Clinical trial NCT00108550
Conditions: Chronic Low Back Pain
Keywords: analgesia antidepressant agents back pain pain
Sponsor: US Department of Veterans Affairs
Start date: 2004-10-01; Completion date: 2009-09-01
Enrollment: 108 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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.

Arms: arm 1: Gabapentin 300 mg orally three times daily up to a maximum of 1200 mg orally three times daily for 12 weeks arm 2: Inert placebo capsules identical in size and shape to the experimental capsules, one to three capsules taken orally three times daily for 12 weeks
Interventions: intervention 1: gabapentin intervention 2: Inert placebo
Intervention descriptions: intervention 1: Gabapentin 300m on Day 1, with daily or weekly increase to 3600 mg (maximum) by mouth by Week 5 of the 12-week trial intervention 2: 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

Protocol documents: