Clinical trial NCT02665286
Conditions: Low Back Pain
Sponsor: Montefiore Medical Center
Start date: 2016-03-01; Completion date: 2017-05-01
Enrollment: 240 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Low back pain is a common cause of visit to emergency department. It is not clear if skeletal muscle relaxants are of benefit for patients with acute low back pain. This is a randomized study to determine if skeletal muscle relaxants, when combined with naproxen, improve outcomes more than naproxen alone

Detailed description:
Patients with acute, non-traumatic, non-radicular low back pain will be enrolled at the time of discharge from the emergency department. Participants will be followed by telephone one week and 3 months after the ED visit

Arms: arm 1: Naproxen 500mg tablets taken twice per day + placebo. Placebo dose will be either 1 capsule orally twice per day or 1 or 2 capsules orally, thrice per day Naproxen 500mg po BID x 10 days #20 + Placebo arm 2: Naproxen 500mg, orally twice per day + orphenadrine 100mg, orally twice per day for 10 days Naproxen 500mg po BID x 10 days #20 + Orphenadrine arm 3: Naproxen 500mg tablets, orally twice per day + methocarbamol 750mg, orally as 1 or 2 tabs, thrice per day Naproxen 500mg po BID x 10 days #20 + Methocarbamol
Interventions: intervention 1: Orphenadrine intervention 2: Methocarbamol intervention 3: Naproxen intervention 4: Placebo
Intervention descriptions: intervention 1: Orphenadrine 100mg PO BID x 7 days intervention 2: Methocarbamol 750mg 1-2 tabs po TID x 7 days intervention 3: Naproxen 500mg PO BID x 7 days intervention 4: 1/2 of placebo packages will be dosed to match methocarbamol: 1-2 tabs po TID x 7days 1/2 of placebo packages will be dosed to match orphenadrine: 1 tab PO BID x 7 days

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
Methocarbamol and Orphenadrine for  
Acute, Non-traumatic, Non-radicular Low Back Pain:  
A Randomized, Placebo Controlled, 3-armed Study 
 
 
 
 
 
 
 
 
 
NCT#: NCT02665286 
Protocol ID: 2015-5903 
Version Date: 01/27/2016 
 
 
 
 
 
 
 
Benjamin W. Friedman, MD 
Professor and Vice-Chair for Clinical Investigations 
Department of Emergency Medicine 
Montefiore Medical Center 
Albert Einstein College of Medicine 
 
 
 
 
 


 
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Specific Aims 
 
Low back pain (LBP) causes 2.4% of visits to US emergency departments (ED) resulting in 2.7 million 
visits annually. (1) In general, outcomes for these patients are unfavorable. One week after ED 
discharge, 70% of patients report persistent back-pain related functional impairment and 69% report 
analgesic use within the previous 24 hours.(2) Three months after the emergency visit, 48% of ED 
LBP patients report functional impairment, 42% report moderate or severe pain, and 46% report 
persistent analgesic use. (2) 
 
It is not clear which medications should be prescribed for acute LBP. Non-steroidal anti-inflammatory 
drugs (NSAID) are more efficacious than placebo with regard to LBP relief, global improvement, and 
requirement of analgesic medication (3) but are insufficient treatment for as many as ½ of ED patients, 
who continue to suffer despite use of NSAIDs. Treatment of LBP with multiple concurrent 
medications is common in the ED--emergency physicians often prescribe skeletal muscle relaxants or 
opioids in combination with NSAIDs.(4) However, work recently completed has revealed that 
combining cyclobenzaprine, a skeletal muscle relaxant, or oxycodone/acetaminophen with an NSAID 
does not improve outcomes.(5) It remains uncertain if adding other skeletal muscle relaxants to 
NSAIDs improves LBP outcomes. 
 
Two specific skeletal muscle relaxants, orphenadrine and methocarbamol, are each used in more than 
250,000 U.S. ED visits for LBP annually, although scant evidence exists to determine the 
appropriateness of this approach.(6) Orphenadrine is centrally acting with prominent anti-cholinergic 
and anti-histaminic properties. Mechanism of action is not understood. Efficacy in low back pain may 
be related to non-specific analgesic properties. Mechanism of action of methocarbamol has also not 
been established. Its efficacy is thought to be related to CNS effects rather than direct effects on 
skeletal muscles. 
 
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 either orphenadrine or methocarbamol with an 
NSAID is more effective than NSAID monotherapy for the treatment of acute, non-traumatic, non-
radicular low back pain. Specifically, we will evaluate the following two hypotheses: 
 
1) A daily regimen of naproxen + orphenadrine will provide greater relief of LBP than naproxen + 
placebo one week after an ED visit, as measured by the Roland Morris Disability Questionnaire 
2) A daily regimen of naproxen + methocarbamol will provide greater relief of LBP than 
naproxen + placebo one week after an ED visit, as measured by the Roland Morris Disability 
Questionnaire 
 
 
 
 


 
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Overview. 
This will be a single center, double-blind, comparative effectiveness study, in which we enroll patients 
during an ED visit for musculoskeletal LBP and follow them by telephone seven days and three 
months later. Every patient will receive standard-of-care therapy, consisting of naproxen and a low 
back pain education session. Patients will be randomized to orphenadrine, methocarbamol, 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. Though 
we could ensure a more homogeneous study population by requiring imaging, we do not believe this is 
clinically useful and it will not facilitate dissemination and utilization of the study results. 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.(7) 
 
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. 
- Absence of non-musculoskeletal etiology of low back, such as urinary tract infection, ovarian cysts, 
or influenza like illness. 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 18-69 Enrollment will be limited to adults younger than 70 years because of the increased risk of 
adverse medication effects in the elderly. 
-Non-radicular pain: pain cannot radiate below the gluteal folds in a radicular pattern. Patients with 
non-radicular pain extending below the gluteal folds will not be excluded 
-Pain duration <2 weeks (336 hours). Patients with more than two weeks of pain are at increased risk 
of poor pain and functional outcomes.(2) 
-Prior to the acute attack of LBP, back pain cannot have occurred once per month or more frequently. 
Patients with more frequent back pain are at increased risk of poor pain and functional outcomes.(2)  
-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 or patients in whom NSAIDS or aspirin have induced allergic manifestations such as asthma, 
nasal polyps, rhinitis, or urticarial 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) hypertension 
(JNC7 stage 2 or worse) 5) Chronic kidney disease 3 or worse 6) Current use of anti-coagulants, 
bleeding with tooth brushing, easy bruisability 7) Hepatitis 8) Alcoholism 


 
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-Contra-indications to orphenadrine: 1) Glaucoma, Prostatic hypertrophy, Myasthenia gravis, Pyloric 
or duodenal obstruction 
-Contra-indications to methocarbamol: 1) Myasthenia gravis, Chronic kidney disease 3 or worse 
 
 
Study arms: 
A. The orphenadrine arm: Naproxen 500mg, orally twice per day + orphenadrine 100mg, orally 
twice per day 
B. The methocarbamol arm: Naproxen 500mg tablets, orally twice per day + methocarbamol 
750mg, orally as 1 or 2 tabs, thrice per day 
C. The control arm: Naproxen 500mg tablets taken twice per day + placebo. Placebo dose will be 
either 1 capsule orally twice per day or 1 or 2 capsules orally, thrice per day 
 
In an effort to maximize effectiveness while minimizing side effects, patients will be instructed to take 
one or two pills of the methocarbamol every 8 hours. If one tablet of the methocarbamol affords 
sufficient relief then there will be no need for the patient to take the second tablet. However, if the 
patient has not experienced sufficient relief within 30 minutes of taking one investigational medication 
tablet, they will be instructed to take the second tablet. Orphenadrine is only manufactured in 100mg 
extended release tablets and is therefore not amenable to flexible dosing. All study patients will be 
given 14 naproxen tablets, a seven day supply, and a sufficient number of investigational tablets to last 
7 days. Optimal dosing of methocarbamol has not been established. We believe the dosing regimen we 
chose is sufficient to determine efficacy while not exposing patients to unnecessary risk.(8-10) 
 
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.(11) 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: “Did you require any medication 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, the PHQ 9, will be assessed at the baseline visit. 
3. 5-item Cassandra questionnaire. These five questions, based on psychological variables, predict poor 
outcomes in an emergency room population.(12) (Reproduced in the Appendix) 
4. 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. 


 
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5. StarT Back LBP questionnaire 
 
Primary outcome 
 
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 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 
 
The following outcomes will be assessed three months after ED discharge 
1. Roland Morris Disability Questionnaire 
2. Worst LBP over the previous week, using a four point ordinal scale: severe, moderate, mild, or none 
and a 0 – 10 verbal integer scale 
3.  Frequency of low back pain over the previous week using the five point Likert scale: Not at all, 
Rarely, Sometimes, Usually, Always 
4. Number of days with LBP since ED discharge 
5. Use of any analgesic or LBP medication within the previous 7 days. 
6. Number of visits to any healthcare provider. 
7. Satisfaction with medication and with the current state of the LBP 
 
Adverse events 
The following adverse medication effects will be assessed at the one week follow-up. 
 
-CNS side effects including drowsiness and dizziness 
 
-GI side effects including dyspepsia, nausea, and bleeding 
 
-All other side effects 
 
 
Randomization and blinding 
The pharmacist will perform randomization in blocks of 6 based on a sequence generated at 
http://randomization.com. Every block of six will contain two orphenadrine assignments, two 
methocarbamol assignments, one placebo assignment dosed as 1 capsule twice daily (to mirror 
orphenadrine dosing), and one placebo assignment dosed as 1-2 capsules thrice daily (to mirror 
methocarbamol dosing). Therefore, though patients will not know whether they have been assigned to 
active medication or placebo, they may deduce to which medication they were not assigned. This does 
not threaten the internal validity of the study because patients will not know whether or not they 
received active medication.  
 


 
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Naproxen will not be masked. Orphenadrine, methocarbamol, 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 vials of medication. The vial containing the naproxen will be labeled in a typical manner. The 
second vial, containing orphenadrine, methocarbamol, or placebo will be labeled as investigational 
medication. Patients will be instructed to the investigational medication only as needed for moderate or 
severe LBP. 
 
Details of protocol 
 
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 naproxen) prior to being approached for study participation. This decision is up 
to the attending physician and is not related to participation in the study. 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 medical vials, one containing naproxen and one containing placebo, orphenadrine, or 
methocarbamol. 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. Follow-up phone calls will be conducted 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. 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. The mean improvement in 
RMDQ among those who receive naproxen 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. 
 
Data Safety Monitoring Committee. This committee will be headed by Dr. XXX and include XXX. 
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. 


 
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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. 
 
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. 
Study subjects will benefit by receiving a medication that is likely to improve their acute LBP. In 
addition to breach of confidentiality, which is unlikely, and inconvenience to the subject, which will 
undoubtedly occur, it is likely that subjects will experience adverse medication effects. For the most 
part, these are nuisance events. Skeletal muscle relaxants such as orphenadrine and methocarbamol 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. 
 
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. 
 
 
 
 


 
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References 
1. 
Friedman BW, Chilstrom M, Bijur PE, Gallagher EJ. Diagnostic testing and treatment of low 
back pain in United States emergency departments: a national perspective. Spine (Phila 
Pa 1976);35(24):E1406-11. 
2. 
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. 
3. 
Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW. Nonsteroidal anti-
inflammatory drugs for low back pain: an updated Cochrane review. Spine. 
2008;33(16):1766-74. 
4. 
Friedman BW, Chilstrom M, Bijur PE, Gallagher EJ. Diagnostic testing and treatment of low 
back pain in United States emergency departments: a national perspective. Spine. 
2010;35(24):E1406-11. 
5. 
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. 
6. 
Chou R, Peterson K. Drug Class Review: Skeletal Muscle Relaxants: Final Report. Portland 
(OR); 2005. 
7. 
Simons DG, Mense S. Understanding and measurement of muscle tone as related to 
clinical muscle pain. Pain. 1998;75(1):1-17. 
8. 
Middleton RS. A comparison of two analgesic muscle relaxant combinations in acute back 
pain. Br J Clin Pract. 1984;38(3):107-9. 
9. 
Sica DA, Comstock TJ, Davis J, Manning L, Powell R, Melikian A, et al. Pharmacokinetics 
and protein binding of methocarbamol in renal insufficiency and normals. Eur J Clin 
Pharmacol. 1990;39(2):193-4. 
10. 
Tisdale SA, Jr., Ervin DK. A controlled study of methocarbamol (Robaxin) in acute painful 
musculoskeletal conditions. Curr Ther Res Clin Exp. 1975;17(6):525-30. 
11. 
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. 
12. 
Dionne CE, Le Sage N, Franche RL, Dorval M, Bombardier C, Deyo RA. Five questions 
predicted long-term, severe, back-related functional limitations: evidence from three 
large prospective studies. Journal of clinical epidemiology. 2011;64(1):54-66. 
 
 
 
 


 
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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 
 
 
 
 


 
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Appendix 2. Cassandra questions 
 
Five item Cassandra Instrument 
 
In the past month, how often were you distressed by: 
 
   1. Feeling everything is an effort 
 
Not at all 0    A little bit1    Moderately2    Quite a bit3   Extremely4   Don’t know 
 
   2.  Trouble getting your breath 
 
Not at all 0    A little bit1    Moderately2    Quite a bit3   Extremely4   Don’t know 
 
   3. Hot or cold spells 
 
Not at all 0    A little bit1    Moderately2    Quite a bit3   Extremely4   Don’t know 
 
   4. Numbness or tingling in parts of your body 
 
Not at all 0    A little bit1    Moderately2    Quite a bit3   Extremely4   Don’t know 
 
   5. Pain in your heart or chest 
 
Not at all 0    A little bit1    Moderately2    Quite a bit3   Extremely4   Don’t know