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Clinical Guidelines |

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 FREE

Roger Chou, MD; and Laurie Hoyt Huffman, MS
[+] Article and Author Information

From the Oregon Evidence-based Practice Center and Oregon Health & Science University, Portland, Oregon.


Disclaimer: No statement in this article should be construed as an official position of the American Pain Society.

Acknowledgments: The authors thank Jayne Schablaske and Michelle Pappas for administrative support.

Grant Support: This article is based on research conducted at the Oregon Evidence-based Practice Center with funding from the American Pain Society.

Potential Financial Conflicts of Interest: Honoraria: R. Chou (Bayer HealthCare Pharmaceuticals).

Requests for Single Reprints: Roger Chou, MD, Oregon Evidence-based Practice Center, 3181 SW Sam Jackson Park Road, Mailcode BICC, Portland, OR 97239; e-mail, chour@ohsu.edu.

Current Author Addresses: Dr. Chou and Ms. Huffman: Oregon Evidence-based Practice Center, 3181 SW Sam Jackson Park Road, Mailcode BICC, Portland, OR 97239.


Ann Intern Med. 2007;147(7):505-514. doi:10.7326/0003-4819-147-7-200710020-00008
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Background: Medications are the most frequently prescribed therapy for low back pain. A challenge in choosing pharmacologic therapy is that each class of medication is associated with a unique balance of risks and benefits.

Purpose: To assess benefits and harms of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, benzodiazepines, antiepileptic drugs, skeletal muscle relaxants, opioid analgesics, tramadol, and systemic corticosteroids for acute or chronic low back pain (with or without leg pain).

Data Sources: English-language studies were identified through searches of MEDLINE (through November 2006) and the Cochrane Database of Systematic Reviews (2006, Issue 4). These electronic searches were supplemented by hand searching reference lists and additional citations suggested by experts.

Study Selection: Systematic reviews and randomized trials of dual therapy or monotherapy with 1 or more of the preceding medications for acute or chronic low back pain that reported pain outcomes, back-specific function, general health status, work disability, or patient satisfaction.

Data Extraction: We abstracted information about study design, population characteristics, interventions, outcomes, and adverse events. To grade methodological quality, we used the Oxman criteria for systematic reviews and the Cochrane Back Review Group criteria for individual trials.

Data Synthesis: We found good evidence that NSAIDs, skeletal muscle relaxants (for acute low back pain), and tricyclic antidepressants (for chronic low back pain) are effective for pain relief. The magnitude of benefit was moderate (effect size of 0.5 to 0.8, improvement of 10 to 20 points on a 100-point visual analogue pain scale, or relative risk of 1.25 to 2.00 for the proportion of patients experiencing clinically significant pain relief), except in the case of tricyclic antidepressants (for which the benefit was small to moderate). We also found fair evidence that acetaminophen, opioids, tramadol, benzodiazepines, and gabapentin (for radiculopathy) are effective for pain relief. We found good evidence that systemic corticosteroids are ineffective. Adverse events, such as sedation, varied by medication, although reliable data on serious and long-term harms are sparse. Most trials were short term (≤4 weeks). Few data address efficacy of dual-medication therapy compared with monotherapy, or beneficial effects on functional outcomes.

Limitations: Our primary source of data was systematic reviews. We included non–English-language trials only if they were included in English-language systematic reviews.

Conclusions: Medications with good evidence of short-term effectiveness for low back pain are NSAIDs, skeletal muscle relaxants (for acute low back pain), and tricyclic antidepressants (for chronic low back pain). Evidence is insufficient to identify one medication as offering a clear overall net advantage because of complex tradeoffs between benefits and harms. Individual patients are likely to differ in how they weigh potential benefits, harms, and costs of various medications.

In the United States, low back pain is the fifth most common reason for all physician office visits and the second most common symptomatic reason (12). Medications are the most frequently recommended intervention for low back pain (1, 3). In 1 study, 80% of primary care patients with low back pain were prescribed at least 1 medication at their initial office visit, and more than one third were prescribed 2 or more drugs (4).

The most commonly prescribed medications for low back pain are nonsteroidal anti-inflammatory drugs (NSAIDs), skeletal muscle relaxants, and opioid analgesics (47). Benzodiazepines, systemic corticosteroids, antidepressant medications, and antiepileptic drugs are also prescribed (8). Frequently used over-the-counter medications include acetaminophen, aspirin, and certain NSAIDs.

A challenge in choosing pharmacologic therapy for low back pain is that each class of medication is associated with a unique balance of benefits and harms. In addition, benefits and harms may vary for individual drugs within a medication class. Previous reviews found only limited evidence to support use of most medications for low back pain. For example, a systematic review published in 1996 found insufficient evidence to support use of any medication for low back pain other than NSAIDs (good evidence) and skeletal muscle relaxants (fair evidence) (9).

This article reviews current evidence on benefits and harms of medications for acute and chronic low back pain. It is part of a larger evidence review commissioned by the American Pain Society and the American College of Physicians to guide recommendations for management of low back pain (10).

Data Sources and Searches

An expert panel convened by the American Pain Society and the American College of Physicians determined which medications would be included in this review. The panel chose acetaminophen, NSAIDs (nonselective, cyclooxygenase-2 selective, and aspirin), antidepressants, benzodiazepines, antiepileptic drugs, skeletal muscle relaxants, opioid analgesics, tramadol, and systemic corticosteroids.

We searched MEDLINE (1966 through November 2006) and the Cochrane Database of Systematic Reviews (2006, Issue 4) for relevant systematic reviews, combining terms for low back pain with a search strategy for identifying systematic reviews. When higher-quality systematic reviews were not available for a particular medication, we conducted additional searches for primary studies (combining terms for low back pain with the medication of interest) on MEDLINE and the Cochrane Central Register of Controlled Trials. Full details of the search strategies are available in the complete evidence report (10). Electronic searches were supplemented by hand searching of reference lists and additional citations suggested by experts. We did not include trials published only as conference abstracts.

Evidence Selection

We included all randomized, controlled trials that met all of the following criteria: 1) reported in the English language, or in a non-English language but included in an English-language systematic review; 2) evaluated nonpregnant adults (>18 years of age) with low back pain (alone or with leg pain) of any duration; 3) evaluated a target medication, either alone or in addition to another target medication (“dual therapy”); and 4) reported at least 1 of the following outcomes: back-specific function, generic health status, pain, work disability, or patient satisfaction (1112).

We excluded trials that compared dual-medication therapy with therapy using a different medication, medication combination, or placebo. We also excluded trials of low back pain associated with acute major trauma, cancer, infection, the cauda equina syndrome, fibromyalgia, and osteoporosis or vertebral compression fracture.

Because of the large number of trials evaluating medications for low back pain, our primary source for trials was systematic reviews. When multiple systematic reviews were available for a target medication, we excluded outdated systematic reviews, which we defined as systematic reviews with a published update, or systematic reviews published before 2000. When a higher-quality systematic review was not available for a particular intervention, we included all relevant randomized, controlled trials.

Data Extraction and Quality Assessment

For each included systematic review, we abstracted information on search methods; inclusion criteria; methods for rating study quality; characteristics of included studies; methods for synthesizing data; and results, including the number and quality of trials for each comparison and outcome in patients with acute (<4 weeks' duration) low back pain, chronic/subacute (>4 weeks' duration) low back pain, and back pain with sciatica. If specific data on duration of trials were not provided, we relied on the categorization (acute or chronic/subacute) assigned by the systematic review. For each trial not included in a systematic review, we abstracted information on study design, participant characteristics, interventions, and results.

We considered mean improvements of 5 to 10 points on a 100-point visual analogue pain scale (or equivalent) to be small or slight; 10 to 20 points, moderate; and more than 20 points, large or substantial. For back-specific functional status, we classified mean improvements of 2 to 5 points on the Roland–Morris Disability Questionnaire (scale, 0 to 24) and 10 to 20 points on the Oswestry Disability Index (scale, 0 to 100) as moderate (13). We also considered standardized mean differences of 0.2 to 0.5 to be small or slight; 0.5 to 0.8, moderate; and greater than 0.8, large (14). Some evidence suggests that our classification of mean improvements and standardized mean differences for pain and functional status are roughly concordant in patients with low back pain (1520). Because few trials reported the proportion of patients meeting specific thresholds (such as >30% reduction in pain score) for target outcomes, it was usually not possible to report numbers needed to treat for benefit. When those were reported, we considered a relative risk (RR) of 1.25 to 2.00 for the proportion of patients reporting greater than 30% pain relief (or a similar outcome) to indicate a moderate benefit.

Two reviewers independently rated the quality of each included trial. Discrepancies were resolved through joint review and a consensus process. We assessed internal validity (quality) of systematic reviews by using the Oxman criteria (Appendix Table 1) (2122). According to this system, systematic reviews receiving a score of 4 or less (on a scale of 1 to 7) have potential major flaws and are more likely to produce positive conclusions about effectiveness of interventions (2223). We classified such systematic reviews as “lower quality”; those receiving scores of 5 or more were graded as “higher quality.”

Table Jump PlaceholderAppendix Table 1.  Quality Rating System for Systematic Reviews

We did not abstract results of individual trials if they were included in a higher-quality systematic review. Instead, we relied on results and quality ratings for the trials as reported by the systematic reviews. We considered trials receiving more than half of the maximum possible quality score to be “higher quality” for any quality rating system used (2425).

We assessed internal validity of randomized clinical trials not included in a higher-quality systematic review by using the criteria of the Cochrane Back Review Group (Appendix Table 2) (26). We considered trials receiving more than half of the total possible score (≥6 of a maximum 11) “higher quality” and those receiving less than half “lower quality” (2425).

Table Jump PlaceholderAppendix Table 2.  Quality Rating System for Randomized, Controlled Trials
Data Synthesis

We assessed overall strength of evidence for a body of evidence by using methods adapted from the U.S. Preventive Services Task Force (27). To assign an overall strength of evidence (good, fair, or poor), we considered the number, quality, and size of studies; consistency of results among studies; and directness of evidence. Minimum criteria for fair- and good-quality ratings are shown in Appendix Table 3.

Table Jump PlaceholderAppendix Table 3.  Methods for Grading the Overall Strength of the Evidence for an Intervention

Consistent results from many higher-quality studies across a broad range of populations support a high degree of certainty that the results of the studies are true (the entire body of evidence would be considered good quality). For a fair-quality body of evidence, results could be due to true effects or to biases operating across some or all of the studies. For a poor-quality body of evidence, any conclusion is uncertain.

To evaluate consistency, we classified conclusions of trials and systematic reviews as positive (the medication is beneficial), negative (the medication is harmful or not beneficial), or uncertain (the estimates are imprecise, the evidence unclear, or the results inconsistent) (22). We defined “inconsistency” as greater than 25% of trials reaching discordant conclusions (positive vs. negative), 2 or more higher-quality systematic reviews reaching discordant conclusions, or unexplained heterogeneity (for pooled data).

Role of the Funding Source

The funding source had no role in the design, conduct, or reporting of this review or in the decision to publish the manuscript.

Literature Reviewed

We reviewed 1292 abstracts identified by searches for systematic reviews. Of these, 21 appeared potentially relevant and were retrieved. We excluded 7 outdated reviews of NSAIDs (28), antidepressants (2931), and multiple drugs (9, 3233) (Appendix Table 4). We also excluded 3 reviews that did not clearly use systematic methods (3436) and 4 systematic reviews that evaluated target medications but did not report results specifically for patients with low back pain (3739). We included 7 systematic reviews (Appendix Table 5) of NSAIDs (4041), antidepressants (4243), skeletal muscle relaxants, and benzodiazepines (4446), or multiple medications (4748) (quality ratings shown in Appendix Table 6).

Table Jump PlaceholderAppendix Table 4.  Excluded Systematic Reviews
Table Jump PlaceholderAppendix Table 5.  Systematic Reviews of Medications for Low Back Pain
Table Jump PlaceholderAppendix Table 6.  Quality Ratings of Systematic Reviews of Medications for Low Back Pain

We conducted 8 additional searches (1586 citations) for randomized trials of acetaminophen, celecoxib, aspirin, the serotonin–norepinephrine reuptake inhibitors duloxetine and venlafaxine, antiepileptic drugs, opioids, tramadol, and systemic corticosteroids.

Acetaminophen

Six unique trials of acetaminophen were included in a Cochrane review of NSAIDs (4041) and a systematic review of multiple medications for low back pain (47). From 134 potentially relevant citations, we identified 3 other trials of acetaminophen that met inclusion criteria (4951). The longest trial of acetaminophen for acute or chronic low back pain lasted 4 weeks. We excluded 2 trials that did not evaluate efficacy of acetaminophen specifically for low back pain and 11 trials that compared dual therapy with acetaminophen plus another medication to a different medication, medication combination, or placebo.

For acute low back pain, 1 lower-quality trial included in the Cochrane review found no difference between acetaminophen (3 g/d) and no treatment (52). Four trials (3 of acute low back pain and 1 of mixed-duration back pain) found no clear differences in pain relief between acetaminophen at dosages up to 4 g/d and NSAIDs (4041).

For chronic low back pain, 1 higher-quality trial found acetaminophen inferior to diflunisal for patients reporting good or excellent efficacy after 4 weeks (53). Several other higher-quality systematic reviews of patients with osteoarthritis (not limited to the back) consistently found acetaminophen slightly inferior to NSAIDs for pain relief (standardized mean difference, about 0.3) (5457).

There is insufficient evidence from 5 trials (1 higher-quality [51]) comparing acetaminophen with interventions other than NSAIDs (other medications, physical therapy, superficial heat, a corset, or spinal manipulation) to accurately judge relative efficacy (4951, 5859).

Adverse events associated with acetaminophen for low back pain were poorly reported in the trials. Data on potentially serious harms, such as gastrointestinal bleeding, myocardial infarction, and hepatic adverse events, are particularly sparse.

NSAIDs

A total of 57 unique trials of NSAIDs were included in 3 systematic reviews (4041, 4748). From 74 potentially relevant citations for aspirin and 85 potentially relevant citations for celecoxib (the only cyclooxygenase-selective NSAID available in the United States), we identified 1 trial of aspirin that met inclusion criteria (60). We excluded 1 trial that did not evaluate aspirin specifically for low back pain (61), 10 trials that evaluated selective NSAIDs not available in the United States, and 3 trials that evaluated celecoxib in postoperative settings.

For acute low back pain, a higher-quality Cochrane review (51 trials) found nonselective NSAIDs superior to placebo for global improvement (6 trials; RR, 1.24 [95%, CI, 1.10 to 1.41]) and for not requiring additional analgesics (3 trials; RR, 1.29 [CI, 1.05 to 1.57]) after 1 week of therapy (4041). For chronic low back pain, an NSAID (ibuprofen) was also superior to placebo in 1 higher-quality trial (62). A second, higher-quality systematic review that included fewer (n = 21) trials reached conclusions consistent with the Cochrane review (47). For back pain with sciatica, 1 higher-quality systematic review found no difference between NSAIDs and placebo on a combined outcome of effectiveness (3 trials; odds ratio, 0.99 [CI, 0.6 to 1.7]) (48).

The Cochrane review found no evidence from 24 trials that any nonselective NSAID is superior to others for pain relief (4041). It also found no clear differences in efficacy between NSAIDs and opioid analgesics or muscle relaxants, although trials were limited by small sample sizes (6 trials, 1 higher-quality; 16 to 44 patients) (4041). Use of NSAIDs also was no more effective than nonpharmacologic interventions (spinal manipulation, physical therapy, bed rest).

The Cochrane review found that nonselective NSAIDs were associated with a similar risk for any adverse event compared with placebo (RR, 0.83 [CI, 0.64 to 1.08]) (4041). However, the trials were not designed to evaluate risks for less common but serious gastrointestinal and cardiovascular adverse events (6365). Data on long-term benefits and harms associated with use of NSAIDs for low back pain are particularly sparse. Only 6 of 51 trials included in the Cochrane review were longer than 2 weeks in duration (the longest evaluated 6 weeks of therapy) (4041).

We found insufficient evidence from 1 lower-quality trial to accurately judge benefits or harms of aspirin (acetylsalicylic acid) for low back pain (60). Evidence regarding gastrointestinal safety of aspirin is primarily limited to trials of aspirin for prophylaxis of thrombotic events (6667).

Antidepressants

Ten unique trials were included in 3 systematic reviews of antidepressants (4243, 47). In all of the trials, the duration of therapy ranged from 4 to 8 weeks. From searches for the serotonin–norepinephrine reuptake inhibitors duloxetine or venlafaxine, we identified no relevant trials from 14 citations.

For chronic low back pain, 2 higher-quality systematic reviews (1 qualitative [43] and 1 quantitative [42]) consistently found antidepressants to be more effective than placebo for pain relief. Effects on functional outcomes were inconsistently reported and did not indicate clear benefits. Pooling data for all antidepressants, the quantitative systematic review (9 trials) estimated a standardized mean difference of 0.41 (CI, 0.22 to 0.61) for pain relief. However, effects on pain were not consistent across antidepressants. Tricyclic antidepressants were slightly to moderately more effective than placebo for pain relief in 4 (43) and 6 (42) trials (2 higher-quality) included in the systematic reviews, but paroxetine and trazodone (antidepressants without inhibitory effects on norepinephrine uptake) were no more effective than placebo in 3 trials. Maprotiline, the only tetracyclic antidepressant evaluated in trials included in the systematic reviews, is not available in the United States. There was insufficient evidence from 1 lower-quality trial (which found no differences) (68) to directly judge relative effectiveness of tricyclic antidepressants versus selective serotonin reuptake inhibitors.

One systematic review found that antidepressants were associated with significantly higher risk for any adverse event compared with placebo (22% vs. 14%), although harms were generally not well reported (42). Drowsiness (7%), dry mouth (9%), dizziness (7%), and constipation (4%) were the most common adverse events. The trials were not designed to assess risks for serious adverse events, such as overdose, increased suicidality, or arrhythmias.

Benzodiazepines

Eight trials of benzodiazepines were included in a higher-quality Cochrane review of skeletal muscle relaxants (4546). The trials ranged from 5 to 14 days in duration.

For acute low back pain, 1 higher-quality trial found no differences between diazepam and placebo (69), but another, lower-quality trial found diazepam superior for short-term pain relief and overall improvement (70). For chronic low back pain, pooled results from 2 higher-quality trials (7172) found tetrazepam to be associated with a greater likelihood of not experiencing pain relief (RR, 0.71 [CI, 0.54 to 0.93]) or global improvement (RR, 0.63 [CI, 0.42 to 0.97]) after 8 to 14 days. A third, lower-quality, placebo-controlled trial of diazepam for chronic low back pain found no benefit (73).

In head-to-head trials included in the Cochrane review, efficacy did not differ between diazepam and tizanidine (1 higher-quality trial of acute low back pain [74]) or cyclobenzaprine (1 lower-quality trial of chronic low back pain [73]). For acute low back pain, a third, higher-quality trial found diazepam inferior to carisoprodol for muscle spasm, functional status, and global efficacy (global rating of “excellent” or “very good,” 70% vs. 45% of patients) (75). One study that pooled data from 20 trials (n = 1553) found no difference between diazepam and cyclobenzaprine for short-term (14 days) global improvement (both were superior to placebo) but was excluded from the Cochrane review because it included patients with back or neck pain (mixed duration) (76).

Central nervous system events, such as somnolence, fatigue, and lightheadedness, were reported more frequently with benzodiazepines than with placebo (4546).

Antiepileptic Drugs

We identified no systematic reviews of antiepileptic drugs for low back pain. From 94 citations, we identified 2 trials of gabapentin (7778) and 2 trials of topiramate (7980) that met inclusion criteria (Appendix Table 7). The trials ranged from 6 to 10 weeks in duration. We identified no other trials of antiepileptic drugs for low back pain.

Table Jump PlaceholderAppendix Table 7.  Randomized, Controlled Trials of Antiepileptic Drugs for Low Back Pain

For low back pain with radiculopathy, 3 small (41 to 80 patients) trials found gabapentin (2 trials [78], 1 higher-quality [77]) and topiramate (1 higher-quality trial [79]) to be associated with small improvements in pain scores compared with placebo (or diphenhydramine as active placebo [79]). One trial reporting functional outcomes found no differences (79). For chronic low back pain with or without radiculopathy, 1 higher-quality trial found topiramate moderately superior to placebo for pain, but only slightly superior for functional status (80).

There was no clear difference between gabapentin and placebo in rates of withdrawal due to adverse events. However, drowsiness (6%), loss of energy (6%), and dizziness (6%) were reported with gabapentin (77). Compared with diphenhydramine (active placebo), topiramate was associated with higher rates of withdrawal due to adverse events (33% vs. 15%), sedation (34% vs. 3%), and diarrhea (30% vs. 10%) in 1 trial (79).

Skeletal Muscle Relaxants

Thirty-six unique trials of skeletal muscle relaxants (drugs approved by the U.S. Food and Drug Administration for treatment of spasticity from upper motor neuron syndromes or spasms from musculoskeletal conditions) were included in 4 systematic reviews (4448). The duration of therapy in all trials was 2 weeks or less, with the exception of a single 3-week trial.

For acute low back pain, a higher-quality Cochrane review found skeletal muscle relaxants moderately superior to placebo for short-term (2 to 4 days' duration) pain relief (at least a 2-point or 30% improvement on an 11-point pain rating scale) (4546). The RRs for not achieving pain relief were 0.80 (CI, 0.71 to 0.89) at 2 to 4 days and 0.67 (CI, 0.13 to 3.44) at 5 to 7 days. There was insufficient evidence to conclude that any specific muscle relaxant is superior to others for benefits or harms (4546). However, there is only sparse evidence (2 trials) on efficacy of the antispasticity drugs dantrolene and baclofen for low back pain. Tizanidine, the other skeletal muscle relaxant approved by the Food and Drug Administration for spasticity, was efficacious for acute low back pain in 8 trials. Only 1 trial of patients with chronic low back pain—a lower-quality trial of cyclobenzaprine that did not report pain intensity or global efficacy—evaluated a skeletal muscle relaxant available in the United States (73).

Two other systematic reviews had a smaller scope than the Cochrane review but reached consistent conclusions (44, 47). One of the systematic reviews included 2 additional lower-quality trials of cyclobenzaprine for chronic or subacute low back or neck pain that reported mixed results compared with placebo (44). Another systematic review (48), which focused on interventions for sciatica, found no difference between tizanidine and placebo in 1 higher-quality trial (81).

Skeletal muscle relaxants were associated with a higher total number of adverse events (RR, 1.50 [CI, 1.14 to 1.98]) and central nervous system adverse events (RR, 2.04 [CI, 1.23 to 3.37]) compared with placebo, although most events were self-limited and serious complications were rare (4546).

Opioid Analgesics

We identified no systematic reviews of opioids for low back pain. From 600 potentially relevant citations, we identified 9 trials of opioid analgesics that met inclusion criteria (Appendix Table 8) (59, 8289). Twelve trials were excluded because they evaluated dual therapy with an opioid plus another medication compared with another medication or medication combination, 1 trial because it evaluated single-dose therapy, 2 trials because they did not report efficacy of opioids specifically for low back pain, and 2 trials because they did not evaluate any included outcome.

Table Jump PlaceholderAppendix Table 8.  Randomized, Controlled Trials of Opioids for Low Back Pain

For chronic low back pain, a single higher-quality trial found that sustained-release oxymorphone or sustained-release oxycodone was superior to placebo by an average of 18 points on a 100-point pain scale (87). However, opioids were titrated to stable doses before randomization, so poorer outcomes with placebo could have been due in part to cessation of opioid therapy and to withdrawal. Two lower-quality trials reported no significant differences between propoxyphene and placebo for back pain of mixed duration (83) or codeine and acetaminophen for acute back pain (59).

Two systematic reviews of placebo-controlled trials of opioids for various noncancer pain conditions (most commonly osteoarthritis and neuropathic pain) found opioids to be moderately effective, with a mean decrease in pain intensity with opioids in most trials of at least 30% (38), or a standardized mean difference for pain relief of −0.60 (CI, −0.69 to −0.50) (39). In 1 of the reviews, opioids were also slightly superior for functional outcomes (standardized mean difference, −0.31 [CI, −0.41 to −0.22]) (39). Estimates of benefit were similar for neuropathic and nonneuropathic pain.

There was no evidence from 5 lower-quality trials that sustained-release opioid formulations are superior to immediate-release formulations for low back pain on various outcomes (8486, 8889). In addition, different long-acting opioids did not differ in 2 head-to-head trials (82, 87).

In 1 higher-quality trial, 85% of patients with low back pain randomly assigned to receive opioids reported adverse events, with constipation and sedation as the most frequent symptoms (87). Trials of opioids were not designed to assess risk for abuse or addiction and generally excluded higher-risk patients. In addition with the exception of 2 longer-term (16 weeks and 13 months) studies (82, 88), all trials lasted fewer than 3 weeks.

Tramadol

Three trials of tramadol (9092) were included in a systematic review of various medications for low back pain (47). From 147 potentially relevant citations, we identified 2 other trials of tramadol that met inclusion criteria (9394). We excluded 3 trials that evaluated dual therapy with tramadol plus another drug versus another drug or drug combination (9597), 1 trial published only as an abstract (98), and 1 small (40 patients) trial cited in an electronic database that we could not locate (99).

For chronic low back pain, tramadol was moderately more effective than placebo for short-term pain and functional status after 4 weeks in 1 higher-quality trial (92). Evidence from 2 trials (1 higher-quality) (9091) was insufficient to judge efficacy of tramadol versus the combination of acetaminophen plus codeine or dextroprofen–trometamol (an NSAID not available in the United States). Two other lower-quality trials found no differences in benefits or harms between sustained-release and immediate-release tramadol for chronic low back pain (9394). No trial compared tramadol with acetaminophen or opioid monotherapy, or with other NSAIDs. Tramadol was associated with similar rates of withdrawal due to adverse events compared with placebo (92) or the combination of acetaminophen plus codeine (91).

Systemic Corticosteroids

We identified no systematic reviews of systemic corticosteroids for low back pain. From 418 potentially relevant citations, we identified 4 trials that met inclusion criteria (Appendix Table 9) (100103). We excluded 3 trials that evaluated systemic corticosteroids in operative or postoperative settings and 1 German-language trial.

Table Jump PlaceholderAppendix Table 9.  Randomized, Controlled Trials of Systemic Corticosteroids for Low Back Pain with or without Sciatica

For acute sciatica or sciatica of unspecified duration, 3 small (33 to 65 patients), higher-quality trials consistently found systemic corticosteroids associated with no clinically significant benefit compared with placebo when given parenterally (single injection) or as a short oral taper (100, 102103). For patients with acute low back pain and a negative result on a straight-leg-raise test, a fourth trial found no difference in pain relief through 1 month between a single intramuscular injection of methylprednisolone (160 mg) and placebo (101).

A large (500-mg) intravenous methylprednisolone bolus was associated with 2 cases of transient hyperglycemia and 1 case of facial flushing in 1 trial (100). Another trial found a smaller (160-mg) intramuscular methylprednisolone injection associated with no cases of hyperglycemia requiring medical attention, infection, or gastrointestinal bleeding (101). Adverse events were poorly reported in the other trials.

Dual-Medication Therapy

Five trials comparing dual therapy with a skeletal muscle relaxant plus an analgesic (acetaminophen or an NSAID) versus the analgesic alone were included in a systematic review of skeletal muscle relaxants (4546). One other trial evaluated an opioid plus an NSAID versus an NSAID alone (88). We identified no other trials evaluating dual-medication therapy versus monotherapy from any of the other systematic reviews or searches.

A higher-quality Cochrane review of skeletal muscle relaxants (4546) found tizanidine combined with acetaminophen or an NSAID to be consistently associated with greater short-term pain relief than acetaminophen or NSAID monotherapy in 3 higher-quality trials. However, 2 lower-quality trials found no benefits from adding orphenadrine to acetaminophen or cyclobenzaprine to an NSAID. Compared with acetaminophen or an NSAID alone, adding a muscle relaxant was associated with a higher risk for adverse events of the central nervous system (4 trials; RR, 2.44 [CI, 1.05 to 5.63]) but a trend toward lower risk for gastrointestinal adverse events (4 trials; RR, 0.54 [CI, 0.26 to 1.14]). Overall risk for adverse events did not significantly differ (4 trials; RR, 1.34 [CI, 0.67 to 2.67]).

For chronic low back pain, 1 small (36 patients) trial found an opioid with naproxen slightly superior to naproxen alone for pain (5 to 10 points on a 100-point scale), anxiety, and depression after 16 weeks, but results are difficult to interpret because doses of naproxen were not clearly specified (88).

This review synthesizes evidence from systematic reviews and randomized, controlled trials of medications for treatment of low back pain. Main results are summarized in Appendix Tables 10 (acute low back pain), 11 (chronic or subacute low back pain), and 12 (low back pain with sciatica).

Table Jump PlaceholderAppendix Table 10.  Summary of Evidence on Medications for Acute Low Back Pain
Table Jump PlaceholderAppendix Table 11.  Summary of Evidence on Medications for Chronic or Subacute Low Back Pain
Table Jump PlaceholderAppendix Table 12.  Summary of Evidence on Medications for Sciatica or Radicular Low Back Pain

We found good evidence that NSAIDs, skeletal muscle relaxants (for acute low back pain), and tricyclic antidepressants (for chronic low back pain) are effective for short-term pain relief. Effects were moderate, except in the case of tricyclic antidepressants (small to moderate effects). We found fair evidence that acetaminophen, tramadol, benzodiazepines, and gabapentin (for radiculopathy) are effective for pain relief. Interpreting evidence on efficacy of opioids for low back pain is challenging. Although evidence on opioids versus placebo or nonopioid analgesics specifically for low back pain is sparse and inconclusive, recent systematic reviews of opioids for various chronic pain conditions found consistent evidence of moderate benefits (3839). For all medications included in this review, evidence of beneficial effects on functional outcomes is limited. We found good evidence that systemic corticosteroids are ineffective for low back pain with or without sciatica. We could not draw definite conclusions about efficacy of other medications for sciatica or radiculopathy because few trials have specifically evaluated patients with this condition. One systematic review identified only 7 trials evaluating medications for sciatica (48).

Assessing comparative benefits between drug classes was difficult because of a paucity of well-designed, head-to-head trials. Gabapentin, for example, has been evaluated in only 2 small, short-term, placebo-controlled trials, and no trials directly compared potent opioids with other analgesics. One exception is acetaminophen, which was slightly but consistently inferior for pain relief compared with NSAIDs—although this conclusion assumes that estimates of pain relief from trials of osteoarthritis can be applied to patients with low back pain (5457).

We also found little evidence of differences in efficacy within medication classes. However, head-to-head trials between drugs in the same class were mostly limited to NSAIDs and skeletal muscle relaxants. Among skeletal muscle relaxants, we found sparse evidence on efficacy of the antispasticity medications baclofen and dantrolene. Among antidepressants, tricyclics are the only class shown to be effective for low back pain, although other drugs with effects on norepinephrine uptake (such as duloxetine and venlafaxine) have not yet been evaluated.

In contrast to limited evidence of clear differences in benefits, we found clinically relevant differences between drug classes in short-term adverse events. For example, skeletal muscle relaxants, benzodiazepines, and tricyclic antidepressants are all associated with more central nervous system events (such as sedation) compared with placebo. Opioids seem to be associated with particularly high rates of short-term adverse events, particularly constipation and sedation. Data on serious (life-threatening or requiring hospitalization) adverse events associated with use of medications for low back pain are sparse. For NSAIDs, this is a critical deficiency because much of the uncertainty regarding their use centers on relative gastrointestinal and cardiovascular safety (63). For opioids and benzodiazepines, reliable evidence on such risks as abuse, addiction, and overdose is not available. Among skeletal muscle relaxants, clinical trials have shown no clear differences in rates of adverse events, but carisoprodol is known to be metabolized to meprobamate (a scheduled drug), dantrolene carries a black box warning for potentially fatal hepatotoxicity, and observational studies have found both tizanidine and chlorzoxazone to be associated with usually reversible and mild hepatotoxicity (104).

Our evidence synthesis has several potential limitations. First, because of the large number of published trials, our primary source of data was systematic reviews. The reliability of systematic reviews depends on how well they are conducted. We therefore focused on results from higher-quality systematic reviews, which are less likely than lower-quality reviews to report positive findings (2223). In addition, overall conclusions were generally consistent between multiple higher-quality systematic reviews of a medication. Second, we only included randomized, controlled trials. Although well-conducted randomized, controlled trials are less susceptible to bias than other study designs, nearly all are “efficacy” trials conducted in ideal settings and selected populations, usually with short-term follow-up. “Effectiveness” trials or well-designed observational studies could provide important insight into benefits and harms of medications for low back pain in real-world practice. Third, high-quality data on harms are sparse. Better assessment and reporting of harms in clinical trials would help provide more balanced assessments of net benefits (105). Fourth, reporting of outcomes was poorly standardized across trials. In particular, the proportion of patients meeting predefined criteria for clinically important differences was rarely reported, making it difficult to assess clinical significance of results. Fifth, language bias could affect our results because we included non–English-language trials only if they were included in English-language systematic reviews. However, only 2 systematic reviews restricted inclusion solely to English-language trials (42, 44). Finally, the systematic reviews included in our evidence synthesis did not assess for potential publication bias. Formal assessments of publication bias would be difficult to interpret because of small numbers of studies and clinical diversity among trials (106).

We also identified several research gaps that limited our ability to reach more definitive conclusions about relative benefits and harms of medications for low back pain. First, no trials formally evaluated different strategies for choosing initial medications. In addition, evidence is sparse on effectiveness of dual-medication therapy relative to monotherapy or sequential treatment, even though patients are frequently prescribed more than 1 medication (4). There is also little evidence on long-term (>4 weeks) use of any medication included in this review, particularly with regard to long-term harms.

In summary, several medications evaluated in this report are effective for short-term relief of acute or chronic low back pain, although each is associated with a unique set of risks and benefits. Individuals are likely to differ in how they prioritize the importance of these various benefits and harms. For mild or moderate pain, a trial of acetaminophen might be a reasonable first option because it may offer a more favorable safety profile than NSAIDs. However, acetaminophen also seems less effective for pain relief. For more severe pain, a small increase in cardiovascular or gastrointestinal risk with NSAIDs in exchange for greater pain relief could be an acceptable tradeoff for some patients, but others may consider even a small increase in these risks unacceptable. For very severe, disabling pain, a trial of opioids in appropriately selected patients (107109) may be a reasonable option to achieve adequate pain relief and improve function, despite the potential risks for abuse, addiction, and other adverse events. Factors that should be considered when weighing medications for low back pain include the presence of risk factors for complications, concomitant medication use, baseline severity of pain, duration of low back symptoms, and costs. As in other medical decisions, choosing the optimal medication for an individual with low back pain should always involve careful consideration and thorough discussion of potential benefits and risks.

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Figures

Tables

Table Jump PlaceholderAppendix Table 1.  Quality Rating System for Systematic Reviews
Table Jump PlaceholderAppendix Table 2.  Quality Rating System for Randomized, Controlled Trials
Table Jump PlaceholderAppendix Table 3.  Methods for Grading the Overall Strength of the Evidence for an Intervention
Table Jump PlaceholderAppendix Table 4.  Excluded Systematic Reviews
Table Jump PlaceholderAppendix Table 5.  Systematic Reviews of Medications for Low Back Pain
Table Jump PlaceholderAppendix Table 6.  Quality Ratings of Systematic Reviews of Medications for Low Back Pain
Table Jump PlaceholderAppendix Table 7.  Randomized, Controlled Trials of Antiepileptic Drugs for Low Back Pain
Table Jump PlaceholderAppendix Table 8.  Randomized, Controlled Trials of Opioids for Low Back Pain
Table Jump PlaceholderAppendix Table 9.  Randomized, Controlled Trials of Systemic Corticosteroids for Low Back Pain with or without Sciatica
Table Jump PlaceholderAppendix Table 10.  Summary of Evidence on Medications for Acute Low Back Pain
Table Jump PlaceholderAppendix Table 11.  Summary of Evidence on Medications for Chronic or Subacute Low Back Pain
Table Jump PlaceholderAppendix Table 12.  Summary of Evidence on Medications for Sciatica or Radicular Low Back Pain

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Overviews are methodically inferior to systematic reviews and contribute to myths of effective drugs
Posted on October 16, 2007
Jan M Bjordal
Inst. Physical Therapy, Bergen University College,
Conflict of Interest: None Declared

In a recent overview encompassing systematic reviews and randomized trials of pharmacotherapy in low back pain (LBP), the authors concluded that there is good evidence that acetaminophen, NSAID and muscle relaxants provide moderate pain relief in acute LBP (1). In another clinical guideline article in the same issue of the Annals (2), the recommended indications for acetaminophen and NSAIDs are extended to include chronic LBP, whereas tramadol, opiods, and benzodiazepines are recommended both in acute and chronic LBP despite the lack of "good" or even "fair" evidence. The methodology used by the authors to review the literature may be flawed in the sense that it merely reiterates what other reviewers have published previously. The current overview does not address crucial differences in focus and protocols of the included reviews, and fails to adequately assess the randomized controlled trials which are the primary sources for information. The criteria list which was used does not imply investigations of the primary sources (RCTs) or the correctness of the trial data cited in the systematic review. The quality assessment method here is inadequate to detect or handle data errors in the review. With multiple data errors, faulty method assessments or misclassification of trials, there is no operationalization of the consequences for method scores. Indeed, some reviewing errors may be grave enough to jeopardize the overreview conclusions completely, but the overview scoring system only opens for a reduction of a single point or two. Misinterpretation of data leads to erroneous conclusions, which in turn may propagate the myth of medication efficacy in LBP. Moreover, the involvement of individuals with industry relations in the making of guidelines is controverisal (3). Indeed, the declaration of conflicts of interest in the form of receiving honoraria from the pharmaceutical industry by principal authors of the clinical guidelines (2) is, in our view, of noteworthy and potentially derogatory significance.

Evidence for a treatment effect is defined as a positive difference in change between the group receiving the active drug and the group receiving otherwise identical treatment with placebo (4). Weaker, indirect evidence of effect can be obtained by analyzing comparative non- inferiority trials or studies which test interventions in similar pathophysiological states at different anatomical localizations.

Acetaminophen There is no direct evidence that acetaminophen is effective in LBP, as no placebo-controlled trials have been performed. The authors refer to a systematic Cochrane review of NSAID and acetaminophen as their primary source (1). This review is not valid, as it was withdrawn from the Cochrane Library in April 2006 (5). As for indirect evidence of acetaminophen effectiveness compared to other treatments in acute LBP, a single small (n=30) high quality trial found acetaminophen to be inferior to a NSAID in acute LBP (6), and one low quality trial did not report any difference between acetaminophen and no treatment (7). Another low quality study showed ambiguous results (8). In the cited Cochrane review (5), 2 low quality trials found no difference between NSAID and acetaminophen (9, 10). However, the current reviewers seem to have missed the fact that one of these trials (9) was not randomized. Comparative studies of acetaminophen and non-pharmacological treatments in high quality RCTs has shown that acetaminophen was inferior to superficial heat (11). In one old trial of lower quality acetaminophen allegedly was slightly inferior to manipulation, but poor reporting of treatment allocation and handling of withdrawals obscures these results (12). As for evidence of acetaminophen effectiveness in non-LBP scenarios, the authors claim that three systematic reviews demonstrate superiority of NSAIDs over acetaminophen in osteoarthritis (OA) with a standardized mean difference (SMD) of approximately 0.3. We have previously reported NSAID effectiveness over placebo in knee OA corresponding to a SMD of 0.31 (13), whereas acetaminophen had clinically insignificant effects in knee OA with a weighted mean difference for pain equalling 3.0 mm [95% CI, 1.4 "“ 4.7] on a visual analogue scale (VAS) (14). In summary, there is no direct evidence and a paucity of indirect evidence for acetaminophen effectiveness in LBP. The authors´ claim of "good evidence of a moderate effect" of acetaminophen in this condition is, in our view, misconstrued and unsubstantiated, and constitutes ill advice for the concerned clinician.

NSAIDs For NSAIDs, the problem of using an outdated Cochrane review also applies (5, 15). However, as the authors use these data for their conclusions, we will address the shortcomings of this source of information. The authors fail to mention that the SMD analysis for pain was non-significant for NSAIDs in acute LBP was -0.53 [95% CI, -2.74 "“ 1.69]. The authors state that the Cochrane review included 6 trials where NSAIDs were superior to placebo in acute LBP with a relative risk for benefit of 1.24 [95% CI, 1.10 "“ 1.41]. Four out of these 6 trials found non-significant differences, whereas two trials reported significantly positive results (16, 17), thus contributing 2/3 of the overall statistical weight. In the first of these studies, groups of patients received intramuscular injections of either dipyrone (metamizole), diclofenac or saline (placebo). Dipyrone, the sodium sulphonate of the obsolete antipyretic agent antipyrine, is not licensed in the US (and many other countries) due to serious side-effects, and is hardly a typical species of the NSAID class of drugs. However, only the data for the dipyrone group in this particular study was entered into the Cochrane analysis. In addition, one of the trials (18) was not randomized and thus not eligible for the current review. Upon removal of this trial from analysis and substitution of dipyrone data with diclofenac data in the other trial, global improvement is rendered insignificant with relative risk for benefit of 1.11 [95% CI, 0.98 "“ 1.26]. The overview also state that ibuprofen was superior to placebo in one trial of chronic LBP, but the trial report clearly states that both groups received ibuprofen, while additional medication was compared to placebo (19). Thus, based on the cited material, the conclusion that there is "good evidence for moderate effect" of NSAIDs in LBP appears to be erroneous and misleading.

New evidence may also go undetected with the overview methodology used. Data which seems to have evaded the scrutiny of Chou & Huffman include a recent trial of NSAID in acute LBP (20) and four NSAID trials in chronic LBP (21-24). Based on these investigations there seems to be fair evidence in favor of a small/moderate effect of NSAIDs in acute LBP corresponding to 10.9 mm [95% CI, 4.2 "“ 17.6] on the VAS, and good evidence of a small effect in chronic LBP of 8.7 mm [95% CI: 6.9 "“ 11.5] on VAS after adjustment for patient selection bias. However, the results from the latter four trials should be considered in light of increasing concern that NSAIDs belonging to the selective COX-2- inhibitor class have a particularly disfavourable long term safety record.

Muscle relaxants For these drugs we face some of the same problems as with NSAIDs. The primary source of information is again a Cochrane-review (25, 26) with meta-analyses. One problem with the overview method used here is the evaluation of the strength of the evidence. According to the overview a "Good" rating is based on consistent positive results among multiple high quality RCTs. But how does it handle the results of meta-analyses with an overall positive result in spite of several RCTs with negative results? The overview states that there is "good" evidence for a "moderate" effect based on 3 high quality and 1 low quality RCTs in acute low back pain. However, 3 out of 4 RCTs in this relative risk analysis for pain have non- significant results with lower 95% confidence intervals below 1. So from the overview´s definition of "Good" evidence, the evidence should have been "Poor". And even moreso when det RCTs behind the positive overall result is more closely scrutinized. Methodological quality assessments with the scale used in the review only yields moderate reliability with Kappa values at 0.36 to 0.80 (27). In other words, if this single RCT had been rated at 5 out of 11 and then excluded from the analysis then the result of the meta-analysis would have been negative. The positive overall result rests more or less on a single RCT from 1982 where Merck (MSD) was responsible for the statistical analysis. In the review 79% of the weight in the statistical analysis came from this trial which has a borderline methodological quality score at exactly the cut-off value (6 out of 11) introduced in the review (28). Again the lack of transparency in the overview is causing trouble as the relative risks given there are different from those reported in the reviews (0.80 and 0.58 respectively) and 1.25 and 1.72 in the overview. We assume that t he overview authors have probably been inverting the relative risks to fit into the overview results format, but this has been done without reporting the trial data or the method of the statistical analysis. When we tried to do the same in the Revman software version 4.2, we were unable to replicate the results from the overview. The authors also claim that tizanidine was efficacious in 8 trials, but according to the cited reviews (25, 29), only 6 of these trials were placebo-controlled and three of them did not find any significant results (30-32).

Benzodiazepines The same reviews (25, 26) are the dominating sources for benzodiazepines conclusions. Again t, which again rest on 2 RCTs (33, 34) with borderline methodological quality (6 out of 11 criteria). The overview reports different relative risks for pain relief of 1.41 and global improvement of 1.59 after 10 to 14 days than the reviews. But the review analyses failed to include to 51 patients who dropped out in one of these studies (33). When we included the withdrawals in a new analysis, the relative risk for pain relief became non-significant at 1,38 (95% CI 0,99 to 1,92).

Conclusion We could go on and show that the overview evidence is not robust for other medications as well, but we think that the examples above are sufficient to support our main message. Overviews have a weaker methodology than systematic reviews, they are less transparent and errors in reviews are less likely to be detected. If we use the overview´s definition of "good evidence" strictly, many of the medications above should have their evidence strength downgraded to "fair" or even "poor". The most dangerous aspect of overviews is perhaps that they will add strength to sensitive and unreliable review conclusions. With the small number of RCTs which conclusions eventually are based on, we see no good reasons for not performing a full systematic review with meta-analyses of randomized placebo-controlled trials when guidelines are being made.

References

1. Chou, R. and L.H. Huffman, 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(7): 505-14.

2. Chou, R., et al., 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(7): 478-91.

3. Taylor, R. and J. Giles, Cash interests taint drug advice. Nature, 2005. 437(7062): 1070-1.

4. Clarke, D. and A. Oxman, Cochrane Reviewers´Handbook, 4.2.0. [update March 2003]. In:The Cochrane Library, Issue 2, 2003. Oxford: Update Software, updated quarterly, 2003.

5. van Tulder, M.W., et al., WITHDRAWN: Non-steroidal anti-inflammatory drugs for low-back pain. Cochrane Database Syst Rev, 2007(3): CD000396.

6. Hickey, R.F., Chronic low back pain: a comparison of diflunisal with paracetamol. N Z Med J, 1982. 95(707): 312-4.

7. Evans, D.P., M.S. Burke, and R.G. Newcombe, Medicines of choice in low back pain. Curr Med Res Opin, 1980. 6(8): 540-7.

8. Milgrom, C., et al., Overexertional lumbar and thoracic back pain among recruits: a prospective study of risk factors and treatment regimens. J Spinal Disord, 1993. 6(3): 187-93.

9. Muckle, D.S., Flurbiprofen for the treatment of soft tissue trauma. Am J Med, 1986. 80(3A): 76-80.

10. Wiesel, S.W., et al., Acute low-back pain. An objective analysis of conservative therapy. Spine, 1980. 5(4): 324-30.

11. Nadler, S.F., et al., Continuous low-level heat wrap therapy provides more efficacy than Ibuprofen and acetaminophen for acute low back pain. Spine, 2002. 27(10): 1012-7.

12. Doran, D.M.L. and D.J. Newell, Manipulation in treatment of low back pain: a multicentre study. Brit Med J, 1975. 2: 161-4.

13. Bjordal, J.M., et al., Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta- analysis of randomised placebo controlled trials. BMJ, 2004. 329(7478): 1317-23.

14. Bjordal, J.M., et al., Short-term efficacy of pharmacotherapeutic interventions in osteoarthritic knee pain: A meta-analysis of randomised placebo-controlled trials. Eur J Pain, 2007. 11(2): 125-38.

15. van Tulder, M.W., et al., Nonsteroidal anti-inflammatory drugs for low back pain: a systematic review within the framework of the Cochrane Collaboration Back Review Group. Spine, 2000. 25(19): 2501-13.

16. Babej-Dolle, R., 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(4): 204-9.

17. Jacobs, J.H. and M.F. Grayson, Trial of an anti-inflammatory agent (indomethacin) in low back pain with and without radicular involvement. Br Med J, 1968. 3(5611): 158-60.

18. Weber, H. and G. Aasand, The effect of phenylbutazone in patients with in acute lumbago-sciatica. A double blind trial. J Oslo City Hosp, 1980. 30(69-72).

19. Berry, H. and D.R. Hutchinson, Tizanidine and ibuprofen in acute low- back pain: results of a double-blind multicentre study in general practice. J Int Med Res, 1988. 16(2): 83-91.

20. Dreiser, R.L., et al., 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(9): 375-85.

21. Birbara, C.A., et al., 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(6): 307-15.

22. Coats, T.L., et al., Effects of valdecoxib in the treatment of chronic low back pain: results of a randomized, placebo-controlled trial. Clin Ther, 2004. 26(8): 1249-60.

23. Pallay, R.M., et al., Etoricoxib reduced pain and disability and improved quality of life in patients with chronic low back pain: a 3 month, randomized, controlled trial. Scand J Rheumatol, 2004. 33(4): 257- 66.

24. Katz, N., et al., 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, 2003. 28(9): 851- 8; discussion 859.

25. van Tulder, M.W., et al., Muscle relaxants for non-specific low back pain. Cochrane Database Syst Rev, 2003(2): CD004252.

26. van der Windt, D.A., et al., Shoulder disorders in general practice: prognostic indicators of outcome. Br J Gen Pract, 1996. 46(410): 519-23.

27. Maher, C.G., et al., Reliability of the PEDro scale for rating quality of randomized controlled trials. Phys Ther, 2003. 83(8): 713-21.

28. Baratta, R.R., A double-blind study of cyclobenzaprine and placebo in the treatment of acute musculoskeletal conditions of the low back. Curr Ther Res, 1982. 32(5).

29. van Tulder, M.W., et al., Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the cochrane collaboration. Spine, 2003. 28(17): 1978-92.

30. Baptista, R., et al., Terapeutica da lombalgia com a tizanidina (DS 103-282) un novo agente mioespasmolitico. Folha Medica, 1988. 96(3): 119- 23.

31. Berry, H. and D.R. Hutchinson, A multicentre placebo-controlled study in general practice to evaluate the efficacy and safety of tizanidine in acute low-back pain. J Int Med Res, 1988. 16(2): 75-82.

32. Lepisto, P., A comparative trial of DS 103-282 and placebo in the treatment of acute skeletal muscle spasms due to disorders of the back. Ther Res, 1979. 26: 454-9.

33. Salzmann, E., et al., Treatment of chronic low back syndrome with tetrazepam in a placebo controlled double blind trial. J Drug Develop, 1992. 4 219-28.

34. Arbus, L., et al., Activity of tetrazepam in low back pain. Clin Trials J, 1990. 27: 258-67.

Conflict of Interest:

None declared

In Response
Posted on December 5, 2007
Roger Chou
Oregon Health & Science University
Conflict of Interest: None Declared

In response:

We thank the authors of the letters for their comments on our low back pain guideline (1) and evidence reviews (2, 3). Dr. Bjordal notes some methodologic concerns with our reviews. To clarify, we performed a systematic review of a broad range of low back pain topics, and when prior systematic reviews were available and of sufficient quality, we included them. The idea that new systematic reviews of the primary literature should always be conducted when developing clinical practice guidelines is both unsupported by any empirical evidence and if implemented could be a poor use of scientific resources (4). Guideline panels need relevant, current, high-quality reviews of the evidence; if existing reviews fulfill those criteria then it is wasteful to ignore them and conduct new reviews. We included systematic reviews published in or after the year 2000 and identified higher-quality reviews using a validated quality rating instrument (5, 6). Although systematic reviews should be updated, there is no compelling reason to ignore higher-quality Cochrane reviews (7) that met our criteria for inclusion and were "withdrawn" only because they did not meet an updating deadline, not because of methodological deficiencies or the publication of contradictory trials (8).

Dr. Bjordal suggests that we graded evidence for acetaminophen too positively. In his letter, Dr. Bjordal describes one trial as evaluating acute low back pain when it actually evaluated chronic low back pain (9). Otherwise, our descriptions of the evidence are similar (Appendix Tables 10 and 11 (2)). We agree that our evidence ratings for acetaminophen were generous given some inconsistency among trials of acute low back pain, and lack of direct evidence and small benefits for chronic low back pain. We re-rated evidence for acetaminophen for acute low back pain fair quality with moderate benefits, and for chronic low back pain fair quality with small benefits (see Correction). Because of acetaminophen's favorable safety profile compared to other pharmacologic therapies, these changes do not change our recommendation to consider it as a first-line option for pharmacologic therapy (1).

For NSAIDs, skeletal muscle relaxants, and benzodiazepines, Dr. Bjordal's focus on single outcomes from placebo-controlled trials reported in Cochrane reviews ignores much of the available evidence. Our assessments are based on both placebo and active-controlled trials, non- Cochrane systematic reviews, data on various outcomes related to pain, function, and global efficacy, and indirect evidence from patients with other pain conditions (Appendix Tables 10 and 11 (2)). We also evaluated consistency between trials and across higher-quality systematic reviews (10). In addition, post-hoc analyses, such as those presented by Dr. Bjordal, can be misleading and should be interpreted cautiously. For example, excluding trials based on small differences in quality scores is problematic given unpredictable associations between summary quality rating scores and estimates of effects (11). We did not report data on mean improvement in pain scores from a Cochrane review of NSAIDs because of substantial, unexplained heterogeneity (p<0.0001) (7).

As Dr. Bjordal surmised, we inverted relative risks (1/relative risk) for "˜no pain relief' with skeletal muscle relaxants and benzodiazepines (as reported in a Cochrane review (12)) to present results for a positive outcome (achieving pain relief) (2). However, this transformation was incorrect, as relative risks (unlike odds ratios) are not a symmetric statistic. We will correct the article to show original results as reported in the Cochrane review (see Corrections). This correction does not change any conclusions, but we thank Dr. Bjordal for noting this error.

We disagree with Dr. Bjordal's assertion that there is enough evidence to establish efficacy of low-level laser therapy (LLLT) and transcutaneous electrical nerve stimulation (TENS). In the case of LLLT, there is substantial diversity across trials in doses and types of laser, some inconsistency among higher-quality trials, and the possibility of publication bias. Our conclusion of insufficient evidence is similar to a recently published Cochrane review (13). For TENS, the highest quality placebo-controlled trial found no benefit in chronic low back pain (14). In addition, it is inappropriate to pool studies of disparate populations and therapies (TENS and neuromuscular stimulation), as proposed by Dr. Bjordal, and two of the trials proposed for pooling found no benefits on pain or function with TENS versus placebo (15, 16).

We disagree with Dr. Ernst that our conclusions regarding rare risk of serious adverse events with spinal manipulation are misleading or downplay the risk of cerebrovascular events (3). Our review deals with low back pain and treatment with lumbar spinal manipulation. There are no reports of cerebrovascular events following lumbar spine manipulation or in patients being treated for low back pain (17, 18). Cervical manipulation is not a subject of our review or practice guideline.

Dr. Bjordal suggests that recommendations for therapy favor pharmacologic over non-pharmacologic options (1). In fact, we recommend either type of therapy as options (Figure 1, Box 9 (1)), and strength of evidence and magnitude of benefits were graded similarly for several pharmacologic and non-pharmacologic therapies (Appendix Tables 5 and 6). However, recommendation 7 on non-pharmacologic therapies in general was graded "weak" because of relatively weak evidence for some suggested options (Appendix Tables 10 and 11 (3)), higher costs compared to first- line pharmacologic therapies, and less convenience (most non-pharmacologic options involving multiple provider visits). It would be appropriate to select a non-pharmacologic over pharmacologic therapy in patients who express such a preference, but the trade-offs should be discussed (19). Superficial heat is already recommended as a self-care option (Figure 2, Interventions box (1)).

Roger Chou, MD Oregon Health & Science University, Portland, Oregon

Paul Shekelle, MD, PhD Veterans Affairs Health Care System and RAND, Santa Monica, California

Amir Qaseem, MD, PhD, MHA The American College of Physicians, Philadelphia, Pennsylvania

Douglas K. Owens, MD, MS Veterans Affairs Palo Alto Health Care System, Palo Alto, and Stanford University, Stanford, California

References

1. Chou R, Qaseem A, Snow V, et al. 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 -491.

2. 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. Annals of Internal Medicine. 2007;147:505-514.

3. Chou R, Huffman LH. Non-pharmacologic therapies for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians Clinical Practice Guideline. Annals of Internal Medicine. 2007;147:492-504.

4. Silagy CA, Stead LF, Lancaster T. Use of systematic reviews in clinical practice guidelines: case study of smoking cessation. BMJ. 2001;323:833-836.

5. Jadad AR, McQuay HJ. Meta-analyses to evaluate analgesic interventions: a systematic qualitative review of their methodology. Journal of Clinical Epidemiology. 1996;49:235-243.

6. Oxman AD, Guyatt GH. Validation of an index of the quality of review articles. Journal of Clinical Epidemiology. 1991;44(11):1271-1278.

7. van Tulder MW, Schotten RJPM, Koes BW, Deyo RA. Non-steroidal anti -inflammatory drugs for low-back pain Cochrane Database of Systematic Reviews. 2000(2).

8. Shojania KG, Sampson M, Ansari MT, Ji J, Doucette S, Moher D. How quickly do systematic reviews go out of date? a survival analysis. Ann Intern Med. 2007;147:224-233.

9. Hickey RF, Hickey RF. Chronic low back pain: a comparison of diflunisal with paracetamol. New Zealand Medical Journal. 1982;95(707):312 -4.

10. GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ. 2004;328:1490-1494.

11. Juni P, Witschi A, Bloch R, Egger M. The hazards of scoring the quality of clinical trials for meta-analysis. JAMA. 1999;282:1054-1060.

12. van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM. Muscle relaxants for non-specific low-back pain Cochrane Database of Systematic Reviews. 2003(4).

13. Yousefi-Nooraie R, Schonstein E, Heidari K, et al. Low level laser therapy for nonspecific low-back pain. Cochrane Database of Systematic Reviews. 2007;2.

14. Deyo RA, Walsh NE, Martin DC, Schoenfeld LS, Ramamurthy S. A controlled trial of transcutaneous electrical nerve stimulation (TENS) and exercise for chronic low back pain. New England Journal of Medicine. 1990;322:1627-34.

15. Herman E, Williams R, Stratford P, Fargas-Babkak A, Trott M. A randomized controlled trial of transcutaneous electrical nerve stimulation (CODETRON) to determine its benefits in a rehabilitation program for acute occupational low back pain. Spine. 1994;19(5):561-568. 16. Moore SR, Shurman J. Combined neuromuscular electrical stimulation and transcutaneous electrical nerve stimulation for treatment of chronic back pain: a double-blind, repeated measures comparison. Arch Phys Med Rehabil. 1997;78:55-60.

17. Ernst E. Cerebrovascular complications associated with spinal manipulation. Physical Therapy Reviews. 2004;9(1):5-15.

18. Ernst E. Adverse effects of spinal manipulation: a systematic review. Journal of the Royal Society of Medicine. 2007;100:330-338.

19. Schunemann HJ, Jaeschke R, Cook DJ, et al. An official ATS statement: Grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations. Am J Respir Crit Care Med. 2006;174:605-614.

Conflict of Interest:

None declared

Correction
Posted on December 5, 2007
Roger Chou
Oregon Health & Science University
Conflict of Interest: None Declared

Correction

We write to provide corrections to the recent joint guideline by the American College of Physicians and the American Pain Society on diagnosis and treatment of low back pain (1) and supporting evidence reviews (2, 3). In the original print version of the guideline, the target populations were described incorrectly (1). The word "not" was inadvertently dropped from a sentence that described populations that were excluded from the guideline. Children or adolescents with low back pain; pregnant women; patients with low back pain from sources outside the back (nonspinal low back pain), fibromyalgia or other myofascial pain syndromes, and thoracic or cervical back pain are not covered by the guideline. The online version of guideline has already been corrected.

In response to a letter to the editor (4) we re-reviewed the evidence on acetaminophen and believe we originally graded the evidence too positively in the guideline and evidence review (1, 2). However, our guideline recommendations remain the same. Acetaminophen for acute low back pain should be rated "˜fair' rather than "˜good' quality. Acetaminophen for chronic low back pain should be rated "˜fair' rather than "˜good' quality and magnitude of benefit "˜small' rather than "˜moderate' (Appendix Tables 5 and 6 in the guideline (1) and Appendix Tables 10 and 11 in the evidence review (2)). The Abstract/Data Synthesis section of the evidence review should read: "We found good evidence that NSAIDs, skeletal muscle relaxants (for acute low back pain), and tricyclic antidepressants (for chronic low back pain) are effective for pain relief"¦We also found fair evidence that acetaminophen, opioids, tramadol, benzodiazepines, and gabapentin (for radiculopathy) are effective for pain relief (2)." The Abstract/Conclusions section should read: "Medications with good evidence of short-term effectiveness for low back pain are NSAIDs, skeletal muscle relaxants (for acute low back pain), and tricyclic antidepressants (for chronic low back pain)." Similar changes should be applied to the Discussion section. As noted, these changes do not affect Recommendation 6 suggesting acetaminophen as an option for first-line pharmacologic therapy (1). This recommendation is based in large part on the safety profile of acetaminophen, when taken in appropriate dosages in patients without a contraindication.

Reference 62 in the evidence review on medications for low back pain is incorrect and should refer to a different trial by the same first author (5).

In the evidence review on medications, we inverted (calculated 1/relative risk) results for "not achieving pain relief" as reported in a Cochrane review (6) in order to report the likelihood of achieving pain relief. This conversion was incorrect because relative risk is not a symmetric statistic. The evidence review (2) will be corrected to state results as originally reported in the Cochrane review: for skeletal muscle relaxants, relative risks for not achieving pain relief 0.80 [CI, 0.71 to 0.89] at 2-4 days and 0.67 [0.13 to 3.44] at 5-7 days and relative risks for not achieving global efficacy 0.49 [CI, 0.25 to 0.95] at 2-4 days and 0.68 [CI, 0.41 to 1.13] at 5-7 days; and for benzodiazepines, relative risks for not achieving pain relief 0.71 [CI, 0.54 to 0.93] and for not achieving global efficacy 0.63 [CI, 0.42 to 0.97] at 8-14 days (6). Similarly, in the evidence review on non-pharmacologic therapies (3), results for a systematic review by Kool et al (7) on exercise therapy should state a relative risk of 0.73 [CI, 0.56 to 0.95] for not returning to work after 1 year . None of these corrections affect conclusions of the evidence reviews or guidelines.

All corrections have been applied to the online version of the articles.

Roger Chou, MD Oregon Health & Science University, Portland, Oregon

Paul Shekelle, MD, PhD Veterans Affairs Health Care System and RAND, Santa Monica, California

Amir Qaseem, MD, PhD, MHA The American College of Physicians, Philadelphia, Pennsylvania

Douglas K. Owens, MD, MS Veterans Affairs Palo Alto Health Care System, Palo Alto, and Stanford University, Stanford, California References

1. Chou R, Qaseem A, Snow V, et al. 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 -491.

2. 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. Annals of Internal Medicine. 2007;147:505-514.

3. Chou R, Huffman LH. Non-pharmacologic therapies for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians Clinical Practice Guideline. Annals of Internal Medicine. 2007;147:492-504.

4. Bjordal JM, Lopes-Martin RAB, Klovning A, Roland PH, Slordal L. Overviews are methodically inferior to systematic reviews and contribute to myths of effective drugs. Annals Online. 17 Oct 2007.

5. Berry H, Bloom B, Hamilton EBD, Swinson DR. Naproxen sodium, diflunisal, and placebo int he treatment of chronic back pain. Ann Rheum Dis. 1982;41:129-132.

6. van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM. Muscle relaxants for non-specific low-back pain Cochrane Database of Systematic Reviews. 2003(4).

7. Kool J, de Bie R, Oesch P, Knusel O, van den Brandt P, Bachmann S. Exercise reduces sick leave in patients with non-acute non-specific low back pain: a meta-analysis. Journal of Rehabilitation Medicine. 2004;36(2):49-62.

Conflict of Interest:

None declared

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Summary for Patients

Diagnosis and Treatment of Low Back Pain: Recommendations from the American College of Physicians/American Pain Society

The summary below is from the full reports titled “Diagnosis and Treatment of Low Back Pain: A Joint Clinical Practice Guideline from the American College of Physicians and the American Pain Society,” “Nonpharmacologic Therapies for Acute and Chronic Low Back Pain: A Review of the Evidence for an American Pain Society/American College of Physicians Clinical Practice Guideline,” and “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.” They are in the 2 October 2007 issue of Annals of Internal Medicine (volume 147, pages 478-491, 492-504 , and 505-514). The authors of the first report are R. Chou, A. Qaseem, V. Snow, D. Casey, J.T. Cross Jr., P. Shekelle, and D.K. Owens, for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians and the American College of Physicians/ American Pain Society Low Back Pain Guidelines Panel, and the authors of the second and third reports are R. Chou and L.H. Huffman.

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Clinical Slide Sets

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The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

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