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Nonopioid Pharmacologic Treatments for Chronic Pain

Systematic Review Draft

This report is available in PDF (Draft Report [1.3 MB]; Draft Appendixes A-K [10.1 MB]) and XSLX only (Draft Appendix E [37.6 KB]; Draft Appendix F [345.6 KB]; Draft Appendix G [26.5 KB]). People using assistive technology may not be able to fully access information in these files. For additional assistance, please contact us.

Purpose of Review

This review evaluates the benefits and harms of nonopioid drugs in randomized controlled trials (RCTs) of patients with specific types of chronic pain, considering the effects on pain, function, quality of life, and adverse events.

Key Messages

  • In the short-term, 
    • Anticonvulsants pregabalin, gabapentin, and oxcarbazepine show small improvements in pain and function in patients with diabetic peripheral neuropathy/post-herpetic neuralgia and fibromyalgia.
    • SNRI antidepressants duloxetine and/or milnacipran show small to moderate improvements in pain, function and quality of life in patients with diabetic peripheral neuropathy/post-herpetic neuralgia and fibromyalgia. Patients with low back pain had small improvements in pain and no improvement in function.
    • NSAIDs show small improvements in pain and function in patients with osteoarthritis and inflammatory arthritis. Acetaminophen did not result in improvements in pain and function in patients with osteoarthritis.
  • In the short- and intermediate-term, limited evidence found memantine to moderately improve pain, function and quality of life in patients with fibromyalgia.
  • For all conditions, evidence on long-term treatment effectiveness, comparative effectiveness, and quality of life is limited
  • Small to moderate, dose-dependent, increases in withdrawal due to adverse events was found with TCAs, SNRIs duloxetine and milnacipran, pregabalin and gabapentin, and NSAIDs. Large increases seen with oxcarbazepine. NSAIDs have increased risk of serious GI and CV adverse events.

Structured Abstract

Objectives. To evaluate the effectiveness and comparative effectiveness of nonopioid pharmacologic agents in patients with specific types of chronic pain, considering the effects of on pain, function, quality of life, and adverse events.

Data sources. Electronic databases (Ovid® MEDLINE®, Embase®, PsycINFO®, CINAHL®, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews), through January 2019, reference lists, data request, and previous reviews.

Review methods. Randomized controlled trials (RCTs) of nonopioid pharmacological agents in patients with chronic pain were selected using predefined criteria and dual review. This review focused on seven common chronic pain conditions (neuropathic pain, fibromyalgia, osteoarthritis, inflammatory arthritis, low back pain, chronic headache, sickle cell disease) with effects analyzed at short term (1 to <6 months following treatment completion), intermediate term (≥6 to <12 months), and long term (≥12 months). Magnitude of effects were described as small, moderate, or large using previously defined criteria and strength of evidence was assessed. Meta-analyses were conducted where data allowed, stratified by duration within each intervention type, using random effects models. We evaluated effect modification through subgroup and sensitivity analyses, including specific drug, dose, study quality, and pain type.

Results. 182 RCTs in 218 publications and 5 systematic reviews were included. In the short-term, anticonvulsants (pregabalin, gabapentin, and oxcarbazepine for neuropathic pain, pregabalin/gabapentin for neuropathic pain), SNRI antidepressants (duloxetine for neuropathic pain, fibromyalgia, osteoarthritis and low back pain, milnacipran for fibromyalgia), and NSAIDs (for osteoarthritis and inflammatory arthritis) were associated with mostly small improvements (e.g. 5 to 20 points on a 0-100 scale) in pain and function. Function was not found to be improved with duloxetine for low back pain or pregabalin/gabapentin for neuropathic pain. Moderate improvement in quality of life was seen with duloxetine in patients with neuropathic pain, but was insufficient to draw conclusions for other drugs and conditions. In limited evidence (1 RCT) memantine moderately improved pain, function and quality of life in patients with fibromyalgia. While most comparisons of drugs and doses did not identify differences, diclofenac improved pain and function moderately more than celecoxib. In the intermediate-term, improvements seen in patients with fibromyalgia with memantine were maintained; improvements in pain, but not function were maintained in the intermediate-term with duloxetine and milnacipran for fibromyalgia. Other drugs studied, including acetaminophen (osteoarthritis), capsaicin (neuropathic pain), cannabis (neuropathic pain), amitriptyline (fibromyalgia, neuropathic pain), and cyclobenzaprine (fibromyalgia) had no clear effects. Withdrawal from study due to adverse events was significantly increased with nonopioid drugs, with the greatest increase over placebo with oxcarbazepine and cannabis. Drug-specific adverse events were also increased frequently in the RCTs. Large increases in risk of adverse events were seen with pregabalin (blurred vision, cognitive effects, dizziness, peripheral edema, sedation and weight gain), gabapentin (blurred vision, cognitive effects, sedation, weight gain), duloxetine (sedation), diclofenac/naproxen (liver events), and cannabis (nausea, dizziness). Dose-reductions reduced the risk of some adverse events with SNRI antidepressants. Increased risk of major coronary events and serious GI events were found with NSAIDs.

Conclusions. In the short-term, small improvements in pain and/or function were seen with SNRI antidepressants for neuropathic pain, fibromyalgia, osteoarthritis and low back pain, pregabalin/gabapentin for neuropathic pain and fibromyalgia, oxcarbazepine for neuropathic pain and NSAIDs for osteoarthritis and inflammatory arthritis. Improvement in function was not found with duloxetine for low back pain and pregabalin/gabapentin for neuropathic pain. Intermediate and long-term outcomes were mostly not assessed. Increased incidence of drug class-specific adverse events led to withdrawal from treatment in some patients, suggesting that careful consideration of patient characteristics is needed in selecting nonopioid drug treatments.