SYSTEMIC PHARMACOLOGIC THERAPIES FOR LOW BACK PAIN: A SYSTEMATIC REVIEW FOR AN AMERICAN COLLEGE OF PHYSICIANS CLINICAL PRACTICE GUIDELINE
 
   

Systemic Pharmacologic Therapies for Low Back Pain:
A Systematic Review for an American College
of Physicians Clinical Practice Guideline

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:
   Frankp@chiro.org
 
   

FROM:   Ann Intern Med. 2017 (Feb 14) [Epub ahead of print]

Roger Chou, MD; Richard Deyo, MD, MPH; Janna Friedly, MD;
Andrea Skelly, PhD, MPH; Melissa Weimer, DO, MCR;
Rochelle Fu, PhD; Tracy Dana, MLS; Paul Kraegel, MSW;
Jessica Griffin, MS; Sara Grusing, BA

From Oregon Health & Science University,
Portland, Oregon;
University of Washington,
Seattle, Washington; and
Spectrum Research,
Tacoma, Washington.


BACKGROUND:   A 2007 American College of Physicians guideline addressed pharmacologic options for low back pain. New evidence and medications have now become available.

PURPOSE:   To review the current evidence on systemic pharmacologic therapies for acute or chronic nonradicular or radicular low back pain.

DATA SOURCES:   Ovid MEDLINE (January 2008 through November 2016), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and reference lists.

STUDY SELECTION:   Randomized trials that reported pain, function, or harms of systemic medications versus placebo or another intervention.

DATA EXTRACTION:   One investigator abstracted data, and a second verified accuracy; 2 investigators independently assessed study quality.

DATA SYNTHESIS:   The number of trials ranged from 9 (benzodiazepines) to 70 (nonsteroidal anti-inflammatory drugs). New evidence found that acetaminophen was ineffective for acute low back pain, nonsteroidal anti-inflammatory drugs had smaller benefits for chronic low back pain than previously observed, duloxetine was effective for chronic low back pain, and benzodiazepines were ineffective for radiculopathy. For opioids, evidence remains limited to short-term trials showing modest effects for chronic low back pain; trials were not designed to assess serious harms. Skeletal muscle relaxants are effective for short-term pain relief in acute low back pain but caused sedation. Systemic corticosteroids do not seem to be effective. For effective interventions, pain relief was small to moderate and generally short-term; improvements in function were generally smaller. Evidence is insufficient to determine the effects of antiseizure medications.

LIMITATIONS:   Qualitatively synthesized new trials with prior meta-analyses. Only English-language studies were included, many of which had methodological shortcomings. Medications injected for local effects were not addressed.

CONCLUSION:   Several systemic medications for low back pain are associated with small to moderate, primarily short-term effects on pain. New evidence suggests that acetaminophen is ineffective for acute low back pain, and duloxetine is associated with modest effects for chronic low back pain.

PRIMARY FUNDING SOURCE:   Agency for Healthcare Research and Quality. (PROSPERO: CRD42014014735).



From the FULL TEXT Article:

Background

Low back pain is one of the most frequently encountered conditions in clinical practice [1, 2]. The most commonly prescribed medications for low back pain are nonsteroidal anti-inflammatory drugs (NSAIDs), skeletal muscle relaxants, antidepressants, and opioids [3–5]; benzodiazepines, systemic corticosteroids, and antiseizure medications are also prescribed [3]. Patients often use over-the-counter acetaminophen and NSAIDs.

A 2007 guideline [6] and associated systematic review [7] from the American College of Physicians (ACP) and American Pain Society (APS) found evidence to support the use of acetaminophen and NSAIDs as first-line pharmacologic options for low back pain; secondary options were skeletal muscle relaxants, benzodiazepines, and antidepressants. New evidence and medications are now available. Here, we review the current evidence on benefits and harms of medications for low back pain. This article has been used by ACP to update a clinical practice guideline, also in this issue.



Methods

Detailed methods and data for our review, including the analytic framework, additional medications (topical capsaicin and lidocaine), nonpharmacologic therapies (addressed in a separate article) [8], search strategies, inclusion criteria, data extraction and quality-rating methods, and additional outcomes (for example, quality of life, global improvement, and patient satisfaction), are available in the full report [9]. The protocol was developed by using a standardized process [10] with input from experts and the public and is registered in the PROSPERO database [11]. This article addresses the key question, what are the comparative benefits and harms of different systemic pharmacologic therapies for acute or chronic nonradicular low back pain, radicular low back pain, or spinal stenosis?

      Data Sources and Searches

A research librarian searched Ovid MEDLINE (January 2007 through April 2015), the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews (through April 2015). We used the prior ACP/APS review [12] to identify earlier studies. Updated searches were performed through November 2016. We also reviewed reference lists and searched ClinicalTrials.gov.

      Study Selection

Two investigators independently reviewed abstracts and full-text articles against prespecified eligibility criteria. The population was adults with nonradicular or radicular low back pain of any duration (categorized as acute [<4 weeks], subacute [4 to 12 weeks], and chronic [≥12 weeks]). Excluded conditions were low back pain due to cancer, infection, inflammatory arthropathy, high-velocity trauma, or fracture; low back pain during pregnancy; and presence of severe or progressive neurologic deficits. We evaluated acetaminophen, NSAIDs, opioids, tramadol and tapentadol, antidepressants, skeletal muscle relaxants, benzodiazepines, corticosteroids, and antiseizure medications versus placebo, no treatment, or other therapies. We also evaluated the combination of 2 medications versus 1 medication alone. Outcomes were long-term (≥1 year) or short-term (≤6 months) pain or function, mood (for antidepressants), risk for surgery (for corticosteroids), and harms.

Given the large number of medications addressed, we included systematic reviews of randomized trials [13, 14]. For each medication, we selected the most recent, most relevant, and highest-quality comprehensive systematic review based on a validated assessment tool [14, 15]. If more than 1 good-quality systematic review was available, we preferentially selected updates of those used in the ACP/APS review. We supplemented systematic reviews with additional trials. Although we did not include systematic reviews identified in update searches, we checked reference lists for additional studies. We excluded non–English-language articles and abstract-only publications.

      Data Extraction and Quality Assessment

One investigator extracted study data, and a second verified accuracy. For systematic reviews, we abstracted details about inclusion criteria, search strategy, databases searched, search dates, number and characteristics of included studies, quality assessment methods and ratings, synthesis methods, and results. For randomized trials, we abstracted details about the setting, sample size, eligibility criteria, population characteristics, treatment characteristics, results, and funding source. Two investigators independently assessed the quality of each study as good, fair, or poor using criteria developed by the U.S. Preventive Services Task Force (for randomized trials) [16] and AMSTAR (A Measurement Tool to Assess Systematic Reviews) [14].

For primary studies included in systematic reviews, we used both the quality ratings and the overall grade (for example, good, fair, or poor, or high or low) as determined in the reviews. We classified the magnitude of effects as small/slight, moderate, or large/substantial based on the definitions in the ACP/APS review (Table 1) [6, 17]. We also reported risk estimates based on the proportion of patients achieving successful pain or function outcomes (for example, >30% or >50% improvement).

      Data Synthesis and Analysis

We synthesized data qualitatively for each medication, stratified according to the duration of symptoms (acute, subacute, or chronic) and presence or absence of radicular symptoms. We reported meta-analysis results from systematic reviews. When statistical heterogeneity was present, we examined the degree of inconsistency and evaluated subgroup and sensitivity analyses. We did not conduct an updated meta-analysis; rather, we qualitatively examined whether results of new studies were consistent with pooled or qualitative findings from prior systematic reviews. Qualitative assessments were based on whether the findings from the new studies were in the same direction as the prior systematic reviews and whether the magnitude of effects was similar; when prior meta-analyses were available, we analyzed whether the estimates and CIs from new studies were encompassed in the CIs from pooled estimates. We assessed the strength of evidence (SOE) for each body of evidence as high, moderate, low, or insufficient based on aggregate study quality, precision, consistency, and directness [18].

      Role of the Funding Source

The Agency for Healthcare Research and Quality (AHRQ) of the U.S. Department of Health and Human Services funded this review. AHRQ staff assisted in developing the scope and key questions. The AHRQ had no role in study selection, quality assessment, or synthesis.



Results

      Literature Search

The search and selection of articles are summarized in the Figure. Database searches found 2847 potentially relevant articles. After dual review of abstracts and titles, we selected 746 articles for full-text dual review; 46 publications met inclusion criteria. Quality ratings are summarized in Supplement Tables 1 and 2


Table 1.   Definitions for Magnitude of Effects, Based on Mean Between-Group Differences

Figure.   Summary of evidence search and selection.


Supplement Table 2-14
Refer to Full-Text


Acetaminophen   Ten trials evaluated acetaminophen; 9 of these (sample sizes, 39 to 456) were included in the ACP/APS review [19]. We identified 1 additional large (n = 1643), good-quality, placebo-controlled trial [20]. Six trials compared acetaminophen with NSAIDs and were included in a systematic review of NSAIDs (Supplement Table 3) [21, 22]. Along with the new trial, 3 others [23–25] were rated good- or high-quality.

For acute low back pain, 1 new trial found no differences between 4 weeks or less of scheduled or as-needed acetaminophen (about 4 g/d) and placebo in pain (differences, ≤0.20 point on a 0- to 10-point scale), function (differences, ≤0.60 point on the 0- to 24-point Roland–Morris Disability Questionnaire [RDQ]), or risk for serious adverse events (about 1% in each group) after 12 weeks (Supplement Table 4) [20]. One trial of acetaminophen versus no treatment included in the ACP/APS review [26] also found no differences.

We found no difference between acetaminophen and NSAIDs in pain intensity (standardized mean difference [SMD], 0.21 [95% CI, –0.02 to 0.43]) at 3 weeks or less based on 3 low-quality trials, although estimates favored NSAIDs [22]. Acetaminophen had a lower risk for adverse events than NSAIDs (relative risk [RR], 0.57 [CI, 0.36 to 0.89]). Evidence was insufficient to determine the effects of acetaminophen versus various nonpharmacologic therapies [24, 27, 28] or amitriptyline [25]; each comparison was evaluated in 1 trial with methodological shortcomings. No study evaluated acetaminophen for chronic or radicular low back pain.

NSAIDs   Seventy trials evaluated NSAIDs; 57 were in the ACP/APS review. Sixty-five trials (total n = 11 237; sample sizes, 20 to 690), 28 of which were high-quality, were included in a systematic review (Supplement Table 3) [22]. We identified 5 additional trials (n = 54 to 525) (Supplement Table 5) [29–33]. One trial was rated good-quality [31], and 4 were rated fair-quality [29, 30].

For acute back pain, 1 systematic review [22] found that NSAIDs were associated with greater mean improvements in pain intensity than placebo (4 trials: weighted mean difference, –8.39 points on a 0- to 100-point scale [CI, –12.68 to –4.10 points]; chi-square test, 3.47 points; P > 0.10) [34–37]. One additional trial (n = 171) reported consistent findings [29]. Three trials in this review found no differences between an NSAID and placebo in the likelihood of pain relief [38–40]. Most trials did not report effects on function, although 1 trial [41] found that NSAIDs were associated with greater improvement on the RDQ than placebo (differences, 2.4 to 2.9 points; P < 0.001).

For chronic low back pain, 1 systematic review [22] found that NSAIDs were associated with greater mean pain relief than placebo after 12 weeks (4 trials: weighted mean difference, –12.40 points on a 0- to 100-point scale [CI, –15.53 to –9.26 points]; chi-square test, 1.82 points; P > 0.50). However, 2 trials that were not included reported smaller effects on pain (0.41 to 0.59 point after 12 to 16 weeks on a 0- to 10-point scale), although NSAIDs were associated with an increased likelihood of pain relief versus placebo in both studies (≥30% pain relief: 56.8% vs. 31.7% and 37.0% vs. 27.0%; P < 0.05 in both studies) [32, 33]. Four trials found that NSAIDs were associated with no to small effects on the RDQ versus placebo (mean differences, about 0.02 to 2 points) [32, 33, 42, 43].

For radiculopathy, the ACP/APS review [22] reported small and inconsistent effects on pain from 2 trials [36, 44]. Neither study assessed effects on function.

Evidence was insufficient to determine the effects of an NSAID plus another intervention versus this intervention alone or an NSAID versus another intervention (other interventions were a skeletal muscle relaxant, doloteffin, exercise therapy, and massage) [30, 31, 38, 45]. Each comparison was evaluated in only 1 trial with methodological shortcomings. There were no clear differences in pain relief between different NSAIDs for acute or chronic low back pain (21 and 6 trials, respectively) [22].

The systematic review [22] found that NSAIDs were associated with more adverse effects than placebo (10 trials: RR, 1.35 [CI, 1.09 to 1.68]), although serious harms were rare. Cyclooxygenase-2-selective NSAIDs had a lower risk for adverse effects than nonselective NSAIDs (4 trials: RR, 0.83 [CI, 0.70 to 0.99]).

Opioids, Tramadol, and Tapentadol   Twenty-seven trials (sample sizes, 21 to 981) evaluated opioids, tramadol (a dual-action analgesic with weak opioid µ-receptor affinity), or tapentadol (a dual-action analgesic with strong µ-receptor affinity) versus placebo or other treatments; 14 were included in the ACP/APS review and 16 (13 rated low risk of bias) were reported in a systematic review (Supplement Table 3) [46]. Three trials (1 higher-quality) [47] were included in the ACP/APS review [47–49]. We identified 8 additional trials (Supplement Table 6) [50–57]: 2 good-quality [50, 51], 5 fair-quality [53–57], and 1 poor-quality [52]. Methodological shortcomings included high attrition (30% to 60% in most trials), use of an enriched enrollment randomized withdrawal design [58] by some trials [47, 52, 56, 57, 59–64], and short follow-up (maximum of 16 weeks) [48]. We also identified 11 trials that compared opioids. Eight trials [47, 48, 65–70] were included in a systematic review [71], but 3 others were not [72–74].

For acute low back pain, 1 trial found no difference between oxycodone or acetaminophen plus naproxen (n = 108) and placebo plus naproxen (n = 107) in pain or function [54].

For chronic low back pain, 1 systematic review [46] found that strong opioids (morphine, oxymorphone, hydromorphone, and tapentadol) were associated with greater short-term relief than placebo for pain (6 trials: SMD, –0.43 [CI, –0.52 to –0.33]; I2 = 0.0%; mean difference, about 1 point on a 0- to 10-point pain scale) and function (4 trials: SMD, –0.26 [CI. –0.37 to –0.15]; I2 = 0.0%; mean difference, about 1 point on the RDQ); 4 additional trials [47, 50, 52, 56] reported consistent results. Tramadol also resulted in greater short-term relief than placebo for pain (5 trials: SMD, –0.55 [CI, –0.66 to –0.44]; I2 = 86%; mean difference, ≤1 point on a 0- to 10-point pain scale) and function (5 trials: SMD, –0.18 [CI, –0.29 to –0.07]; I2 = 0%; mean difference, about 1 point on the RDQ); 2 additional trials [51, 53] reported consistent results. Two trials found that buprenorphine patches were associated with greater short-term pain relief (about 1 point on a 0- to 10-point scale) than placebo patches, with inconsistent effects on function [63, 75–77]; 1 additional trial [57] of buccal buprenorphine reported consistent results. Three trials in this review [46] reported inconsistent effects of opioids versus NSAIDs for pain relief [48, 78]; 1 of the trials [48] found no difference in function.

The review [46] found that opioids had a higher risk for nausea, dizziness, constipation, vomiting, somnolence, and dry mouth than placebo. Trials were not designed to assess long-term harms or the risk for overdose, abuse, or addiction.

For symptomatic spinal stenosis, a small (n = 21) trial found no differences between single-dose immediate-release oxymorphone and placebo in pain, function, or other outcomes [55].

Four trials found no clear differences among various long-acting opioids in pain or function [47, 65, 66, 72, 74]. Six trials found no clear differences between long- and short-acting opioids in pain [48, 67–70, 73]. Although some trials found long-acting opioids associated with greater pain relief, patients randomly assigned to these drugs also received higher doses.

Skeletal Muscle Relaxants   Twenty-five trials (sample sizes, 20 to 562) evaluated skeletal muscle relaxants; 22 (17 high-quality) were included in a systematic review (Supplement Table 3) [79] used in the ACP/APS review. We identified 3 additional fair-quality trials (Supplement Table 7) [54, 80, 81].

For acute low back pain, the systematic review [79] found skeletal muscle relaxants superior to placebo for short-term pain relief (≥2-point or 30% improvement on a 0- to 10-point visual analogue scale [VAS]) after 2 to 4 days (4 trials: RR, 1.25 [CI, 1.12 to 1.41]; I2 = 0%) and 5 to 7 days (3 trials: RR, 1.72 [CI, 1.32 to 2.22]; I2 = 0%) [79]. An additional trial (n = 562) reported consistent findings [81]. Evidence was insufficient to determine effects on function, which most trials did not report. Compared with placebo, skeletal muscle relaxants were associated with increased risk for any adverse event (8 trials: RR, 1.50 [CI, 1.14 to 1.98]) and central nervous system events (primarily sedation) (8 trials: RR, 2.04 [CI, 1.23 to 3.37]; I2 = 50%) [79].

Evidence was insufficient from 3 small placebo-controlled trials with inconsistent results and methodological shortcomings to determine the effects of skeletal muscle relaxants on chronic low back pain [82–84]. Four trials showed inconsistent effects of a skeletal muscle relaxant plus an NSAID versus an NSAID alone [54, 79, 80]. Although estimates from 3 trials favored the combination for effects on pain intensity, the fourth trial found no effects on pain or function [54]. Three trials in the review [79] found no differences among various skeletal muscle relaxants on any outcome [85–87].

Benzodiazepines   Nine trials (sample sizes, 30 to 152) evaluated benzodiazepines; 8 of these trials (5 high-quality) were included in a systematic review [79] used in the ACP/APS review (Supplement Table 3 The ninth, a good-quality trial (n = 60) (Supplement Table 8, evaluated benzodiazepines for radicular pain [88].

For acute nonradicular low back pain, 2 trials reported inconsistent effects of benzodiazepines versus placebo [89, 90]; the higher-quality trial (n = 50) [89] found no difference between diazepam and placebo in the likelihood of reduced pain and tenderness at 5 days (76% vs. 72%; RR, 1.06 [CI, 0.76 to 1.47]). For chronic nonradicular low back pain, 2 high-quality trials (n = 50 and 152) [91, 92] found tetrazepam associated with a lower likelihood of no improvement in pain at 5 to 7 days (RR, 0.82 [CI, 0.72 to 0.94]) and 10 to 14 days (RR, 0.71 [CI, 0.54 to 0.93]) than placebo. Evidence was inconsistent from 2 trials on the effects of benzodiazepines versus skeletal muscle relaxants [93, 94].

The new trial found no difference in function between diazepam, 5 mg 3 times daily, and placebo for acute radiculopathy (median improvement on the RDQ at 1 week, 3.0 vs. 5.0 points [P = 0.67]; median improvement on the RDQ at 1 year, 2 vs. 1 point) [88]. Diazepam was less likely to be associated with pain relief of 50% or greater at 1 week (41% vs. 79%; RR, 0.5 [CI, 0.3 to 0.8]).

A systematic review [79] found that compared with placebo, benzodiazepines were associated with greater risk for central nervous system adverse events, such as somnolence, fatigue, and lightheadedness, although harms were not well-reported. No trial was designed to evaluate risk for addiction, abuse, or overdose.

Antidepressants   Sixteen trials (n = 16 to 404) evaluated antidepressants; 7 were used in the ACP/APS review, and 10 trials (7 high-quality) were included in a systematic review (Supplement Table 3) [95]. We identified 6 additional trials (Supplement Table 9): 1 good-quality [96], 3 fair-quality [97–99], and 2 poor-quality [100, 101]. Two trials required patients to have depression and low back pain [102, 103]. No trial evaluated antidepressants for acute low back pain.

For chronic low back pain, a systematic review [95] found no difference in pain between tricyclic antidepressants (4 trials: SMD, –0.10 [CI, –0.51 to 0.31]; I2 = 32%) or selective serotonin reuptake inhibitors (3 trials: SMD, 0.11 [CI, –0.17 to 0.39]; I2 = 0%) and placebo. Antidepressants were not associated with reduced depression (SMD, 0.06 [CI, –0.29 to 0.40]; I2 = 0%) or improved function (SMD, –0.06 [CI, –0.40 to 0.29]; I2 = 0%), but each outcome was evaluated in only 2 trials.

Three trials not in that review found that the serotonin norepinephrine reuptake inhibitor duloxetine, 60 mg/d, was associated with lower pain intensity at 12 to 13 weeks, although effects were small (differences, 0.60 to 0.79 point on the 0- to 10-point Brief Pain Inventory severity scale) [96–98]. One trial of duloxetine also found an increased likelihood of 50% or greater pain relief after 12 weeks (49% vs. 35%; RR, 1.41 [CI, 1.11 to 1.78]) [97]. All 3 trials found that duloxetine was associated with greater improvement in function than placebo on the Brief Pain Inventory interference scale (mean between-group difference, 0.58 to 0.74 point), but 1 trial found no difference on the RDQ (mean change from baseline, –2.69 vs. –2.22 points; P = 0.26) [97]. There were no differences between duloxetine and placebo in the risk for serious adverse events [96–98], although duloxetine was associated with increased risk for withdrawal due to adverse events (3 trials: odds ratio, 2.72 [CI, 1.74 to 4.24]; I2 = 0%). Duloxetine was associated with increased risk for nausea (P < 0.05).

Evidence to directly compare serotonin norepinephrine reuptake inhibitors with other antidepressants was very limited. One fair-quality trial (n = 85) found no differences between duloxetine and escitalopram (a selective serotonin reuptake inhibitor) in pain or function [96, 99]. One small trial (n = 25) provided insufficient evidence to determine the effects of duloxetine for radicular pain [101].

Antiseizure Medications   Twelve trials (n = 29 to 309) evaluated antiseizure medications; 4 [104–107] were reported in the ACP/APS review (Supplement Table 3). We identified 8 additional trials (Supplement Table 10) [108–115]. Seven of these [108–113, 115] evaluated pregabalin and 1 [114] evaluated gabapentin. Of the 12 antiseizure medication trials, 6 [106, 108, 109, 111–113] were rated fair-quality and 6 [104, 105, 107, 110, 114, 115] were rated poor-quality.

No trial evaluated antiseizure medications for acute low back pain. For chronic nonradicular back pain, 2 fair-quality trials found that pregabalin was associated with no effects on pain intensity versus placebo (differences, 0.14 to 0.21 point on a 0- to 10-point scale) [108, 111]. One trial found no effect on function on the Oswestry Disability Index (ODI) [108], and the other found that pregabalin had slightly worse scores on the RDQ (13 vs. 11 points; P = 0.01) [111]. Evidence was insufficient to determine adverse effects of topiramate or pregabalin versus placebo because of inconsistent findings.

For chronic radicular back pain, 3 poor-quality trials reported inconsistent findings for gabapentin (dose titrated up to 1200 to 3600 mg/d) versus placebo [105, 107, 114]. Effects on pain intensity ranged from 0.3 to 1.9 points on a 0- to 10-point scale. One fair-quality and 1 poor-quality trial reported inconsistent effects of topiramate, with small to moderate effects on some measures of pain [104, 106]; no effects on leg pain or the ODI were reported in 1 of the trials [106].

Evidence was insufficient from single trials with methodological shortcomings to determine the effects of pregabalin versus other medications [110, 113, 115] or pregabalin plus another medication versus the other medication alone [109, 112, 113].

Systemic Corticosteroids   Ten trials (sample size, 29 to 269) evaluated systemic corticosteroids; 4 [116–119] were included in the ACP/APS review (Supplement Table 3). We identified 6 additional trials (Supplement Table 11) [120–125]. Treatment ranged from a single dose to a 21-day course; corticosteroid doses varied. Eight trials evaluated patients with radiculopathy; of these, 3 [116, 124, 125] required imaging correlation. Four trials [116, 117, 121, 125] were rated good-quality, 5 fair-quality [118–120, 122, 124], and 1 poor-quality [123].

For acute nonradicular low back pain, 2 trials (n = 86 and 67) found no differences between a single intramuscular injection or a 5-day course of systemic corticosteroids and placebo in pain or function [117, 120]. For spinal stenosis, 1 trial (n = 61) found no differences through 12 weeks of follow-up between a 3-week course of prednisone and placebo in pain intensity or the RDQ [124]. No trial evaluated systemic corticosteroids for chronic nonradicular pain.

For radicular low back pain of varying duration, 6 trials consistently found no differences between systemic corticosteroids and placebo in pain [116, 118, 119, 121, 123, 125]. For function, the largest (n = 269) good-quality trial found that systemic corticosteroids were associated with small effects (difference in ODI at 52 weeks, 7.4 [CI, 2.2 to 12.5]) [125], but 2 other trials found no effects [121, 123]. Two trials found no effects of systemic corticosteroids on the likelihood of spine surgery [116, 125].

In the largest trial, oral prednisone (initial dose, 60 mg/d) increased risk for any adverse event (49% vs. 24%; P < 0.001), insomnia (26% vs. 10%; P = 0.003), nervousness (18% vs. 8.0%; P = 0.03), and increased appetite (22% vs. 10%; P = 0.02) [125]. A smaller (n = 39) trial found that a tapering course of intramuscular dexamethasone (initial dose, 64 mg/d) was associated with increased risk for any adverse effect (32% vs. 5.0%; RR, 6.32 [CI, 0.84 to 47.7]), but there were no withdrawals due to adverse events [122]. Serious harms were not reported in any trial, but harms were not well-reported in some trials.



Discussion

Many systemic pharmacologic therapies have some evidence of effectiveness in acute (Table 2 and Supplement Table 12) or chronic low back pain (Table 3 and Supplement Table 13). Benefits were generally observed for short-term (generally <3 months) pain and were small (5 to 10 points on a 100-point VAS) to moderate (10 to 20 points), based on the ACP/APS categories [19]. Function was reported less consistently than pain, and effects were typically smaller or not observed. Evidence on other outcomes (for example, quality of life, mood, work, analgesic use, or health care use) was sparse and is described in the full report [9]. As in the ACP/APS review, evidence on pharmacologic therapies for radiculopathy was very limited (Table 4). The SOE ratings are summarized in Supplement Table 14.


Table 2.   Pharmacologic Therapies
Versus Placebo for Acute
Low Back Pain


Table 3.   Pharmacologic Therapies
Versus Placebo for Chronic
Low Back Pain


Table 4.   Pharmacologic Therapies
Versus Placebo for Radicular
Low Back Pain



Supplement Table 12   Pharmacological therapies
versus active comparators
for acute low back pain


Supplement Table 13   Pharmacological therapies versus
active comparators for chronic low back pain


Supplement Table 14
Strength of evidence

Refer to Full-Text



New evidence affected findings for several medications. The ACP/APS review concluded that acetaminophen was effective for acute low back pain, primarily based on trials showing similar effectiveness of acetaminophen compared with NSAIDs. However, the first large, well-conducted, placebo-controlled trial found that acetaminophen was ineffective for acute low back pain (low SOE) [20]. Newer trials reported that NSAIDs had smaller benefits than placebo for chronic low back pain than previously observed [32, 33]. For antidepressants, several trials found duloxetine, a serotonin norepinephrine reuptake inhibitor introduced after the prior ACP/APS review, to be more effective than placebo for chronic low back pain, although effects were small (moderate SOE) [96–98]. Previous reviews found that tricyclic antidepressants were modestly effective for chronic low back pain; however, a meta-analysis with newer trials found no differences versus placebo (moderate SOE) [95]. For antiseizure medications, new placebo-controlled trials on pregabalin for radicular low back pain are available but had methodological shortcomings and reported inconsistent results (insufficient SOE) [108, 111]. A recent trial on radiculopathy found that compared with placebo, benzodiazepines were associated with no difference in function but more pain (low SOE) [88].

Other conclusions were relatively unchanged. Skeletal muscle relaxants relieved short-term acute low back pain but caused sedation (moderate SOE). Systemic corticosteroids do not seem to be effective for radicular or nonradicular low back pain in improving pain (moderate SOE), although a recent trial reported small effects on function [125]. Evidence on benzodiazepines for nonradicular back pain remains sparse (insufficient SOE) [23]. For opioids, evidence remains limited to short-term trials showing modest effects versus placebo for chronic low back pain (moderate SOE) [46]. Trials were not designed to assess the risk for overdose or opioid use disorder because of relatively small samples, short follow-up, and exclusion of higher-risk patients; in addition, many studies used an enriched enrollment randomized withdrawal design, which could underestimate harms [58]. Observational studies have found an association between prescribed opioids and serious harms, such as overdose [126], and clinical guidelines recommend risk assessment, careful patient selection, use of lower doses, and close monitoring and follow-up of patients prescribed these drugs [127]. For nonopioid medications, serious harms were generally not observed, although the studies were not designed to assess uncommon or longer-term harms.

Relatively few studies compared the effectiveness of different medications for low back pain or a combination of 2 medications versus 1 medication alone. There were no clear differences between opioids and NSAIDs, benzodiazepines and skeletal muscle relaxants, or acetaminophen and NSAIDs.

We categorized the magnitude of effects for pain and function using the thresholds in the ACP/APS review (Table 1). Effects that were classified as small (for example, 5 to 10 points on a 0- to 100-point scale for pain or function) are below some of the proposed thresholds for the minimum clinically important difference (for example, 15 points on a 0- to 100-point VAS for pain, 2 points on a 0- to 10-point numerical rating scale for pain or function, 5 points on the RDQ, and 10 points on the ODI) [17]. Factors that may support the use of interventions associated with small effects include low risk for harms, low costs, or strong patient preferences; in addition, some patients will have greater-than-average effects. The magnitude of effects might vary depending on baseline severity [128]; most trials enrolled patients with at least moderate pain (for example, >5 points on a 0- to 10-point numerical rating scale).

Our findings have implications for clinical practice. Guidelines currently recommend acetaminophen as a first-line option for acute and chronic low back pain [6, 129]. The use of opioids for chronic pain has become an area of increasing concern [130]. Since the ACP/APS guideline was published, the antidepressant duloxetine has been approved by the U.S. Food and Drug Administration for low back pain and seems to be more effective and safer than tricyclic antidepressants.

Our review has limitations. Reviewing all primary literature was not feasible because of the large number of medications addressed. We included higher-quality, recent systematic reviews that were most relevant to the scope of our review [131], supplemented with additional primary trials. Although we did not update meta-analyses reported in systematic reviews, we evaluated the consistency of results from new trials against prior pooled estimates. We excluded non–English-language articles and did not search for abstract-only publications. Some systematic reviews that we used included such articles but did not affect our conclusions. Our ability to assess for publication bias was limited because of methodological limitations in the trials and study heterogeneity and because few trials were available for many comparisons. Although we did not include new or updated systematic reviews identified in update searches [132–134], we used these searches to identify additional trials. Our findings were generally concordant with new reviews. We did not evaluate the effectiveness of medications injected for local effects; epidural steroid injections were recently reviewed elsewhere [135].

The evidence base has limitations. Effects on pain and function were typically reported as mean differences. Few studies reported the likelihood of clinically significant improvements [136]. Data were sparse for several medications, and many studies had methodological flaws. Some studies did not clearly describe important patient characteristics, such as the duration of symptoms, presence of radiculopathy, or use of co-interventions. Older adults were underrepresented, and most antidepressant trials excluded or included few patients with depression [95]. Therefore, evidence to determine how medication effectiveness varies in important subgroups is lacking. Most studies were funded by industry. For example, all placebo-controlled trials of duloxetine for nonradicular low back pain were funded by the manufacturer and nearly all trials of opioids were industry-funded.

More research is needed to determine effective treatments for radicular low back pain. Trials with longer-term follow-up are needed to help understand whether benefits are sustained. Studies are particularly needed on the long-term effectiveness and harms of opioids for chronic low back pain in clinically representative populations. More research is also needed to better understand whether combining medications is associated with incremental benefits and which combinations and sequences of medications are the most effective. Trials should routinely assess important outcomes, such as mood, quality of life, return to work, and health care use, and more consistently and rigorously evaluate and report harms.

In conclusion, several systemic pharmacologic therapies for low back pain are associated with small to moderate, primarily short-term effects on pain. Effects on function were generally smaller than effects on pain. New evidence suggests that acetaminophen is ineffective for acute low back pain and that duloxetine is associated with modest effects for chronic low back pain. More research is needed to understand the optimal selection of medications, the best combinations and sequencing of treatments, and the most effective medications for radicular low back pain.



References:

  1. Deyo RA, Mirza SK, Martin BI.
    Back pain prevalence and visit rates: estimates from U.S. national surveys, 2002.
    Spine (Phila Pa 1976). 2006;31:2724-7

  2. Walker BF.
    The prevalence of low back pain: a systematic review of the literature from 1966 to 1998.
    J Spinal Disord. 2000;13:205-17

  3. Carey TS, Freburger JK, Holmes GM, Castel L, Darter J, Agans R, et al.
    A long way to go: practice patterns and evidence in chronic low back pain care.
    Spine (Phila Pa 1976). 2009;34:718-24

  4. Fritz JM, Brennan GP, Hunter SJ, Magel JS. Initial management decisions after a new consultation for low back pain: implications of the usage of physical therapy for subsequent health care costs and utilization.
    Arch Phys Med Rehabil. 2013;94:808-16

  5. Ivanova JI, Birnbaum HG, Schiller M, Kantor E, Johnstone BM, Swindle RW.
    Real-world practice patterns, health-care utilization, and costs in patients with low back pain: the long road to guidelineconcordant care.
    Spine J. 2011;11:622-32

  6. Chou R, Qaseem A, Snow V, Casey D, Cross JT Jr, Shekelle P, et al;
    Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society.
    Ann Intern Med. 2007;147:478- 91

  7. Chou R, Huffman LH;
    Medications for acute and chronic low back pain:
    a review of the evidence for an American Pain Society/
    American College of Physicians clinical practice guideline.

    Ann Intern Med. 2007;147:505-14

  8. Chou R, Deyo R, Friedly J, Skelly A, Hashimoto R, Weimer M, et al.
    Nonpharmacologic therapies for low back pain: a systematic review for an American College of Physicians clinical practice guideline.
    Ann Intern Med. 2017

  9. Chou R, Deyo R, Friedly J, Skelly A, Hashimoto R, Weimer M, et al.
    Noninvasive Treatments for Low Back Pain. Comparative Effectiveness Review no. 169. (Prepared by the Pacific Northwest Evidencebased Practice Center under contract no. 290-2012-00014-I.) AHRQ publication no. 16-EHC004-EF. Rockville: Agency for Healthcare Research and Quality; 2016.

  10. Owens D, Lohr KN, Atkins D, Treadwell J, Reston J, Bass E, et al. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville: Agency for Healthcare Research and Quality; 2011.

  11. Noninvasive treatments for low back pain. PROSPERO 2014: CRD42014014735. Accessed at www.crd.york.ac.uk/PROSPERO /display_record.asp?ID=CRD42014014735 on 21 June 2016.

  12. Chou R, Huffman L, eds; American Pain Society; American Academy of Pain Medicine. Guideline for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain. Evidence Review. Chicago: American Pain Society; 2009.

  13. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ publication no. 10(14)-EHC063-EF. Rockville: Agency for Healthcare Research and Quality; 2014.

  14. Shea BJ, Hamel C, Wells GA, Bouter LM, Kristjansson E, Grimshaw J, et al.
    AMSTAR is a reliable and valid measurement tool to assess the methodological quality of systematic reviews.
    J Clin Epidemiol. 2009;62:1013-20

  15. Agency for Healthcare Research and Quality.
    Integrating bodies of evidence: existing systematic reviews and primary studies.
    In: Agency for Healthcare Research and Quality;
    U.S. Department of Health and Human Services, eds.
    Draft Methods Guidance.
    Rockville: Agency for Healthcare Research and Quality; 2015.

  16. U.S. Preventive Services Task Force.
    U.S. Preventive Services Task Force Procedure Manual.
    AHRQ publication no. 08-05118-EF.
    Rockville: Agency for Healthcare Research and Quality; 2015.

  17. Ostelo RW, Deyo RA, Stratford P, Waddell G, Croft P, Von Korff M, et al.
    Interpreting change scores for pain and functional status in low back pain: towards international consensus regarding minimal important change.
    Spine (Phila Pa 1976). 2008;33:90-4

  18. Owens DK, Lohr KN, Atkins D, Treadwell JR, Reston JT, Bass EB, et al.
    AHRQ series paper 5: grading the strength of a body of evidence when comparing medical interventions—Agency for Healthcare Research and Quality and the effective health-care program.
    J Clin Epidemiol. 2010;63:513-23

  19. Chou R, Huffman L.
    Guideline for the Evaluation and Management of Low Back Pain: Evidence Review.
    Glenview, IL: American Pain Society; 2007.

  20. Williams CM, Maher CG, Latimer J, McLachlan AJ, Hancock MJ, Day RO, et al.
    Efficacy of paracetamol for acute low-back pain: a double-blind, randomised controlled trial.
    Lancet. 2014;384:1586-96

  21. Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW.
    Nonsteroidal anti-inflammatory drugs for low back pain: an updated Cochrane review.
    Spine (Phila Pa 1976). 2008;33:1766-74

  22. Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW.
    Non-steroidal anti-inflammatory drugs for low back pain.
    Cochrane Database Syst Rev. 2008:CD000396

  23. Hickey RF.
    Chronic low back pain: a comparison of diflunisal with paracetamol.
    N Z Med J. 1982;95:312-4

  24. Nadler SF, Steiner DJ, Erasala GN, Hengehold DA, Hinkle RT, Beth Goodale M, et al.
    Continuous low-level heat wrap therapy provides more efficacy than ibuprofen and acetaminophen for acute low back pain.
    Spine (Phila Pa 1976).

  25. Stein D, Peri T, Edelstein E, Elizur A, Floman Y.
    The efficacy of amitriptyline and acetaminophen in the management of acute low back pain.
    Psychosomatics. 1996;37:63-70

  26. Milgrom C, Finestone A, Lev B, Wiener M, Floman Y.
    Overexertional lumbar and thoracic back pain among recruits: a prospective study of risk factors and treatment regimens.
    J Spinal Disord. 1993; 6:187-93

  27. Doran DM, Newell DJ.
    Manipulation in treatment of low back pain: a multicentre study.
    Br Med J. 1975;2:161-4

  28. Hackett GI, Seddon D, Kaminski D.
    Electroacupuncture compared with paracetamol for acute low back pain.
    Practitioner. 1988; 232:163-4

  29. Herrmann WA, Geertsen MS.
    Efficacy and safety of lornoxicam compared with placebo and diclofenac in acute sciatica/lumbo-sciatica: an analysis from a randomised, double-blind, multicentre, parallel-group study.
    Int J Clin Pract. 2009;63:1613-21

  30. Majchrzycki M, Kocur P, Kotwicki T.
    Deep tissue massage and nonsteroidal anti-inflammatory drugs for low back pain: a prospective randomized trial.
    ScientificWorldJournal. 2014;2014:287597.

  31. Shirado O, Doi T, Akai M, Hoshino Y, Fujino K, Hayashi K, et al;
    Japan Low back-pain Exercise Therapy Study. Multicenter randomized controlled trial to evaluate the effect of home-based exercise on patients with chronic low back pain: the Japan Low back pain Exercise Therapy Study.
    Spine (Phila Pa 1976). 2010;35:E811-9

  32. Katz N, Borenstein DG, Birbara C, Bramson C, Nemeth MA, Smith MD, et al.
    Efficacy and safety of tanezumab in the treatment of chronic low back pain.
    Pain. 2011;152:2248-58

  33. Kivitz AJ, Gimbel JS, Bramson C, Nemeth MA, Keller DS, Brown MT, et al.
    Efficacy and safety of tanezumab versus naproxen in the treatment of chronic low back pain.
    Pain. 2013;154:1009-21

  34. Amlie E, Weber H, Holme I.
    Treatment of acute low-back pain with piroxicam: results of a double-blind placebo-controlled trial.
    Spine (Phila Pa 1976). 1987;12:473-6

  35. Babej-Dolle R, Freytag S, Eckmeyer J, Zerle G, Schinzel S, Schmeider G, et al.
    Parenteral dipyrone versus diclofenac and placebo in patients with acute lumbago or sciatic pain: randomized observer-blind multicenter study.
    Int J Clin Pharmacol Ther. 1994;32: 204-9

  36. Dreiser RL, Le Parc JM, Ve´ licitat P, Lleu PL.
    Oral meloxicam is effective in acute sciatica: two randomised, double-blind trials versus placebo or diclofenac.
    Inflamm Res. 2001;50 Suppl 1:S17-23

  37. Szpalski M, Hayez JP.
    Objective functional assessment of the efficacy of tenoxicam in the treatment of acute low back pain. A double-blind placebo-controlled study.
    Br J Rheumatol. 1994;33: 74-8

  38. Basmajian JV.
    Acute back pain and spasm. A controlled multicenter trial of combined analgesic and antispasm agents.
    Spine (Phila Pa 1976). 1989;14:438-9

  39. Goldie I.
    A clinical trial with indomethacin (Indomee®) in low back pain and sciatica.
    Acta Orthop Scand. 1968;39:117-28

  40. Weber H, Aasand G.
    The effect of phenylbutazone on patients with acute lumbago-sciatica. A double blind trial.
    J Oslo City Hosp. 1980;30:69-72

  41. Dreiser RL, Marty M, Ionescu E, Gold M, Liu JH.
    Relief of acute low back pain with diclofenac-K 12.5 mg tablets: a flexible dose, ibuprofen 200 mg and placebo-controlled clinical trial.
    Int J Clin Pharmacol Ther. 2003;41:375-85

  42. Birbara CA, Puopolo AD, Munoz DR, Sheldon EA, Mangione A, Bohidar NR, et al;
    Etoricoxib Protocol 042 Study Group. Treatment of chronic low back pain with etoricoxib, a new cyclo-oxygenase-2 selective inhibitor: improvement in pain and disability—a randomized, placebo-controlled, 3-month trial.
    J Pain. 2003;4:307-15

  43. Katz N, Ju WD, Krupa DA, Sperling RS, Bozalis Rodgers D, Gertz BJ, et al;
    Vioxx Chronic Low Back Pain Study Group. Efficacy and safety of rofecoxib in patients with chronic low back pain: results from two 4-week, randomized, placebo-controlled, parallel-group, double-blind trials.
    Spine (Phila Pa 1976). 2003;28:851-8

  44. Weber H, Holme I, Amlie E.
    The natural course of acute sciatica with nerve root symptoms in a double-blind placebo-controlled trial evaluating the effect of piroxicam.
    Spine (Phila Pa 1976). 1993;18: 1433-8

  45. Chrubasik S, Model A, Black A, Pollak S.
    A randomized doubleblind pilot study comparing Doloteffin and Vioxx in the treatment of low back pain.
    Rheumatology (Oxford). 2003;42:141-8

  46. Chaparro LE, Furlan AD, Deshpande A, Mailis-Gagnon A, Atlas S, Turk DC.
    Opioids compared to placebo or other treatments for chronic low-back pain.
    Cochrane Database Syst Rev. 2013: CD004959

  47. Hale ME, Dvergsten C, Gimbel J.
    Efficacy and safety of oxymorphone extended release in chronic low back pain: results of a randomized, double-blind, placebo- and active-controlled phase III study.
    J Pain. 2005;6:21-8

  48. Jamison RN, Raymond SA, Slawsby EA, Nedeljkovic SS, Katz NP.
    Opioid therapy for chronic noncancer back pain. A randomized prospective study.
    Spine (Phila Pa 1976)

  49. Wiesel SW, Cuckler JM, Deluca F, Jones F, Zeide MS, Rothman RH.
    Acute low-back pain. An objective analysis of conservative therapy.
    Spine (Phila Pa 1976). 1980;5:324-30

  50. Cloutier C, Taliano J, O’Mahony W, Csanadi M, Cohen G, Sutton I, et al.
    Controlled-release oxycodone and naloxone in the treatment of chronic low back pain: a placebo-controlled, randomized study.
    Pain Res Manag. 2013;18:75-82

  51. Lee JH, Lee CS; Ultracet ER Study Group.
    A randomized, doubleblind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of the extended-release tramadol hydrochloride/acetaminophen fixed-dose combination tablet for the treatment of chronic low back pain.
    Clin Ther. 2013;35:1830-40

  52. Rauck RL, Nalamachu S, Wild JE, Walker GS, Robinson CY, Davis CS, et al.
    Single-entity hydrocodone extended-release capsules in opioid-tolerant subjects with moderate-to-severe chronic low back pain: a randomized double-blind, placebo-controlled study.
    Pain Med. 2014;15:975-85

  53. Schiphorst Preuper HR, Geertzen JH, van Wijhe M, Boonstra AM, Molmans BH, Dijkstra PU, et al.
    Do analgesics improve functioning in patients with chronic low back pain? An explorative triple-blinded RCT.
    Eur Spine J. 2014;23:800-6

  54. Friedman BW, Dym AA, Davitt M, Holden L, Solorzano C, Esses D, et al.
    Naproxen with cyclobenzaprine, oxycodone/acetaminophen, or placebo for treating acute low back pain: a randomized clinical trial.
    JAMA. 2015;314:1572-80

  55. Markman JD, Gewandter JS, Frazer ME, Murray NM, Rast SA, McDermott MP, et al.
    A randomized, double-blind, placebo-controlled crossover trial of oxymorphone hydrochloride and propoxyphene/acetaminophen combination for the treatment of neurogenic claudication associated with lumbar spinal stenosis.
    Spine (Phila Pa 1976). 2015;40:684-91

  56. en W, Sitar S, Lynch SY, He E, Ripa SR.
    A multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of single-entity, once-daily hydrocodone tablets in patients with uncontrolled moderate to severe chronic low back pain.
    Expert Opin Pharmacother. 2015;16:1593-606

  57. Rauck RL, Potts J, Xiang Q, Tzanis E, Finn A.
    Efficacy and tolerability of buccal buprenorphine in opioid-naive patients with moderate to severe chronic low back pain.
    Postgrad Med. 2016;128:1-11

  58. Furlan A, Chaparro LE, Irvin E, Mailis-Gagnon A.
    A comparison between enriched and nonenriched enrollment randomized withdrawal trials of opioids for chronic noncancer pain.
    Pain Res Manag. 2011;16:337-51

  59. Hale M, Khan A, Kutch M, Li S.
    Once-daily OROS hydromorphone ER compared with placebo in opioid-tolerant patients with chronic low back pain.
    Curr Med Res Opin. 2010;26:1505-18

  60. Hale ME, Ahdieh H, Ma T, Rauck R;
    Oxymorphone ER Study Group 1. Efficacy and safety of OPANA ER (oxymorphone extended release) for relief of moderate to severe chronic low back pain in opioid-experienced patients: a 12-week, randomized, double-blind, placebo-controlled study.
    J Pain. 2007;8:175-84

  61. Katz N, Rauck R, Ahdieh H, Ma T, Gerritsen van der Hoop R, Kerwin R, et al.
    A 12-week, randomized, placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain.
    Curr Med Res Opin. 2007;23:117-28

  62. Schnitzer TJ, Gray WL, Paster RZ, Kamin M.
    Efficacy of tramadol in treatment of chronic low back pain.
    J Rheumatol. 2000;27:772-8

  63. Steiner DJ, Sitar S, Wen W, Sawyerr G, Munera C, Ripa SR, et al.
    Efficacy and safety of the seven-day buprenorphine transdermal system in opioid-na?¨ve patients with moderate to severe chronic low back pain: an enriched, randomized, double-blind, placebo-controlled study.
    J Pain Symptom Manage. 2011;42:903-17

  64. Vorsanger GJ, Xiang J, Gana TJ, Pascual ML, Fleming RR.
    Extended-release tramadol (tramadol ER) in the treatment of chronic low back pain.
    J Opioid Manag. 2008;4:87-97

  65. Allan L, Richarz U, Simpson K, Slappendel R. Transdermal fentanyl versus sustained release oral morphine in strong-opioid naive patients with chronic low back pain.
    Spine (Phila Pa 1976). 2005;30: 2484-90

  66. Rauck RL, Bookbinder SA, Bunker TR, Alftine CD, Ghalie R, Negro-Vilar A, et al.
    The ACTION study: a randomized, open-label, multicenter trial comparing once-a-day extended-release morphine sulfate capsules (AVINZA) to twice-a-day controlled-release oxycodone hydrochloride tablets (OxyContin) for the treatment of chronic, moderate to severe low back pain.
    J Opioid Manag. 2006; 2:155-66

  67. Hale ME, Fleischmann R, Salzman R, Wild J, Iwan T, Swanton RE, et al.
    Efficacy and safety of controlled-release versus immediaterelease oxycodone: randomized, double-blind evaluation in patients with chronic back pain.
    Clin J Pain. 1999;15:179-83

  68. Salzman RT, Roberts MS, Wild J, Fabian C, Reder RF, Goldenheim PD.
    Can a controlled-release oral dose form of oxycodone be used as readily as an immediate-release form for the purpose of titrating to stable pain control?
    J Pain Symptom Manage. 1999;18: 271-9

  69. Hale M, Speight K, Harsanyi Z, Iwan T, Slagle N, Lacouture P, et al.
    Efficacy of 12 hourly controlled-release codeine compared with as required dosing of acetaminophen plus codeine in patients with chronic low back pain.
    Pain Res Manag. 1997;2:33-8.

  70. Gostick N, Allen J, Cranfield R, Currie J, Grillage M, Hildebrand P, et al.
    A comparison of the efficacy and adverse effects of controlled-release dihydrocodeine and immediate-release dihydrocodeine in the treatment of pain in osteoarthritis and chronic back pain.
    In: Twycross RG, ed.
    Proceedings of The Edinburgh Symposium on Pain Control and Medical Education.
    London: Royal Soc Medicine Pr; 1989:137-43.

  71. Carson S, Thakurta S, Low A, Smith B, Chou R.
    Drug Class Review: Long-Acting Opioid Analgesics: Final Update 6 Report. Drug Class Reviews.
    Portland: Oregon Health & Science Univ; 2011

  72. Nicholson B, Ross E, Sasaki J, Weil A. Randomized trial comparing polymer-coated extended-release morphine sulfate to controlled-release oxycodone HCl in moderate to severe nonmalignant pain. Curr Med Res Opin. 2006;22:1503-14

  73. Beaulieu AD, Peloso P, Bensen W, Clark AJ, Watson CP, Gardner-Nix J, et al. A randomized, double-blind, 8-week crossover study of once-daily controlled-release tramadol versus immediaterelease tramadol taken as needed for chronic noncancer pain. Clin Ther. 2007;29:49-60

  74. Ueberall MA, Mueller-Schwefe GH. Safety and efficacy of oxycodone/naloxone vs. oxycodone vs. morphine for the treatment of chronic low back pain: results of a 12 week prospective, randomized, open-label blinded endpoint streamlined study with prolongedrelease preparations. Curr Med Res Opin. 2015;31:1413-29

  75. Gordon A, Callaghan D, Spink D, Cloutier C, Dzongowski P, O’Mahony W, et al. Buprenorphine transdermal system in adults with chronic low back pain: a randomized, double-blind, placebo-controlled crossover study, followed by an open-label extension phase. Clin Ther. 2010;32:844-60

  76. Miller K, Yarlas A, Wen W, Dain B, Lynch SY, Ripa SR, et al.
    The impact of buprenorphine transdermal delivery system on activities of daily living among patients with chronic low back pain: an application of the international classification of functioning, disability and health.
    Clin J Pain. 2014;30:1015-22

  77. Yarlas A, Miller K, Wen W, Lynch SY, Munera C, Pergolizzi JV Jr, et al.
    Buprenorphine transdermal system compared with placebo reduces interference in functioning for chronic low back pain.
    Postgrad Med. 2015;127:38-45

  78. O’Donnell JB, Ekman EF, Spalding WM, Bhadra P, McCabe D, Berger MF.
    The effectiveness of a weak opioid medication versus a cyclo-oxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug in treating flare-up of chronic low-back pain: results from two randomized, double-blind, 6-week studies.
    J Int Med Res. 2009;37: 1789-802

  79. Karjalainen KA, Malmivaara A, van Tulder MW, Roine R, Jauhiainen M, Hurri H, et al.
    WITHDRAWN: biopsychosocial rehabilitation for upper limb repetitive strain injuries in working age adults.
    Cochrane Database Syst Rev. 2009:

  80. Pareek A, Chandurkar N, Chandanwale AS, Ambade R, Gupta A, Bartakke G.
    Aceclofenac-tizanidine in the treatment of acute low back pain: a double-blind, double-dummy, randomized, multicentric, comparative study against aceclofenac alone.
    Eur Spine J. 2009; 18:1836-42

  81. Ralph L, Look M, Wheeler W, Sacks H.
    Double-blind, placebo-controlled trial of carisoprodol 250-mg tablets in the treatment of acute lower-back spasm.
    Curr Med Res Opin. 2008;24:551-8

  82. Casale R.
    Acute low back pain: symptomatic treatment with a muscle relaxing drug.
    Clin J Pain. 1988;4:81-8.

  83. Basmajian JV.
    Cyclobenzaprine hydrochloride effect on skeletal muscle spasm in the lumbar region and neck: two double-blind controlled clinical and laboratory studies.
    Arch Phys Med Rehabil. 1978; 59:58-63

  84. Pratzel HG, Alken RG, Ramm S.
    Efficacy and tolerance of repeated oral doses of tolperisone hydrochloride in the treatment of painful reflex muscle spasm: results of a prospective placebo-controlled double-blind trial.
    Pain. 1996;67:417-25

  85. Rollings H.
    Management of acute musculoskeletal conditions—thoracolumbar strain or sprain: a double-blind evaluation comparing the efficacy and safety of carisoprodol with cyclobenzaprine hydrochloride.
    Curr Ther Res. 1983;34:917-28.

  86. Bragstad A, Bilkra G.
    Evaluation of a new skeletal muscle relaxant in the treatment of low back pain (a comparison of DS 103-282 with chlorzoxazone).
    Curr Ther Res. 1979;26:39-43.

  87. Pipino F, Menarini C, Lombardi G, Guerzoni P, Ferrini A, Pizzoli A, et al.
    A direct myotonolytic (pridinol mesylate) for the management of chronic low back pain: a multicentre, comparative clinical evaluation.
    European Journal of Clinical Research. 1991;1:55-70.

  88. Brotz D, Maschke E, Burkard S, Engel C, Manz C, Ernemann U, et al.
    Is there a role for benzodiazepines in the management of lumbar disc prolapse with acute sciatica?
    Pain. 2010;149:470-5

  89. Hingorani K.
    Diazepam in backache. A double-blind controlled trial.
    Ann Phys Med. 1966;8:303-6

  90. Moll W.
    [Therapy of acute umbovertebral syndromes through optimal muscle relaxation using diazepam. Results of a double-blind study on 68 cases].
    Med Welt. 1973;24:1747-51

  91. Arbus L, Fajadet B, Aubert D, Morre M, Goldberger E.
    Activity of tetrazepam (Myolastan) in low back pain. A double-blind trial v. placebo.
    Clin Trials J. 1990;27:258-67.

  92. Salzmann E, Pforringer W, Paal G, Gierend M.
    Treatment of chronic low-back syndrome with tetrazepam in a placebo controlled double-blind trial.
    Journal of Drug Development. 1992;4:219-28.

  93. Hennies OL.
    A new skeletal muscle relaxant (DS 103-282) compared to diazepam in the treatment of muscle spasm of local origin.
    J Int Med Res. 1981;9:62-8

  94. Boyles WF, Glassmann JM, Soyka JP.
    Management of acute musculoskeletal conditions: thoracolumbar strain or sprain. A double-blind evaluation comparing the efficacy and safety of carisoprodol with diazepam.
    Today's Therapeutic Trends. 1983;1:1-16.

  95. Urquhart DM, Hoving JL, Assendelft WW, Roland M, van Tulder MW.
    Antidepressants for non-specific low back pain.
    Cochrane Database Syst Rev. 2008:CD001703

  96. Skljarevski V, Ossanna M, Liu-Seifert H, Zhang Q, Chappell A, Iyengar S, et al.
    A double-blind, randomized trial of duloxetine versus placebo in the management of chronic low back pain.
    Eur J Neurol. 2009;16:1041-8

  97. Skljarevski V, Zhang S, Desaiah D, Alaka KJ, Palacios S, Miazgowski T, et al.
    Duloxetine versus placebo in patients with chronic low back pain: a 12-week, fixed-dose, randomized, double-blind trial.
    J Pain. 2010;11:1282-90

  98. Skljarevski V, Desaiah D, Liu-Seifert H, Zhang Q, Chappell AS, Detke MJ, et al.
    Efficacy and safety of duloxetine in patients with chronic low back pain.
    Spine (Phila Pa 1976). 2010;35:E578-85

  99. Mazza M, Mazza O, Pazzaglia C, Padua L, Mazza S.
    Escitalopram 20 mg versus duloxetine 60 mg for the treatment of chronic low back pain.
    Expert Opin Pharmacother. 2010;11:1049-52

  100. Farajirad S, Behdani F, Hebrani P, Farajirad M.
    Comparison between the effects of amitriptyline and bupropione on the quality of life and the reduction in the severity of pain in patients with chronic low-back pain.
    Neurosurg Q. 2013;23:227-9.

  101. Schukro RP, Oehmke MJ, Geroldinger A, Heinze G, Kress HG, Pramhas S.
    Efficacy of duloxetine in chronic low back pain with a neuropathic component: a randomized, double-blind, placebo-controlled crossover trial.
    Anesthesiology. 2016;124:150-8

  102. Dickens C, Jayson M, Sutton C, Creed F.
    The relationship between pain and depression in a trial using paroxetine in sufferers of chronic low back pain.
    Psychosomatics. 2000;41:490-9

  103. Pheasant H, Bursk A, Goldfarb J, Azen SP, Weiss JN, Borelli L.
    Amitriptyline and chronic low-back pain. A randomized double-blind crossover study.
    Spine (Phila Pa 1976). 1983;8:552-7

  104. Khoromi S, Patsalides A, Parada S, Salehi V, Meegan JM, Max MB.
    Topiramate in chronic lumbar radicular pain.
    J Pain. 2005;6:829-36

  105. McCleane GJ.
    Does gabapentin have an analgesic effect on background, movement and referred pain? A randomised, double-blind, placebo controlled study.
    The Pain Clinic. 2001;13: 103-7.

  106. Muehlbacher M, Nickel MK, Kettler C, Tritt K, Lahmann C, Leiberich PK, et al.
    Topiramate in treatment of patients with chronic low back pain: a randomized, double-blind, placebo-controlled study.
    Clin J Pain. 2006;22:526-31

  107. Yildirim K, Sisecioglu M, Karatay S, Erdal A, Levent A, Ugur M, et al.
    The effectiveness of gabapentin in patients with chronic radiculopathy.
    The Pain Clinic. 2003;15:213-8.

  108. Baron R, Freynhagen R, Tolle TR, Cloutier C, Leon T, Murphy TK, et al; A0081007 Investigators.
    The efficacy and safety of pregabalin in the treatment of neuropathic pain associated with chronic lumbosacral radiculopathy.
    Pain. 2010;150:420-7

  109. Baron R, Martin-Mola E, Muller M, Dubois C, Falke D, Steigerwald I.
    Effectiveness and safety of tapentadol prolonged release (PR) versus a combination of tapentadol PR and pregabalin for the management of severe, chronic low back pain with a neuropathic component: a randomized, double-blind, phase 3b study.
    Pain Pract. 2015;15:455-70

  110. Kalita J, Kohat AK, Misra UK, Bhoi SK.
    An open labeled randomized controlled trial of pregabalin versus amitriptyline in chronic low backache.
    J Neurol Sci. 2014;342:127-32

  111. Markman JD, Frazer ME, Rast SA, McDermott MP, Gewandter JS, Chowdhry AK, et al.
    Double-blind, randomized, controlled, crossover trial of pregabalin for neurogenic claudication.
    Neurology. 2015; 84:265-72

  112. Pota V, Barbarisi M, Sansone P, Moraci M, Pace MC, Passavanti MB, et al.
    Combination therapy with transdermal buprenorphine and pregabalin for chronic low back pain.
    Pain Manag. 2012;2:23-

  113. Romano CL, Romano D, Bonora C, Mineo G.
    Pregabalin, celecoxib, and their combination for treatment of chronic low-back pain.
    J Orthop Traumatol. 2009;10:185-91

  114. Yaksi A, Ozgonenel L, Ozgonenel B.
    The efficiency of gabapentin therapy in patients with lumbar spinal stenosis.
    Spine (Phila Pa 1976). 2007;32:939-42

  115. Sakai Y, Ito K, Hida T, Ito S, Harada A.
    Pharmacological management of chronic low back pain in older patients: a randomized controlled trial of the effect of pregabalin and opioid administration.
    Eur Spine J. 2015;24:1309-17

  116. Finckh A, Zufferey P, Schurch MA, Balague´ F, Waldburger M, So AK.
    Short-term efficacy of intravenous pulse glucocorticoids in acute discogenic sciatica. A randomized controlled trial.
    Spine (Phila Pa 1976). 2006;31:377-81

  117. Friedman BW, Holden L, Esses D, Bijur PE, Choi HK, Solorzano C, et al.
    Parenteral corticosteroids for emergency department patients with non-radicular low back pain.
    J Emerg Med. 2006;31:365-70

  118. Haimovic IC, Beresford HR.
    Dexamethasone is not superior to placebo for treating lumbosacral radicular pain.
    Neurology. 1986; 36:1593-4

  119. Porsman O, Friis H.
    Prolapsed lumbar disc treated with intramuscularly administered dexamethasonephosphate. A prospectively planned, double-blind, controlled clinical trial in 52 patients.
    Scand J Rheumatol. 1979;8:142-4

  120. Eskin B, Shih RD, Fiesseler FW, Walsh BW, Allegra JR, Silverman ME, et al.
    Prednisone for emergency department low back pain: a randomized controlled trial.
    J Emerg Med. 2014;47:65-70

  121. Friedman BW, Esses D, Solorzano C, Choi HK, Cole M, Davitt M, et al.
    A randomized placebo-controlled trial of single-dose IM corticosteroid for radicular low back pain.
    Spine (Phila Pa 1976). 2008;33: E624-9

  122. Hedeboe J, Buhl M, Ramsing P.
    Effects of using dexamethasone and placebo in the treatment of prolapsed lumbar disc.
    Acta Neurol Scand. 1982;65:6-10

  123. Holve RL, Barkan H.
    Oral steroids in initial treatment of acute sciatica.
    J Am Board Fam Med. 2008;21:469-74

  124. Rodrigues LC, Natour J.
    A double-blind, randomized controlled, prospective trial assessing the effectiveness of oral corticoids in the treatment of symptomatic lumbar canal stenosis.
    J Negat Results Biomed. 2014;13:13

  125. Goldberg H, Firtch W, Tyburski M, Pressman A, Ackerson L, Hamilton L, et al.
    Oral steroids for acute radiculopathy due to a herniated lumbar disk: a randomized clinical trial.
    JAMA. 2015;313: 1915-23

  126. Chou R, Deyo R, Devine B, Hansen R, Sullivan S, Jarvik JG, et al.
    The Effectiveness and Risks of Long-Term Opioid Treatment of Chronic Pain.
    Evidence Report/Technology Assessment no. 218.
    (Prepared by the Pacific Northwest Evidence-based Practice Center under contract no. 290-212-00014-I.)
    AHRQ publication no. 14-E005-EF.
    Rockville: Agency for Healthcare Research and Quality; 2014.

  127. Dowell D, Haegerich TM, Chou R.
    CDC guideline for prescribing opioids for chronic pain—United States, 2016.
    JAMA. 2016;315: 1624-45

  128. Licciardone JC, Kearns CM, Minotti DE.
    Outcomes of osteopathic manual treatment for chronic low back pain according to baseline pain severity: results from the OSTEOPATHIC Trial.
    Man Ther. 2013;18:533-40

  129. National Institute for Health and Care Excellence.
    Low back pain in adults.
    Clinical guideline no. CG88. May 2009. Accessed at www.nice.org.uk/guidance/cg88/chapter/1-guidance
    on 10 March 2015.

  130. Chou R, Turner JA, Devine EB, Hansen RN, Sullivan SD, Blazina I, et al.
    The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop.
    Ann Intern Med. 2015;162:276-86

  131. Whitlock EP, Lin JS, Chou R, Shekelle P, Robinson KA.
    Using existing systematic reviews in complex systematic reviews.
    Ann Intern Med. 2008;148:776-82

  132. Enthoven WT, Roelofs PD, Deyo RA, van Tulder MW, Koes BW.
    Non-steroidal anti-inflammatory drugs for chronic low back pain.
    Cochrane Database Syst Rev. 2016;2:CD012087

  133. Abdel Shaheed C, Maher CG, Williams KA, Day R, McLachlan AJ.
    Efficacy, tolerability, and dose-dependent effects of opioid analgesics for low back pain: a systematic review and meta-analysis.
    JAMA Intern Med. 2016;176:958-68

  134. Saragiotto BT, Machado GC, Ferreira ML, Pinheiro MB, Abdel Shaheed C, Maher CG.
    Paracetamol for low back pain.
    Cochrane Database Syst Rev. 2016:CD012230

  135. Chou R, Hashimoto R, Friedly J, Fu R, Bougatsos C, Dana T, et al.
    Epidural corticosteroid injections for radiculopathy and spinal stenosis: a systematic review and meta-analysis.
    Ann Intern Med. 2015;163:373-81

  136. Moore RA, Derry S, Wiffen PJ.
    Challenges in design and interpretation of chronic pain trials.
    Br J Anaesth. 2013;111:38-45



Return to PRESCRIPTION RIGHTS and EXPANDED PRACTICE Page

Since 2-17-2017

         © 1995–2017 ~ The Chiropractic Resource Organization ~ All Rights Reserved