SPINE Volume 28, Number 17, pp 1978–19922003, Lippincott Williams & Wilkins, Inc.
Muscle Relaxants for Nonspecific Low Back Pain:
A Systematic Review Within the Framework of the
Cochrane Collaboration

Maurits W. van Tulder, PhD,*† Tony Touray, MD,* Andrea D. Furlan, MD,‡Sherra Solway, MSc, BSc (PT),‡ and Lex M. Bouter, PhD* Study Design. A systematic review of randomized
on acute low back pain. Four trials studied benzodiaz- and/or double-blinded controlled trials.
epines, 11 nonbenzodiazepines, and 2 antispasticity mus- Summary of Background Data. The use of muscle re-
cle relaxants in comparison with placebo. Results laxants in the management of nonspecific low back pain showedthat there is strong evidence that any of these is controversial. It is not clear if they are effective, and muscle relaxants are more effective than placebo for pa- concerns have been raised about the potential adverse tients with acute low back pain on short-term pain relief.
effects involved.
The pooled relative risk for nonbenzodiazepines versus Objectives. The aim of this review was to determine if
placebo after 2 to 4 days was 0.80 (95% confidence inter- muscle relaxants are effective in the treatment of nonspe- val: 0.71 to 0.89) for pain relief and 0.49 (95% confidence cific low back pain.
interval: 0.25 to 0.95) for global efficacy. Adverse events, Methods. A computer-assisted search of the Cochrane
however, with a relative risk of 1.50 (95% confidence in- Library (Issue 2, 2002), MEDLINE (1966 up to October terval: 1.14 to 1.98) were significantly more prevalent in 2001), and EMBASE (1988 up to October 2001) was car- patients receiving muscle relaxants and especially the ried out. These databases were searched using the algo- central nervous system adverse effects (relative risk 2.04; rithm recommended by the Cochrane Back Review 95% confidence interval: 1.23 to 3.37). The various muscle Group. References cited in the identified articles and relaxants were found to be similar in performance.
other relevant literature were screened. Randomized Conclusions. Muscle relaxants are effective in the
and/or double-blinded controlled trials, involving patients management of nonspecific low back pain, but the ad- diagnosed with nonspecific low back pain, treated with verse effects require that they be used with caution. Trials muscle relaxants as monotherapy or in combination with are needed that evaluate if muscle relaxants are more other therapeutic methods, were included for review.
effective than analgesics or nonsteroidal anti-inflamma- Two reviewers independently carried out the method- tory drugs. [Key words: systematic review, Cochrane Col- ologic quality assessment and data extraction of the tri- laboration, effectiveness, muscle relaxants, low back als. The analysis comprised not only a quantitative anal- pain] Spine 2003;28:1978 –1992
ysis (statistical pooling) but also a qualitative analysis("best evidence synthesis"). This involved the appraisalof the strength of evidence for various conclusions using Muscle relaxants are one of the many treatments cur- a rating system based on the quality and outcomes of thestudies included. Evidence was classified as "strong," rently employed in the management of nonspecific low "moderate," "limited," "conflicting," or "no" evidence.
back pain (LBP). Thirty-five percent of patients visiting a Results. Thirty trials met the inclusion criteria. Twenty-
primary care physician for LBP are prescribed muscle three trials (77%) were of high quality; 24 trials (80%) were relaxants.1 The term "muscle relaxants" is very broadand includes a wide range of drugs with different indica-tions and mechanisms of action. Muscle relaxants can bedivided into two main categories: antispasmodic and an-tispasticity medications.
From the *Institute for Research in Extramural Medicine and †Depart-ment of Clinical Epidemiology and Biostatistics, VU University Medi- Antispasmodics are used to decrease muscle spasm cal Center, Amsterdam, the Netherlands, and the ‡Institute for Work associated with painful conditions such as LBP. Anti- & Health, Toronto, Ontario, Canada.
spasmodics can be subclassified into benzodiazepines Andrea Furlan is supported by a CIHR fellowship and by the Univer-sity of Toronto, Centre for Study of Pain. Internal funding came from the Institute for Research in Extramural Medicine, VU University Med- Benzodiazepines (e.g., diazepam, tetrazepam) are ical Center, Amsterdam, the Netherlands and from the Institute for used as anxiolytics, sedatives, hypnotics, anticonvul- Work & Health, Toronto, Ontario, Canada.
Acknowledgment date: April 4, 2003. Acceptance date: April 25, 2003.
sants, and/or skeletal muscle relaxants.2 In general, there One of the authors (Lex Bouter) is co-ordinating editor of the Cochrane is no evidence that any one benzodiazepine is more ef- Back Review Group. Editors are required to conduct at least one Co- fective than another if adequate dosage is given; how- chrane review. This requirement ensures that editors are aware of theprocesses and commitment needed to conduct reviews. None of the ever, pharmacokinetic differences between the drugs may editors are first authors. This involvement does not seem to be a source be important considerations in prescription choice.
of conflict of interest in the Back Review Group. Any editor who is a Nonbenzodiazepines include a variety of drugs that reviewer is excluded from editorial decisions on the review in whichthey are contributors.
can act at the brain stem or spinal cord level.2 The mech- Address correspondence to Maurits van Tulder, PhD, VU University anisms of action with the central nervous system are still Medical Center, Institute for Research in Extramural Medicine not completely understood. Cyclobenzaprine is structur- (EMGO), Van der Boechorststraat 7, 1081 BT Amsterdam, the Neth-erlands; E-mail: [email protected] ally similar to the tricyclic antidepressants; however, it

Muscle Relaxants for Low Back Pain van Tulder et al 1979
has strong side effects such as sedation.3 It is currently cle relaxants even if they are conditionally discouraged believed that cyclobenzaprine acts in the brain stem rather than at the spinal cord level. Carisoprodol and The role of muscle spasm in the pathophysiology of metaxalone have moderate antispasmodic effects and are LBP is also controversial. Low back pain is generally mildly sedative. Carisoprodol blocks interneuronal ac- considered to be the result of a self-perpetuating cycle of tivity in the descending reticular formation and spinal pain and spasm. Some physicians have questioned this cord. Carisoprodol is metabolized to meprobamate.
model and thus, the efficacy of muscle relaxants.11 Oth- Meprobamate was introduced as an antianxiety agent in ers view muscle spasm as a protective physiologic re- 1955 and is prescribed primarily to treat anxiety, ten- sponse that should not be inhibited by muscle relax- sion, and associated muscle spasms. Its onset and dura- ants.12 Muscle spasm secondary to a pathologic lesion in tion of action are similar to the intermediate-acting bar- the lumbosacral region (e.g., facet joints, discs, muscles, biturates; however, therapeutic doses of meprobamate or ligaments) will immobilize the back and therefore produce less sedation and toxicity than barbiturates. Ex- contribute to the healing process.
cessive use can result in psychological and physical de- Controversies surrounding muscle relaxants have re- pendence. Chlorzoxazone acts at the spinal cord and sulted in some resistance to their use in patient care.
subcortical levels, inhibiting multisynaptic reflex arcs.
Studies have been published which suggest a potential The mechanism of action of methocarbamol in humans role for muscle relaxants in clinical practice13; however, has not been established, but may be due to central ner- there is a lack of good quality research on the clinical vous system depression. It has no direct action on the application of these drugs.14 contractile mechanism of striated muscle, the motor end-plate, or the nerve fiber. Cyclobenzaprine and or- phenadrine have anticholinergic activity (which is re- The aim of this systematic review was to determine if sponsible for some side effects such as dry mouth).
muscle relaxants are effective in the treatment of nonspe- Tolperisone has a lidocaine-like activity and stabilizes cific LBP. The following comparisons were investigated: nerve membranes. It blocks in a dose-dependent manner 1) Muscle relaxants versus placebo mono- and polysynaptic reflexes at the spinal level. Tol- 2) Muscle relaxants versus paracetamol/acetaminophen perisone is supposed to mediate muscle relaxation with-out concomitant sedation or withdrawal phenomena.4 3) Muscle relaxants versus NSAIDs Some antispasmodic drugs (e.g., Tizanidine) have 4) Muscle relaxants versus mscle relaxants showed in animal studies that in addition to muscle re- 5) Muscle relaxants ⫹ analgesics/NSAIDs versus pla- laxant and antinociceptive effect they have also gastro- cebo ⫹ analgesics/NSAIDs protective effects which may favor the combination ofantispasmodics with nonsteroidal anti-inflammatory Criteria for Considering Studies for This Review
Antispasticity medications are used to reduce spastic- ity that interferes with therapy or function, such as in Types of studies. Only randomized controlled trials (RCTs) cerebral palsy, multiple sclerosis, and spinal cord inju- and double-blind controlled clinical trials (CCTs) were ries.6 The mechanism of action of the antispasticity drugs with the peripheral nervous system (e.g., dantrolene so- Types of Participants. Only trials involving patients diag- dium) is the blockade of the sarcoplasmic reticulum cal- nosed with "nonspecific low back pain" were included. Non- cium channel. This reduces calcium concentration and specific LBP was defined as pain localized between the scapulas diminishes actin-myosin interaction. Baclofen is a and inferior gluteal folds that may or may not radiate down gamma aminobutyric acid (GABA) derivative with cen- towards the knees, for which specific etiologies such as infec- tral nervous system action. It inhibits transmission at tions, neoplasms, metastases, osteoporosis, fractures, rheuma- spinal level and also depresses the central nervous tological disorders, neurologic disorders, and other relevantpathologic entities have been ruled out clinically.
Trials involving patients with various musculoskeletal dis- The use of muscle relaxants for low back pain contin- orders were included if results were presented separately for the ues to be a source of controversy among physicians, subgroup of LBP patients or if more than 50% of the study mainly because of their side effects. In addition to seda- population consisted of LBP patients.
tion, potential adverse effects include drowsiness, head-ache, blurred vision, nausea, and vomiting. Potential for Types of Interventions. The use of muscle relaxants as abuse and dependency has also been reported.8 The con- monotherapy or in combination with other therapeutic meth-ods was included. The muscle relaxants that are included in this troversy is evident in the recommendations found in na- review are: benzodiazepines (diazepam and tetrazepam), non- tional clinical guidelines for the management of low back benzodiazepines antispasmodics (cyclobenzaprine, carisop- pain in primary care. Some guidelines recommend mus- rodol, chlorzoxazone, meprobamate, methocarbamol, metaxa- cle relaxants alone or in combination with NSAIDs as lone, orphenadrine, tizanidine and flupirtine), and optional, others clearly do not recommended using antispasticity drugs (baclofen and dantrolene sodium). We ex- them.9 Despite this, 91% of physicians report using mus- cluded the muscle relaxant chlormezanone (Trancopal) from

1980 Spine Volume 28 Number 17 2003
this review because this drug was discontinued worldwide in 4) Blinding of patients 1996 by its manufacturer due to confirmed serious and rare 5) Blinding of care provider cutaneous reactions (toxic epidermal necrolysis) associatedwith this drug.15 We also excluded botulinum toxin because it 6) Equal cointerventions is not usually classified as a muscle relaxant.
7) Adequate compliance 8) Identical timing of outcome assessment Types of Outcome Measures. Trials using one or more of the following outcome measures were included: 9) Blinded outcome assessment 10) Withdrawals and dropouts adequate Pain intensity (e.g., visual analogue scale [VAS] or numer- 11) Intention-to-treat analysis ical rating scale [NRS]) at rest or during the day Global measure (overall improvement, proportion of pa-tients recovered) assessed by the patient All items were scored as positive (⫹), negative (⫺), or un- Back pain specific functional status (e.g., Roland Disabil- clear (?). High quality was defined as fulfilling 6 or more of the ity Questionnaire, Oswestry Scale) 11 quality criteria. A sensitivity analysis in which the effect of Return to work (return-to-work status, number of days variations in the cutoff point distinguishing studies of high and low methodologic quality was conducted. We did not contact Physiologic outcomes (e.g., muscle spasm, range of mo- the authors for additional information because most studies tion, spinal flexibility, Lasegue test, or muscle strength) had been published many years ago with only 7 studies pub- Generic functional status (e.g., SF-36, Nottingham lished in or after 1990.
Health Profile, Sickness Impact Profile) Data Extraction. The data extraction was carried out by the
Search Strategy for Identification of Studies. A computer-
same reviewers who performed the quality assessment using a assisted search of the Cochrane Library (Issue 2, 2002), MED- standardized data extraction sheet. The studies were not LINE (up to October 2001), and EMBASE (up to October blinded for authors, institutions, or journals in which the stud- 2001) was carried out. These databases were searched using the ies were published. A pilot test was conducted using a trial on algorithm recommended in the Cochrane Collaboration Hand- NSAIDs for back pain that is not included in the present sys- book16 and the Back Review Group. Pertinent references cited tematic review.
in the identified articles were also screened as well as references The following data were extracted from the studies: of other systematic reviews.13,14,17 A language restriction ex-cluding studies not published in English, Dutch, German, Span- 1) Characteristics of the studies ish, or Portuguese was applied to the selection process because The sponsors of the study and their contributions as well as the authors were not able to read and understand any other languages. If possible, studies published in other languages will 2) Characteristics of study population be included in a future update of this review.
Data pertaining to the sample sizes and gender and age ofthe patients in the samples. The diagnosis of the patients was General Procedure of the Review. The review started with a
also noted. A distinction was made between acute/subacute literature search. Studies meeting the inclusion criteria were LBP (duration of symptoms less than 12 weeks) and chronic screened and analyzed for methodologic quality. This was fol- LBP (duration of symptoms 12 weeks or more). The pres- lowed by the extraction and analysis of the relevant data. The ence or absence of sciatica and muscle spasms was also selection of studies, methodologic quality assessment, and data extraction were carried out by two independent reviewers.
Nineteen studies that were originally identified in MEDLINE, 3) Characteristics of interventions EMBASE, and the Cochrane Library were independently as- The muscle relaxants investigated and the reference treat- sessed by one pair of reviewers (T.T. and M.vT.). Eleven stud- ments to which they were compared were noted. Specifi- ies4,5,18–26 identified through reference checking were included cally, the type of muscle relaxant (benzodiazepine, nonben- at a later stage and were independently assessed by another pair zodiazepine antispasmodics, or antispasticity drug), the of reviewers (M.vT. and S.S.; A.F. and S.S.). Results at each doses administered, and the frequency and duration of the stage were compared and discrepancies were resolved in a con- administration of the treatments were registered.
sensus meeting.
4) Characteristics of outcomes The outcome parameters used in the various trials and the Methodologic Quality Assessment. The methodologic
performance of the treatments as recorded on these param- quality of each RCT was assessed using the criteria recom- eters was extracted. The performance of the treatments was mended by the Cochrane Back Review Group.27 The studies regarded positive (in favor of intervention) if the difference were not blinded for authors, institutions, or the journals in from the control group was statistically significant (P ⬍ which the studies were published. A pilot test was conducted 0.05). For pain outcomes, we considered pain at rest (first) using a trial on NSAIDs for back pain that is not included in the and pain during the day (second). With regard to global present systematic review. Only the criteria pertaining to inter- improvement, if the authors reported both physician's and nal validity were applied: patient's opinion, we extracted only the patient's opinion. Ifthey reported only the physician's assessment, then we used 1) Adequate allocation concealment this data. We also assessed whether there was a clinically 2) Adequate method of randomization important difference of pain outcomes.28,29 We considered 3) Similarity of baseline characteristics a clinically important difference in VAS to be ⬎16 mm or

Muscle Relaxants for Low Back Pain van Tulder et al 1981
⬎30% decrease. For an 11-point NRS, this was 2 points or A total of 28 studies30–57 identified in electronic data- bases or through reference checking were excluded.
The following studies were identified in the compari- Data Analysis. A quantitative or meta-analysis was con-
sons investigated (some studies included more than one ducted if studies provided sufficient data. The results were tab- comparison, so the total is more than 30): ulated and formally tested for homogeneity. If data were sta-tistically heterogeneous, reasons for heterogeneity were 1) Muscle relaxants versus placebo explored. Data were pooled using the random effects model.
1a) Benzodiazepines versus placebo25,58–60 The results were plotted as relative risks (RR) with correspond-ing 95% confidence intervals (95% CI). All RRs were calcu- 1b) Nonbenzodiazepines versus placebo4,18,19,23,59,61–66 lated so that an RR smaller than 1 indicated a positive effect of 1c) Antispasticity versus placebo67,68 muscle relaxants. For example, an RR of 0.74 (95% CI 0.55– 2) Muscle relaxants versus paracetamol/aceta- 0.98) means that the chance of "not getting pain relief" is 26%less in the muscle relaxants group compared to the placebo minophen (no studies) group, with a CI of 2% to 45%. The data entered in the meta- 3) Muscle relaxants versus NSAIDs (no studies) analyses were adversive outcomes, that is, number of patients with "no pain relief," "no global improvement," "no improve- ment in muscle spasms," etc. The analyses were performedseparately for drug types (benzodiazepines, nonbenzodiaz- 5) Muscle relaxants ⫹ analgesics/NSAIDs versus pla- epines, and antispasticity drugs), for various outcome mea- cebo ⫹ analgesics/NSAIDs5,21,71–74 sures, and for various follow-up moments.
A qualitative analysis ("best evidence synthesis") was con- ducted using a rating system consisting of the following levels Other studies compared ethoheptazine plus meprobam- ate plus aspirin versus NSAID (mefenamic acid),75 or-phenadrine versus phenobarbital,63 orphenadrine plus Level 1—strong evidence: generally consistent findings in paracetamol versus aspirin,76 and diazepam plus parac- multiple high quality trials etamol-codeine versus levomepromazine plus paraceta- Level 2—moderate evidence: generally consistent findings in mol-codeine.26 These studies are summarized in Table 1, multiple low quality trials and/or one high quality trial but not included in the results section because they could Level 3a—limited evidence: only one low quality trial not be classified in one of the predefined comparisons.
Level 3b— conflicting evidence: inconsistent findings inmultiple trials Methodologic Quality of Included Studies
The median score for methodologic quality of all the Level 4 —no evidence: no RCTs and no double-blind trials included studies was 6 with a range of 3 to 9 (Table 2). Using Subgroup analyses were planned for the following a cutoff point of 6 out of 11 criteria, 23 of the 30 studies (77%) were of high quality.4,5,18–23,25,58,61,62,64–71,73,74,76 a) Low back pain with and without sciatica or muscle The most common methodologic shortcomings in the studies involved (in order of frequency): b) Different doses of muscle relaxants c) Ambulant versus bed rest patients Inadequate concealment of the drug allocation pro-cedures (93% scored "negative" or "unclear") d) Injection versus oral therapy Failing to evaluate compliance (83% scored "nega- tive" or "unclear") Inadequate method of randomization (80% scored Literature Search and Study Selection
"negative" or "unclear") The computer-assisted literature search produced a yield Nonequivalent cointerventions (60% scored "neg- of 7 references in the Cochrane Library, 25 in MED- ative" or "unclear") LINE, and 25 in EMBASE. Taking into account 11 arti- Failing to apply intention-to-treat analysis (60% cles that were cross-referenced in the 3 databases, a net scored "negative" or "unclear") total of 46 articles were found to be potentially eligible.
Dissimilarity of the baseline characteristics (47% Further assessment of the articles and application of the scored "negative" or "unclear") inclusion and exclusion criteria resulted in 19 articles.
Inadequate dropouts (33% scored "negative" or Eleven additional studies were identified through refer- ence checking,4,5,18,26 resulting in a total of 30 studies.
Not all studies included in the systematic review of Almost all studies had identical timing of outcome mea- cyclobenzaprine for back pain13 were included in the sures (90%) and had adequately blinded patients (93%), present review, because some of them had included a outcome assessments (93%), and care provider (93%).
mixed population of patients with various musculoskel- Comparison of the scores by the reviewers for each study etal disorders. We only included studies if results were demonstrated a reviewer concurrence rate of 73%. The presented separately for LBP patients or if more than disagreement in 27% of the scores could be attributed to 50% of the study population consisted of LBP patients.
subtle differences in interpretation of the criteria. This

1982 Spine Volume 28 Number 17 2003
Table 1. Methodological Quality Assessment of Randomized and Double-Blind Controlled Trials on the Effectiveness
of Muscle Relaxants for Nonspecific Low Back Pain

1) Adequate allocation concealment, 2) Adequate method of randomization, 3) Similarity of baseline characteristics, 4) Blinding of patients, 5) Blinding of careprovider, 6) Equal co-interventions, 7) Adequate compliance, 8) Identical timing of outcome assessment, 9) Blinded outcome assessment, 10) Withdrawals anddrop outs adequate, 11) Intention-to-treat analysis.
⫹ ⫽ positive; ⫺ ⫽ negative; ? ⫽ unclear.
was reflected in the systematic nature of the discrepan- had to be diagnosed with muscle spasms. However, the cies in scoring. Random errors in reading of the articles accuracy of this diagnosis was not discussed in any of and recording of the assessments, as well as ambiguities these studies.
in the presentation of information in the articles, also Eight studies were identified which included benzodi- played a role. All disagreements were resolved in a con- azepines,22,25,26,58 – 60,69,73 23 studies nonbenzodiaz- sensus meeting.
epines,4,5,18 –24,59,61– 66,69 –72,74 –76 and 2 studies anti-spasticity drugs.67,68 Five studies made use of injection therapy. In one of Twenty-two studies declared at least one relationship these studies, the efficacy of a single intravenous injection with the pharmaceutical industry. These relationships was evaluated,65 whereas in the other four studies, an varied from authors affiliated with the pharmaceutical intramuscular injection was followed by oral industry, drugs supplied by the industry, support re- ceived (in terms of statistical evaluations, medical, scien-tific, and editorial assistance), and explicit declaration Effectiveness of Muscle Relaxants
that the study was conducted with grants from the phar-maceutical industry or was directly conducted by them.
Benzodiazepines Versus Placebo. Four studies were iden-
In eight studies, there was nothing declared with regards tified, one on acute LBP60 and three on chronic to any relationship with the pharmaceutical industry, but in some studies, they used the precommercial name of themuscle relaxant drug, such as DS 103-282 for tizanidine.
Acute Low Back Pain. The one low quality trial on acute
LBP showed that there is limited evidence (1 trial; 50
Data on sample size, age and gender, type and dura- people) that an intramuscular injection of diazepam fol- tion of symptoms, and setting are summarized in Table lowed by oral diazepam for 5 days is more effective than 1. Twenty-four studies included patients with acute LBP placebo for patients with acute LBP for short-term pain and 6 studies chronic LBP.4,24,25,58,59,66 No studies spe- relief and better overall improvement, but is associated cifically reported on patients with sciatica. Fourteen with substantially more central nervous system side studies explicitly stated that the population to be treated

Muscle Relaxants for Low Back Pain van Tulder et al 1983
Table 2. Characteristics of Randomized and Double-blind Controlled Trials on the Effectiveness of Muscle Relaxants
for Nonspecific Low Back Pain

Design and participants (I) Tetrazepam 50 mg t.i.d./10 days.
Mean (SD) pain at baseline, day 7 and day 14 (from 1 to double-blind trial. Sponsored by 5): (I) 3.4 (0.82), 2.5 (0.94) and 1.73 (1.31); (R): 3.36 Sanofi. N ⫽ 50; Male/Female (%): ? (R) Placebo t.i.d./10 days. N ⫽ 24.
(0.62), 3.1 (0.71) and 2.38 (1.08).
Age: 18–80 years. Diagnosis: [stat. sign. day 7] chronic LBP with or without Number of patients with difference in pain scores of at least 1 point at day 7 and day 14: (I): 4 and 15; (R): 1 Placebo responders were excluded.
and 8. [stat. sign. day 7 and 14] Number of patients with at least 1.5 points decrease in muscle spasm (score 1 to 3), at day 7 and day 14: (I):2 and 11; (R): 0 and 4. [stat. sign. day 7 and 14] Overall efficacy by physician: (I): 64%, (R): 29.2%.
stat. sign.] Multicenter, double-blind, placebo (I1) Tizanidine 2 mg t.i.d./8 days.
No differences in percentage pain at rest, muscle spasm controlled trial. Sponsorship: none and daily inactivity at baseline, day 3 and day 7.
declared. N ⫽ 267; Male/Female (I2) Tizanidine 4 mg t.i.d./8 days.
Global measure of improvement at day 7: (inefficacious (%): 35.6/60.4. Age: 17–64 years; ⫹ somewhat efficacious)/(satisfactory ⫹ excellent): mean ⫽ 41.7 years. Diagnosis: (R) Placebo t.i.d./8 days. N ⫽ 89.
(I): 29/47; (R): 32/43.
painful spasms of paravertebralmuscles (acute LBP). Setting:outpatient.
(I) Cyclobenzaprine 10 mg t.i.d.– Proportion of patients who showed improvement (⬎2 double-blind trial.
q.i.d./10 days. N ⫽ 58.
points): in pain, at days 2–4, 5–7 and 8–12: (I): 21%, Merck Sharp & Dohme performed (R) Placebo t.i.d.–q.i.d./10 days.
53% and 81%; (R): 0%, 15% and 49% [stat. sign.] statistical evaluation of data.
Proportion of patients improved (⬎2 points) in muscle N ⫽ 120; Male/Female (%): 59/41; spasm, at days 2–4, 5–7 and 8–12: (I): 10%, 44% and Mean age: 36 (21–60).
72%; (R): 0%, 8% and 39% [stat. sign.] Physicians' Diagnosis: Acute LBP. Patients with global evaluation (5-point ordinal scale): (I): 23, 18, 10, moderate to severe degree of 7 and 0; (R): 2, 13, 24, 20 and 0. [stat. sign.].
muscle spasm and local pain.
Proportion of patients improved (⬎2 points) in ADL at Setting: Primary care.
days 2–4, 5–7 and 8–12: (I): 21%, 53% and 78%; (R):2%, 28% and 47%. [significant on days 5–7 and 8–12].
(I1) Cyclobenzaprine 10 mg t.i.d./14 No measurement of pain, global efficacy or activity of double-blind trial. Supported by daily living.
Merck Sharp & Dohme.
Mean decrease of muscle spasm (1–5 point scale) from N ⫽ 76; Male/Female (%): ? Mean (I2) Diazepam 5 mg t.i.d./14 days.
baseline to days 13–18: (I1): 3.2 to 2.2; (I2): 2.9 to 1.9; (R): 3.2 to 2.1. [no differences among groups] Diagnosis: Chronic LBP. Muscle (R) Placebo t.i.d./14 days. N ⫽ 35.
spasm, limitation of motion andADL, pain and tenderness onpalpation.
(I) Tizanidine 4 mg t.i.d./7 days.
Pain at night, at rest and on movement. Mean (SD) pain double-blind trial. Sandoz Ltd.
at rest (diary; 100 mm VAS) at baseline, day 3 and day supplied medication. TIL (Medical) (R) Placebo t.i.d./7 days. N ⫽ 53.
7: (I): 51 (29.4), 39 (29.6) and 19 (23.2); (R): 51 (26.9), 34 (27.9) and 19 (22.9) [no differences]. Proportion of Organized and monitored study.
patients improved (4-point scale), on day 3 and 7: (I): N ⫽ 112; Male/Female (%): 51/49.
47%, 75% (R): 37%, 63%. [stat. sign. on day 7].
Mean age: 41 (16–69) Global efficacy: (I): very helpful at day 3 ⫽ 17%, some Diagnosis: Acute LBP.
help at day 7 ⫽ 84%; (R): very helpful at day 3 ⫽ 8% Setting: Primary care.
and some help at day 7 ⫽ 44%. [no differences].
(I) Tizanidine 4 mg plus ibuprofen Mean (SD) change in pain at rest (diary; 100 mm VAS) double-blind trial. Sandoz Ltd.
400 mg t.i.d./7 days. N ⫽ 51.
from baseline to day 3 and day 7: (I): 18 (25.3) and 29 supplied medication; TIL (Medical) (R) Placebo plus ibuprofen 400 mg (43.3); (R): 16 (24.9) and 33 (32.9). [no differences].
t.i.d./7 days. N ⫽ 54.
Proportion of patients with moderate ⫹ severe pain/no Organized and monitored study.
pain ⫹ mild pain at rest, on day 3 and day 7: (I): 5/46 N ⫽ 105; Male/Female (%): 55/45.
and 3/43; (R): 15/39 and 12/40) [stat. sign.] Age: 42.5 (20–66) Global efficacy (% improved) on day 3 and day 7: (I) 76% Diagnosis: Acute LBP.
and 85%; (R): 67% and 81%. [no statistical testing].
Setting: Primary care.
(I) Cyclobenzaprine 10 mg t.i.d.– Mean spontaneous pain (1–5 point scale) at baseline, double-blind trial. Merck Sharp & q.i.d./14 days. N ⫽ 24.
day 7 and day 14: (I): 3.7, 1.3, 1.0 (R): 3.6, 1.9, 1.3 [stat.
Dohme provided editorial (R) Placebo t.i.d.–q.i.d./14 days.
sign. On day 7, not day 14].
Mean limitation of daily activities (1 to 5) at baseline, day N ⫽ 48; Male/Female (%): 54/46.
7 and day 14: (I): 1.4, 1.0 (R): 2.0, 1.2 [stat. sign. on day Mean age: 46 (19–67) 7, not on day 14].
Diagnosis: Acute LBP (75%) or neck Global improvement on day 4, 7 and 14: complete ⫹ pain (25%). Moderate to severe satisfactory/unsatisfactory ⫹ worsening: (I): 20/3, 20/2 muscle spasm.
and 20/0; (R): 9/13, 14/6 and 15/0 [stat. sign. on day 4 and 7, not on day 14].
Randomized, open-label trial.
(I) Cyclobenzaprine 10 mg/8 hrs/14 Pain (0 to 20 NRS), descriptive pain scale (from 0 to 3), Supported by Merck Sharp & Dohme.
days plus naproxen 500 mg no. of days to resolution of pain: (I): 8.5, (R): 12.5. [no N ⫽ 40; Male/Female (%): 70/30 initially, followed by 250 mg/6 Mean age: 34.5 (20–57) hrs/14 days.
Muscle spasm (0 ⫽ none to 3 ⫽ severe). (I): 2.0; (R): 3.0.
Diagnosis: Acute, mild to moderate [stat. sign.].
(R) Placebo plus naproxen 500 mg Functional capacity (0–3 scale): (I): 9; (R): 15. [no initially, followed by 250 mg/6 hrs/14 days. N ⫽ 20.
Global efficacy (0 ⫽ poor to 4 ⫽ excellent). [no (Table continues)

1984 Spine Volume 28 Number 17 2003
Table 2. Continued
Design and participants Randomized, double-blind trial.
(I1) Carisoprodol 350 mg q.i.d./7 Pain (100-mm VAS) day 7—baseline (I): 58 (I2): 48; N ⫽ 80; Male/Female (%): 48/52 muscle stiffness (I): 59 (I2): 42; activity (I): 58 (I2): 41; Mean age: 39 (19–65) overall relief: (I): 75, (I2): 56. [stat. sign. For muscle Diagnosis: Acute LBP.
(I2) Diazepam 5 mg q.i.d./7 days.
stiffness, activity, and relief].
Overall improvement (very good ⫹ excellent): (I): 70%, Randomized, double-blind trial.
(I1) Tizanidine 2 mg t.i.d., 7 days.
Difference (4-point scale) at baseline and day 7 for pain Sponsorship not declared, but most likely (I): 2.29, 0.83 (I2): 2.31, 0.73, for muscle tension (I): 2.57, Sandoz Ltd supplied the medication.
(I2): Chlorzoxazone 500 mg t.i.d., 7 0.71 (I2): 2.69, 0.44; for limitation of movement (I): 2.0, N ⫽ 27; Male/Female (%): ? 1.0 (I2): 2.15, 0.9. [no differences].
Mean age: 37 (21–63) Overall effectiveness by patient at end of the trial: excellent/ Diagnosis: Acute LBP and muscle good (I): 11 (I2): 9; moderate/poor (I): 3 (I2): 3.
spasms of disc origin.
Setting: secondary care—hospitalized (7), ambulant (20).
Randomized, placebo-controlled, double- (I) Dantrolene sodium 25 mg o.i.d./ Pain during maximal voluntary movements (% variation blind trial. Medication supplied by 4 days, N ⫽ 10.
on VAS): (I): 50%; (R): 8.6%. [stat. sign.] (R) Placebo o.i.d./4 days. N ⫽ 10.
Muscle spasm (5-points) proportion improved on day 3 N ⫽ 20; Male/Female (%): 75/25; Mean and 4: (I): 85%, 85%; (R): 10%, 30%.
age: 46.9 (37–58) Pain behavior stat. sign. Better in (I) than (R) on day 4.
Diagnosis: acute episode of chronic LBP.
Setting: secondary care.
Placebo-controlled, double-blind trial.
(I) Tizanidine 4 mg t.i.d. ⫹ Pain (4-point scale) on movement at baseline, day 3 and Sponsorship: none declared.
paracetamol 500 mg/7 days. N 7: (I): 2.0, 1.1, 0.3; (R): 2.0, 1.8, 1.4. Pain at rest: (I): 1.8, N ⫽ 50; Male/Female (%): 46/54 0.6, 0.2; (R): 1.8, 1.2, 1.0; Pain at night: (I): 1.8, 0.3, 0.1; Mean age: 50 (range 32–63) in muscle (R) Placebo t.i.d. ⫹ paracetamol (R): 1.7, 1.0, 0.8. [stat. Sign.] relaxant group and 53 (41–68) in 500 mg/7 days. N ⫽ 24.
Muscle spasm (4-point scale) at baseline, day 3 and day placebo group.
7: (I): 2.0, 1.1, 0.3; (R): 2.1, 1.7, 1.5. [stat. sign.].
Diagnosis: Acute LBP.
Activity daily living (4-point scale) at baseline, day 3 and day 7: (I): 2.0, 0.8, 0.5; (R): 1.9, 1.6, 1.2. [stat. sign.].
Global efficacy (1 ⫽ excellent, 2 ⫽ good, 3 ⫽ moderate and 4 ⫽ poor) at the end of treatment: (I): 20, 3, 0, 3;(R): 4, 3, 3, 14.
Randomized, placebo-controlled, double- (I) Baclofen 10 mg, 1–2 tablets For group of patients with severe pain at baseline (63 blind trial.
t.i.d.–q.i.d./10 days. N ⫽ 100.
baclofen, 60 placebo): Sponsored by Ciba-Geigy.
(R) Placebo 1–2 tablets t.i.d.–q.i.d./ Local pain (5-point scale) at baseline, day 4 and day 10: N ⫽ 200; Male/Female (%): 48/52 10 days. N ⫽ 100.
(I): 4.1, 2.6, 2.0 (R): 4.1, 3.0, 2.5 [stat. sign.] Mean age: 42.2 (17–74) Muscle spasm (5-point scale) at baseline, day 4 and day Diagnosis: Acute LBP; muscle spasm 10: (I): 3.8, 2.5, 1.5 (R): 3.8, 2.8, 2.0 [stat. sign. on day and functional disability ⬍2 wks of at least moderate severity.
Patient's opinion (5-point scale) at baseline, day 4 and day 10: (I): 4.0, 2.7, 1.8 (R): 4.0, 3.0, 2.2 [stat. sign.] Data for patients with moderate pain (N ⫽ 77) not given.
Authors reported that baclofen was sign. better indaily activity on day 4. No differences on day 10.
Randomized, placebo-controlled, double- (I) Orphenadrine 100 mg b.i.d./7 Reduced pain at 2 days: (I): 9/20; (R1): 3/20; (R2): 4/20 [(I) blind trial. Supported by Riker days. N ⫽ 20.
stat. sign. better than (R1) and (R2)].
Laboratories, Inc.
(R1) Phenobarbital 32 mg b.i.d./7 Overall improvement at 2 days: (I): 7/20; (R1): 3/20; (R2): N ⫽ 60; Male/Female (%): ? days. N ⫽ 20.
0/20. [(I) stat. sign. better than (R2)].
(R2) Placebo b.i.d./7 days. N ⫽ 20.
Diagnosis: Acute LBP and muscle Randomized, double-blind trial.
(I1) Tizanidine, 4 mg t.i.d., 7 days.
Pain (4-point scale) at baseline, day 3 and day 7: Sponsorship not declared but most likely (I): 2.3, 1.3, 0.6; (R): 2.2, 1.7, 1.1. Number of cases with Sandoz Ltd supplied medication.
(I2) Diazepam 5 mg t.i.d., 7 days.
pain improvement on day 3 and 7: (I): 13, 13; (R): 8, 11.
N ⫽ 30; Male/Female (%): 33/67 [stat. sign. on day 3].
Mean age: 47.5 (25–70) Percentage of pain relief at end of trial: (I): 77.4%, (R): Diagnosis: Acute spasm of back (80%) and neck (20%) muscles, actual no. of Patient self-assessment of pain (4-point scale) at baseline, weeks of duration unknown).
day 3 and day 7: (I): 2.2, 1.1, 0.5; (R): 2.2, 1.7, 1.0.
Setting: ‘ambulant patients'.
Daily activities at baseline and after 7 days: (I): 2.1, 0.4, (R): 2.2, 0.8. Number of cases with improvement of dailyactivities on day 3 and 7: (I): 12, 13; (R): 10, 14.
Randomized, placebo-controlled, double- (I) Carisoprodol 350 mg q.i.d./4 Pain (100 mm VAS) at baseline, day 2 and day 4: (I): 86.0, blind trial.
days. N ⫽ 16.
33.0, 15.5; (R1): 75.2, 58.7, 49.1 (R2): 65.5, 58.5, 64.0. [(I) Medications were provided by Wallace (R1) Butabarbital 15 mg q.i.d./4 stat. sign. Better than (R1) and (R2)].
days. N ⫽ 16.
Muscle spasm (4-point scale) at baseline, day 2 and day N ⫽ 48; Male/Female (%): 56/44 (R2) Placebo q.i.d./4 days. N ⫽ 16.
4: (I): 3.1, 2.4, 1.8 (R1): 3.1, 2.8, 2.6 (R2): 3.0, 2.9, 2.9. [no Mean age: 38.4 (18–70) Diagnosis: Acute LBP. Mexican migrant The three groups were Interference with daily activities (4-point scale) at farm laborers with acute lumbar strain significantly different at baseline, day 2 and day 4: (I): 3.7, 2.4, 1.8 (R1): 3.3, 2.9, baseline on scores of pain, 2.7 (R2): 3.1, 3.1, 3.4. [(I) stat. sign. better than (R2)].
daily activities, global severity Number of patients with global improvement excellent/ and patient estimate of pain.
good (I): 12 (R1): 2 (R2): 2. [(I) stat. sign. better than The carisoprodol group showed (R1) and (R2)].
more severe complaints thanthe other groups.
(Table continues)

Muscle Relaxants for Low Back Pain van Tulder et al 1985
Table 2. Continued
Design and participants Double-blind, placebo-controlled trial.
(I) Diazepam injections: 10 mg IM/ Subjective results (pain and tenderness), no. of patients Roche Ltd. acknowledged for their "help 6 hrs/24 hrs. Oral: 2 mg q.i.d./5 improved, no change and worse at the end of and cooperation." days plus calcium aspirin 10 g treatment: (I) 19, 5, 1 (R): 18, 5, 2. [no differences].
N ⫽ 50; Male/Female (%): 80/20 t.i.d./5 days. N ⫽ 25.
Objective results (range of motion, straight leg raising (R) Placebo injections: water IM/6 and neurological signs), number of patients improved, Diagnosis: Acute LBP severe enough to hrs/24 hrs. Oral: placebo q.i.d./5 no change and worse at the end of treatment: (I): 16, require admission to hospital.
days plus calcium aspirin 10 g 7, 2 (R): 15, 8, 2. [no differences].
Setting: secondary care. All patients t.i.d./5 days. N ⫽ 25.
were hospitalized and treated withcomplete bed rest and 8/25 in (I) and6/25 in (R) received additional therapy.
Randomized, placebo-controlled, double- (I) Orphenadrine 35 mg ⫹ Number of patients with improvement in pain (4-point blind trial. Cooperation and assistance paracetamol 450 mg 2 tablets scale) at the end of the trial: (I): 37 (R): 34 [no from Riker Laboratories Inc. is t.i.d./7 days. N ⫽ 48.
(R) Aspirin 100 mg t.i.d./7 days.
N ⫽ 99; Male/Female (%): 61/39 Mean age: 43.5Diagnosis: Acute LBP of sufficient severity to require inpatient treatment.
Setting: secondary care.
Randomized, placebo-controlled, double- (I) Orphenadrine 60 mg Number of patients with self assessment of pain as blind trial. Four authors were affiliated intravenously, single dose.
none, slight, moderate or severe (45 min. After with the Clinical Research Department injection): (I): 5, 30, 5, 0 (R): 0, 4, 31, 5.
of Riker Laboratories.
(R) Placebo intravenously, single Physician's assessment of spasm (% better): (I): 95% (R): N ⫽ 80; Male/Female (%): 81/19 dose. N ⫽ 40.
10%. [(I) stat. sign. better than (R)] Mean age: 33.8 (14–62) Global improvement (%, better): (I): 92% (R): 12% [(I) stat.
Diagnosis: Acute LBP and muscle sign. Better than (R)].
Setting: tertiary care.
Randomized, placebo-controlled, double- (I): Tizanidine 2 mg, t.i.d., 7 days.
Mean back pain (4-point scale) at baseline, days 2, 3, 5 blind trial. Sponsorship: none and 7: (I): 2.5, 2.0, 1.7, 1.3, 1.0 (R): 2.6, 2.2, 1.9, 1.4, 1.0.
(R): Placebo, t.i.d., 7 days. N ⫽ 15.
[no difference].
N ⫽ 30; Male/Female (%): 50/50.
Mean score of muscle spasm (4-point scale), at baseline, Mean age: 42.5 (18–62) (I) and 40.8 (27– days 2, 3, 5 and 7. (I): 2.9, 1.9, 1.3, 1.0, 0.7 (R): 2.7, 2.3, 1.8, 1.2, 1.2. [stat. sign. only on day 3].
Diagnosis: moderate to severe acute Patient's assessment of overall response (excellent, spasms due to disk prolapse in good, moderate, poor): (I): 6, 6, 2, 1 (R): 2, 4, 7, 2 [no lumbar (n ⫽ 26) and thoracic (n ⫽ 4) Setting: secondary care—hospitalized Randomized, placebo-controlled, double- (I) Diazepam IM injection 10 mg (2 Patients' assessment 1 hr after IM injection, 24 hrs, blind trial. Sponsorship not declared.
ml) ⫹ 2 tablets t.i.d. for 5 days.
between 48–72 hs and either at day 5 or day 10 to 14.
N ⫽ 68; Male/Female (%): 56/44 Day 5–10 2 tablets t.i.d. or less Therapeutic effect at end of treatment period (0 ⫽ no, Mean age: 45.6 (23–72) if good response.
1 ⫽ moderate, 2 ⫽ good, 3 ⫽ very good). Mean (SD) Diagnosis: Acute LBP and number of patients with scores of 2 and 3: (I): 1.8 (R) Placebo IM injection (2 ml) ⫹ (1.2) 21; (R): 0.3 (0.8) 6. [(I) stat. sign better than (R)] 2 placebo tablets t.i.d. for 5days. Day 5–10 2 placebotablets t.i.d. or less if goodresponse. N ⫽ 35.
Note:Groups were not similar at Randomized single-blind clinical trial.
(I1) Pridinol mesilate 4 mg IM Mean (SD) pain intensity (VAS) at baseline, day 4 and Sponsorship: none declared.
injection b.i.d. ⫻ 3 days day 7: (I): 62.8 (10.8); 45.8 (12.4); 30.0 (13.9); (I2) 63.5 N ⫽ 120; Male/Female (%): 42.5/57.5 followed by 2 mg b.i.d. orally ⫻ (10.8); 46.4 (12.4); 30.1 (15.5). [no differences].
Mean age: 54.4 (20–77) (I) and 51.7 (24– 4 days. N ⫽ 60.
Patient rated global efficacy: (I) 47/60 ⫽ good & very (I2) Thiocolchicoside 4 mg IM good; (I2) 39/60 ⫽ good & very good.
Diagnosis: chronic LBP with muscle injection b.i.d. ⫻ 3 days followed by 8 mg b.i.d. orally ⫻ Setting: secondary care—inpatients and 4 days. N ⫽ 60.
Randomized, placebo-controlled, double- (I) Tolperisone 100 mg t.i.d., 21 Clinical global impression of efficacy on day 10 and day blind trial. One of the authors affiliated 21 (1 ⫽ very good, 4 ⫽ ineffective) (I): 2.65, 2.20 (R): with Strathmann AG.
2.85, 2.45. [no differences].
N ⫽ 112; Male/Female (%): 78/27 (R) Placebo t.i.d./21 days. N ⫽ 70.
Number of patients with overall assessment of efficacy Mean age: 50.8 (I) and 47.8 (R) by the patient after 21 days: very Diagnosis: chronic LBP with painful good/good/moderate/ineffective: (I): 15, 17, 19, 5; (R): 6, reflex muscle spasms.
21, 15, 14. [(I) sign. better than (R)].
Setting: secondary care—rehabilitation Randomized, placebo-controlled, double- (I1) Carisoprodol 350 mg q.i.d./7 Pain (100 mm VAS) at baseline and day 8: (I): 70, 30; (I2): blind trial.
74, 28. Muscle spasm: (I): 64, 22; (I2): 67, 25. Activity Sponsorship: none declared.
impairment: (I): 74, 32; (I2): 76, 26.
N ⫽ 78; Male/Female (%): 53/47 (I2) Cyclobenzaprine 10 mg q.i.d./7 Overall improvement (very good to excellent) at end of Mean age: 42 (19–65) days. N ⫽ 39.
treatment: (I): 70%, (I2): 70%. No differences between Diagnosis: Acute LBP of at least moderate intensity with musclespasms of 7 days or less.
(Table continues) 1986 Spine Volume 28 Number 17 2003
Table 2. Continued
Design and participants Randomized, placebo-controlled double- (I): Tetrazepam 50 mg t.i.d./14 days Percentage of patients reporting ⬎66.6% reduction of blind trial. Sponsored by Sanofi plus physiotherapy. N ⫽ 79.
daytime pain at day 3, 7 and 14: (I): 7.3, 29.1, 45.5; (R): (R): Placebo t.i.d/14 days plus 2.1, 8.3, 27.1. [stat. sign. difference at day 7]. Clinical N ⫽ 152; Male/Female (%): 59/41 physiotherapy. N ⫽ 73.
global impression (marked, moderate, Mean age: 44.4 (I) and 46.3 (R) slight/unchanged, deteriorated) at baseline, day 3, 7 Diagnosis: chronic LBP without benefit and 14: (I): 5/50, 39/16, 46/9, 45/8 (R): 1/47, 31/17, 41/7, from physiotherapy.
39/9 [no differences].
Setting: secondary care—outpatient.
Data only presented for 103 patients in per protocol Randomized, placebo-controlled, double- (I) Tizanidine 2 mg plus diclofenac Mean pain at rest (4-point scale) at baseline, day 4 and blind trial. Sponsored by Novartis 50 mg b.i.d./7 days. N ⫽ 185.
day 8: (I): 1.98, 0.89, 0.53 (R): 1.87, 1.21, 0.92. [stat.
Pharma AG, Basel.
(R): Placebo plus diclofenac 50 mg N ⫽ 405; Male/Female (%): 48/52 b.i.d./7 days. N ⫽ 176.
Mean muscle tension (4-point scale at baseline, day 4 and day 8: (I): 1.98, 0.77, 0.29 (R): 1.99, 1.20, 0.77. [stat.
Diagnosis: patients with local pain syndromes (back, neck or shoulder) of Mean disability score (5-point scale) at baseline, day 4 recent onset and clinically discernible and day 8: (I): 2.01, 0.98, 0.61 (R): 1.97, 1.27, 0.92. [stat.
muscle spasms; ⬎50% low back pain.
Setting: not specified.
Overall assessment of efficacy at end of treatment (good/ very good): (I): 72% (R): 58% [stat. sign.] Randomized, placebo-controlled, double- Chlormezanone: excluded from Number of patients experiencing moderate and severe blind trial. Sponsorship: none pain at baseline, day 1 and day 7: (I): 25/40, 17/40, 8/ (I) Meprobamate 150 mg plus 41; (R): 27/37, 19/32, 6/39 [no differences].
N ⫽ 122; Male/Female (%): 53/47 ethoheptazine 75 mg plus Pain diary (4-point scale) (25% failed to complete).
Mean age: 41.3 (?) aspirin 250 mg 2 tablets t.i.d./7 Day 0 and day 7: 1.45, 0.8; (R): 1.4, 0.7. [no differences] Diagnosis: Acute LBP (1–28 days).
days. N ⫽ 40.
Patient's overall assessment (some and marked (R) Mefenamic acid 500 mg t.i.d./7 improvement) on day 7: (I2): 22; (R): 24 [no difference].
days. N ⫽ 40.
Randomized, placebo-controlled, double- (I) Orphenadrine 60 mg (2 ml) IM Mean (SE) duration of disability: (I): 8.6 (0.6) days; (R): blind trial. Sponsorship: none followed by orphenadrine (35 12.9 (1.2) days. [stat. sign.].
mg) ⫹ paracetamol (450 mg) 2 Subjective impressions of the treatments: no difference N ⫽ 50; Male/Female (%): 34/66 tablets t.i.d., 7 days. N ⫽ 25.
between groups (15 minutes after injection and in the (R) Saline 2 ml IM followed by first follow-up visit).
Diagnosis: Acute LBP. 38/50 no previous paracetamol (450 mg) 2 tablets Note: Baseline measurements, 15 minutes after injection.
episodes. 37/50 acute onset of t.i.d., 7 days. N ⫽ 25.
symptoms. 16/50 work injury.
Double-blind, controlled clinical trial.
(I) Diazepam t.i.d (7 mg, 7 mg, 10 Pain intensity (10-point scale) daily during 6 days.
Sponsorship: none declared.
mg)/6 days ⫹ paralgin Forte (I) 21/33 patients with satisfactory effect; mean grade N ⫽ 78; Male/Female (%): 60/40 (paracetamol 400 mg, codeine 5.30 (R) 26/45 satisfactory effect; mean grade 5.82. [no Mean age: 46.2 (I) and 47.4 (R) 20 mg, promethazine 5 mg) Diagnosis: Acute lumbago-sciatica and t.i.d./3 days, then prn. N ⫽ 33.
cervical pain; majority LBP (R) Levomepromazine t.i.d (7.5 mg Setting: Secondary care—hospital.
⫹ 7.5 mg ⫹ 15 mg) 6 days ⫹paralgin Forte t.i.d./3 days, thenprn. N ⫽ 45.
Randomized, placebo-controlled, double- Chlormezanone. Excluded from Reduction in pain intensity by 2 categories (5-point blind trial. One author affiliated with this review.
verbal scale) at day 7: (I): 54.3%; (R): 33.4%. [no ASTA Medica.
(I) Flupirtin 100 mg q.i.d./7 days.
N ⫽ 107; Male/Female (%): 43/57 Reduction in muscle spasm by 2 categories (5-point (R) Placebo q.i.d./7 days. N ⫽ 54.
verbal scale) at day 7 (I): 47.8%; (R): 33.4%. [no Diagnosis: Chronic LBP Overall assessment by the physician (very good ⫹ good ⫹ satisfactory): (I): 84.8%; (R): 54.3%. [(I) better than (R)].
Chronic Low Back Pain. The 2 high quality trials on
chronic LBP25,58 showed that there is strong evidence (2 Eleven studies were identified, eight on acute trials; 222 people) that tetrazepam 50 mg 3 times daily is LBP18,19,23,61–65 and three on chronic LBP.4,59,66 more effective than placebo for patients with chronicLBP for short-term pain relief and overall improvement.
Acute Low Back Pain. One high quality study on acute
The pooled RRs and 95% CIs for pain intensity were LBP65 showed that there is moderate evidence (1 trial; 80 0.82 (0.72– 0.94) after 5 to 7 days follow-up and 0.71 people) that a single intravenous injection of 60 mg (0.54 – 0.93) after 10 to 14 days. The pooled RR and orphenadrine is more effective than placebo for imme- 95% CI for overall improvement was 0.63 (0.42– 0.97) diate relief of pain and muscle spasm for patients with after 10 to 14 days follow-up. One high quality trial58 showed that there is moderate evidence (1 trial; 50 peo- Three high quality23,61,62 and 1 low quality trial63 ple) that tetrazepam is more effective than placebo for showed that there is strong evidence (4 trials; 294 peo- short-term decrease of muscle spasm. One low quality ple) that oral nonbenzodiazepines are more effective than trial showed that there is limited evidence (1 trial; 76 placebo for patients with acute LBP for short-term pain people) that there is no difference between diazepam and relief, global efficacy, and improvement of physical out- placebo for short-term decrease of muscle spasm.59 comes. The pooled RR and 95% CIs for pain intensity Muscle Relaxants for Low Back Pain van Tulder et al 1987
were 0.80 (0.71– 0.89) after 2 to 4 days (4 trials; 294 are more effective than placebo for patients with acute people) and 0.58 (0.45– 0.76) after 5 to 7 days follow-up LBP for short-term pain relief, reduction of muscle (3 trials; 244 people). The pooled RR and 95% CIs for spasm, and overall improvement after 10 days.
global efficacy were 0.49 (0.25– 0.95) after 2 to 4 days (4trials; 222 people) and 0.68 (0.41–1.13) after 5 to 7 days follow-up (4 trials; 323 people). The pooled RR and No RCTs or double-blind trials were identified.
95% CIs for physical outcomes were 0.76 (0.66 – 0.88) Muscle Relaxants Versus Nonsteroidal Anti-
after 2 to 4 days (3 trials; 252 people) and 0.55 (0.40 – 0.77) after 5 to 7 days follow-up (3 trials; 251 people).
No RCTs or double-blind trials were identified.
Of the three high quality trials18,19,64 that could not be included in the statistical pooling due to insufficient Muscle Relaxants versus Muscle Relaxants
data, 1 large trial (267 people) reported no differences Eight studies were identified, five high quali- after 3 and 7 days in pain relief and global efficacy be- ty20,22,64,69,70 and three low quality trials.18,24,59 tween tizanidine and placebo.18 Two small trials (48 Carisoprodol. This muscle relaxant was investigated in
people each) reported that oral nonbenzodiazepines are two high quality studies on acute LBP. The first study more effective than placebo regarding pain intensity, compared carisoprodol with diazepam.69 Carisoprodol global efficacy, and muscle spasm after 7 and 14 days19 was superior in performance on all outcome parameters and on pain intensity after 4 days.64 However, in the last measured. Comparison of carisoprodol with cyclobenza- trial, groups were not similar at baseline, which may prine-hydrochloride in the second study revealed no sta- have biased the results.
tistically significant differences between the two Strong evidence from all 8 trials on acute LBP (724 people) showed that muscle relaxants are associated withmore total adverse effects and central nervous system Chlorzoxazone. This muscle relaxant was compared
adverse effects than placebo, but not with more gastro- with tizanidine in one high quality study in a very small intestinal adverse effects; RRs and 95% CIs were 1.50 sample of patients (27 people) with degenerative lumbar (1.14 –1.98), 2.04 (1.23–3.37) and 0.95 (0.29 –3.19), re- disc disease.20 No differences were found between the spectively. The most commonly and consistently re- ported adverse events involving the central nervous sys- compared with diazepam in a low quality trial on gastrointestinal tract, this was nausea. The incidence of chronic LBP, but no significant differences between the other adverse events associated with muscle relaxants treatments were identified.59 There was also no signifi- was negligible.
cant difference between cyclobenzaprine and carisop- Chronic Low Back Pain. One high quality trial66 showed
rodol in one high quality study on acute LBP.70 that there is moderate evidence (1 trial; 107 people) that Diazepam. In comparison with carisoprodol, diazepam
flupirtine is more effective than placebo for patients with was found to be inferior in performance for muscle chronic LBP for short-term pain relief and overall im- spasm, global efficacy, and functional status in a high provement after 7 days, but not for reduction of muscle quality trial on acute LBP.69 In a very small high quality spasm. One high quality trial4 showed that there is mod- trial (30 people) comparing diazepam with tizanidine, erate evidence (1 trial; 112 people) that tolperisone is there were no differences in pain, functional status, and more effective than placebo for patients with chronic muscle spasm after 7 days.22 LBP for short-term overall improvement after 21 days,but not for pain relief and reduction of muscle spasm.
Tizanidine. This muscle relaxant was compared with
The low quality trial59 showed that there is limited evi- chlorzoxazone and diazepam in two very small high dence (1 trial; 76 people) that there is no difference on quality trials.20,22 Both trials did not find any differences short-term reduction of muscle spasm after 18 days be- in pain, functional status, and muscle spasm after 7 days.
tween cyclobenzaprine and placebo for patients with Pridinol Mesilate. One low quality trial showed no dif-
chronic LBP. The two high quality trials did not show a ferences between this muscle relaxant and thiocolchico- difference in side effects.
side on pain relief and global efficacy.24 Antispasticity Drugs Versus Placebo
Muscle Relaxants Analgesics/NSAIDs versus
Acute Low Back Pain. Two high quality trials67,68
Six studies were identified on acute LBP, five high qual- showed that there is strong evidence (2 trials; 220 peo- ity5,21,71,73,74 and one low quality trial.72 Five trials eval- ple) that antispasticity muscle relaxants are more effec- uated nonbenzodiazepines and only one trial tive than placebo for patients with acute LBP for short- term pain relief and reduction of muscle spasm after 4days. One high quality trial68 also showed that there is Acute Low Back Pain. Three high quality trials showed
moderate evidence that antispasticity muscle relaxants that there is strong evidence (3 trials; 560 people) that 1988 Spine Volume 28 Number 17 2003
tizanidine plus analgesics21 or NSAIDs5,71 is more effec- or another muscle relaxant. No trial compared injection tive than placebo plus analgesics or NSAIDs for patients with oral medication.
with acute LBP for short-term pain relief and decrease of The first high quality study made use of an initial muscle spasm after 3 to 4 and 7 to 8 days. The other high course of diazepam therapy administered intramuscu- quality trial showed no difference on global efficacy, but larly at a dose of 10 mg every 6 hours for 24 hours.73 the orphenadrine plus paracetamol group had statisti- This was followed by a course of oral therapy plus cal- cally significantly fewer disability days than the placebo cium aspirin. No differences were found between the di- plus paracetamol group.74 The low quality trial showed azepam and placebo groups at the end of the trial, and statistically significantly greater decrease of muscle the effect of the injection therapy was not clear.
spasm for cyclobenzaprine plus NSAIDs after 14 days, The second high quality study found shorter duration of but no differences on pain intensity and global efficacy.72 disability with 60 mg of orphenadrine administered intramus- Data on adverse events from four studies (556 people) cularly followed by oral tablets plus paracetamol compared were pooled.5,71,72,74 Using the random effects model, with placebo. There was no difference in global efficacy. Drop- the RR and 95% CI was 1.34 (0.67–2.67), indicating out rate in this trial was high.74 that there was no statistically significant difference in One high quality study using 60 mg of orphenadrine total adverse effects. However, the RRs and 95% CIs for administered intravenously compared to placebo found central nervous system and gastrointestinal adverse ef- significant relief of pain and spasm 45 minutes after a fects were 2.44 (1.05–5.63) and 0.54 (0.26 –1.14), re- single injection.65 spectively, showing that combination therapy was re- One low quality trial showed a better therapeutic ef- sponsible for significantly more central nervous system fect with intramuscular diazepam followed by oral tab- adverse effects.
lets compared with placebo, but groups were different at One high quality trial showed no differences on sub- jective and objective outcomes between a benzodiaz- The other low quality trial showed no differences be- epine (diazepam) plus calcium aspirin versus placebo tween pridinol mesilate and thiocolchicoside intramus- plus calcium aspirin.73 cular followed by oral tablets.24 Preplanned Subgroup Analyses
A best-case analysis was carried out in which internal Low Back Pain With and Without Sciatica and Muscle
validity criteria that were scored as unclear ("?") were Spasms. No trials specifically addressed sciatica. We could
scored as positive. This obviously increased the number not perform a subgroup analysis of the studies in which of high quality studies and resulted in only two studies muscle spasms were identified because the accuracy of these still being considered low quality.59,63 This procedure measurements is not described and because we cannot as- changed the results of benzodiazepines versus placebo sume that the trials that did not mention muscle spasm for acute LBP from limited to moderate evidence, but reflect in reality patients without muscle spasm.
had no consequences for any of the other results.
Different Doses of Muscle Relaxants. Various muscle re-
Lowering the threshold distinguishing higher and laxants were investigated in multiple studies, but the lower quality studies from 6 out of 11 criteria to 5 out of studies either included the same doses (for example, all 11 criteria changed 3 studies from low to high quali- studies evaluating cyclobenzaprine used a dose of 10 mg ty.24,60,75 This produced the same consequences de- 3 times daily) or were found to be too heterogeneous in scribed in the paragraph above, changing the results of terms of control interventions and outcome parameters benzodiazepines versus placebo for acute LBP from lim- to be able to make any comparisons.
ited to moderate evidence.
Raising the threshold from 6 out of 11 to 7 out of 11 Ambulant Patients Versus Bed Rest Patients. Two high
criteria consequently decreased the number of high qual- quality studies involved patients prescribed bed rest. One ity studies; 10 trials with quality score of 6 were consid- study compared an antispasticity muscle relaxant (ba- ered low quality in this sensitivity analysis. The evidence clofen) with placebo and incorporated bed rest in the on pain relief and global efficacy for tetrazepam versus therapeutic regimen.68 In comparison with placebo, placebo for chronic LBP changed from strong to moderate, there was significant relief of pain and improvement in and the moderate evidence on muscle spasm to limited. The terms of global efficacy. Relief of spasm did not reach evidence that flupirtine is more effective than placebo for statistical significance. The second study investigated a patients with chronic LBP changed from moderate to lim- benzodiazepine (diazepam) plus calcium aspirin versus ited. There were no other implications on results.
placebo plus calcium aspirin and involved patientstreated with complete bed rest.73 No difference was found between the two treatments in this trial.
Literature Search and Study Selection
Injection Therapy. Five studies made use of injection
The results of this review must be interpreted against therapy, of which four evaluated an intramuscular injec- several potential sources of bias involving the literature tion followed by oral medication compared with placebo search and selection process. A language restriction was Muscle Relaxants for Low Back Pain van Tulder et al 1989
applied to the selection process in which studies not pub- Performance of Muscle Relaxants Versus Placebo
lished in English, Dutch, German, Spanish, or Portu- The results demonstrate strong evidence for significant guese were not admitted for further review. Although we symptomatic relief and overall improvement within a acknowledge that systematic reviews should aim at in- week of therapy for nonbenzodiazepines for acute LBP.
clusion of all relevant trials independent of language, Regarding benzodiazepines, there was strong evidence identifying trials published in any language is difficult, for short-term pain relief and overall improvement with time consuming, and costly. We will attempt to include tetrazepam for chronic LBP. However, tetrazepam is other language trials in a future update of this review. In only available in some European countries and in Mex- addition, no efforts were undertaken to track down and ico. Also, the evidence for benzodiazepines comes from include the results of unpublished studies. It was noted fewer trials than for nonbenzodiazepines. The evidence that no studies were identified that demonstrated nega- of benzodiazepines for acute and nonbenzodiazepines tive results for muscle relaxants. This suggests the possi- for chronic LBP is less convincing.
bility of publication bias. It has been demonstrated that The results of the review indicate that muscle relax- medication trials with positive outcomes are more likely ants could be of benefit to patients, reducing the duration to be published.77 of their discomfort and accelerating recovery. Thesefindings are consistent with the results of a systematicreview on cyclobenzaprine for back pain,13 which showed that cyclobenzaprine is more effective than pla- Using a cutoff point of 6 out of 11 criteria, 77% of the cebo at the price of greater adverse effects. An exception included studies were found to be of high quality. A large was dantrolene sodium,67 one of the antispasticity mus- proportion of these high quality studies fulfilled six cri- cle relaxants identified in the review. In comparison with teria, indicating that there is still room for improvement placebo, this drug demonstrated more significant relief of in the quality of execution and reporting of trials involv- pain and spasm with no side effects at the dose used. The ing muscle relaxants. The most common methodologic study by Casale67 involved a very small sample size (n ⫽ flaws involved the concealment of treatment allocation, 20), rendering the applicability of the results uncertain.
compliance, and randomization procedure, which were Although dantrolene circumvents the central nervous only adequate in 2, 4, and 6 of the 30 trials, respectively.
system and thus avoids the characteristic side effects, it is Most authors failed to explicitly specify the method or associated with severe hepatotoxicity and muscular person responsible for concealing the treatment alloca- tion and did not evaluate compliance or failed to explic- Although a positive treatment effect was found for itly report compliance data. Taking into account the type antispasticity muscle relaxants, for acute LBP the clinical of side effects associated with muscle relaxants and the relevance of this finding for the LBP population is ques- fact that the majority of the studies involved patients tionable as these medications are typically prescribed for treated outside the controlled environment of a second- neurologic disorders such as cerebral palsy, multiple scle- ary care setting (i.e., outpatient or primary care setting), rosis, and spinal cord injuries.
more attention should have been devoted to compliance.
Compliance gives an indication of the tolerability and Performance of Muscle Relaxants Versus
acceptability of these drugs to patients. In many studies, authors merely stated that the trial was "randomized," The results of the analysis of the various muscle relaxants which does not give the reader confidence that a trial has identified in this review showed that one high quality been properly randomized or that the randomization study found carisoprodol to be superior to diazepam.
procedure was adequate. Finally, in 13 of the 30 studies None of the other muscle relaxants was superior to an- (43%), the baseline status of the patients in the various other. They were all similar in performance adhering to trial arms was found not to be similar. Very often this the characteristic pattern of good efficacy and limited was the result of authors failing to report information on relevant prognostic factors that must be equally dividedbetween study groups to prevent bias. This was also true Muscle Relaxants as Adjunctive Therapy
of cointerventions. In 18 of the 30 trials (60%), cointer- It has been suggested in the literature that muscle relax- ventions were either not avoided or not equally distrib- ants in practice could be more useful as an adjunct to uted between study groups, making it difficult to assess other therapeutic methods, specifically analgesics/ the significance of the trial outcomes. To reduce the im- NSAIDs.79 This was confirmed in this review. There was pact of these methodologic deficiencies on the quality of strong evidence that combination with analgesics or the review, the authors of the various trials could have NSAIDs improved and accelerated recovery, but at the been contacted to request missing information and data.
cost of increased central nervous system adverse effects.
This, however, seemed futile, as many of the studies wereover a decade old, rendering the possibility of locating the authors and receiving the desired information The results indicate that muscle relaxants are associated with adverse events. Central nervous system events were 1990 Spine Volume 28 Number 17 2003
more prevalent in patients on muscle relaxants, with the Farrar et al28 suggest that a 2-point or 30% reduction on most common complaints being drowsiness and dizzi- an 11-point pain intensity rating scale relates to clinical ness. These effects were consistently reported with all importance for individuals with chronic pain, and Gal- benzodiazepines and nonbenzodiazepines reviewed. The lagher et al84 found the MCID for acute abdominal pain incidence of other central nervous system events was to be 16 mm on a pain intensity visual analogue scale negligible. For the gastrointestinal events, the difference (95% CI 13–18 mm). Because of the heterogeneity of with placebo was not significant, with the most common how data were reported, differences in scales used, and complaint being nausea. These adverse effects, especially lack of relevant criteria for MCID in the LBP population those involving the central nervous system adverse ef- and specifically in acute LBP, we were not able to include fects, indicate that muscle relaxants must be used with the MCID in our results. In the trials we reviewed, most caution. These findings concur with the recommenda- studies reported pain outcome data as a summary statis- tions on use of muscle relaxants in the management of tic for each group (i.e., mean scores). If the differences in LBP as cited in the United Kingdom, American, and the scores had been large, the clinical importance may Dutch guidelines17,80,81 and other guidelines.9 have been more obvious but because the changes were Chlorzoxazone is implicated in serious (including fa- often small, it was difficult to determine what should be tal) hepatocellular toxicity; however, this is a rare event.
considered clinically important. This has to do in part Another drug, chlormezanone, has been implicated in with the nature of a mean score when considering the genesis of Stevens-Johnson syndrome and toxic epi- whether to apply the results to an individual patient28,84; dermal necrolysis. Rare side effects are rarely seen in for example, if a mean change of 10 mm in pain on a VAS clinical trials with small sample sizes. A case-control in a population is required before the treatment can be study compared 245 people who were hospitalized be- considered to produce an important effect, it does not cause of these conditions and 1147 patients hospitalized imply that the same change of 10 mm is clinically impor- for other reasons. Data were obtained through surveil- tant for an individual.83 Thus, to facilitate more easily lance networks in France, Germany, Italy, and Portugal.
understandable clinical importance of results of efficacy Among the 245 cases, 13 (5%) used chlormezanone 1 to trials, we suggest future trials incorporate the recommen- 21 days before the index day, whereas only 1 among the dation of Farrar et al28 that investigators report the pro- control group used this drug. Based on the findings in this portion of subjects who observe a clinically important study, chlormezanone was discontinued in 1996 improvement in the groups being compared.
Minimally Clinical Important Difference
Implications for Practice
When evaluating the effectiveness of a treatment inter- The results of this review illustrate strong evidence that vention, statistical significance is a necessary but insuffi- nonbenzodiazepines are effective for acute LBP. The ev- cient criterion.28,29 The issue of clinical importance must idence on benzodiazepines for acute and nonbenzodiaz- also be considered, a concept that adds to the challenge epines for chronic LBP is less convincing. It is unknown if of interpreting results of trials to guide patient care.28,82 muscle relaxants are more effective than analgesics or But what constitutes a clinically importance change or NSAIDs, because there are no trials that directly com- difference in scores in an outcome of interest? For out- pared these drugs. Muscle relaxants must be used with comes such as survival, death, or hospitalization, the caution. The mechanism by which they induce their ben- answer may be clear, but for subjective outcomes such as eficial effects is also responsible for the intractable side pain, clinical importance is often difficult to effects associated with the central nervous system (drowsiness, dizziness). Therefore, it must be left to the The concept termed minimally clinical importance discretion of the physician to weigh the pros and cons, difference (MCID) has varying definitions. They all con- taking into account the needs and preferences of the in- tain the common idea of being the smallest change or dividual patient to determine whether or not a specific difference in scores that has been defined in some way as patient is a suitable candidate for a course of muscle being important.82 Among other things, the determina- tion of a MCID is dependent on the nature of scorescompared (e.g., within or between group), population(e.g., acute or chronic LBP), intervention (e.g., muscle Implications for Research
relaxants vs. placebo or vs. active treatments), and Large high quality trials are needed that directly compare whose perspective of importance is taken into consider- muscle relaxants to analgesics or NSAIDs. Another area ation (e.g., patient or clinician). Attempts to ascertain of interest is the use of peripherally acting muscle relax- MCID values for pain intensity in the LBP population ants for LBP. These agents could potentially induce the revealed a paucity of literature. Although not necessarily same beneficial effects as those that act through the cen- generalizable to the population of the current review, tral nervous system, but without the associated side ef- Muscle Relaxants for Low Back Pain van Tulder et al 1991
fects. Future studies should focus on reducing the inci- origin. Clinical evaluation of Flexeril (Cyclobenzaprine HCL/MSD). Minne- dence and severity of side effects.
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A Production Guidefor North Carolina North Carolina Cooperative Extension ServiceNorth Carolina State University North Carolina State University Description and Stages of Growth . 3 General Culture . 4 Site Selection . 4 Shade Requirements . 5 Site Preparation . 5 Transplanting Roots . 7 Shade Management . 8 Fertilization . 8 Pest Management. 8 Seed Production, Harvesting, and Handling. 9