HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Ann Emerg Manuscript Author Med. Author Manuscript Author manuscript; available in PMC 2020 October 01. Published in final edited form as: Ann Emerg Med. 2019 October ; 74(4): 512–520. doi:10.1016/j.annemergmed.2019.02.017. A randomized, placebo controlled trial of ibuprofen + metaxalone, tizanidine, or baclofen for acute low back pain Benjamin W. Friedman, MD MS1, Eddie Irizarry, MD1, Clemencia Solorzano, PharmD2, Eleftheria Zias, RPh2, Scott Pearlman, MD1, Andrew Wollowitz, MD1, Michael P. Jones, MD1, Purvi D. Shah, MD MSc1, E. John Gallagher, MD1 1Department of Emergency Medicine, Albert Einstein College of Medicine, Montefiore, Bronx, NY, USA 2Pharmacy Department, Montefiore, Bronx, NY, USA Abstract Background: Patients with low back pain (LBP) are often treated with non-steroidal antiinflammatory drugs (NSAID) and skeletal muscle relaxants (SMR). We compared functional outcomes and pain among acute LBP patients randomized to a one week course of ibuprofen + placebo versus ibuprofen + one of three SMRs: baclofen, metaxalone, or tizanidine. Methods: This was a randomized, double-blind, parallel group, 4-arm study conducted in two urban emergency departments (ED). Patients with non-radicular LBP for <=two weeks were eligible if they had a score >5 on the Roland-Morris Disability Questionnaire (RMDQ), a 24-item inventory of functional impairment due to LBP. All participants received 21 tablets of ibuprofen 600mg, to be taken TID, as needed. Additionally, they were randomized to baclofen 10mg, metaxalone 400mg, tizanidine 2mg, or placebo. Participants were instructed to take one or two of these capsules, TID, as needed. All participants received a 10 minute educational session. The primary outcome was improvement on the RMDQ between ED discharge and 1week later. Secondary outcomes included pain intensity one week after ED discharge (severe, moderate, mild, or none). Results: 320 patients were randomized. One week later, the mean RMDQ score of patients randomized to placebo improved by 11.1(95%CI:9.0,13.3), baclofen improved by 10.6 (95%CI: 8.6,12.7), metaxalone improved by 10.1 (95%CI:8.0,12.3) and tizanidine improved by 11.2 (95%CI:9.2, 3.2). At one week follow-up, 30% (95%CI: 21, 41%) of placebo patients reported moderate/severe LBP versus 33% (95%CI: 24, 44%) of baclofen, 37% (95%CI: 27, 48%) of metaxalone and 33% (95%CI: 23, 44%) of tizanidine patients. Corresponding author: Benjamin W. Friedman, MD, MS, Department of Emergency Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY, 10467, [email protected], (718) 920-6626. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Friedman et al. Page 2 Conclusion: Adding baclofen, metaxalone, or tizanidine to ibuprofen does not appear to Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author improve functioning or pain any more than placebo + ibuprofen one week after an ED visit for acute LBP. Background Low back pain (LBP) is exceedingly common, with a global point prevalence of 18%.(1) Non-steroidal anti-inflammatory drugs (NSAIDs) are considered first line pharmacological treatment.(2, 3) NSAIDs alone often provide inadequate analgesia for patients with symptoms of sufficient severity to warrant an emergency department (ED) visit, as 1/3 of these patients who receive NSAIDs alone report moderate or severe LBP one week later.(4) Importance Skeletal muscle relaxants (SMR) are commonly used to treat LBP both in the ED(5) and in ambulatory practice,(6) often in combination with NSAIDs. Evidence supporting efficacy of SMRs in this role is generally of lower quality.(2, 7) Previous clinical trials similarly indicate that use of naproxen, in combination with cyclobenzaprine,(8) orphenadrine,(9) methocarbamol,(9) or diazepam(10) does not improve LBP outcomes among ED patients any more than naproxen alone. In this study, we sought to determine whether there is any benefit from combining three other commonly used SMRs--baclofen, metaxalone, or tizanidine--with an NSAID. Goal of this investigation In this randomized, 4-arm clinical trial conducted among a population of ED patients with acute, functionally-impairing, non-radicular LBP, we wished to determine whether a daily regimen of ibuprofen plus baclofen, metaxalone, or tizanidine would provide greater relief of LBP than ibuprofen plus placebo one week after an ED visit, as measured by improvement on the Roland Morris Disability Questionnaire (RMDQ). The RMDQ is a 24- item inventory of functional impairment due to LBP, commonly used in LBP clinical research. (11) Methods Study design and setting This was a randomized, double-blind, parallel group, comparative effectiveness study, in which we enrolled patients during an ED visit for musculoskeletal LBP, and then followed them by telephone two and seven days later. Every patient received standard-of-care therapy, consisting of ibuprofen and a LBP education session. Patients were randomized to placebo, baclofen, metaxalone, or tizanidine. This study was registered online at http:// clinicaltrials.gov, identifier: NCT03068897. The Albert Einstein College of Medicine Institutional Review Board reviewed and approved the protocol and provided continuing oversight. All participants provided written informed consent. This trial is reported in accordance with CONSORT guidelines. Ann Emerg Med. Author manuscript; available in PMC 2020 October 01. Friedman et al. Page 3 This study was performed in the two academic EDs of Montefiore Medical Center (Bronx, Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author NY) with a combined annual census of 180,000 adult visits. Salaried, full-time, bilingual (English and Spanish) technician-level research associates, staffed both EDs 24 hours per day, seven days per week during the study period. Selection of participants We enrolled adults aged 18-64 who presented to one of our EDs primarily for management of acute, non-radicular, non-traumatic, musculoskeletal LBP, defined as pain originating between the lower border of the scapulae and the upper gluteal folds. Participants were required to have had LBP for no longer than 2 weeks. If they had prior episodes of back pain, they could not have had it as frequently as once per month. Participation required functional impairment due to LBP, which we defined as a baseline score of > 5 on the Roland-Morris Disability Questionnaire (http://www.rmdq.org). Patients were excluded from participation if they were unavailable for follow-up, if they were pregnant or breast-feeding, using medication for a chronic pain syndrome, which we defined as use of any analgesic medication on a daily or near-daily basis, or for allergy to, intolerance of, or contraindication to any of the investigational medications. Interventions Patients were randomized in a 1:1:1:1 ratio to one of these four medication regimens: 1) The control arm: Ibuprofen 600mg + placebo, orally, both every 8 hours as needed 2) The baclofen arm: Ibuprofen 600mg+ baclofen 10- 20mg, orally, both every 8 hours as needed 3) The metaxalone arm: Ibuprofen 600mg+ metaxalone 400- 800mg, orally, both every 8 hours as needed 4) The tizanidine arm: Ibuprofen 600mg+ tizanidine 2- 4mg, orally, both every 8 hours as needed In an effort to maximize effectiveness while minimizing side effects, patients were instructed to take one ibuprofen plus one or two muscle relaxant capsules every 8 hours as needed. If one capsule of the muscle relaxant afforded sufficient relief, there was no need for the patient to take the second. However, if the participant did not experience sufficient relief within 60 minutes of taking one investigational medication capsule, they were instructed to take the second. All study participants were given a seven day supply of ibuprofen and the muscle relaxant or placebo. The pharmacist performed randomization in blocks of 8 based on a sequence generated at http://randomization.com. Ibuprofen was not masked. Metaxalone, tizanidine, baclofen, and placebo were masked by placing tablets into identical capsules, which were then packed with scant amounts of lactose and sealed. Research personnel presented participants with two bottles of medication capsules. The bottle containing the ibuprofen was labeled in a typical manner. The second bottle, containing the muscle relaxant or placebo was labeled as Ann Emerg Med. Author manuscript; available in PMC 2020 October 01. Friedman et al. Page 4 investigational medication. Thus the investigators, clinicians, participants and research Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author associates/ outcome assessors were blinded to treatment received. Patients were instructed to take the medications only as needed for LBP. Research personnel provided each participant with a 10-minute educational intervention. This was based on NIAMS’s Handout on Health: Back Pain information webpage (available at https://www.niams.nih.gov/health-topics/back-pain). Research personnel reviewed