asking the patient whether he or she would want to receive the same medication again. RESULTS: One hundred nine patients received dexamethasone and 111 received methylprednisolone acetate. We obtained primary outcome data from 101 dexamethasone patients and 106 methylprednisolone acetate patients. Dexamethasone patients reported 3.0 headache days and methylprednisolone acetate 3.3 headache days (95% confidence interval for rounded mean difference of 0.4 days: -0.4 to 1.1). Of 107 dexamethasone patients with analyzable data, 10 (9%) reported complete freedom from headache at 1 week versus 6 of 110 (5%) methylprednisolone acetate patients (95% confidence interval for difference of 4%: -3% to 11%). In the dexamethasone group, 76 of 101 (75%) patients would want the same medication again versus 75 of 106 (71%) of methylprednisolone acetate patients (95% confidence interval for difference of 4%: -8% to 17%). Other than injection site reactions, which were more common in the methylprednisolone acetate group, there were no substantial differences in frequency of adverse events. CONCLUSION: Methylprednisolone acetate does not decrease the frequency of post-ED discharge headache days compared with dexamethasone. Most migraine patients are likely to continue to experience headache during the week after ED discharge.

A Randomized, Double-Blind, Placebo-Controlled Trial of Naproxen With or Without Orphenadrine or Methocarbamol for Acute Low Back Pain.

STUDY OBJECTIVE: In US emergency departments (EDs), patients with low back pain are often treated with nonsteroidal anti-inflammatory drugs and muscle relaxants. We compare functional outcomes among patients randomized to a 1-week course of naproxen+placebo versus naproxen+orphenadrine or naproxen+methocarbamol. METHODS: This was a randomized, double-blind, comparative effectiveness trial conducted in 2 urban EDs. Patients presenting with acute, nontraumatic, nonradicular low back pain were enrolled. The primary outcome was improvement on the Roland-Morris Disability Questionnaire (RMDQ) between ED discharge and 1 week later. All patients were given 14 tablets of naproxen 500 mg, to be used twice a day, as needed for low back pain. Additionally, patients were randomized to receive a 1-week supply of orphenadrine 100 mg, to be used twice a day as needed, methocarbamol 750 mg, to be used as 1 or 2 tablets 3 times per day as needed, or placebo. All patients received a standardized 10-minute low back pain educational session before discharge. RESULTS: Two hundred forty patients were randomized. Baseline demographic characteristics were comparable. The mean RMDQ score of patients randomized to naproxen+placebo improved by 10.9 points (95% confidence interval [CI] 8.9 to 12.9). The mean RMDQ score of patients randomized to naproxen+orphenadrine improved by 9.4 points (95% CI 7.4 to 11.5). The mean RMDQ score of patients randomized to naproxen+methocarbamol improved by 8.1 points (95% CI 6.1 to 10.1). None of the between-group differences surpassed our threshold for clinical significance. Adverse events were reported by 17% (95% CI 10% to 28%) of placebo patients, 9% (95% CI 4% to 19%) of orphenadrine patients, and 19% (95% CI 11% to 29%) of methocarbamol patients. CONCLUSION: Among ED patients with acute, nontraumatic, nonradicular low back pain, combining naproxen with either orphenadrine or methocarbamol did not improve functional outcomes compared with naproxen+placebo.

Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine.

OBJECTIVE: To determine outcomes among patients with migraine in the emergency department (ED) who receive IV hydromorphone vs IV prochlorperazine + diphenhydramine. METHODS: This study was conducted in 2 EDs in New York City. Patients who met international criteria for migraine were eligible for participation if they had not used an opioid within the previous month. Clinicians, participants, investigators, and research personnel were blinded to treatment. Patients were randomized in blocks of 4. Participants received hydromorphone 1 mg or prochlorperazine 10 mg + diphenhydramine 25 mg. Diphenhydramine was administered to prevent akathisia, a common side effect of IV prochlorperazine. 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 that level for 48 hours without the requirement of rescue medication. A planned interim analysis was conducted once 48-hour data were available for 120 patients. RESULTS: The trial was halted by the data monitoring committee after 127 patients had been enrolled. The primary outcome was achieved in the prochlorperazine arm by 37 of 62 (60%) participants and in the hydromorphone arm by 20 of 64 (31%) participants (difference 28%, 95% confidence interval 12-45, number needed to treat 4, 95% confidence interval 2-9). CONCLUSIONS: IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the ED and should not be used as first-line therapy. CLINICALTRIALSGOV IDENTIFIER: NCT02389829. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients in the ED with migraine, IV prochlorperazine + diphenhydramine is superior to IV hydromorphone.

Diazepam Is No Better Than Placebo When Added to Naproxen for Acute Low Back Pain.

STUDY OBJECTIVE: Low back pain causes more than 2.5 million visits to US emergency departments (EDs) annually. Low back pain patients are often treated with nonsteroidal anti-inflammatory drugs and benzodiazepines. The former is an evidence-based intervention, whereas the efficacy of the latter has not been established. We compare pain and functional outcomes 1 week and 3 months after ED discharge among patients randomized to a 1-week course of naproxen+diazepam versus naproxen+placebo. METHODS: This was a randomized, double-blind, comparative efficacy clinical trial conducted in an urban health care system. Patients presenting with acute, nontraumatic, nonradicular low back pain of no more than a duration of 2 weeks were eligible for enrollment immediately before discharge from an ED if they had a score greater than 5 on the Roland-Morris Disability Questionnaire, a validated 24-item inventory of functional impairment caused by low back pain. Higher scores on the questionnaire indicate greater functional disability. The primary outcome in the trial was improvement in the score between ED discharge and 1 week later. Secondary outcomes included pain intensity 1 week and 3 months after ED discharge, as measured on a 4-point descriptive scale (severe, moderate, mild, and none). All patients were given 20 tablets of naproxen 500 mg, to be taken twice a day as needed for low back pain. Additionally, patients were randomized to receive either 28 tablets of diazepam 5 mg or identical placebo, to be received as 1 or 2 tablets every 12 hours as needed for low back pain. All patients received a standardized 10-minute low back pain educational session before discharge. Using a between-group mean difference of 5 Roland-Morris Disability Questionnaire points, a previously validated threshold for clinical significance, we calculated the need for at least 100 patients with primary outcome data. RESULTS: Enrollment began in June 2015 and continued for 9 months. Five hundred forty-five patients were screened for eligibility. One hundred fourteen patients met selection criteria and were randomized. Baseline demographic characteristics were not substantially different between the 2 groups. One hundred twelve patients (98%) provided 1-week outcome data. The mean Roland-Morris Disability Questionnaire score of patients randomized to naproxen+diazepam improved by 11 (95% confidence interval [CI] 9 to 13), as did the mean score of patients randomized to naproxen+placebo (11; 95% CI 8 to 13). At 1-week follow-up, 18 of 57 diazepam patients (32%; 95% CI 21% to 45%) reported moderate or severe low back pain versus 12 of 55 placebo patients (22%; 95% CI 13% to 35%). At 3-month follow-up, 6 of 50 diazepam patients (12%; 95% CI 5% to 24%) reported moderate or severe low back pain versus 5 of 53 placebo patients (9%; 95% CI 4% to 21%). Adverse events were reported by 12 of 57 diazepam patients (21%; 95% CI 12% to 33%) and 8 of 55 placebo patients (15%; 95% CI 7% to 26%). CONCLUSION: Among ED patients with acute, nontraumatic, nonradicular low back pain, naproxen+diazepam did not improve functional outcomes or pain compared with naproxen+placebo 1 week and 3 months after ED discharge.

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.

Treatment with Dalteparin is Associated with a Lower Risk of Bleeding Compared to Treatment with Unfractionated Heparin in Patients with Renal Insufficiency.

BACKGROUND: Low molecular weight heparins (LMWHs) have been cautiously used in patients with chronic kidney disease (CKD) due to fear of accumulation. Dalteparin, however, has shown minimal tendency to accumulate in patients with CKD and may be safe to use in this patient population. OBJECTIVE: We compared the incidence of clinically significant bleeding in patients with CKD receiving therapeutic doses of dalteparin to that of patients with CKD receiving therapeutic doses of UFH. DESIGN: This was a retrospective cohort study. SUBJECTS: Inpatients with CKD (GFR < 60 ml/min) who were treated with therapeutic dalteparin or UFH were included in the study MAIN MEASURES: Primary outcome was major bleeding within 10 days of anticoagulation, identified by ICD-9 code and confirmed by chart review. Demographic characteristics, laboratory values, comorbidities, prior bleeding history and inpatient medications were extracted for each admission from the electronic medical record. Logistic regression models were created to examine the association between choice of anticoagulant and bleeding rates, after adjustment for demographic and clinical characteristics. KEY RESULTS: Dalteparin-treated patients were significantly less likely to experience a major bleed than patients treated with UFH (1.14 % vs. 3.49 %, p < 0.001). The reduced likelihood of bleeding associated with dalteparin treatment remained significant after adjustment for patient characteristics (HR 0.39, 95 % CI: 0.21-0.70, p < 0.0001). A stratified analysis for subgroups with GFR< 30 mL/min and with GFR between 30 and 60 mL/min showed that dalteparin was still associated with lower odds of bleeding compared to treatment with unfractionated heparin, but the difference was nonsignificant for GFR< 30 (HR 0.35, 95 % CI: 0.11-1.15), even after adjustment (OR 0.37, 95 % CI: 0.11-1.22). CONCLUSION: In patients with CKD, treatment with therapeutic dose dalteparin was associated with lower rates of bleeding than treatment with unfractionated heparin. For patients with severe CKD (GFR< 30), dalteparin was shown to be at least as safe as unfractionated heparin.

Naproxen With Cyclobenzaprine, Oxycodone/Acetaminophen, or Placebo for Treating Acute Low Back Pain: A Randomized Clinical Trial.

IMPORTANCE: Low back pain (LBP) is responsible for more than 2.5 million visits to US emergency departments (EDs) annually. These patients are usually treated with nonsteroidal anti-inflammatory drugs, acetaminophen, opioids, or skeletal muscle relaxants, often in combination. OBJECTIVE: To compare functional outcomes and pain at 1 week and 3 months after an ED visit for acute LBP among patients randomized to a 10-day course of (1) naproxen + placebo; (2) naproxen + cyclobenzaprine; or (3) naproxen + oxycodone/acetaminophen. DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, 3-group study was conducted at one urban ED in the Bronx, New York City. Patients who presented with nontraumatic, nonradicular LBP of 2 weeks' duration or less were eligible for enrollment upon ED discharge if they had a score greater than 5 on the Roland-Morris Disability Questionnaire (RMDQ). The RMDQ is a 24-item questionnaire commonly used to measure LBP and related functional impairment on which 0 indicates no functional impairment and 24 indicates maximum impairment. Beginning in April 2012, a total of 2588 patients were approached for enrollment. Of the 323 deemed eligible for participation, 107 were randomized to receive placebo and 108 each to cyclobenzaprine and to oxycodone/acetaminophen. Follow-up was completed in December 2014. INTERVENTIONS: All participants were given 20 tablets of naproxen, 500 mg, to be taken twice a day. They were randomized to receive either 60 tablets of placebo; cyclobenzaprine, 5 mg; or oxycodone, 5 mg/acetaminophen, 325 mg. Participants were instructed to take 1 or 2 of these tablets every 8 hours, as needed for LBP. They also received a standardized 10-minute LBP educational session prior to discharge. MAIN OUTCOMES AND MEASURES: The primary outcome was improvement in RMDQ between ED discharge and 1 week later. RESULTS: Demographic characteristics were comparable among the 3 groups. At baseline, median RMDQ score in the placebo group was 20 (interquartile range [IQR],17-21), in the cyclobenzaprine group 19 (IQR,17-21), and in the oxycodone/acetaminophen group 20 (IQR,17-22). At 1-week follow-up, the mean RMDQ improvement was 9.8 in the placebo group, 10.1 in the cyclobenzaprine group, and 11.1 in the oxycodone/acetaminophen group. Between-group difference in mean RMDQ improvement for cyclobenzaprine vs placebo was 0.3 (98.3% CI, -2.6 to 3.2; P = .77), for oxycodone/acetaminophen vs placebo, 1.3 (98.3% CI, -1.5 to 4.1; P = .28), and for oxycodone/acetaminophen vs cyclobenzaprine, 0.9 (98.3% CI, -2.1 to 3.9; P = .45). CONCLUSIONS AND RELEVANCE: Among patients with acute, nontraumatic, nonradicular LBP presenting to the ED, adding cyclobenzaprine or oxycodone/acetaminophen to naproxen alone did not improve functional outcomes or pain at 1-week follow-up. These findings do not support use of these additional medications in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01587274.

Randomized trial of IV valproate vs metoclopramide vs ketorolac for acute migraine.

OBJECTIVE: We compared the efficacy of IV valproate with metoclopramide and with ketorolac in patients presenting to an emergency department (ED) with acute migraine. METHODS: This was a double-blind comparative efficacy trial. Patients were randomized to 1,000 mg sodium valproate, 10 mg metoclopramide, or 30 mg ketorolac, each administered as an IV drip over 15 minutes. The primary outcome was improvement in headache by 1 hour, measured on a verbal 0 to 10 scale, at baseline and 60 minutes later. Important secondary outcomes included (1) need for rescue medication in the ED, and (2) sustained headache freedom. RESULTS: Three hundred thirty patients were enrolled over 30 months beginning in October 2010. Baseline characteristics were comparable among the 3 arms. On the primary outcome, patients receiving IV valproate improved by a mean of 2.8 (95% confidence interval [CI]: 2.3, 3.3) on the 0 to 10 scale; those receiving IV metoclopramide improved by 4.7 (95% CI: 4.2, 5.2); and those receiving IV ketorolac improved by 3.9 (95% CI: 3.3, 4.5). On the secondary endpoints, 69% (95% CI: 60%, 78%) of patients receiving valproate required rescue medication, compared with 33% (95% CI: 24%, 42%) of metoclopramide patients and 52% (95% CI: 42%, 63%) of those assigned to ketorolac. Sustained headache freedom was achieved in 4% (95% CI: 0%, 7%) of those randomized to valproate, 11% (95% CI: 5%, 17%) of metoclopramide patients, and 16% (95% CI: 9%, 23%) receiving ketorolac. In the metoclopramide arm, 6% (95% CI: 3%, 12%) of patients reported feeling "very restless" after investigational medication administration. CONCLUSIONS: Valproate was less efficacious than either metoclopramide or ketorolac. Metoclopramide demonstrated superiority to ketorolac on several endpoints. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in ED patients with acute migraine, IV valproate is inferior to metoclopramide or ketorolac in improving headache 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.

A randomized controlled trial of a comprehensive migraine intervention prior to discharge from an emergency department.

OBJECTIVES: Patients who use an emergency department (ED) for acute migraine headaches have higher migraine disability scores, lower socioeconomic status, and are unlikely to have used a migraine-specific medication prior to presentation to the ED. The objective was to determine if a comprehensive migraine intervention, delivered just prior to ED discharge, could improve migraine impact scores 1 month after the ED visit. METHODS: This was a randomized controlled trial of a comprehensive migraine intervention versus typical care among patients who presented to an ED for management of acute migraine. At the time of discharge, for patients randomized to comprehensive care, the research team reinforced their diagnosis, shared a migraine education presentation from the National Library of Medicine, provided them with six tablets of sumatriptan 100 mg and 14 tablets of naproxen 500 mg, and if they wished, provided them with an expedited free appointment to the institution's headache clinic. Patients randomized to typical care received the care their attending emergency physicians (EPs) felt was appropriate. The primary outcome was a between-group comparison of the Headache Impact Test (HIT-6) score, a validated headache assessment instrument, 1 month after ED discharge. Secondary outcomes included an assessment of satisfaction with headache care and use of migraine-specific medication within that 1-month period. RESULTS: Over a 19-month period, 50 migraine patients were enrolled. One-month follow-up was successfully obtained in 92% of patients. Baseline characteristics were comparable. One-month HIT-6 scores in the two groups were nearly identical (59 vs. 56, 95% confidence interval [CI] for difference of 3 = -5 to 11), as was dissatisfaction with overall headache care (17% vs. 18%, 95% CI for difference of 1% = -22% to 24%). Patients randomized to the comprehensive intervention were more likely to be using triptans or migraine-specific therapy (43% vs. 0%, 95% CI for difference of 43% = 20 to 63%) 1 month later. CONCLUSIONS: A comprehensive migraine intervention, when compared to typical care, did not improve HIT-6 scores (a validated measure of the effect of migraine on one's daily life) 1 month after ED discharge. Future work is needed to define a migraine intervention that is practical and useful in an ED, where many underserved patients, of necessity, present for care.

Effect of risedronate on bone in renal transplant recipients.

Bisphosphonates may prevent or treat the bone loss promoted by the immunosuppressive regimens used in renal transplantation. Risedronate is a commonly used third-generation amino-bisphosphonate, but little is known about its effects on the bone health of renal transplant recipients. We randomly assigned 42 new living-donor kidney recipients to either 35 mg of risedronate weekly or placebo for 12 months. We obtained bone biopsies at the time of renal transplant and after 12 months of protocol treatment. Treatment with risedronate did not affect bone mineral density (BMD) in the overall cohort. In subgroup analyses, it tended to preserve BMD in female participants but did not significantly affect the BMD of male participants. Risedronate did associate with increased osteoid volume and trabecular thickness in male participants, however. There was no evidence for the development of adynamic bone disease. In summary, further study is needed before the use of prophylactic bisphosphonates to attenuate bone loss can be recommended in renal transplant recipients.

Metoclopramide for acute migraine: a dose-finding randomized clinical trial.

STUDY OBJECTIVE: Intravenous metoclopramide is effective as primary therapy for acute migraine, but the optimal dose of this medication is not yet known. The objective of this study is to compare the efficacy and safety of 3 different doses of intravenous metoclopramide for the treatment of acute migraine. METHODS: This was a randomized, double-blind, dose-finding study conducted on patients who presented to our emergency department (ED) meeting International Classification of Headache Disorders criteria for migraine without aura. We randomized patients to 10, 20, or 40 mg of intravenous metoclopramide. We coadministered diphenhydramine to all patients to prevent extrapyramidal adverse effects. The primary outcome was improvement in pain on an 11-point numeric rating scale at 1 hour. Secondary outcomes included sustained pain freedom at 48 hours and adverse effects. RESULTS: In this study, 356 patients were randomized. Baseline demographics and headache features were comparable among the groups. At 1 hour, those who received 10 mg of intravenous metoclopramide improved by a mean of 4.7 numeric rating scale points (95% confidence interval [CI] 4.2 to 5.2 points); those who received 20 mg improved by 4.9 points (95% CI 4.4 to 5.4 points), and those who received 40 mg improved by 5.3 points (95% CI 4.8 to 5.9 points). Rates of 48-hour sustained pain freedom in the 10-, 20-, and 40-mg groups were 16% (95% CI 10% to 24%), 20% (95% CI 14% to 28%), and 21% (95% CI 15% to 29%), respectively. The most commonly occurring adverse event was drowsiness, which impaired function in 17% (95% CI 13% to 21%) of the overall study population. Akathisia developed in 33 patients. Both drowsiness and akathisia were evenly distributed across the 3 arms of the study. One month later, no patient had developed tardive dyskinesia. CONCLUSION: Twenty milligrams or 40 mg of metoclopramide is no better for acute migraine than 10 mg of metoclopramide.

Angiotensin converting enzyme inhibitor use soon after renal transplantation: a randomized, double-blinded placebo-controlled safety study.

Activation of the renin-angiotensin system (RAS) followed by increased inflammatory cytokines may be important in the pathogenesis of chronic allograft dysfunction. As many renal transplant recipients show chronic changes on biopsy within the first year, early RAS blockade with angiotensin converting enzyme inhibitor (ACEI) could be beneficial. However, it remains unclear that early ACEI use is safe. We conducted a prospective, randomized, placebo-controlled trial to assess the safety of enalapril 5 mg during the early post-transplant period. Subjects took the study medication for six months. Primary endpoints were serum potassium (K) >5.9 mEq/L and 30% increase in baseline creatinine. A total of 53 subjects were randomized, and of them, 27 received the study drug. Twenty-nine subjects, 14 ACEI and 15 controls, completed the six-month protocol without reaching an endpoint. Patients on ACEI had higher K and higher BUN at six months. Serum creatinine, hematocrit, and urinary protein were not different. There was no difference in urinary TGF-ß1. Twenty-four subjects reached study endpoints. When the common clinical endpoints of elevated creatinine and hyperkalemia were combined, ACEI group had significantly increased endpoints vs. control (10/13, 77% vs. 5/11, 45%, p < 0.05). We conclude that ACEI use in the early post-transplant period can be safe but patients must be carefully selected and monitored for elevations in serum creatinine and potassium. Whether early ACEI is beneficial in preserving allograft function requires further study.

Treating headache recurrence after emergency department discharge: a randomized controlled trial of naproxen versus sumatriptan.

STUDY OBJECTIVE: Multiple parenteral medications are used to treat migraine and other acute primary headaches in the emergency department (ED). Regardless of specific headache diagnosis, no medication eliminates the frequent recurrence of primary headache after ED discharge. It is uncertain which medication primary headache patients should be given on discharge from an ED. The aim of this study is to compare the efficacy of oral sumatriptan with naproxen for treatment of post-ED recurrent primary headache. METHODS: This was a randomized, double-blind efficacy trial. We randomized patients to either naproxen 500 mg or sumatriptan 100 mg for headache recurrence after ED discharge. Patients were eligible if they received parenteral therapy for an acute exacerbation of a primary headache in the ED. Patients who met established criteria for migraine without aura were designated a priori as a homogenous subgroup of interest. We followed all patients by telephone 48 hours after ED discharge. The primary endpoint was the between-group difference in change in pain intensity during the 2-hour period after ingestion of either 500 mg naproxen or 100 mg sumatriptan. This difference was measured on a validated 11-point (0 to 10) verbal numeric rating scale (NRS). Satisfaction with the medication and adverse effects were also assessed. Patients who met criteria for migraine without aura were analyzed twice according to a priori design: once as a homogenous subgroup and then again combined with all other primary headaches. RESULTS: Of 410 patients randomized, 383 (93%) had outcome data available for analysis. Two hundred eighty (73%; 95% confidence interval [CI] 68% to 77%) reported headache post-ED discharge and 196 (51%; 95% CI 44% to 58%), including 88 with migraine, took the investigational medication provided to them. The naproxen group improved by a mean of 4.3 NRS points, whereas the sumatriptan group improved by 4.1 points (95% CI for difference of 0.2 points: -0.7 to 1.1 points). Findings were virtually identical among the migraine subset (4.3 versus 4.2 NRS points; 95% CI for difference of 0.1 points: -1.3 to 1.5 points). Seventy-one percent (95% CI 62% to 80%) of naproxen patients and 75% (95% CI 66% to 84%) of sumatriptan patients would want to take the same medication the next time. Adverse effect profiles were also comparable. CONCLUSION: In this trial, nearly three quarters of patients reported headache recurrence within 48 hours of ED discharge. Naproxen 500 mg and sumatriptan 100 mg taken orally relieve post-ED recurrent primary headache and migraine comparably. Clinicians should be guided by medication costs, contraindications, and a patient's previous experience with the medication.

A randomized trial of diphenhydramine as prophylaxis against metoclopramide-induced akathisia in nauseated emergency department patients.

STUDY OBJECTIVE: Akathisia, an adverse effect observed at times after administration of parenteral metoclopramide, is an unpleasant symptom complex characterized by restlessness and agitation. Some try to limit the development of akathisia by coadministering diphenhydramine when using parenteral metoclopramide. The goal of this investigation is to determine whether concomitant administration of diphenhydramine 25 mg decreased the rate of development of akathisia after administration of 10 mg or 20 mg of intravenous metoclopramide. METHODS: This was a randomized, double-blind, factorial design trial. Patients who presented to our emergency department with a primary or secondary chief complaint of nausea were randomized to one of the following 4 groups: (1) metoclopramide 10 mg+diphenhydramine 25 mg; (2) metoclopramide 10 mg+placebo; (3) metoclopramide 20 mg+diphenhydramine 25 mg; (4) metoclopramide 20 mg+placebo. The medications were inserted into a 50-mL bag of normal saline solution and administered as an intravenous drip during 15 minutes. Primary outcome was development of akathisia within 60 minutes of medication administration, as measured by blinded assessors using a short akathisia instrument, or use of rescue medication for treatment of akathisia by blinded clinical staff. Patients were also asked at baseline and 30 minutes later whether they felt restless. RESULTS: Two hundred eighty-nine patients were randomized and 286 patients were included in the final analysis. Within 1 hour of medication administration, 17 of 143 patients randomized to diphenhydramine (12%; 95% confidence interval [CI] 8% to 18%) and 17 of 143 (12%; 95% CI 8% to 18%) randomized to placebo developed akathisia (95% CI for difference of 0%: -8% to 8%). Thirteen of 143 patients randomized to metoclopramide 10 mg (9%; 95% CI 5% to 15%) and 21 of 143 randomized to metoclopramide 20 mg (15%; 95% CI 10% to 22%) developed akathisia (95% CI for difference of 6%: -2% to 14%). In those administered prophylactic diphenhydramine, odds of akathisia relative to placebo were 1.0 (95% CI 0.5 to 2.0). Odds of akathisia in those administered 20 mg of metoclopramide relative to the 10-mg dose were 1.7 (95% CI 0.8 to 3.6). Among patients who received 20 mg of metoclopramide, subjective restlessness was reported by 7 of 72 (9.7%) patients who received diphenhydramine and 14 of 71 (19.7%) patients who received placebo (95% CI for difference of 10%: -2% to 22%). CONCLUSION: Routine prophylaxis with diphenhydramine to prevent akathisia is unwarranted when intravenous metoclopramide is administered over 15 minutes. For patients administered 20 mg of metoclopramide, prophylactic diphenhydramine may decrease subjective restlessness.