Clinical trial NCT03068897
Conditions: Low Back Pain
Sponsor: Montefiore Medical Center
Start date: 2017-05-03; Completion date: 2018-10-11
Enrollment: 320 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized study, based in emergency departments, in which the investigators determine the utility of adding various skeletal muscle relaxants to standard therapy, which consists of ibuprofen and an educational session. Patients will be enrolled at the time of an emergency visit and followed for three months to determine outcomes.

Detailed description:

Arms: arm 1: Ibuprofen 600mg mg + metaxalone 400-800mg every 8 hours, as needed for low back pain, x 7 days.

All participants receive a brief educational intervention. arm 2: Ibuprofen 600mg mg + tizanidine 2-4mg every 8 hours, as needed for low back pain, x 7 days.

All participants receive a brief educational intervention. arm 3: Ibuprofen 600mg mg + baclofen 10-20 mg every 8 hours, as needed for low back pain, x 7 days.

All participants receive a brief educational intervention. arm 4: Ibuprofen 600mg mg + placebo, 1 or 2 capsules, every 8 hours, as needed for low back pain, x 7 days.

All participants receive a brief educational intervention.
Interventions: intervention 1: Metaxalone intervention 2: Tizanidine intervention 3: Baclofen intervention 4: Ibuprofen 600 mg intervention 5: Educational intervention
Intervention descriptions: intervention 1: Metaxalone 400-800mg intervention 2: Tizanidine 2-4mg intervention 3: Baclofen 10-20mg intervention 4: Ibuprofen intervention 5: Research personnel will provide each patient with a 15-minute educational intervention. This will be based on NIAMS's Handout on Health: Back Pain information webpage (available at http://www.niams.nih.gov/Health\_Info/Back\_Pain/default.asp) Research personnel will review each section of the information sheet with the patient and elicit questions.

Protocol documents:
Prot_SAP_000.pdf: 
Ibuprofen plus metaxolone, tizanidine, or baclofen for LBP. A randomized trial Version 
03272017
1
Ibuprofen plus metaxolone, tizandine, or baclofen for low back pain. A randomized trial
IRB NUMBER: 2017-7566
IRB APPROVAL DATE: 03/29/2017


Ibuprofen plus metaxolone, tizanidine, or baclofen for LBP. A randomized trial Version 
03272017
2
Specific Aims
Up to ½ of emergency department (ED) patients with acute, new onset low back pain (LBP) report 
persistent moderate or severe pain one week after the ED visit.(1, 2) Skeletal muscle relaxants (SMR) 
are commonly used to treat LBP though evidence supporting efficacy is generally lower quality. We 
have demonstrated previously that two commonly used SMRs, cyclobenzaprine(1) and diazepam(2), 
when combined with an NSAID, do not improve LBP outcomes more than NSAIDs used alone. This 
proposal seeks to determine whether there is any benefit from other commonly used SMRs.
The first SMR to be included in this study is baclofen. The precise mechanism of action of baclofen is 
unknown. Baclofen inhibits monosynaptic and polysynaptic reflexes at the spinal level, although 
actions at supraspinal sites may contribute to its clinical effect. Baclofen is an analog of the 
neurotransmitter GABA, but it is uncertain whether GABA is involved in its clinical effects. In a 
randomized, placebo controlled study, 200 patients with acute LBP were randomized to baclofen or 
placebo.(3) Patients randomized to baclofen reported modestly better outcomes four and ten days later.
The second investigational SMR is tizanidine. Tizanidine is a centrally acting alpha-2-adrenergic 
agonist. It reduces muscle spasticity by increasing presynaptic inhibition of motor neurons. In a 
randomized, placebo controlled trial, 112 patients with acute LBP were randomized to tizanidine. In 
this study, patients randomized to tizanidine tended to use less aspirin.(4) In an RCT of tizanidine + 
ibuprofen versus ibuprofen alone, the combination of medications outperformed ibuprofen 
monotherapy on some pain outcomes.(5)
The third investigational SMR is metaxalone, a CNS depressant whose mechanism of action is not yet 
understood. In a randomized study of 228 patients with acute symptoms, patients randomized to 
metaxolone reported improved performance of daily activities than patients who received placebo.(6) 
Results were similar in two other RCTS of metaxolone versus placebo, each of which enrolled 100 
patients.(7)
Given the poor pain and functional outcomes that persist beyond an ED visit for acute LBP, we 
propose a clinical trial to determine whether combining a muscle relaxant with an NSAID is more 
effective than NSAID monotherapy for the treatment of acute, non-traumatic, non-radicular low back 
pain. NSAIDs are provided to all patients because these medications are considered standard-of-care 
therapy for LBP. We will test the following three hypotheses:
1) A daily regimen of ibuprofen + metaxolone will provide greater relief of LBP than ibuprofen + 
placebo one week after an ED visit, as measured by the Roland Morris Disability Questionnaire
2) A daily regimen of ibuprofen + tizanidine will provide greater relief of LBP than ibuprofen + 
placebo one week after an ED visit, as measured by the Roland Morris Disability Questionnaire
3) A daily regimen of ibuprofen + baclofen will provide greater relief of LBP than ibuprofen + 
placebo one week after an ED visit, as measured by the Roland Morris Disability Questionnaire
IRB NUMBER: 2017-7566
IRB APPROVAL DATE: 03/29/2017


Ibuprofen plus metaxolone, tizanidine, or baclofen for LBP. A randomized trial Version 
03272017
3
Overview.
This will be a double-blind, comparative effectiveness study, in which we enroll patients during an ED 
visit for musculoskeletal LBP and follow them by telephone two and seven days and three months 
later. Every patient will receive standard-of-care therapy, consisting of ibuprofen and a low back pain 
education session. Patients will be randomized to metaxolone, tizanidine, baclofen, or placebo.
Subject selection. 
Our goal is to include in this study a broad representation of patients with musculoskeletal back pain 
who are likely to respond to the investigational medications and who would not be considered 
candidates for spinal surgery or targeted epidural intervention. We hope for a widely generalizable 
study and therefore will not require diagnoses to be contingent on advanced imaging studies. The 
presence or absence of palpable spasm of the paraspinal muscles will be recorded but not used as an 
entry criterion because the clinical significance and reliability of this finding is uncertain.(8)
Inclusion criteria:
-Present to ED primary for management of LBP, defined as pain originating between the lower border 
of the scapulae and the upper gluteal folds. Flank pain, that is pain originating from tissues lateral to 
the paraspinal muscles, will not be included.
- Musculoskeletal etiology of low back. Patients with non-musculoskeletal etiologies such as urinary 
tract infection, ovarian cysts, or influenza like illness will be excluded. The primary clinical diagnosis, 
at the conclusion of the ED visit, must be a diagnosis consistent with non-traumatic, non-radicular, 
musculoskeletal LBP.
-Patient is to be discharged home. Patients admitted to the hospital are more likely to be treated with 
parenteral medication and therefore are not appropriate for this study.
- Age 18-64 Enrollment will be limited to adults younger than 65 years because of the increased risk of 
adverse medication effects in the elderly.
-Non-radicular pain. Patients will be excluded if the pain radiates below the gluteal folds in a radicular 
pattern. 
-Pain duration <2 weeks (336 hours). Patients with more than two weeks of pain are at increased risk 
of poor pain and functional outcomes.(9)
-Prior to the acute attack of LBP, back pain cannot occur more frequently than once per month. 
Patients with more frequent back pain are at increased risk of poor pain and functional outcomes.(9) 
-Non-traumatic LBP: no substantial and direct trauma to the back within the previous month
-Functionally impairing back pain: A baseline score of > 5 on the Roland-Morris Disability 
Questionnaire (Appendix)
Exclusion criteria:
-Not available for follow-up
-Pregnant or breast-feeding
-Chronic pain syndrome defined as use of any analgesic medication on a daily or near-daily basis
-Allergic to or intolerant of investigational medications
-Contra-indications to non-steroidal anti-inflammatory drugs: 1) history of hypersensitivity to NSAIDs 
or aspirin 2) active or history of peptic ulcer disease, chronic dyspepsia, or active or history of 
gastrointestinal bleed 3) Severe heart failure (NYHA 2 or worse) 4) uncontrolled blood pressure 
(>160/100) 5) GFR <60ml/min 6) Current use of anti-coagulants 7) cirrhosis or liver enzymes 2xULN 
IRB NUMBER: 2017-7566
IRB APPROVAL DATE: 03/29/2017


Ibuprofen plus metaxolone, tizanidine, or baclofen for LBP. A randomized trial Version 
03272017
4
8) Alcoholism 9) MI/ stroke/ unstable angina within the previous 3 months 10) high dose diuretics or 
ace inhibitors
-Contra-indications to muscle relaxants: 1) Concurrent use of centrally acting opioids; 2) GFR <60 
ml.min; 3) Abnormal LFTs 4) Use of any of the following medications: fluvoxamine, 
flouroquinolones, amiodarone, mexiletine, propafenone, verapamil, cimetidine, famotidine, acyclovir, 
ticlopidine, oral contraceptive pills
Study arms.
A. The metaxolone arm: Ibuprofen 600mg+ metaxolone 400-800mg, orally, every 8 hours
B. The tizanidine arm: Ibuprofen 600mg+ tizanidine 2-4mg, orally, every 8 hours
C. The baclofen arm: Ibuprofen 600mg+ baclofen 10- 20mg, orally, every 8 hours
D. The control arm: Ibuprofen 600mg + placebo, orally, every 8 hours
In an effort to maximize effectiveness while minimizing side effects, patients will be instructed to take 
one ibuprofen plus one or two muscle relaxant pills every 8 hours. If one tablet of the muscle relaxant 
affords sufficient relief then there will be no need for the patient to take the second muscle relaxant 
tablet. However, if the patient has not experienced sufficient relief within 60 minutes of taking one 
investigational medication tablet, they will be instructed to take the second tablet. All study patients 
will be given a seven day supply of ibuprofen and the muscle relaxant. 
Outcome measures
1. Roland Morris LBP Disability Questionnaire (RMDQ)--Reproduced in the Appendix. This 24-item 
LBP functional scale is recommended for use in LBP research.(10) Its yes/ no format is amenable to 
telephone follow-up. We have used it successfully to obtain post-ED follow-up in five previous LBP 
studies involving more than 1500 patients.
2. Ordinal pain scale (“severe”, “moderate”, “mild”, or “none”). Study participants will be asked to 
describe their worst back pain in the previous 24 hours.
3. Medication requirements: “What medications did you use to treat your low back pain in the previous 
24 hours?” 
4. Low back pain frequency: “Over the last 24 hours, how often were you in pain?  Not at all, Rarely, 
Sometimes, Usually, Always”.  Low back pain symptomatology is quite variable. Some patients may 
experience no pain unless they move a certain way. Others may experience a constant low level of 
pain. This question will help determine the burdensomeness of the LBP in the patient’s daily life.
5. Satisfaction, as measured by response to this question: The next time you go to the ER with low 
back pain, do you want to get the same combination of medications?
Baseline measures
1. Roland Morris LBP disability questionnaire
2. Patient Health Questionnaire depression module will be assessed at the baseline visit.
3. Perceived risk of not recovering. Pain outcomes may be influenced by expectations. After providing 
an educational intervention, we will ask study participants to estimate how long they believe they will 
continue to suffer from pain.
4. StarT Back LBP questionnaire
Primary outcome
IRB NUMBER: 2017-7566
IRB APPROVAL DATE: 03/29/2017


Ibuprofen plus metaxolone, tizanidine, or baclofen for LBP. A randomized trial Version 
03272017
5
The change in Roland Morris scale between the baseline ED visit and the one week follow-up (Roland-
Morris baseline - Roland-Morris 1week ). The baseline questions will refer to the time period immediately 
prior to ED presentation (Before you came to the ER today, were you able to…..)..
Secondary outcomes
   The following outcomes will be assessed 48 hours and one week after ED discharge
1. Day post ED discharge able to return to all usual activities
2. Satisfaction with treatment
3. Number of visits to any healthcare provider.
4. Worst LBP over the previous 24 hours, using a four point ordinal scale: severe, moderate, mild, or 
none and a 0 – 10 verbal integer scale
5. Use of any analgesic or LBP medication within the previous 24 hours.
6. Frequency of low back pain using the five point Likert scale: Not at all, Rarely, Sometimes, Usually, 
Always
7.Absolute RMDQ score
8. Frequency of adverse events including 
-CNS side effects (drowsiness and dizziness)
-GI side effects (dyspepsia, nausea, and bleeding)
-CV side effects (chest pain, shortness of breath, edema)
-renal side effects (fluid retention, development of hypertension as defined by JNC-7 or 
worsening of blood pressure)
-All other side effects
The following will be assessed 3 months after ED discharge
9. Roland Morris Disability Questionnaire
10. Worst LBP over the previous week, using a four point ordinal scale: severe, moderate, mild, or 
none and a 0 – 10 verbal integer scale
11.  Frequency of low back pain over the previous week using the five point Likert scale: Not at all, 
Rarely, Sometimes, Usually, Always
12. Number of days with LBP since ED discharge
13. Use of any analgesic or LBP medication within the previous 7 days.
14. Number of visits to any healthcare provider.
15. Satisfaction with medication and with the current state of the LBP
Randomization and blinding
The pharmacist will perform randomization in blocks of 8 based on a sequence generated at 
http://randomization.com.  Ibuprofen will not be masked. Metaxolone, tizanidine, baclofen, and 
placebo will be masked by placing tablets into identical capsules, which will be packed with scant 
amounts of lactose and sealed. This masking will take place in a secure location inaccessible to ED 
personnel. Patients will be presented with two bottles of medication tablets. The bottle containing the 
ibuprofen will be labeled in a typical manner. The second vial, containing the muscle relaxant or 
placebo will be labeled as investigational medication. Patients will be instructed to take the 
investigational medication only as needed for moderate or severe LBP.
Details of protocol
IRB NUMBER: 2017-7566
IRB APPROVAL DATE: 03/29/2017


Ibuprofen plus metaxolone, tizanidine, or baclofen for LBP. A randomized trial Version 
03272017
6
Prior to discharge from the ED and after the patient’s pain has been controlled, the attending 
emergency physician will refer appropriate patients to study personnel for screening. Eligible patients 
would have already received different and various medications in the ED for their pain 
(potentially including NSAIDs) prior to being approached for study participation. Patients will be 
screened and consented. Research associates will ascertain baseline socio-demographic information, 
low back pain history, and baseline variables discussed above. A urine pregnancy test will be 
performed. Research personnel will provide each patient with a 15-minute educational intervention. 
This will be based on NIAMS’s Handout on Health: Back Pain information webpage (available at 
http://www.niams.nih.gov/Health_Info/Back_Pain/default.asp) Research personnel will review each 
section of the information sheet with the patient and elicit questions. Patients will be discharged with 
two medication vials, one containing ibuprofen and one containing metaxolone, tizanidine, baclofen, or 
placebo. Patients will be cautioned not to take off protocol LBP medications without first consulting 
with a healthcare provider. Patients will be cautioned not to drink alcohol or use other centrally-acting 
substances while using study medications. Patients will be cautioned not to drive after taking the study 
medications. Patients will be instructed to dispose of unused medication by mixing with an unpalatable 
substance such as coffee grounds and sealing in a plastic bag. Patients will be encouraged to follow-up 
with their primary care physician. Follow-up phone calls will be conducted 48 hours, one week, and 
three months after ED discharge. Follow-up will be attempted daily until successful. For patients 
difficult to contact, express courier or home visit will be used to obtain follow-up information.
Analysis. An intention-to-treat analysis will be performed among all patients for whom primary 
outcome data is available. The primary outcome will be a comparison of the change in RMDQ 
between baseline and one week. Results will be reported as means with 95%CI. A t-test for 
independent samples will be used to determine statistically significant differences between placebo and 
each of the active medications. Secondary outcomes will be reported as rates with 95%CI. A per 
protocol efficacy analysis will be conducted among those patients who use the investigational 
medication at least once.
Sample size calculation
We based assumptions on a recently completed RCT of LBP treatment.(1) The mean improvement in 
RMDQ among those who receive an NSAID alone was 10.2. The standard deviation was 8.9. A widely 
accepted minimum clinically important improvement of 5 points on the RMDQ would require those 
randomized to active medication to demonstrate a mean improvement of 15.2 on the RMDQ. Using a 
standard alpha of 0.05 and a beta of 0.20, we determined the need for 50 subjects in each arm. To 
account for protocol violations and patients lost-to-follow-up (typical lost-to-follow-up rate is 5%) and 
to ensure sufficient power for the per protocol analysis (in our previous ED-based LBP studies, up to 
1/3 of enrolled patients have not used the medication more than once), we intend to enroll 80 patients 
in each arm (total n= 320)
Data Safety Monitoring Committee. This committee will be headed by Dr. Polly Bijur, PhD, an 
epidemiologist and include Dr. Esses, MD, the director of the Moses ED. The committee will meet 
every month with the PI to 1) monitor adverse events and develop strategies to minimize these; and, 2) 
monitor recruitment and enrollment. There will not be an interim analysis.
Registration. The study will be registered at http://www.clinicaltrials.gov.
Consent. Study personnel will obtain informed consent once the patient’s pain has been controlled and 
the patient is ready for discharge from the ED. The attending physician will assess the patient’s 
IRB NUMBER: 2017-7566
IRB APPROVAL DATE: 03/29/2017


Ibuprofen plus metaxolone, tizanidine, or baclofen for LBP. A randomized trial Version 
03272017
7
capacity to consent to participate in this study. Because pain may compromise cognition and judgment, 
the principal investigator or his designee will assess the capacity of the patient to provide ethically and 
legally adequate informed consent and will document this in the research record.
Risks/Benefits
Non-steroidals are used in 50% of more than 2.5 million annual US ED visits for LBP. Skeletal muscle 
relaxants are used in 43% of these visits. Regardless of results, this study will have a national impact. 
All study subjects receive ibuprofen and thus are likely to benefit. In addition, those who receive active 
drug may have greater benefit as they will receive a medication that will possibly improve their acute 
LBP. In addition to breach of confidentiality, which is unlikely, and inconvenience to the subject, 
which will undoubtedly occur, some subjects will possibly experience adverse medication effects. For 
the most part, these are minor events. Skeletal muscle relaxants such as tizanidine, metaxalone and 
baclofen are generally well tolerated but can cause substantial drowsiness and when combined with 
alcohol or other centrally acting substances may be lethal. Non-steroidals can cause life-threating 
gastro-intestinal bleeding, but this is unlikely in patients screened for gastro-intestinal illness who will 
take the medication for one week only. Non-steroidals increase cardiovascular and and risk of renal 
injury and may worsen blood pressure control
Data Storage & Confidentiality
Data will be stored and maintained in REDCap. Data analysis will occur on password-protected 
computers. Consent documents will be maintained in locked research cabinets. Only study personnel 
will have access to the data and consent documents.
IRB NUMBER: 2017-7566
IRB APPROVAL DATE: 03/29/2017


Ibuprofen plus metaxolone, tizanidine, or baclofen for LBP. A randomized trial Version 
03272017
8
References
1.
Friedman BW, Dym AA, Davitt M, Holden L, Solorzano C, Esses D, et al. Naproxen With 
Cyclobenzaprine, Oxycodone/Acetaminophen, or Placebo for Treating Acute Low Back 
Pain: A Randomized Clinical Trial. JAMA. 2015;314(15):1572-80.
2.
Friedman BW, Irizarry E, C. S, Khankel N, Zapata J, Zias E, et al. Diazepam is no better than 
placebo when added to naproxen for acute low back pain. Annals of emergency medicine. 
2017.
3.
Dapas F, Hartman SF, Martinez L, Northrup BE, Nussdorf RT, Silberman HM, et al. Baclofen 
for the treatment of acute low-back syndrome. A double-blind comparison with placebo. 
Spine (Phila Pa 1976). 1985;10(4):345-9.
4.
Berry H, Hutchinson DR. A multicentre placebo-controlled study in general practice to 
evaluate the efficacy and safety of tizanidine in acute low-back pain. J Int Med Res. 
1988;16(2):75-82.
5.
Berry H, Hutchinson DR. Tizanidine and ibuprofen in acute low-back pain: results of a 
double-blind multicentre study in general practice. The Journal of international medical 
research. 1988;16(2):83-91.
6.
Dent RW, Jr., Ervin DK. A study of metaxalone (Skelaxin) vs. placebo in acute 
musculoskeletal disorders: a cooperative study. Curr Ther Res Clin Exp. 1975;18(3):433-
40.
7.
Fathie K. A Second Look at a Skeletal Muscle Relaxant: A Double-Blind Study of 
Metaxalone. Curr Ther Res Clin Exp. 1964;6:677-83.
8.
Simons DG, Mense S. Understanding and measurement of muscle tone as related to 
clinical muscle pain. Pain. 1998;75(1):1-17.
9.
Friedman BW, O'Mahony S, Mulvey L, Davitt M, Choi H, Xia S, et al. One-week and 3-month 
outcomes after an emergency department visit for undifferentiated musculoskeletal low 
back pain. Annals of emergency medicine. 2012;59(2):128-33 e3.
10.
Deyo RA, Battie M, Beurskens AJ, Bombardier C, Croft P, Koes B, et al. Outcome measures 
for low back pain research. A proposal for standardized use. Spine. 1998;23(18):2003-13.
IRB NUMBER: 2017-7566
IRB APPROVAL DATE: 03/29/2017


Ibuprofen plus metaxolone, tizanidine, or baclofen for LBP. A randomized trial Version 
03272017
9
Appendix 1. Roland Morris low back pain disability questionnaire
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Over the last 24 hours, I have stayed home most of the time because of my back pain:
Over the last 24 hours, I changed position frequently to try to get my back comfortable:
Over the last 24 hours, I walked more slowly than usual because of my back:
Over the last 24 hours, I have not been doing any jobs that I usually do around the house 
because of my back pain:
Over the last 24 hours, I used a handrail to get upstairs because of my back pain:
Over the last 24 hours, I lay down to rest more often because of my back pain:
Over the last 24 hours, I have had to hold on to something to get out of an easy chair 
because of my back pain
Over the last 24 hours, I have tried to get other people to do things for me because of my 
back pain:
Over the last 24 hours, I got dressed more slowly than usual because of my back pain:
Over the last 24 hours, I only stood up for short periods of time because of my back pain:
Over the last 24 hours, I tried not to bend or kneel down because of my back pain:    
Over the last 24 hours, I found it difficult to get out of a chair because of my back pain:    
Over the last 24 hours, my back was painful almost all of the time:    
Over the last 24 hours, I found it difficult to turn over in bed because of my back pain:    
Over the last 24 hours, my appetite was not very good because of my back pain:    
Over the last 24 hours, I have had trouble putting on my socks ( or stockings) because of 
the pain in my back or leg:
Over the last 24 hours,  I could only walk short distances because of my back pain:
Over the last 24 hours, I slept less well because of my back:    
Over the last 24 hours, I got dressed with the help of someone else because of my back 
pain:   
Over the last 24 hours, I sat down for most of the day because of my back:   
Over the last 24 hours, I avoided heavy jobs around the house because of my back pain:    
Over the last 24 hours, I was more irritable and bad tempered with people than usual 
because of my back pain,
Over the last 24 hours, I went upstairs more slowly than usual  because of my back pain
Over the last 24 hours, I stayed in bed most of the time because of my back pain:    
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
No0     Yes1
IRB NUMBER: 2017-7566
IRB APPROVAL DATE: 03/29/2017