REVIEW ARTICLE

Disease-modifying Antirheumatic Drugs for the Treatment of Low Back Pain: A Systematic Review of the Literature Khalid M. Malik, MD; Ariana Nelson, MD; Honorio Benzon, MD Department of Anesthesiology, Northwestern University, Chicago, Illinois, U.S.A.

& Abstract: Low back pain (LBP) is a common source of pain and disability, which has an enormous adverse impact on affected individuals and the community as a whole. The etiologies of LBP are protean and local inflammation contributes to the majority of these processes. Although an array of potent disease-modifying anti-rheumatic drugs (DMARDs), which are typically anti-inflammatory in character, have become clinically available only corticosteroids are routinely used for the treatment of LBP. To further investigate this potentially underutilized therapy, we reviewed the available literature to determine the role of DMARDs in the treatment of LBP. Our results show that the current DMARD use for LBP is indeed limited in scope and is characterized by isolated use and empiric selection of drugs from a range of available DMARDs. Moreover, the dose, frequency, and route of drug administration are selected arbitrarily and deviated from treatment protocols proposed for the management of other inflammatory conditions. The literature published on this topic is of low quality, and the results of the reviewed trials were inconclusive or demonstrated only short-term efficacy of these medications. Based on the findings of this review, we recommend that the future DMARD use for LBP is initially limited to patients with debilitating disease who are unresponsive to conventional treatments, and the criteria for drug selection and routes of drug administration are clearly

Address correspondence and reprint requests to: Khalid M. Malik, MD, Department of Anesthesiology, Northwestern University, Suite 5-704, 251 E Huron Street, Chicago, IL 60611, U.S.A. E-mail: [email protected]. Submitted: February 4, 2015; Revision accepted: April 7, 2015 DOI. 10.1111/papr.12323

© 2015 World Institute of Pain, 1530-7085/16/$15.00 Pain Practice, Volume 16, Issue 5, 2016 629–641

defined and may be modeled after treatment protocols for other inflammatory conditions. & Key Words: disease-modifying agents, disease-modifying antirheumatic drugs, DMARD, low back pain, systematic review

INTRODUCTION Low back pain (LBP) is a common source of pain and disability which has enormous adverse impact on affected individuals and the community as a whole.1,2 The direct and indirect costs of LBP exceed 100 billion dollars each year in the United States alone.3 LBP may originate from a variety of conditions, the most common of which are herniated and degenerated disks, arthritic and stenotic spinal changes and ligamental and myofascial disorders.4,5 Although the pathological processes causing LBP are myriad, local inflammatory response has emerged as a key mediator of pain.6,7 The proinflammatory properties of herniated nucleus pulposus are well recognized8,9 and degenerated and herniated disks are also known to produce elevated levels of proinflammatory cytokines.10 Conceivably, anti-inflammatory drugs could play a prominent role in the treatment of LBP. Yet despite the host of anti-inflammatory drugs available, only systemic NSAIDs and systemic or epidural corticosteroids are routinely used for the treatment of LBP.11 Disease-modifying antirheumatic drugs (DMARDs) are a large class of drugs, the majority with anti-inflammatory characteristics, that have become increasingly available in the past few decades.12

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DMARDs fall into two categories: biological or nonbiological.12 While nonbiological DMARDs are a diverse group of molecules, such as sulfasalazine, levamisole, and methotrexate, biological DMARDs are monoclonal antibodies that bind and inhibit key cytokines such as TNF-a, IL-1, and IL-6.12,13 Unlike corticosteroids and nonbiological DMARDs, biological DMARDs target extracellular cytokines and therefore have few metabolic side effects although they may increase susceptibility to infections. DMARDs are currently used to treat a host of inflammatory and autoimmune conditions such as rheumatoid arthritis, Crohn’s disease, inflammatory bowel disease, psoriasis, and ankylosing spondylitis.13 The DMARD treatment protocols for these conditions are characterized by one or more drugs and typically biological and nonbiological DMARDs are used in combination.14 To determine the current state of DMARD use in patients with LBP, we performed a systematic review of the literature in order to assess their efficacy and provide recommendations for their potential clinical use in patients with LBP and to guide possible future research.

METHODS Search Strategy We performed a PubMed, Ovid MEDLINE, EMBASEmbase, Cochrane Library and hand search of bibliography of the articles reviewed (January 2013 and repeat search in November 2014) using no limits and used the search terms “back pain AND drug,” “sciatica AND drug,” “epidural injection AND drug”. The “drug” in the search was each of the commonly available DMARDs and included: abatacept, azathioprine, chloroquine, cyclophosphamide, cyclosporine, leflunomide, methotrexate, mycophenolate mofetil, rituximab, sulfasalazine, tocilizumab, adalimumab, certolizumab, etanercept, golimumab, infliximab, ranibizumab, and bevacizumab. Corticosteroids/glucocorticoids were excluded. After accounting for the duplicate studies that appeared under various search headings 346 distinct publications were identified. The number of studies retrieved for each DMARD is listed in Table 1.

Table 1. Search Results for DMARD use Related to Back Pain and/or Sciatica Drug

Articles retrieved

Pain from HNP/DDD

Search terms used: DMARD and Back pain, DMARD and Sciatica, DMARD and Epidural injection 47 16 Etanercept—Enbrelâ Abatacept—Orenciaâ 3 0 28 0 Azathioprine—Imuranâ Chloroquine 6 0 72 0 Cyclophosphamide—Cytoxanâ Cyclosporine—Neoralâ, 19 0 Sandimmuneâ â Leflunomide—Arava 7 0 86 1 Methotrexate—Rheumatrexâ, Trexallâ Mycophenolate Mofetil – Cellceptâ 1 0 Rituximab—Rituxanâ 10 0 Sulphasalazine 43 0 â 1 1 Tocilizumab—Actemra Adalimumab—Humiraâ 21 3 4 0 Golimumab—Simponiâ Infliximab—Remicadeâ 52 16 Bevacizumab—Avastinâ 4 0 0 0 Ranibizumab—Lucentisâ Total search results = 404 citations, 346 distinct publications. Relevant articles = 37. Articles reviewed = 34 (after excluding duplicates and non-English articles).15–48 DMARD, Disease-modifying antirheumatic drugs; DDD, Degenerative Disc Disease; HNP, Herniated Nucleus Pulposus.

degenerative condition. The excluded publications discussed a range of topics which included the use of DMARDs for various spondyloarthritic conditions, particularly the reports of spinal adverse effects, such as epidural abscess, from DMARD use. Articles not in the English language and duplicate studies were excluded. Data Extraction The abstract of each study retrieved was reviewed independently by two authors (KMM and AMN). In any instance where the information attained from the abstract was ambiguous, the full text was reviewed. Disagreements were resolved by mutual consensus. Of the 346 articles retrieved, 34 publications met the inclusion criteria and were further reviewed.15–48 The study analysis focused on the specific drug used, dose and mode of drug administration, efficacy of the drug, any safety measures adopted for the novel drug use, and the adverse effects reported.

Study Eligibility Criteria Inclusion criteria were use of a DMARD in a study as a treatment option for low back pain, radicular pain, sciatica, herniated disk, or any other painful spinal

Qualitative Analysis The internal validity of the reviewed trials was based on recommendations from several research groups,

DMARDs for Low Back Pain  631

which were dependent upon the adequacy of randomization and blinding techniques used, the extent of availability of patient follow-up data and the suitability of the statistical techniques used in the assessed trials (Table 2).49–51 The presence of these various study attributes rendered a positive score, while their absence, or if an element could not be ascertained, earned no score. From a possible maximum score of 15 points, a score below 10 points indicated significant failures in randomization, blinding and/or unacceptable attrition of the study population and the trial was graded as a “low-quality” trial. A score between 10 and 12 points indicated acceptable study parameters but omission of at least one key element, which rendered it an “intermediate-quality” trial. A score above 12 points suggested proper randomization, blinding and low attrition rate and designated a “high-quality” trial.

Table 2. Criteria for Assessing Internal Validity the Trials Presence of an item rendered a + score while its absence (or if an element could not be ascertained) ensued no score

Score

Eligibility

Yes/No/Unsure

Randomization

Attrition

Blinding

Data Analysis

Low-quality Trial Intermediatequality Trial High-quality Trial

Eligibility criteria specified Trial described as randomized Use of effective random allocation technique described Concealment of random allocation described Assigned intervention received by all subjects Withdrawals and drop-outs accounted for Dropouts < 15% Study described as double-blinded Blinding of all study participants Blinding of all treatment providers Blinding of all evaluators Baseline characteristics described Similar or adjusted baseline characteristics Between-group comparisons Primary outcome defined

Yes/No/Unsure Yes/No/Unsure

Yes/No/Unsure Yes/No/Unsure Yes/No/Unsure Yes/No/Unsure Yes/No/Unsure

Efficacy of the drugs used in the reviewed studies was determined using the best evidence hypothesis which relies on the highest quality evidence available in lieu of the data of lesser value (Table 3).52 This review methodology is particularly suitable when pooling across the studies is not possible due to the small number of studies reporting on multiple study categories. Similar to the standard for meta-analysis, the standards for evidence and study selection criteria in best evidence method are predetermined. However, additional study details are provided to permit readers the opportunity to formulate their own opinion of the reviewed literature. The trials analyzed in this review reported use of multiple drugs given at dissimilar doses and employed several routes of drug administration. Consequently, the data acquired was heterogeneous and was not suitable for pooling and meta-analysis. The randomized controlled trials (RCTs) available on the topic were considered the strongest evidence available and were therefore graded using the above-mentioned criteria, and the efficacy of the drugs used was evaluated using the best evidence hypothesis.

RESULTS Of the 34 publications reviewed (Figure 1), 19 were clinical15–33 and 10 were animal model studies.34–43 The DMARDs used and their mode of administration, including dose and route of drug administration, is presented in Table 4. Of the range of available DMARDs, only four—etanercept, infliximab, adalimumab, and tocilizumab—were used clinically in ten,15–20,25–28 six,21,22,29–32 two,23,33 and one24 study, respectively. Methotrexate was used in only 2 animal

Yes/No/Unsure

Table 3. Qualitative Analysis—Best Available Evidence

Yes/No/Unsure

The best scientific evidence

Level of evidence

Yes/No/Unsure

Strong evidence: Consistent +ve results in multiple high-quality trials Moderate evidence: Consistent +ve results in a highquality and one or more lowquality trials Limited evidence: Consistent +ve results in a highquality or more than one lowquality trials Inconclusive evidence: Positive results in a low-quality or inconclusive results in a highquality trials

Level A: Benefits greatly outweigh risks treatment offered routinely Level B: Benefits outweighs risks treatment can be offered

Yes/No/Unsure Yes/No/Unsure Yes/No/Unsure Yes/No/Unsure

Major flaws in randomization and/or blinding and/or unacceptable attrition Acceptable randomization, blinding and attrition, however, some specifics omitted Adequate randomization and blinding techniques described with low attrition rate

Adapted from Furlan,49 Moher,50 and Andrews.51

Analysis of Efficacy

< 10 10–12 > 12

Adapted from Slavin.52

Level C: Narrow risk–benefit ratio treatment offered in specific circumstances Level D: Risks outweighs any benefits treatment should not be routinely offered

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346 Distinct Publications

5 Review Articles44-48

9 Observational Studies25-33

3 of subcutaneous etanercept injections25-27 1 of epidural etanercept injection28 4 of intravenous infliximab infusion29-32 1 of subcutaneous adalimumab injections33

10 Randomized Trials15-24

4 of epidural etanercept injections15-18 1 of intradiscal etanercept injections19 1 of subcutaneous etanercept injection20 2 of single infliximab intravenous infusion21,22 1 of subcutaneous adalimumab injections23 1 of epidural tocilizumab injection24

10 Animal Studies34-43

8 Rat model studies34-41 2 Pig model studies42,43

34 Publications Reviewed15-48

model studies.33,43 Of the five prior review articles,44–48 only one was a systematic review, which was focused primarily on the clinical efficacy of anti-TNF drugs for LBP.48 As none of the reviewed trials employed any form of DMARD combination, the results are grouped further under the subheadings of the DMARD used. The mode of drug use, including the dose and route of drug administration precedes a summary and validity evaluation of the analyzed trials, which is followed by assessment of its efficacy for the respective clinical condition. Etanercept In clinical studies, etanercept injections were administered epidurally in five,15–18,28 subcutaneously in four,20,25–27 and intradiscally in one study.19 For epidural injection, etanercept was diluted in either sterile water or local anesthetic and only the transforaminal injection technique was employed. Even though the epidural etanercept dose ranged from 0.5 to 25 mg, in the majority of studies, the dose employed was < 10 mg and either a single injection was administered or a second injection was given after a two-week interval

Figure 1. Flow Diagram Reviewed Studies.

of

the

(Table 4). Although the subcutaneous etanercept dose was consistent (25 mg) across studies, the number and frequency of the injections given varied significantly.20,25–27 In one study, which evaluated intradiscal etanercept injections, the drug was diluted in sterile water and the dose ranged from 0.1 to 1.5 mg.19 In the four studies using animal models, etanercept was injected locally around an experimental nerve injury site in two,37,40 subcutaneously in one,42 and intradiscally in one study.38 Of the six available RCTs focusing on etanercept use,15–24 four used the epidural route of administration (Table 5).15–18 Three such trials were in patients with lumbar radicular pain (LRP) from herniated disk (HD).15–17 A trial of 24 patients (four groups in 3:1 ratio) compared two epidural injections given two weeks apart of escalating etanercept doses (2, 4, or 6 mg) to placebo (normal saline) and reported efficacy of epidural etanercept injections at all three doses compared to placebo (Table 5).15 With adequate methodology, this trial was graded as “high quality” (Table 6); however, un-blinding occurred at 4 weeks and thus only the short-term results were valid. Another trial of 49 patients (in four groups) received two

DMARDs for Low Back Pain  633

Table 4. Use of DMARDs for Low Back Pain Syndromes Drug used

Route

Infliximab

IV

Etanercept

IP Epidural ID Epidural TF Locally applied SC

Dosage

Study type

Single infusion of 3–5 mg/kg over 2 hours Multiple infusions (3 mg/kg) @ 0, 2, 6 and 14 weeks. Intravenous infusion of variable dosages Single injection of 2 mg Single injection 0.5 or 5 mg/kg & 2.5 mg/kg Single injection in dosages of 0.1, 0.25, 0.5, 0.75, 1.0, or 1.5 mgs. 100 lgms in AS 1–2 injections (2 weeks apart) in variable dosages ranging from 0.5 to 12.5 mgs Variable dosages and intervals Single to multiple 25 mg injections at variable time intervals Variable dosages and intervals

21,22,29–31

5 CS 1 CS32

3 AS39,42,43 1 AS35 2 AS39,41 1 CS19 1 AS38 5 CS15–18,28 2 AS37,40 4 CS20,25–27 1 AS42

Adalimumab

SC

2 injections of 40 mg 1 week apart

2 CS23,33

Tocilizumab

Epidural TF

1 injection 80 mg in 2 cc of lidocaine

1 CS24

Methotrexate

Epidural and IT IV

1 mg/kg 50 mg

1 AS34 1 AS33

Synopsis 1. Clinically used only by IV route 2. Typically used as a single infusion but up to 4 infusion several weeks apart were given in 1 study24 3. Clinically used dosages were fairly consistent ranging from 3 to 5 mg/kg 4. Used epidurally and IP in AS only 1. Has been used systemically by SC injections and locally by epidural (TF) and ID route and by direct application 2. Clinically TF epidural route was most common followed by SC administration 3. Epidural dosage varied widely from 0.1 to 25 mg—typically < 10 mg 4. SC dosage was consistent—25 mg 5. Epidural injections were typically limited to 1–2 injections compared to multiple SC injections 1. Used clinically only once, 2 SC injections 1 week apart, however, results were published separately at 6 months and 3 years 1. Only one clinical study of single epidural TF injection 2. Typical clinical dose 4 to 8 mg/kg every 4 weeks by IV infusion 1. No clinical study 2. In AS used epidurally and IV at 1 mg/kg and 50 mg, respectively 3. Typical clinical dose 30 mg oral or 25 mg SC once a week

Antirat TNF-a IV 1 injection (10 mg/kg) @ day 0, 6 or 20 1 AS36 antibody The number of animal studies is higher due to the multiple drugs used by various routes in some of the studies AS, Animal study; CS, Clinical study; DMARD, Disease-modifying antirheumatic drugs; ID, Intradiscal; IP, Intraperitoneal; IT, Intrathecal; IV, Intravenous; SC, Subcutaneously; TF, Transforaminal.

epidural injections two weeks apart of etanercept (0.5, 2.5, or 12.5 mg) or placebo (exact nature of placebo was not evident).16 The results reported efficacy of etanercept relative to placebo, for up to six months, but only in patients receiving the lowest etanercept dose (0.5 mg— Table 5). Almost 40% of the patients randomized were excluded from the final analysis for various reasons, and this trial therefore was graded as “intermediate quality” (Table 6). Moreover, the results can be regarded as inconsistent as efficacy was reported in only 1 of the 3 treatment groups and this was the group using the lowest drug dose. The third trial compared epidural etanercept to similarly administered steroids and placebo.17 The patients (n = 84) in three equal groups received two epidural injections two weeks apart of etanercept (4 mg), methylprednisolone (60 mg), or placebo (normal saline). The study methods of this trial were graded “high quality” (Table 6), and it reported relative efficacy of the steroids compared to etanercept and placebo at 4 weeks – efficacy of etanercept was similar to placebo (Table 5). Consequently, with two “high-quality” trials reporting conflicting results and

one “intermediate-quality” trial reporting inconsistent results, no valid conclusion can be drawn regarding the efficacy of epidural etanercept relative to placebo in patients with LRP from HD (Table 3). The fourth trial examined patients with LRP from spinal stenosis and compared epidural etanercept to similarly administered epidural steroids.18 The patients (n = 80) in two equal groups received a single epidural injection of etanercept (10 mg) or dexamethasone (3.3 mg) and relative efficacy of etanercept was reported at four weeks. This trial was not blinded and was inadequately randomized and was therefore graded “low quality” (Table 6). Therefore with positive results in one “low-quality” trial, we find level D evidence (Table 3—routine use not recommended) for use of epidural etanercept relative to steroids in patients with LRP from spinal stenosis. Intradiscal etanercept was studied in a single trial in patients with LBP/LRP from suspected intervertebral disk pathology.19 The patients (n = 36) in six groups received either escalating dosages of etanercept (0.1, 0.25, 0.5, 0.75, 1.0, 1.5 mg) or placebo (sterile water), and there was no reported difference between the groups

RCT, LQT

DB, RCT, HQT

DB, RCT, LQT

RCT, LQT

RCT, LQT

DB, RCT, HQT

RCT, LQT

2012: Ohtori18

2007: Cohen19

2010: Okoro20

2005: Korhonen21

2006: Korhonen22

2010 Genevay23

2012: Ohtori24

TFEI of 80 mg tocilizumab or 3.3 mg of dexamethasone in 2.0 cc of lidocaine

Two 40 mg SCI of adalimumab at 1 week interval or placebo

Single 5 mg/kg IVI of infliximab or NS over 2 hours

Single 5 mg/kg IVI of infliximab or NS over 2 hours

Single SCI of etanercept (25 mg) or NS in perispinal area

Two TFEI 2 weeks apart of either 60 mg MP or 4 mg etanercept in NS TFEI of 10 mg etanercept or 3.3 mg of dexamethasone in 2.0 cc of lidocaine Single IDI of 0.1, 0.25, 0.5, 0.75, 1.0, or 1. 5 mg etanercept or sterile water

Two TFEI of 0.5, 2.5 or 12.5 mg etanercept or placebo given at 2 weeks

Two TFEI of etanercept (2, 4 or 6 mgs) 2 weeks apart or NS

Treatment

60 patients with LRP/SS, 30 received tocilizumab & 30 dexamethasone

61 patients with LRP/HD, 31 had adalimumab & 30 placebo

40 pts with LRP/HD, 21 received infliximab & 19 NS

40 pts with LRP/HD, 21 received infliximab & 19 NS

15 patients with LRP/HD, 8 received etanercept and 7 placebo

36 patients with suspected LRP/LBP from disc pathology received escalating doses of etanercept or SW in 5:1 ratio

84 patients with LRP/HD in three equal groups received either steroids, etanercept or NS 80 patients with LRP/SS in two equal groups received either etanercept or dexamethasone

24 patients, 4 groups, with LRP/HD had escalating dose of etanercept or NS in 3:1 ratio 49 patients with LRP/HD in 4 groups received a specific etanercept dose or placebo

Methodology

No significant difference between the groups at 1 year. Nonserious AEs (diarrhea, otitis, sinusitis) in 3 patients in infliximab group PO (leg VAS) same in both groups; SSI at 6 months only in adalimumab group. No AEs from adalimumab use SSI in VAS and ODI scores at 4 weeks. No AEs

No significant difference between the groups at 3 months. No AEs

Using VAS and ODI no difference in between the groups. Only patients with improved symptoms at 1 month followed for 6 months. No AEs No difference in VAS and ODI scores between the groups at 3 months. No AEs

Using VAS & ODI, SSI in all etanercept groups vs. saline at 1 and 6 months. No clinical, imaging or histological AEs 0.5 mg group had SSI in pain at 2-weeks to 6 months —P < 0.1. AE: nonspecific and similar in 2 groups; 3 DO in 12.5 mg and 1 in placebo from worsening LRP VAS and ODI at 1 month were lower in steroid group but results not SS. AE: possible worsening of pain n = 7 SSI in VAS and ODI scores in etanercept group at 4 week P < 0.05. No AEs

Follow-up and Results

Improvement from epidural tocilizumab compared to steroids

SC adalimumab reduced LRP and need for surgery

Inadequate support for the use of infliximab for LRP from HD

Inadequate support for the use of infliximab for LRP from HD

No benefit of etanercept over placebo in sciatica from HD

Single IDI of etanercept not effective for LRP or discogenic LBP

Epidural etanercept may be useful for LRP from SS

Epidural steroids may be more efficacious than epidural etanercept in LRP

TFEI of etanercept significantly reduced LRP compared to placebo

Epidural etanercept holds promise in the treatment of LRP

Author conclusion

1. Poor randomization 2. Nonblinded trial 3. Short-termed – 4-weeks

1. No difference in PO between the groups except @ 6 months

1. 15 patients recruited over 4 years 2. High attrition—20% 3. Poorly randomized, nonblinded 1. Inadequate randomization 2. Blinding techniques not described 3. Small size trial 1. Inadequate randomization 2. Blinding techniques not described 3. Small size trial

1. Not blinded after 1 month 2. Short-term results 3. A small trial of only 36 patients with 6 study group in 5:1 ratio

1. Nonblinded 2. Short follow-up

1. Not blinded after 1 month 2. A small trial of only 24 patients with 4 study group in 3:1 ratio 1. Only one-third etanercept groups showed +ve results 2. Four groups of < 13 patients each 3. High attrition/exclusion rate of almost 40% 1. Inconclusive results 2. Short-term follow-up

Limitations

AE, Adverse effects; DB, Double blinded; DO, Drop-outs; HD, Herniated disc; HQT, High-quality trial; IDI, Intradiscal injection; IQT, Intermediate-quality trial; IVI, Intravenous infusion; LBP, Low back pain; LRP, Lumbar radicular pain; LQT, Low-quality trial; MP, Methylprednisolone; NS, Normal saline; ODI, Oswestry disability index; PO, Primary outcome; RCT, Randomized controlled trial; SCI, Subcutaneous injection; SSI, Statistically significant improvement; SS, Spinal stenosis; TFEI, Transforaminal epidural injection.

DB, RCT, HQT

2012: Cohen17

DB, RCT, HQT

Type

DB, RCT, IQT

15

2013 Freeman16

2009: Cohen

Study

Table 5. Randomized Controlled Trials

634  MALIK ET AL.

++++

++ ++ ++

++++ + +

++ + ++

Cohen (2009)15 Freeman (2013)16 Cohen (2012)17 Ohtori (2012)18 Cohen (2007)19 Okoro (2010)20 Korhonen (2005)21 Korhonen (2006)22 Genevay (2010)23 Ohtori (2012)24

RCT, Randomized controlled trials; DB, Double blinded; BLC, Baseline characteristics; LQT, Low-quality trial: Major flaws in randomization and/or blinding and/or unacceptable attrition; IQT, Intermediate-quality trial: Acceptable randomization, blinding and attrition, however, some specifics omitted; HQT, High-quality trial: Adequate randomization and blinding techniques described with low attrition rate.

HQT IQT HQT LQT HQT LQT LQT LQT HQT LQT ‒ ‒ ‒ ‒ ‒ ‒ ‒ ‒ ‒ ‒ 15/15 12/15 15/15 07/15 15/15 07/15 09/15 09/15 15/15 06/15 ++++ ++++ ++++ +++ ++++ + + ++++ ++++ ++++ +++ ++++ ++++ ++++

+ + + + + + + + + +

++

+ + + + + + + + + +

Eligibility 1. Criteria described

+++ ++ +++ + +++ + + + + + + +++ +

Randomization 1. Trial described as randomized 2. Effective random allocation 3. Allocation concealed 4. Assigned intervention received Trial 1. +ve score if attribute is present 2. –ve score if it is absent or if unsure

Table 6. Assessment of Internal Validity of the RCTs

Attrition 1. Dropouts accounted 2. Less than 15% dropouts

Blinding 1. Study described DB 2. Blinding of study participants 3. Blinding of all providers 4. Blinding of all evaluators

Data Analysis 1. BLC described 2. Similar/adjusted BLC 3. Between-group comparison 4. Primary outcome defined

Score 1. Total score 15 2. Score 9 or less LQT 3. Score 10–12 IQT 4. Score > 12 HQT

DMARDs for Low Back Pain  635

at 1 month (Table 5). This trial was graded “high quality” (Table 6); however, it provided no evidence to substantiate the use of intradiscal etanercept. Subcutaneous etanercept administration was studied in a trial of 15 patients with LRP from HD.20 The participants received either a single subcutaneous “perispinal” injection of etanercept (25 mg, n = 8) or placebo (saline, n = 7), and no difference in outcomes between the groups was reported at three months (Table 5). The trial was not blinded and was inadequately randomized, only 15 patients were recruited over a four-year period and the dropout rate was nearly 20%. It was graded “low quality” (Table 6), and it provided no evidence to substantiate the use of subcutaneous “perispinal” etanercept in patients with LRP from HD. Infliximab Infliximab was the second most common DMARD encountered in the reviewed articles (Table 4). In humans, infliximab was administered exclusively by intravenous route, by a single infusion in five studies21,22,29–31 and by multiple infusions in one study.32 Even though the frequency of infliximab administration varied the dose administered was generally consistent and ranged from 3 to 5 mg/kg. In animal studies, infliximab was administered intravenously in three studies,39,42,43 epidurally in two studies,39,41 and intraperitoneally in one study (Table 4).35 There are two RCTs of infliximab use in patients with LBP. However, its use was studied in only one group of patients with LRP from HD (n = 40) and the results were reported at 3 months and 1 year in two separate publications.21,22 The participants received a solitary intravenous infusion of infliximab (5 mg/kg given over 2 hours, n = 21) or placebo (saline, n = 19), and no differences in outcomes were reported at 3 months21 or 1 year.22 This trial was not blinded and was inadequately randomized and hence graded “low quality” (Table 6), and its results did not support the use of intravenous infliximab in patients with LRP from HD. Adalimumab In the only RCT of adalimumab use, 61 patients with LRP from HD received two subcutaneous injections, 1 week apart, of either adalimumab (40 mg, n = 31) or placebo (saline n = 30).23 The primary outcome (pain score in the leg) was similar in both groups at all time points with the exception of the 6 month time point,

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MALIK ET AL.

when the pain scores were lower for patients in the adalimumab group (Table 5). Consequently, although graded as “high quality” (Table 6), this trial provided inconsistent evidence for the efficacy of subcutaneous adalimumab in patients with LRP from HD. Tocilizumab Tocilizumab was evaluated in one RCT of 60 patients with LRP from spinal stenosis.24 The participants in two groups received either a single epidural injection of tocilizumab (80 mg in 2 cc of lidocaine) or dexamethasone (3.3 mg), and patients in tocilizumab group had lower pain and disability scores for up to 4 weeks (Table 5). This trial was not blinded and was inadequately randomized and was therefore graded “low quality” (Table 6). Hence, we find level D evidence (Table 3, risks outweigh any benefits and treatment should not be routinely offered) of the short-term efficacy of epidural tocilizumab in patients with LRP from spinal stenosis.

etanercept was injected in the epidural space in an animal model.15 In the clinical arm of this study, a relatively small dose of etanercept was injected in the epidural space (2, 4, or 6 mg at two-week intervals) and the patients were evaluated at one and 6 months by MR imaging for evidence of neural toxicity. The observations made in the animal model, and the clinical study showed no evidence of neural injury from the epidural etanercept injection. Given this reassurance, epidural etanercept administration in the subsequent three trials16–18 used higher drug doses and did not adopt any specific safety measures. The only study of tocilizumab use for LBP patients administered the drug into the epidural space (normally recommended for subcutaneous or intravenous injections only). Although the dose injected (80 mg) was lower than the recommended systemic tocilizumab dose, this study did not employ any additional safety measures.24 None of the studies we reviewed sought investigational new drug (IND) status from the Food and Drug Administration (FDA). Adverse Effects

Methotrexate We encountered only two studies examining the efficacy of methotrexate and both of these were in animal models. One administered the study drug epidurally and the other administered it intravenously. The dose given varied according to the animal model studied (Table 4).33,43 As these were animal model studies, further analysis to determine their internal validity and drug efficacy was not performed.

To document any adverse effects we analyzed all the clinical studies—including the observational studies (Table 7). No significant drug-related adverse effects were reported in the majority of studies we reviewed. Worsening of pain was reported in two studies,16,18 minor nonspecific adverse events such as otitis media and sinusitis were reported in two studies,18,22 and “serious allergic reaction” as a reason for discontinuation of therapy was reported in one study.32

Safety Measures

DISCUSSION

The initial DMARD studies for LBP adhered to recommended intravenous and subcutaneous routes of drug administration and described the DMARD use as offlabel.21,22,25–27,29–32 The first study that deviated from manufacturer recommendations examined intradiscal injection of etanercept.19 In this trial, etanercept was injected into the disk in incremental doses starting with a relatively low dose (single etanercept dose of 0.1, 0.25, 0.5, 0.75, 1.0, or 1.5 mg was given compared to the recommended subcutaneous injection dose of 25 mg given twice a week). No adverse effects from intradiscal etanercept injection were reported in this study. Similarly, the first RCT of epidural etanercept injections also assessed safety of this route of etanercept administration and was accompanied by a preclinical study where

Our review of the literature suggests that despite a range of DMARDs available, etanercept and infliximab are the only drugs used with any regularity for treating LBP. Adalimumab and tocilizumab were used in only one group of patients each and methotrexate was used only in animal studies (Table 4). The reason for the few drugs studied and the selection of exclusively biological agents was not apparent. Further, the drug doses, routes of drug administration and frequency with which drugs were administered varied greatly and differed from the administration protocols recommended for other chronic inflammatory conditions.12 For instance, the standard administration of etanercept is twice weekly 25 mg subcutaneous injections, yet the etanercept administration seen in the publications reviewed was

RS

CS/HC

RS

CR

CS/HC

CR

CS/HC

CR

2003: Tobinick25

2004: Genevay26

2004: Tobinick27

2007: Malik28

2003: Karppinen29

2004: Atcheson30

2004: Korhonen31

2005: Sakellariou32

Infliximab IVI (3 mg/kg) @ 0, 2, 6, and 14 weeks

Single IVI of infliximab 3 mg/kg over 2 hours

Single IVI of infliximab 3.35 mg/kg

Single IVI of infliximab 3 mg/kg over 2 hours

Average of 2.3 doses of 25 mg perispinal SC etanercept at mean interval of 13.6 days Single TFEI of 25 mg etanercept

Etanercept 25 mg SC at days 1, 4, and 7

1–5 perispinal 25 mg SC injections of etanercept

Treatment Chart review of 20 patients with neck/back pain from various etiologies 10 patients with LRP, who received etanercept, were compared to 10 unrelated patients who received 250 mg of MP 204 patients received etanercept for presumed disc pain of which VAS scores were available on 143 patients included in the study A patient with 3-week history of LRP/HD received TFEI of etanercept and TFEI of 80 mg MP at 3 weeks 10 Patients with acute LRP/HD received IVI of infliximab & were compared to 62 unrelated patients who received epidural saline Infliximab given to a patient with LRP/HD who had failed CT for 8 months 10 Patients with LRP/HD who received infliximab were compared to 62 unrelated patients who received epidural saline Report of 2 patients with painful Schmorl’s nodes

Methodology

Improved VAS scores and resolution of Schmorl’s nodes on MRI

VAS and ODI scores improved at 1 year in favor of infliximab group—P < 0.01

Improvement in pain and function for up 6 months

From 2 to 12 weeks 60% of patients who received infliximab had > 75% decrease in pain scores compared to 16% in controls

No pain relief from etanercept but relief from steroid

Mean ODI reduced range from 30 to 76–0 to 52 at mean of 230 days—range 49 to 518 Improved VAS and ODI scores up to 6 weeks in patients who received etanercept; these scores were lower than controls Improvement in VAS seen for up to 1 month

Results

TNF-a blockade effective for painful Schmorl’s nodes

A single infusion of infliximab was highly efficacious for long-termed treatment of LRP from HD

Recommend clinical trial of infliximab use in sciatica

Anti-TNF-a therapy was promising treatment option for sciatica

Inefficacy of etanercept may be due to rapid absorption of its non-depot preparation

Perispinal etanercept led to improvement in patients with disc-related pain

Significant improvement in resistant discogenic pain from perispinal etanercept TNF-a inhibition was beneficial in patients with sciatica

Authors’ conclusion

Allergic reaction in one patient—no details given

No significant adverse effects

No significant adverse effects

No significant adverse effects

No significant adverse effects

No significant adverse effects

No significant adverse effects

No significant adverse effects

Adverse effects

CR, Case report; CS/HC, Case series with historical controls; CT, Conservative treatment; HD, Herniated disc; IVI, Intravenous infusion; LRP, Lumbar radicular pain; MP, Methylprednisolone; ODI, Oswestry Disability Index; RS, Retrospective study; SC, Subcutaneous; TFEI, Transforaminal epidural injection; VAS, Visual Analogue Scale.

Type

Study

Table 7. Observational Studies

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638 

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regularly by epidural injection and used substantially lower doses significantly less frequently.15–20,28 One explanation for the substantially lower epidural etanercept dose is the lower dose of epidural opioids compared to parenteral dose,15,17,19 even though no pharmacologic relationship exists between opioids and DMARDs. Even when etanercept was given by its recommended subcutaneous route either a single injection was performed,20 and in the case of multiple injections, the number was limited and the interval between the injections was highly variable.25–27 In the case of infliximab use for LBP (recommended dose 3 to 5 mg/ kg given by intravenous infusion, repeated at two, six, and eight weeks) only a single intravenous infliximab infusion was given in all the studies21,22,29–31 with one exception.32 Similarly, adalimumab (recommended dose 40 to 80 mg subcutaneous injection every 2 weeks) was limited to two 40 mg subcutaneous injections given 1 week apart.23 Equally, tocilizumab use (recommended dose 4 to 12 mg/kg intravenous infusion every week) was limited to a single 80-mg epidural injection.24 Additionally, biological DMARDs were used as a sole therapy and none of the nonbiological DMARDs were used. We did not find any studies examining the therapeutic effects of abatacept, azathioprine, chloroquine, cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil, rituximab, sulfasalazine, certolizumab, golimumab, ranibizumab, and bevacizumab for LBP. The current use of DMARDs for the treatment of LBP can therefore be characterized as: (1) exceedingly narrow empiric selection of drugs; (2) significant variation from the recommended drug dosing, frequency of drug administration and routes of drug delivery; (3) absence of any nonbiological DMARD use; (4) utilization of substantially lower cumulative drug dosing; and (5) the absence of combination DMARD therapy. The epidural route was a frequent choice for DMARD administration in the publications we reviewed. This preference appeared to be based upon the common practice of epidural steroid injections for LBP.11 However, steroids injected in the epidural space are typically in sustained-release formulations, which presumably maximize and prolong their local antiinflammatory activity, the epidural and parenteral dose of steroids administered is generally comparable and epidural steroids are generally well tolerated.11 Moreover, corticosteroids have extensive anti-inflammatory properties and they inhibit the genetic expression of almost all pro-inflammatory cytokines.12,13,53 In contrast, biological DMARDs are highly soluble peptide

molecules that are not amenable to encapsulation and their biodegradable sustained-release depot formulations have not yet been manufactured. Consequently, even though the trials of epidural DMARDs for LBP are a likely response to the limited efficacy of epidural steroids, and epidural biological DMARDs appears to be well tolerated, it is doubtful that their isolated use at diminutive doses would be superior to epidural steroid injections. Also, given that they are readily absorbable, biological DMARDs injected in the epidural space will likely have no additional therapeutic advantage over their established route of parenteral administration. Our review confirms that overall the biological DMARDs injected in the epidural space were of little benefit. Hence, if epidural administration of DMARDs for the treatment of LBP is to be tested, further we recommend the following: (1) use of potent DMARDs requiring small volumes and infrequent administration; (2) use of epidural dose comparable to the recommended parenteral dose; (3) development and utilization of sustainedrelease preparations of DMARDs. Systemic DMARD therapy for LBP is characterized by isolated use of single biologic drugs given at substantially lower cumulative dosages. It is plausible that the observed limited efficacy of systemically administered DMARDs for LBP was the result of inadequate treatment.20–23 Combination DMARD therapy is routinely offered early in the course of several chronic inflammatory conditions to prevent progressive deformities and permanent end-organ damage.14 This is common practice despite the greater risk of adverse events and requisite monitoring for opportunistic infections, blood dyscrasias, and metabolic abnormalities while on these medications.13,14 LBP syndromes, in contrast, are usually self-limiting and few patients progress to a chronic disabled state.54 The risks of combination DMARD therapy for LBP may therefore outweigh any potential benefits and it may only be considered in patients with severe and disabling LBP who have not responded to traditional treatments. When used for treatment of LBP, combination systemic DMARD therapy should be based on a protocol driven approach already in place for other chronic inflammatory conditions. When investigating a drug or a drug class for a new indication, especially when administered through a novel delivery route, extreme care must be taken to ensure that the drug is safe. None of the studies we reviewed are typical phase I safety trials intended to carefully evaluate a medication’s pharmacokinetics or

DMARDs for Low Back Pain  639

ED95 for a given route of drug administration. However, safety measures were adopted in the studies of intradiscal and epidural etanercept administration that showed no adverse effects and no signs of neurological injury from these diverse routes of drug administration. Although the epidural etanercept doses administrated in the trials where safety measures were adopted were relatively small, higher doses were used in the subsequent trials and these also showed no adverse neurological sequelae. The only study of tocilizumab injection in the epidural space reported no adverse neurologic consequences. As biological DMARDs are peptide molecules similar in structure, it may be safe to assume that epidural administration of biological DMARDs in general may be safe. However, further safety studies for this route of administration should be conducted to confirm the safety of these drugs for routine epidural administration. The safety of nonbiological DMARDs in this group of patients remains largely untested. The greatest risk of systemic biological DMARD use is the increased risk of infection; therefore, treatment with biological DMARDs is contra-indicated in patients who are immunocompromised or have known infections.12 Our analysis of the literature did not find any instances of severe infectious complication from the use of biological DMARDs. The relative absence of infectious complications in this context was likely due to the lower cumulative DMARD doses used and the fact that recruited patients had otherwise normal immune function. It follows that if higher doses or combination DMARD therapy for LBP are studied in the future, the incidence of infection and other complications may be higher than observed in our review. With few exceptions, the analyzed studies were small in size, compared multiple study groups and were likely underpowered to detect differences between groups.15,16,19,20 Moreover, often the benefit reported was either inconsistent or short term.16,23 Hence, the overall quality of the literature published on this topic is weak and there is a need for well-designed trials comparing DMARD therapy to conventional treatments.

REFERENCES 1. Deyo RA, Tsui-Wu YJ. Descriptive epidemiology of low back pain and its related medical care in United States. Spine. 1987;12:264–268. 2. Andersson GB. Epidemiological features of chronic low-back pain. Lancet. 1999;354:581–585.

3. Katz JN. Lumbar disc disorders and low back pain: socioeconomic factors and consequences. J Bone Joint Surg Am. 2006;88:21–24. 4. Teasell RW, White K. Clinical approaches to low back pain. Part 1. Epidemiology, diagnosis, and prevention. Can Fam Physician. 1994;40:481–486. 5. Malik KM, Cohen SP, Walega DR, Benzon HT. Diagnostic criteria and treatment of discogenic pain: a systematic review of the recent clinical literature. Spine J. 2013;13:1675–1689. 6. Marshall LL, Trethewie ER. Chemical irritation of nerve-root in disc prolapse. Lancet. 1973;2:320. 7. McCarron RF, Wimpee MW, Hudkins PG, Laros GS. The inflammatory effect of nucleus pulposus: a possible element in the pathogenesis of low back pain. Spine. 1987;12:760–764. 8. Olmarker K, Blomquist J, Str€ omberg J, Nannmark U, Thomsen P, Rydevik B. Inflammatogenic properties of nucleus pulposus. Spine. 1995;20:665–669. 9. Olmarker K, Rydevik B, Nordborg C. Autologous nucleus pulposus induces neurophysiologic and histologic changes in porcine cauda equina nerve roots. Spine. 1993;18:1425–1432. 10. Burke JG, Watson RW, McCormack D, Dowling FE, Walsh MG, Fitzpatrick JM. Intervertebral discs which cause low back pain secrete high levels of proinflammatory mediators. J Bone Joint Surg Br. 2002;84:196–201. 11. Kozlov N, Benzon HT, Malik K. Epidural steroid injections: update on efficacy, safety, and newer medications for injection. Minerva Anestesiol. 2014. (Epub ahead of print) 12. Rainsford KD. Anti-inflammatory drugs in the 21st century. Subcell Biochem. 2007;42:3–27. 13. Dinarello CA. Anti-inflammatory agents: present and future. Cell. 2010;140:935–950. 14. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biological agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64:625–639. 15. Cohen SP, Bogduk N, Dragovich A, et al. Randomized, double-blind, placebo-controlled, dose response, and preclinical safety study of transforaminal epidural etanercept for the treatment of sciatica. Anesthesiology. 2009;110:1116– 1126. 16. Freeman BJC, Ludbrook GL, Hall S, et al. Randomized, double-blind, placebo-controlled, trial of transforaminal epidural etanercept for the treatment of symptomatic lumbar disc herniation. Spine. 2013;38:1986–1994. 17. Cohen SP, White RL, Kurihara C, et al. Epidural steroids, etanercept, or saline in subacute sciatica: a multicenter, randomized trial. Ann Intern Med. 2012; 156:551–559. 18. Ohtori S, Miyagi M, Eguchi Y, et al. Epidural administration of spinal nerves with the tumor necrosis factor-alpha inhibitor, etanercept, compared with dexamethasone for

640 

MALIK ET AL.

treatment of sciatica in patients with lumbar spinal stenosis. Spine. 2012;37:439–444. 19. Cohen SP, Wenzell D, Hurley RW, et al. A doubleblind, placebo-controlled, dose–response pilot study evaluating intradiscal etanercept in patients with chronic discogenic low back pain or lumbosacral radiculopathy. Anesthesiology. 2007;107:99–105. 20. Okoro T, Tafazal SI, Longworth S, Sell PJ. Tumor necrosis a-blocking agent (etanercept): a triple blind randomized controlled trial of its use in treatment of sciatica. J Spinal Disord Tech. 2010;23:74–77. 21. Korhonen T, Karppinen J, Paimela L. The treatment of disc herniation-induced sciatica with infliximab: results of a randomized, controlled, 3-month follow-up study. Spine. 2005;30:2724–2728. 22. Korhonen T, Karppinen J, Paimela L, et al. The treatment of disc herniation-induced sciatica with infliximab: one-year follow-up results of FIRST II, a randomized controlled trial. Spine. 2006;31:2759–2766. 23. Genevay S, Viatte S, Finckh A, Zufferey P, Balague F, Gabay C. Adalimumab in severe and acute sciatica: a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2010;62:2339–2346. 24. Ohtori S, Miyagi M, Eguchi Y, et al. Efficacy of epidural administration of anti-interleukin-6 receptor antibody onto spinal nerve for treatment of sciatica. Eur Spine J. 2012;21:2079–2084. 25. Tobinick EL, Britschgi-Davoodifar S. Perispinal TNFalpha inhibition for discogenic pain. Swiss Med Wkly. 2003;133:170–177. 26. Genevay S, Stingelin S, Gabay C. Efficacy of etanercept in the treatment of acute, severe sciatica: a pilot study. Ann Rheum Dis. 2004;63:1120–1123. 27. Tobinick E, Davoodifar S. Efficacy of etanercept delivered by perispinal administration for chronic back and/ or neck disc related pain: a study of clinical observations in 143 patients. Curr Med Res Opin. 2004;20:1075–1085. 28. Malik K. Epidural etanercept for lumbar radiculopathy. Anaesth Intensive Care. 2007;35:301–302. 29. Karppinen J, Korhonen T, Malmivaara A, et al. Tumor necrosis factor-a monoclonal antibody, infliximab, used to manage severe sciatica. Spine. 2003;28:750–754. 30. Atcheson SG, Dymeck T. Rapid resolution of chronic sciatica with intravenous infliximab after failed epidural steroid injections. Spine. 2004;29:248–250. 31. Korhonen T, Karppinen J, Malmivaara A, et al. Efficacy of infliximab for disc herniation-induced sciatica: one-year follow-up. Spine. 2004;29:2115–2119. 32. Sakellariou GT, Chatzigiannis I, Tsitouridis I. Infliximab infusions for persistent back pain in two patients with Schmorl’s nodes. Rheumatology. 2005;44:1588–1590. 33. Genevay S, Finckh A, Zufferey P, Viatte S, Balague F, Gabay C. Adalimumab in acute sciatica reduces the long-term need for surgery: a 3-year follow-up of a randomized doubleblind placebo-controlled trial. Ann Rheum Dis. 2012;71:560– 562.

34. Hashizumea H, Rutkowskia MD, Weinsteinb JN, DeLeo JA. Central administration of methotrexate reduces mechanical allodynia in an animal model of radiculopathy/ sciatica. Pain. 2000;87:159–169. 35. Onda A, Murata Y, Rydevik B, Larsson K, Kikuchi S, Olmarker K. Infliximab attenuates immunoreactivity of brainderived neurotrophic factor in a rat model of herniated nucleus pulposus. Spine. 2004;29:1857–1861. 36. Sasaki N, Kikuchi S, Konno S, Sekiguchi M, Watanabe K. Anti-TNF-a antibody reduces pain-behavioral changes induced by epidural application of nucleus pulposus in a rat model depending on the timing of administration. Spine. 2007;32:413–416. 37. Zanella JM, Burright EN, Hildebrand K, et al. Effect of etanercept, a tumor necrosis factor-alpha inhibitor, on neuropathic pain in the rat chronic constriction injury model. Spine. 2008;33:227–234. 38. Horii M, Orita S, Nagata M, et al. Direct application of the tumor necrosis factor-a inhibitor, etanercept, into a punctured intervertebral disc decreases calcitonin gene-related peptide expression in rat dorsal root ganglion neurons. Spine. 2011;36:80–85. 39. Nakamae T, Ochi M, Olmarker K. Pharmacological inhibition of tumor necrosis factor may reduce pain behavior changes induced by experimental disc puncture in the rat. Spine. 2011;36:232–236. 40. Watanabe K, Yabuki S, Sekiguchi M, Kikuchi S, Konno S. Etanercept attenuates pain-related behavior following compression of the dorsal root ganglion in the rat. Eur Spine J. 2011;20:1877–1884. 41. Kim NR, Lee JW, Jun SR, et al. Effects of epidural TNF-a inhibitor injection: analysis of the pathological changes in a rat model of chronic compression of the dorsal root ganglion. Skeletal Radiol. 2012;41:539–545. 42. Olmarker K, Rydevik B. Selective inhibition of tumor necrosis factor-alpha prevents nucleus pulposus-induced thrombus formation, intraneural edema, and reduction of nerve conduction velocity: possible implications for future pharmacologic treatment strategies of sciatica. Spine. 2001;26:863–869. 43. Olmarker K. Neovascularization and neoinnervation of subcutaneously placed nucleus pulposus and the inhibitory effects of certain drugs. Spine. 2005;30:1501–1504. 44. Mulleman D, Mammou S, Griffoul I, Watier H, Goupille P. Pathophysiology of disk-related low back pain and sciatica. Evidence supporting treatment with TNF-a antagonists. Joint Bone Spine. 2006;73:270–277. 45. Goupille P, Mulleman D, Paintaud G, Watier H, Valat JP. Can sciatica induced by disc herniation be treated with tumor necrosis factor a blockade? Arthritis Rheum. 2007;56:3887–3895. 46. Burnett C, Day M. Recent advancements in the treatment of lumbar radicular pain. Curr Opin Anaesthesiol. 2008;21:452–456. 47. Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother. 2010;10:985– 1002.

DMARDs for Low Back Pain  641

48. Pimentel DC, El Abd O, Benyamin RM, et al. Antitumor necrosis factor antagonists in the treatment of low back pain and radiculopathy: a systematic review and meta-analysis. Pain Physician. 2014;17:27–44. 49. Furlan AD, Pennick V, Bombardier C, van Tulder M. 2009 updated method guidelines for systematic reviews in the Cochrane Back Review Group. Spine. 2009;34:1929– 1941. 50. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336–341.

51. Andrews J, Guyatt G, Oxman AD, et al. GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations. J Clin Epidemiol. 2013 Jul;66:719–725. 52. Slavin RE. Best evidence synthesis: an intelligent alternative to meta-analysis. J Clin Epidemiol. 1995;48:9–18. 53. Depo-Medrol package insert, Pfizer Inc. New York, NY 10017. 2-2014. 54. Benoist M. The natural history of the lumbar disc herniation and radiculopathy. Joint Bone Spine. 2002;69:155– 160.

Disease-modifying Antirheumatic Drugs for the Treatment of Low Back Pain: A Systematic Review of the Literature.

Low back pain (LBP) is a common source of pain and disability, which has an enormous adverse impact on affected individuals and the community as a who...
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