Is oral orphenadrine beneficial for acute low back pain?

Journal reference:Friedman BW, Cisewski D, Irizarry E, et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Naproxen With or Without Orphenadrine or Methocarbamol for Acute Low Back Pain. Ann Emerg Med 2018 Mar;71(3):348-56 e5

Link: https://dx.doi.org/10.1016/j.annemergmed.2017.09.031

Published: March 2018

Evidence cookie says…

Orphenadrine provides no benefit when used in addition to naproxen for acute low back pain  the point estimate is close to zero, with the imprecision of the estimate well within the minimal clinically significant difference it should not be used routinely in the management of acute low back pain

The article was published in the August 2018 issue of Medical Observer, under the title “Mulling muscle relaxants”.

Clinical scenario

Harry, a 55-year-old hospital cleaner saw me with acute low back pain after lifting a heavy linen bag.  I recalled reading that skeletal muscle relaxants might be helpful in acute low back pain.  Another of my patients had been prescribed orphenadrine citrate (Norflex™), one of the few non-benzodiazepine muscle relaxants available in Australia, in the emergency department (ED) for the same indication.  I wondered if this a good option for Harry?  What is the evidence?

Clinical question

What is the effect of oral orphenadrine citrate on acute low back pain recovery?

What does the research evidence say?

Step 1: The Cochrane Library

A rather old (published in 2003) Cochrane systematic review exists for the question of “muscle relaxants” for low back pain [1].  Although this review suggested that non-benzodiazepines may be effective, most of the included trials used other agents, and the few that used orphenadrine were decades old and problematic.

Step 2: TripDatabase

I conducted a search using the TripDatabase PICO search tool (Participant: “low back pain”, Intervention: “orphenadrine”, Comparator: “placebo”, Outcomes: blank).  The TRIP search engine identified a new key randomised trial from 2017 as the first hit [2].  This trial compared orphenadrine, and another muscle relaxant, added to an NSAID compared to the NSAID alone.  I did a quick search through PubMed, and this appeared to be the most appropriate piece of evidence to review.  Let’s look at Friedman et al. (2017) published in the Annals of Emergency Medicine in more detail.

Critical appraisal

I will use the randomised controlled trial appraisal sheet from the Centre for Evidence Based Medicine [3].

PICO

Participants: who was studied?

240 adults (aged 18-69 years), recruited from two academic EDs in New York, USA, presenting with acute low back pain (the patient was required to have received a diagnosis consistent with non-traumatic, non-radicular, musculoskeletal low back pain, and was to be discharged home).

Important exclusions: radicular pain below the gluteal folds, pain duration greater than 2 weeks, a baseline back pain frequency of at least once a month, direct trauma to the back within the previous month, pregnancy, breastfeeding, use of any analgesic medication daily, or near daily.

The mean age was 39-years-old, 55% were male, median duration of low back pain of 2-3 days.

Intervention: what was the exposure?

orphenadrine group: naproxen 500 mg bd + orphenadrine 100 mg bd × 7 days

methocarbamol group: naproxen 500 mg bd + methocarbamol 750 mg 1-2 tabs tds PRN × 7 days

Comparator: what was the control/alternative?

placebo group 1: naproxen 500 mg bd + placebo 1 cap bd

placebo group 2: naproxen 500 mg bd + placebo 1-2 cap tds PRN

Outcomes: what was measured?

Primary outcome: improvement in low back pain at 1 week, and 3 months after an ED visit, as measured by the Roland-Morris Disability Questionnaire (RMDQ) – note: this is a validated 24-item low back pain functional scale (0 = no low back pain-related functional impairment, and 24 = maximum impairment).

Internal validity: are the trial results valid?

Randomised patient assignment?

Yes.  A research pharmacist performed the randomisation.

Groups similar at the start?

Yes.  The groups were very similar (see Table 1 from the paper) [2].

Groups treated equally apart from assigned treatment?

Yes.  Though both clinician and patient would have been able to guess whether there were in the placebo vs orphenadrine, or placebo vs methocarbamol arms.  It is reasonable to assume that this did not have an important effect on the outcome.

All patients accounted for?

Yes.  Relatively few participants who dropped out and the analysis was conducted on an intention-to-treat basis.

Measures objective?  Or patients and clinicians kept blinded?

Yes.  The authors undertook an assessment of blinding, and this it seems that participants were successfully kept blinded (Table E4 in the appendix of this paper) [2].

What were the results?

Primary outcomes – the difference in low back pain-related impairment between the placebo group, and orphenadrine group at one-week were:

• 1.5 RMDQ points (95% CI -1.4 to 4.3) (result favouring placebo)
• Note: the “minimal clinically important difference” (see Stat Facts) for the RMDQ is estimated to be 4 or 5 points [4].

Discussion and conclusion

This was a well-conducted study effectiveness trial conducted in the American ED setting.  It is likely informative, and probably externally valid in Australian general practice.

Although the aforementioned Cochrane systematic review identified that non-benzodiazepine skeletal muscle relaxants (and potentially oral orphenadrine) may have a beneficial effect for acute low back pain when used alone compared to placebo therapy, it was not at all certain how these agents compared to other known effective pharmacotherapy for acute low back pain [1].

This study demonstrated no meaningful benefits to adding orphenadrine to naproxen.  The point estimate is close to zero, and the extent of the 95% confidence interval most favouring benefit is still well within the minimal clinically significant difference for RMDQ scores.  There was similarly no benefit from the other agent, methocarbamol, which is not available in Australia.

Currently acute low back pain guidelines recommend against the routine use of pharmacotherapy and notably, the median time to recovery with no medicines is approximately two-and-a-half weeks [5].  When pharmacotherapy is used, NSAIDs might be reasonable, though side-effects need to be considered [6].

For Harry, I gave him reassurance that he will recover, to try to stay active with usual activities, to use heat packs, and to avoid bedrest.  I did not recommend orphenadrine.

Stat Facts

Minimal clinically important difference

The minimal clinically important difference is a patient-centred concept that defines the “smallest amount an outcome must change to be meaningful to patients” [7].  When looking at study results, it is not enough that a difference between groups exist (statistically significant, or otherwise), but whether it is of sufficient magnitude to be important.

References

1. van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM. Muscle relaxants for non-specific low back pain. Cochrane database of systematic reviews 2003(2):CD004252.
2. Friedman BW, Cisewski D, Irizarry E, et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Naproxen With or Without Orphenadrine or Methocarbamol for Acute Low Back Pain. Ann Emerg Med 2018 Mar;71(3):348-56 e5.
3. Centre for Evidence-Based Medicine. Critical Appraisal tools.  2014  [cited 2015 2015 Dec 1]; Available from: http://www.cebm.net/critical-appraisal/
4. Maughan EF, Lewis JS. Outcome measures in chronic low back pain. Eur Spine J 2010 Sep;19(9):1484-94.
5. Williams CM, Maher CG, Latimer J, et al. Efficacy of paracetamol for acute low-back pain: a double-blind, randomised controlled trial. Lancet 2014 Nov 1;384(9954):1586-96.
6. Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW. Non-steroidal anti-inflammatory drugs for low back pain. Cochrane database of systematic reviews 2008(1):CD000396.
7. McGlothlin AE, Lewis RJ. Minimal clinically important difference: defining what really matters to patients. JAMA : the journal of the American Medical Association 2014 Oct 1;312(13):1342-3.