Chronic Lower Back Pain Treatment Comparison eAnswers

8/13/2019 Chronic Lower Back Pain Treatment Comparison eAnswers

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Chronic Lower Back Pain

Background

The following is an overview of drugs used to treat chronic lower back pain, organized by their place in treatment.

First-line therapies: Acetaminophen has minimal toxicity, a low cost, and established efficacy, although some studies suggest it may not be aseffective as nonsteroidal anti-inflammatory drugs (NSAIDs). 1

,2

,3

NSAIDs ( celecoxib , diclofenac monotherapy and diclofenac /misoprostol , etodolac , fenoprofen , flurbiprofen , ibuprofen , indomethacin ,ketoprofen , meclofenamate , mefenamic acid , meloxicam , nabumetone , naproxen , oxaprozin , piroxicam , sulindac , and tolmetin ) maybe more effective than acetaminophen, 1

,2

,3 but they are associated with a number of serious adverse effects, including

gastrointestinal (GI) bleeding, cardiovascular events, and hypersensitivity reactions. 1,4

,5

,6

,7

,8

,9

,10

,11

,12

,13

,14

,15

,16

,17

,18

,19

,20

,21 As

a result, the lowest effective dosage should be used for the shortest time needed, and the addition of a proton pump inhibitor (PPI) should be considered. 1

Among NSAIDs, ibuprofen and naproxen are first-line options because of the availability of over-the-counter (OTC) genericformulations.Celecoxib , a cyclooxygenase 2 (COX-2) selective inhibitor, is a first-line NSAID for patients at high risk of GI bleeding.Diclofenac /misoprostol is an alternative to celecoxib for patients at high risk of GI bleeding, because the combinationreduces the risk of NSAID-related GI adverse effects. However, misoprostol is associated with diarrhea and abdominalpain. 22Indomethacin is associated with a risk of GI and psychological adverse effects, including psychosis, making it a last-lineoption among NSAIDs. 11

Second- and third-line therapies: Opioid analgesics ( codeine , fentanyl , hydrocodone , hydromorphone , levorphanol , meperidine ,methadone , morphine , oxycodone , oxymorphone , tapentadol , and tramadol ) have proven efficacy as painrelievers, 23

,24

,25

,26

,27

,28

,29

,30

,31

,32

,33

,34 and they are recommended for patients whose back pain is not currently or likely to be

controlled with NSAIDs or acetaminophen. However, the use of opioid analgesics is associated with serious risks, including abuse

and addiction, 1 and their long-term efficacy in the treatment of chronic low back pain has not been studied. 35Evidence supporting opioid use in chronic low back pain is conflicting and insufficient for recommendation of one opioid over others. 2

,3

,35

,36

,37

Weak opioid analgesics, such as codeine , tramadol , and hydrocodone , may be used as second-line or add-on therapies;strong opioids, such as fentanyl , hydromorphone , oxycodone , oxymorphone , and morphine , are third-line options.Methadone is a low-cost alternative to proprietary controlled-release and extended-release formulations of opioids, but itshighly variable half-life and propensity to prolong the QT interval contribute to serious safety concerns. 29 A growingconsensus suggests that methadone should only be used under the supervision of experienced clinicians. 38

Third-line therapies:Some evidence suggests that skeletal muscle relaxants ( baclofen , carisoprodol , chlorzoxazone , cyclobenzaprine , methocarbamol ,orphenadrine , and tizanidine ) are effective in treating acute and chronic low back pain, 3

,39

,40 but these drugs are associated with

a number of adverse effects, including central nervous system (CNS) effects such as sedation, abuse, and, , , , , , , , , ,


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.Benzodiazepines are not recommended for long-term use, and they are associated with CNS adverse effects and the risk of abuse and addiction. 1

Although evidence supporting the efficacy of the serotonin and norepinephrine reuptake inhibitor (SNRI) duloxetine for chronic lowback pain is limited, an uncontrolled extension of a placebo-controlled trial showed that duloxetine resulted in ongoing

improvement in pain and function over 41 weeks. 48

Limited evidence is available to support the use of salicylates ( aspirin , choline m agnesium trisalicylate , diflunisal , and salsalate ) inthe treatment of chronic low back pain, 1 but these drugs may be an alternative analgesic option for patients who are intolerant of acetaminophen or NSAIDs. Similar to NSAIDs, salicylates are associated with a risk of severe GI adverse effects, 49

,50

,51

,52 and

diflunisal is associated with an increased risk of cardiovascular events. 51

Fourth-line therapies:

Evidence supporting the use of tricyclic antidepressants (TCAs) ( amitriptyline , amoxapine , clomipramine , desipramine , doxepin ,imipramine , nortriptyline , protriptyline , and trimipramine ) in the treatment of low back pain is inconsistent, 2,36

,53

,54 and these

drugs are associated with a variety of serious adverse effects and potential drug interactions. 55,56

,57

,58

,59

,60

,61

,62

,63

Limited evidence suggests that the anticonvulsant gabapentin has short-term benefits for the treatment of radiculopathy, but thebenefits are small. The efficacy of gabapentin has not been directly compared with other treatment options for low back pain. 1

Other therapies:The antiarrhythmic mexiletine is not recommended, because it has potential toxicities and there is a lack of evidence supportingits use.

The opioid analgesic meperidine is not recommended for use as an analgesic, because there is an increased risk of seizuresassociated with buildup of its metabolite, normeperidine. 64

Review of Comparative Research

Clinical Guidelines

Clinica l Guide line Source Type of evidence

Clinical Summary

2009 InterventionalTherapies, Surgery,and InterdisciplinaryRehabilitation for Low Back Pain: An

Evidence-BasedClinical PracticeGuideline From the

American PainSociety 65

AmericanPainSociety

Systematicevidencereview of randomizedcontrolled

trials

Purpose of Guideline: The authors state, The purpose of this guideline is topresent evidence-based recommendations for use of invasive diagnostic tests,interventional therapies, surgery, and interdisciplinary rehabilitation for nonradicular low back pain, radiculopathy with herniated disc, and symptomatic spinalstenosis. 65 A guideline previously published by the same organization (discussed

below) focused on the evaluation and management of low back pain in a primarycare setting and provided recommendations on pharmacotherapy. 1

Key Points: The key points of the guideline include the following:Provocative discography is not recommended, because its diagnosticaccuracy is unclear, false-positives are not uncommon in patients without lowb k i d li i l t h t b h t i ith it


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benefits.Decisions regarding surgery should be guided by a shared decision-makingprocess that includes a detailed discussion of risks, moderate averagebenefits, and treatment alternatives. As compared with nonsurgical therapy,benefits of fusion surgery for nonradicular pain tend to be experienced only bya narrow population of low back pain patients.Evidence regarding surgery for spinal stenosis and prolapsed lumbar disc isstronger than for nonradicular low back pain surgery. However, a shareddecision-making process is also recommended.Decisions regarding spinal cord stimulation for patients with persistent painfollowing surgery for herniated disc should be guided by a shared decision-making process that includes a complete discussion of risks and benefits. 65

Notes: This guideline is scheduled to be updated in 2012. There is some debateregarding differences between this guideline and the 2009 American Society of Interventional Pain Physicians guideline on interventional techniques in themanagement of chronic spinal pain. 66

,67

,68

,69

2007 Diagnosis andTreatment of LowBack Pain: A JointClinical PracticeGuideline From the

American College of Physicians and the

American PainSociety 1

AmericanCollege of Physiciansand

AmericanPainSociety

Systematicevidencereview of randomizedcontrolledtrials andexpertconsensus

Purpose of Guideline: The authors state, The purpose of this guideline is topresent the available evidence for evaluation and management of acute and chroniclow back pain. 1

Recommendations Regarding Drug Therapies for Low Back Pain:The guideline provides the following specific recommendation regardingpharmacotherapy: For patients with low back pain, clinicians should consider the use of medication with proven benefits in conjunction with back careinformation and self-care. Clinicians should assess severity of baseline pain andfunctional deficits, potential benefits, risks, and relative lack of long-term efficacyand safety data before initiating therapy (st rong recommendation, moderateevidence). For most patients, first-line medication options are acetaminophenand nonsteroidal anti-inflammatory drugs. 1

Pharmaceutical interventions for subacute or chronic low back pain (> 4wk): The following drugs were supported by at least fair-quality evidence of moderate or small benefit but no significant harms, costs, or burdens:acetaminophen, NSAIDs, TCAs, benzodiazepines, tramadol, and other opioids.Evidence was not sufficient to recommend skeletal muscle relaxants. No

intervention was supported by good-quality evidence of substantial benefit.

Pharmaceutical interventions for acute low back pain (< 4 wk): In contrastto the recommendations for subacute and chronic low back pain, the use of skeletal muscle relaxants was supported by at least fair-quality evidence of

d t ll b fit b t i ifi t h t b d h


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dosage of NSAIDs for the shortest time necessary. The risk of GI adverse effectsin high-risk patients can be minimized by coadministration of a PPI.

Aspirin: Evidence is insufficient to recommend for or against aspirin for treatinglow back pain.

Opioid analgesics: Opioid analgesics, including tramadol, are an option inpatients with acute or chronic low back pain that is not controlled or not likely tobe controlled by acetaminophen or NSAIDs, but they should be used judiciously.Opioid analgesics are associated with substantial risks, including aberrant drug-related behaviors with long-term use, particularly in patients who are vulnerable toabuse or addiction. There is insufficient evidence to recommend one opioid over another. It should be noted that tapentadol, which is both a mu opioid agonistand a norepinephrine reuptake inhibitor, was not available at the time thisguideline was created.

Skeletal muscle re laxants: Tizanidine has been well studied in patients withlow back pain. However, there is little evidence to support the use of other skeletal muscle relaxants, such as baclofen or dantrolene, in the treatment of low back pain. All skeletal muscle relaxants are associated with a risk of CNSadverse effects, primarily sedation. There is little evidence supporting a differencein efficacy or safety among skeletal muscle relaxants. However, because their

mechanisms of action vary substantially, it is possible that their risk-benefitprofiles vary as well. Carisoprodol is metabolized to meprobamate, which carriesa risk of abuse and overdose. Tizanidine and chlorzoxazone carry a risk of hepatotoxicity, although it is often reversible.

Antidepressants: TCAs can be prescribed for pain relief in patients with chroniclow back pain and no contraindications. SSRIs and trazodone have not beenshown to be efficacious in relieving low back pain. SNRIs have not been studied

in patients with low back pain. However, depression is common in patients withchronic low back pain and should be treated appropriately.

Gabapentin: Evidence suggests that gabapentin has small, short-term benefitsin radiculopathy, but its efficacy has not been compared directly with other drug

treatment options. It is not FDA approved for the treatment of low back pain.

Benzodiazepines: Evidence suggests that benzodiazepines and skeletalmuscle relaxants are similarly efficacious for short-term pain relief, butbenzodiazepines are associated with risks of abuse, addiction, and increasedtolerance. If they are prescribed, a limited duration of therapy is recommended.Benzodiazepines are not FDA approved for the treatment of low back pain.

S t i ti t id E id h t h th t t i


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CNS central nervous systemCOX-2 cyclooxygenase 2FDA US Food and Drug AdministrationGI gastrointestinal

NSAIDs nonsteroidal anti-inflammatory drugsPPI proton pump inhibitor SNRI serotonin and norepinephrine reuptake inhibitor SSRI selective serotonin reuptake inhibitor TCA tricyclic antidepressant

Meta-Analyses

Meta-analyses Drug (Class) Study Population Study

Endpoints

Clinical Findings

A SystematicReview on theEffectiveness of PharmacologicalInterventions for Chronic Non-Specific Low-

Back Pain 36

Desipramine(TCA), Naproxen(NSAID),Nortriptyline(TCA), Oxycodone(opioidanalgesic),

Oxymorphone(opioidanalgesic),Tramadol (opioidanalgesic)

N = 3,662 (for pain outcomes); 17 randomizedcontrolled trials on NSAIDs (n = 4), antidepressants(n = 5), and opioids (n = 8) were included; NSAIDsincluded in the analysis were naproxen, etoricoxib,rofecoxib, and valdecoxib; antidepressants includedin the analysis were bupropion, desipramine,fluoxetine, maprotiline, nortriptyline, and paroxetine;

opioids included in the analys is were oxymorphone,tramadol, tramadol/acetaminophen, oxycodone,and oxycodone/naltrexone; no eligible studies werefound on skeletal muscle relaxants in the treatmentof chronic low back pain; selection criteria includedan adult study population (aged 18 y) with chronicnonspecific low back pain ( 12 wk) and evaluationof pain, functional status, and perceived recovery or

return to work; chronic nonspecific low back paincould include discopathy or any other nonspecificdegenerative pathology, such as osteoarthritis;trials on specific low back pain due to conditionssuch as vertebral spinal stenosis, ankylosingspondylitis, scoliosis, and coccydynia wereexcluded

Pain intensity

Functionalstatus

Adverseevents

Opioids andNSAIDs providedsomewhat better pain relief thanplacebo in patientswith chronicnonspecific low

back pain (NSAIDsvs placebo: WMDof change frombaseline on 100-mm VAS, 12.4;95% CI, 15.53 to9.26; opioids vsplacebo: SMD,

0.54; 95% CI,0.72 to 0.36).

Opioids improvedfunction in selectpatients who hadan exacerbation of

their symptomsafter stoppingmedication, but theeffect was small(SMD in disability,0.19; 95% CI,

0 31 t 0 08)


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Of the 4 trials of NSAIDs, only 1evaluated a nonCOX-2 select iveNSAID.

Antidepressantswere no moreefficacious thanplacebo in relievingpain in patientswith chronicnonspecific lowback pain (SMD,0.02; 95% CI,0.26 to 0.22).

Of the 12 includedstudies on NSAIDsor opioids, 8 onlyevaluated patients

who wereresponding totreatment and had

significant painflares during awashout period,which could have

resulted in anoverestimation of positive results .

Reported resultswere based onstudies lasting < 3mo.

The overall qualityof the evidencewas low.

Antidepressants Amitriptyline N = 689; 10 studies comparing antidepressants Pain intensity Antidepressants


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,0.06; 95% CI,0.4 to 0.29).

Qualitativeevidence was

conflictingregarding theefficacy of antidepressants inreducing painintensity in chroniclow back paincompared withplacebo.

In an analysis of specific types of antidepressants,neither SSRIs(SMD, 0.11; 95%

CI, 0.17 to 0.39)

nor TCAs (SMD,0.1; 95% CI,0.51 to 0.31)were moreefficacious thanplacebo in relievingchronic low backpain.

The findings werenot altered bysensitivityanalysis, whichallowed for inclusion of moretrials.

The meta-analysiswas limited byvariation in patientcharacteristicsbetween includedt i l th b


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Back Pain 3 Flurbiprofen

(NSAID),Ibuprofen(NSAID),Indomethacin(NSAID),Ketoprofen(NSAID),Mefenamic acid(NSAID),Naproxen(NSAID),Piroxicam(NSAID)

controlled trials of NSAIDs in adult patients withnonspecific low back pain with or without sciatica

Adverseevents

effective short-termsymptomatic painrelief in patientswith acute lowback pain without

sciat ica; however,the effect sizeswere small (meandifference inchange in 100-mmVAS pain score,7.69; 95% CI,12.08 to 3.3).

In patients with

sciatica, NSAIDswere no moreefficacious thanplacebo (meandifference inchange in 100-mm

VAS pain score,0.16; 95% CI,11.92 to 11.59).

Overall, NSAIDswere significantlymore efficaciousthan placebo when

follow-up was 3wk (meandifference inchange in 100-mmVAS pain score8.39; 95% CI,12.68 to 4.1),but they were

associated withsignificantly moreadverse events (RR= 1.35; 95% CI,1.09 to 1.68).

NSAID l


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associated withsignificantly moreadverse events (RR= 1.24; 95% CI,1.07 to 1.43).

Moderate evidencesuggested thatNSAIDs andacetaminophen

were similarlyefficacious for acute low back

pain (SMD of painintensity on variousscales, 0.21;95% CI, 0.43 to0.02), but NSAIDsled to moreadverse events (RR= 1.76; 95% CI,

1.12 to 2.76).

No statisticaldifference wasfound betweenNSAIDs andmuscle relaxantsor opioids in the

treatment of acutelow back pain.Because of heterogeneity of the data,estimations of RRwere notperformed.

Strong evidencesuggested thatselec tive COX-2inhibitors andnonselectiveNSAID


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efficacious for chronic low backpain (meandifference inchange in 100-mm

VAS pain score, 2;95% CI, 1.92 to5.92).

COX-2 inhibitorswere associatedwith a lower risk of adverse events

than traditionalNSAIDs in patientswith subacute or chronic low backpain (RR = 0.67;95% CI, 0.45 to 1)or chronic lowback pain (RR =

0.89; 95% CI, 0.7to 1.13), but theresults did notreach s tatisticalsignificance.

Medications for Acute and

Chronic LowBack Pain: AReview of theEvidence for an

American PainSociety/AmericanCollege of Physicians

Clinical PracticeGuideline 2

Acetaminophen , Aspirin

(salicylate),Benzodiazepines,Duloxetine(SNRI),Gabapentin(anticonvulsant),NSAIDs, Opioidanalgesics,Skeletal musclerelaxants, TCAs

A total number of patients was not provided, as thisreview of evidence included systematic reviews as

well as randomized controlled trials; drugs coveredby systematic reviews included NSAIDs,antidepressants, skeletal muscle relaxants,benzodiazepines, and multiple medications;randomized controlled trials examinedacetaminophen, celecoxib, aspirin, duloxetine,venlafaxine, anticonvulsants, opioid analgesics,tramadol, and systemic corticosteroids; good

evidence was defined as that including consistentresults from well-designed, well-conducted s tudiesin representative populations that directly assesseffects on health outcomes 2 ; fair evidence wasdefined as that sufficient to determine effects onhealth outcomes, but the strength of the evidence

Benefits andharms of

drugs used totreat acuteand chroniclow back pain(this summaryprovidesinformationabout chronic

low back pain)

Evidence from 5trials in patients

with varyingdurations of lowback pain and 4systemic reviewsof pain in patientswith osteoarthritisof varying locationssuggested that the

benefit of acetaminophen iseither equivalent or slightly inferior tothat of NSAIDs.


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associated withacetaminophenincludedasymptomaticelevations of liver function testresults attherapeuticdosages.

Good evidencefrom 10 trialssupported a small

to moderate effectfor antidepressantsin chronic or subacute low backpain, as well astheir efficacy vsplacebo.

Amongantidepressants,only TCAs havebeen shown to beefficacious for lowback pain. Noevidence wasavailable on

duloxetine or venlafaxine.

Poor evidence from1 trial ontopiramatesuggested thatantiepileptics havea small tomoderate netbenefit and areefficacious vsplacebo in chroniclow back pain; fair

id f 1


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Fair evidence from3 trials supported amoderate netbenefit for benzodiazepines inchronic or subacute low backpain, althoughthere was someinconsistency inthe resultsshowing greater efficacy than

placebo.

Good evidencefrom 6 trialssupported amoderate netbenefit for NSAIDsin treating chronic

or subacute lowback pain, and 1trial showedefficacy vsplacebo.

There wasinsufficient

evidence todetermine thebenefits and harmsof aspirin or celecoxib for lowback pain.

Fair evidence from7 trials suggesteda moderate netbenefit for opioidsin chronic or subacute low backpain, and data from1 t i l t d


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back pain.

Because only poor evidence wasavailable onskeletal musclerelaxantsobtainable in theUnited States, theauthors were notable to estimate anet benefit for their use in chronic or subacute low back

pain.

Fair evidencesupported amoderate netbenefit for tramadolin chronic or subacute low back

pain and greater efficacy thanplacebo.

This article was asystematic reviewof the literature,including clinical

trials and meta-analyses;independent meta-analyses were notperformed.

Opioids for Chronic Low-

Back Pain 37

Morphine (opioidanalgesic),

Oxycodone (opioidanalgesic),Naproxen

(NSAID),Tramadol (opioidanalgesic)

N = 950; the meta-analysis included 4 trials thatwere randomized or quasi-randomized, assessed

the use of opioids as monotherapy or incombination therapy for chronic low back pain inadults, and compared noninjectable opioids with

other treatments or placebo; trials that comparedopioids with other opioids were excluded

Pain relief

Functionalstatus

Adverseevents

Results from 3trials showed that

tramadol was moreefficacious thanplacebo for

relieving pain(SMD, 0.71; 95%CI 0 39 to 1 02)


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nausea (RD, 9%;95% CI, 6% to12%), somnolence(RD, 9%; 95% CI,5% to 13%), andconstipation (RD,8%; 95% CI, 4% to12%).

Results from 1 trialrevealed thatopioids (morphineand oxycodone)were no more

efficacious thannaproxen for relieving pain(SMD, 0.58; 95%CI, 1.42 to 0.26)or improvingfunction (SMD,0.06; 95% CI,

0.88 to 0.76).

The authors notethat few high-quality studies areavailable evaluatingthe efficacy of opioids for long-

term managementof chronic low backpain.

SystematicReview: OpioidTreatment for Chronic BackPain: Prevalence,Efficacy, and

Association withAddiction 35

Opioid analgesics N = 1,008; the meta-analysis included 9 studies; 4studies compared opioids with placebo or anonopioid control, and 5 studies compared opioidswith other opioids; selection criteria included anadult population; a nonobstetric sample; use of atopical, oral, or transdermal opioid; and a focus onchronic back pain

Pain intensity

Prevalence of lifetimesubstanceabusedisorders

The long-term (16 wk) efficacy of opioid therapy for chronic low backpain is unclear.

Opioids were foundto be no more


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with anonsignificantreduction in painfrom baseline in ameta-analysis of 5studies comparingdifferent opioids(composite SMD,0.93; 1.89 to0.03; P = 0.055).

Poor-qualityevidencesuggested that

lifetime substanceabuse disordershad a prevalenceranging from 36%to 56%.

Poor-qualityevidence

suggested thatcurrent substanceuse disorders werepresent in 3% to43% of patientsreceiving opioids.

Poor-quality

evidence

suggested that arange of 5% to24% of patientsreceiving opioidsdisplayed aberrantmedication-takingdisorders.

The authorscaution that theoverall quality of the availablestudies was low


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Meta-Analysis of RandomizedClinical Trials 70

(NSAID),Naproxen(NSAID)

with patients treated with nonselective NSAIDs(diclofenac, ibuprofen, naproxen, ketoprofen, or loxoprofen) for 4,386 patient-years (n = 13,990); a3-member expert end point committee blinded totreatment group and study adjudicated thecardiovascular events; included studies involved

patients with osteoarthritis (n = 21), rheumatoidarthritis (n = 4), osteoarthritis and rheumatoidarthritis (n = 6), ankylosing spondylitis (n = 2), lowback pain (n = 4), or Alzheimer disease (n = 2); allstudies were from Pfizer's celecoxib drug safetydatabase

Cardiovascular death

Compositeoutcome of

nonfatalmyocardialinfarction,nonfatalstroke, andcardiovascular death

outcomes (RR =1.11; 95% CI, 0.47to 2.67; P = 0.81;NNH = 454).

Compared with

placebo, celecoxibwas notassociated with asignificantlyincreased risk of cardiovascular death (RR = 1.26;95% CI, 0.33 to

4.77; P = 0.74),nonfatalmyocardialinfarction (RR =1.56; 95% CI, 0.21to 11.9; P = 0.67),or nonfatal stroke(RR = 0.8; 95% CI,

0.19 to 3.31; P =0.75).

Celecoxib andnonselective

NSAIDs wereassociated withsimilar incidencerates of combinedcardiovascular outcomes (RR =0.9; 95% CI, 0.6 to1.33; P = 0.59;NNH = 625,favoring celecoxib).

Compared withnonselectiveNSAIDs, celecoxibwas notassociated with asignificantlyincreased risk of


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CI, 0.23 to 1.1; P =0.09).

The results werenot altered bycelecoxib dosage,

aspirin usage, or the presence of cardiovascular riskfactors.

The authors notethat a limitation of the meta-analysis

is that none of thestudies comparingcelecoxib withnonselectiveNSAIDs had > 1 yof patient follow-up,with the exception

of 1 small study.

Results from the APC, PreSAP, and ADAPT trials werenot included,because they wereongoing andresults wereblinded at the timeof this analysis.

This study relied inwhole or in part onindustry funding.

SystematicReview of

Antidepressantsin the Treatmentof Chronic LowBack Pain 71

Amitriptyline(TCA),Imipramine(TCA),Nortriptyline (TCA)

N = 440; 7 trials on chronic low back pain wereincluded; all trials had a randomized, placebo-controlled trial design and sufficient data to assesstreatment response in patients with chronic backpain; included trials were published between 1976and 2000; drugs examined in the included studies

Pain intensity

Functionalstatus

Data from 5studies suggestedthat tricyclic or tetracyclicantidepressantsproduce moderate


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with low back pain.

The analgesiceffect sizeassociated withnortriptyline, based

on data from 1study, was 0.43,and the reductionin pain withnortriptyline was22% vs 9% for placebo ( P = 0.05).

Trazodone did notbenefit patientswith chronic low

back pain in termsof pain relief or functional status,and SSRIs did notbenefit patients in

terms of pain relief.

There wereinsufficient data toconduct a meta-analysis.

Muscle

Relaxants for Nonspecific LowBack Pain: ASystematicReview Within theFramework of theCochraneCollaboration 39

Baclofen (skeletal

muscle relaxant),Carisoprodol(skeletal musclerelaxant),Chlorzoxazone(skeletal musclerelaxant),Cyclobenzaprine(skeletal musclerelaxant),Diazepam(benzodiazepine),Orphenadrine(skeletal musclerelaxant)

N = 2,884; 30 trials were included; 24 trials

examined acute low back pain; 23 trials were of high quality; all trials were published between 1966and 1998; the trials examined benzodiazepines vsplacebo (n = 4), nonbenzodiazepines vs placebo (n= 11), antispasticity muscle relaxants vs placebo (n= 2), muscle relaxants vs muscle relaxants (n = 8),and muscle relaxants plus analgesics or NSAIDsvs placebo plus analgesics or NSAIDs (n = 6);

selection criteria included randomized and/or double-blinded, controlled trial design, subjects withnonspecific low back pain, and treatment with amuscle relaxant as monotherapy or in combinationwith other therapies

Pain relief

Adverseevents

Limited evidence

was available onthe treatment of chronic low backpain withnonbenzodiazepinemuscle relaxants,includingcarisoprodol,

chlorzoxazone,cyclobenzaprine,methocarbamol,orphenadrine, andtizanidine.


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tetrazepam wasmore efficaciousthan placebo inrelieving pain inpatients withchronic low backpain, both after 5to 7 d of follow-up(RR = 0.82; 95%CI, 0.72 to 0.94)and after 10 to 14

d of follow-up (RR= 0.71; 95% CI,

0.54 to 0.93).

Moderate evidencefrom 1 trialsuggested thatflupirtine is moreefficacious thanplacebo for overall

muscleimprovement andshort-term painrelief in low backpain after 7 d, butnot for reduction of muscle spasm.

In 1 high-qualitytrial, tolperisonewas shown to bemore efficaciousthan placebo for short-term overallimprovement, butnot for pain relief and reduction of muscle spasm.

In trials of acutelow back pain,muscle relaxantswere associated


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conclude thatmuscle relaxantsare effective in themanagement of acute and chronicnonspecific low

back pain, but theadverse effectsrequire that theybe used withcaution. 39

The authors note

that there wassome dissimilarityamong patientcharacteristics intreatment armsand that co-interventions wereallowed in many

trials.

The Effect of AntidepressantTreatment onChronic BackPain 54

Amitriptyline(TCA),Desipramine(TCA), Doxepin(TCA),

Imipramine(TCA),Nortriptyline (TCA)

N = 504; 9 randomized controlled trials with 10treatment arms were included; 7 treatment armsincluded patients with major depression; allincluded trials were published between 1976 and2000; antidepressants included in the analysis

were amitripty line, desipramine, doxepin,imipramine, maprotiline, nortriptyline, paroxetine,and trazodone; selection criteria included patientswith low back discomfort for 2 mo, randomized,placebo-controlled trial design, and measurableoutcomes; patients had chronic back pain for anaverage of 10.4 y

Pain severity

Act ivities of daily living

Adverseevents

Antidepressantswere more likelythan placebo toreduce painseverity (SMD,

0.41; 95% CI, 0.22to 0.61) but not toimprove activitiesof daily living(SMD, 0.24; 95%CI, 0.21 to 0.69).

For the outcome of

pain severity, therewas no evidence of heterogeneity of effect sizes amongstudies or of publication bias.


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. .

Antidepressantswere associatedwith a greater frequency of

adverse eventsthan placebo (22%vs 14%; P = 0.01).

ADAPT Alzheimer's Disease Anti-Inflammatory PreventionAPC Adenoma Prevention With CelecoxibCI confidence intervalCOX-2 cyclooxygenase 2NNH number needed to harmNSAIDs nonsteroidal anti-inflammatory drugsPreSAP Prevention of Colorectal Sporadic Adenomatous PolypsRD risk differenceRR relative riskSMD standardized mean differenceSNRI serotonin and norepinephrine reuptake inhibitor

SSRI selective serotonin reuptake inhibitor TCA tricyclic antidepressantVAS visual analog scaleWMD weighted mean difference

Comparative Efficacy Trials

Drug (Class) Clinica lTrial

Study Population Dose/Duration Study Endpoints Clinical Findings

Tapentadol(opioidanalgesic) 72

Open-label,randomizedcontrolledtrial

N = 1,095 (ITTpopulation); patients(aged 18 y) withmoderate to severechronic knee or hiposteoarthritis pain or lowback pain wererandomized 4:1 toextended-releasetapentadol (n = 876) or controlled-releaseoxycodone (n = 219);inclusion criteria

Controlled-releaseoxycodone: Adjustabledosage of 20 to 50 mgtaken orally twice daily

Initial titrationperiod: 10 mgtwice daily for 3 dFor the next 4 d,the dosage wasincreased to 20mg twice daily

Safety of extended-releasetapentadoldosed twicedaily over 1 y

Average painintensity on an11-point NRSover a 24-hperiod

Extended-releasetapentadol andcontrolled-releaseoxycodone weresimilarly efficacious inreducing pain intensityscores, but tapentadolwas associated withfewer adverse events.

Mean pain intensityscores were similar inthe extended-release


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brain neoplasm

After the first week, thedosages of oxycodoneand tapentadol could beadjusted under the

supervision of a physician

Treatment duration, 1 y

similar in both theextended-releasetapentadol andcontrolled-releaseoxycodone groups(85.7% vs 90.6%).

A minority of patients inboth the extended-release tapentadol group(46.2%) and thecontrolled-releaseoxycodone group (35%)completed treatment.

More patients in thecontrolled-releaseoxycodone groupdiscontinued treatmentbecause of treatment-related adverse eventscompared with the

extended-releasetapentadol group (36.8%vs 22.7%).

Treatment-related GIadverse events caused8.6% of patients in thetapentadol group and21.5% of patients in theoxycodone group todiscontinue treatment.

Extended-releasetapentadol wasassociated with a higher rate of psychiatricdisorders thancontrolled-releaseoxycodone (21.5% vs13.5%).

The most commonadverse events in the

Thi d li d i


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This study relied inwhole or in part onindustry funding.

Duloxetine(SNRI) 48

Dose-blindedextension of a double-blinded,placebo-controlledtrial

N = 181; patients (aged 18 y) with chronic lowback pain for 6 mocontinued duloxetinetreatment from theplacebo-controlled trial(n = 83) or wereswitched from placeboto duloxetine (n = 98);inclusion criteria

included pain restrictedto the low back or radiating to the proximalthigh; pertinentexclusion criteriaincluded radiculopathy,spinal stenosis, high-grade spondylolisthesis,

and major depressivedisorder

Duloxetine 60 or 120 mgdaily taken orally

Patients who hadreceived duloxetine 60mg or 120 mg daily at theend of the placebo-controlled study remainedon their respectivedosages

Patients in the placebogroup entered a 2-wktitration period: 30 mgdaily for 1 wk followed by60 mg daily for 1 wk

After the 2-wk tit ration

period, patients who hadbeen switched fromplacebo to duloxetineentered a 39-wktreatment period

Patients takingduloxetine 60 mg daily

could increase their dosage to 120 mg dailybeginning 9 wk into theextension phase

Patients takingduloxetine 120 mg dailycould not return toduloxetine 60 mg dailyunless they withdrewfrom the study

Regular usage of NSAIDsor acetaminophen was

30% reductionin Brief PainInventoryaverage painscore

50% reductionin Brief PainInventoryaverage pain

score

30% reductionin Brief PainInventoryaverage painscore at the endof the extension

phase

Adverse events

Patients who continuedduloxetine therapy andpatients who wereswitched from placebo toduloxetine experiencedfurther decreases inmean Brief PainInventory scores.

About 85% of patients in

the continued duloxetinegroup and about 75% of patients in the placebo-to-duloxetine groupexperienced 30%reduction in Brief PainInventory average painscores.

The difference inresponse rates wassimilar for 50%reduction in Brief PainInventory average painscore (80% vs 70%)and a 30% reduction at

the end of the extensionphase (65% vs 55%).

More patients in theplacebo-to-duloxetinegroup discontinued theextension phasebecause of adverseevents compared withthe continued duloxetinegroup (13.3% vs 6%).

More patients in theplacebo to duloxetine


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Celecoxib(NSAID),Tramadol(opioidanalgesic) 73

2randomized,double-blind,double-dummystudies

N = 1,598; patients(aged 18 y) withchronic low back painfor 12 wk and requiringregular use of analgesics 4 d per week were randomizedto celecoxib (n = 404) or tramadol (n = 389) instudy 1 and celecoxib (n= 396) or tramadol (n =396) in study 2;pertinent exclusioncriteria included ahistory of rheumatoidarthritis;spondyloarthropathy;spinal stenosisassociated withneurological impairment;malignancy;fibromyalgia; infectionsof the brain, spinal cord,or peripheral nerves; aherniated discassociated withneurological impairmentwithin the past 2 y;psoriasis; and seizuredisorder

Celecoxib 200 mg twicedaily taken orally

Tramadol 50 mg 4 timesdaily taken orally

Both studies had a 14-dwashout period duringwhich acetaminophen 2g daily was allowed

Concomitant aspirin andacetaminophen werepermitted for thetreatment of other conditions

No rescue medicationwas allowed during theactive phase

Study duration, 6 wk

Successfulresponse,defined ascompleting 6 wkof treatment andhaving 30%improvement onan NRS for pain

Adverse events

Discontinuations

Celecoxib wasnoninferior to tramadol inachieving a successfulresponse and wasassociated with fewer adverse events.

More evaluable patientsin the celecoxib groupthan in the tramadolgroup respondedsuccessfully totreatment in both study 1(RD = 0.092; 95% CI,0.022 to 0.161) andstudy 2 (RD = 0.058;95% CI, 0.0112 to0.1277).

Exclusion from theevaluable population wasmost commonly due to

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