Chronic Low Back Pain Research Project
Condition: Chronic Low Back Pain
MeSH terms: Back Pain; Low Back Pain
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to determine whether gabapentin is efficacious as an analgesic
      for chronic low back pain.
    

Detailed description: 
      Chronic low back pain (CLBP) is a major health problem for the VA, affecting up to 15% of all
      veterans. Nationally, its medical and disability costs exceed $50 billion annually. Despite
      its impact, relatively little research evaluates treatment for CLBP. Wide variation in
      patterns of care suggests uncertainty over effective therapy. Most chronic back cases are not
      surgical candidates. The mainstays of medical treatment have been non-steroidal
      anti-inflammatory drugs (NSAIDs), muscle relaxants, opioids, and antidepressants.
      Non-steroidal drugs and muscle relaxants are effective for acute but not for chronic back
      pain. Opioids may provide analgesia but safety limits their use. Tricyclic antidepressants
      provide modest pain relief, separate from effects on depression. But it is clear additional
      research is needed to develop more effective pharmacotherapy. One approach favored by many
      authorities is determining if agents effective for one type of chronic pain syndrome (e.g.,
      diabetic neuropathy) can be generalized to other syndromes, like chronic back pain. Another
      is to identify effective drug combinations, based on selecting drugs with differing
      therapeutic mechanisms.

      This research is a program of rigorous randomized clinical trials testing the efficacy of
      antidepressants for analgesia in chronic back pain. Because chronic pain is a complex
      disorder, the program features a multidisciplinary research team, involving specialists in
      psychiatry, orthopedic surgery, psychology, anesthesiology, clinical pharmacology, and
      biomathematics. The research has both pragmatic and explanatory aims. Our strategy has been
      to test antidepressants with differing, and selective properties in an attempt to isolate
      therapeutic mechanisms. Thus, we began with trials using selective norepinephrine reuptake
      inhibitors, and selective serotonin reuptake inhibitors (SSRIs), rather than those with dual
      noradrenergic and serotonergic effects (e.g., amitriptyline, imipramine). To ensure
      applicability of results, we have used rigorous diagnostic procedures to identify patients
      with chronic back pain due to degenerative disk disease. To enhance generalizability we
      recruit primary care patients rather than tertiary pain clinic samples. Patients without
      major depression are studied to examine analgesia separate from antidepressant effects.
      Secondary outcomes address function and life quality.

      We have conducted three controlled trials using identical recruitment and assessment
      methodology. The first, comparing a noradrenergic antidepressant (nortriptyline) with
      placebo, indicated that the noradrenergic agent provided clinically relevant analgesia. The
      second was a head-to-head comparison of a selective noradrenergic agent (maprotiline) with a
      selective serotonin reuptake inhibitor (SSRI, paroxetine). The noradrenergic agent
      outperformed the SSRI, which was equivalent to placebo. To clarify these results we explored
      whether efficacy might be evident only at specific drug concentrations. Therefore, the third
      study, has a prospective concentration design comparing the most potent and selective
      noradrenergic antidepressant (desipramine) to the standard SSRI, fluoxetine. Subjects were
      randomized to placebo or predetermined concentration windows reflecting low, medium, and high
      exposure to study drugs and followed for 12 weeks. Interim analysis suggests that low
      concentration desipramine outperforms placebo (p<0.05). It is also superior to
      mid-concentration and high exposure desipramine--as well as all exposure levels of the SSRI,
      which are equivalent to placebo.

      In sum, all three studies supported noradrenergic analgesia in CLBP, and the two studies that
      evaluated SSRIs failed to find analgesia. This suggests noradrenergic activity, perhaps
      within a therapeutic window, may be primarily responsible for back pain analgesia. These
      findings have led us away from studies proposing combining noradrenergic and serotonergic
      agents. An alternative approach which builds on these data, but first employs another class
      of agents, seems reasonable. This strategy is to assess if gabapentin, a calcium channel
      blocker agent with demonstrated efficacy in neuropathic pain, can be extended to chronic back
      pain.

      We conducted a double-blind, randomized assignment, 12-week, placebo controlled clinical
      trial of the efficacy of gabapentin. Non-depressed chronic low back pain patients (N = 130)
      will be randomized to placebo or high dose gabapentin (3600 mg/day or maximum tolerable
      dose). Analysis was by intent to treat. The primary efficacy assessment is mean pain
      intensity (Descriptor Differential Scale, DDS) at exit. Secondary outcomes are function and
      life quality (Oswestry Disability Index, Short Form-36, Quality of Well-Being Scale). Safety
      evaluation includes rating adverse events (Scandinavian Society of Psychopharmacology
      Committee on Clinical Investiagations Side Effects Rating Scale, UKU), standardized physical
      examination, and clinical laboratory testing. Results could provide explanatory insight into
      mechanisms of back pain, and address the pragmatic clinical need by primary care providers
      and others for effective therapy.
    

Intervention name(s): gabapentin; Inert placebo
Intervention type(s): Drug; Drug
Intervention description(s): Gabapentin 300m on Day 1, with daily or weekly increase to 3600 mg (maximum) by mouth by Week 5 of the 12-week trial; Inactive placebo capsule, one capsule on Day 1 with daily or weekly increase to 9 capsules daily by Week 5 of the 12-week trial
Other intervention name(s): Neurontin; sugar pill
Intervention MeSH terms: Gabapentin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: analgesia; antidepressant agents; back pain; pain