Evidence-Based Treatment Paradigms for Depressed Patients With Pain and Physical Symptoms
David A. Fishbain, MD
Departments of Psychiatry and Behavioral Sciences, Neurological Surgery, and Anesthesiology, University of Miami Miller School of Medicine, Miami, Fla
Antidepressants as Analgesics
Since the 1970s, numerous clinical studies have explored the effects of antidepressants on painful physical symptoms to answer 2 main questions: Do antidepressants alleviate pain? If so, are the analgesic properties independent from the improvement in depression? Unfortunately, early studies addressing these questions were riddled with methodological problems, such as small sample sizes, poor study designs, and inconsistent patient populations. Therefore, these studies produced conflicting results.
Not until the early 1990s did an answer materialize concerning the role of antidepressant treatment in alleviating pain. Two meta-analyses of controlled studies—one of 39 trials1 and one of 67 trials2—determined that antidepressants did indeed alleviate general pain. However, these meta-analyses did not distinguish results of neuropathic from nonneuropathic pain. A subsequent meta-analysis3 of 21 placebo-controlled trials did find that antidepressants were effective analgesics for neuropathic pain (AV 1), including diabetic neuropathy, postherpetic neuralgia, atypical facial pain, and central pain.
Fishbain et al.4 found that antidepressants were effective analgesics for psychogenic pain and somatoform pain disorder, with a large effect size (mean = 0.48). This meta-analysis4 of 11 controlled studies raised the issue of the validity of the diagnosis of psychogenic pain and somatoform pain disorder because analgesics, in general, should not have an effect on psychogenic or somatoform pain disorder above that of the placebo response.
In addition to neuropathic pain and psychogenic/somatoform pain, antidepressants may be efficacious for chronic lower back pain and pain associated with osteoarthritis, rheumatoid arthritis, and healing ulcers.5 Evidence5–7 also indicates that antidepressants improve pain as well as various other somatic symptoms, such as sleep, in patients with fibromyalgia.
Single-Action Vs Dual-Action Antidepressants
Dual-action agents, that is, medications that inhibit both serotonin and norepinephrine, may have greater antinociceptive effects than antidepressants with selective serotonergic or noradrenergic effects (AV 2).8 For example, an evidence-based structured review9 of neuropathic pain animal models and antidepressant treatment studies found an analgesic effect in 100% of the trials with serotonin-norepinephrine reuptake inhibitors (SNRIs), 88.9% of trials with noradrenergic antidepressants, and 14.3% of trials with serotonergic antidepressants. Further, meta-analyses5,6,10,11 of human studies have suggested that dual-action antidepressants have a more consistent analgesic effect than serotonergic antidepressants for some types of pain.
Lower back pain. A review11 of lower back pain studies reported that selective serotonin reuptake inhibitors (SSRIs) were not effective in the 3 trials with these agents, whereas tricyclic or tetracyclic antidepressants that also inhibit noradrenergic reuptake produced improvement on at least 1 outcome measure in 4 of the 5 trials examined.
Neuropathic pain. Duloxetine, an SNRI, is the first antidepressant approved by the U.S. Food and Drug Administration (FDA) for the treatment of diabetic peripheral neuropathic pain. In a large study (N=457),12 duloxetine demonstrated efficacy for improving pain within 1 week of treatment initiation compared with placebo (AV 3).
Rowbotham et al.13 found that, at higher dosages, venlafaxine, another SNRI, was effective for neuropathic pain ( AV 4). Because this effect may be dose related, separation from placebo did not occur until week 3, after doses had been titrated to therapeutic levels.
Fibromyalgic pain. Duloxetine has also been approved by the FDA for the treatment of fibromyalgia. Milnacipran and venlafaxine, other SNRIs, have also been studied for efficacy in fibromyalgia treatment. Milnacipran14 and duloxetine15,16 have shown efficacy in decreasing fibromyalgia pain (particularly in women) in large controlled trials, but the same level of evidence does not exist for venlafaxine.
Individual studies of SSRIs in fibromyalgia have shown some evidence of efficacy for pain, but results have been mixed. Arnold et al.17 found that, compared with placebo, fluoxetine significantly improved Fibromyalgia Impact Questionnaire total scores (p = .005), pain scores (p = .002), and McGill Pain Questionnaire scores (p = .01). However, no significant differences were found between fluoxetine and placebo on tender point counts and myalgic scores. In 2 trials,18,19 citalopram showed no significant advantage over placebo in patients with fibromyalgia. This evidence suggests that dual-action antidepressants, including tricyclics and SNRIs, have a more consistent analgesic effect than SSRIs.
Antidepressant comparison. Head-to-head trials of SNRIs and SSRIs would be ideal for determining the efficacy of these agents in treating pain, but no such trials have yet been conducted. To circumvent the problem of lacking head-to-head trials, the number-needed-to-treat (NNT) concept can be used. The NNT is the number of patients who would have to be treated with an agent to obtain 1 patient with ≥ 50% response. The best NNT is 1, because that means a response was obtained in each patient treated. For various forms of neuropathic pain, dual-action tricyclics have the lowest NNT at 2.2; noradrenergic tricyclics have an NNT of 2.5; SNRIs have NNTs between 4.6 and 5.7; and SSRIs have the highest NNT at 6.8.20,21
Independence of Analgesic Effect
Are the analgesic properties of antidepressants due to their antidepressant effects, or is the analgesic effect an independent function? Goldstein et al.12 found that the direct effect of 120 mg/day of duloxetine on diabetic peripheral neuropathic pain accounted for 88.6% of the total pain improvement, whereas improvement in depression accounted for only 11.4% of pain improvement.
Fishbain et al.22 conducted a post-hoc analysis of 6 placebo-controlled trials of duloxetine in 900 patients with major depressive disorder and diabetic peripheral neuropathy, measuring pain with the Visual Analog Scale. The researchers theorized that, if the analgesic response was dependent on the antidepressant response, then the antidepressant response should occur first. However, in the study, the median time to analgesic effect occurred earlier (28 days to response) than the antidepressant effect (42 days to response). In addition, no correlation was found between the analgesic response curve and the antidepressant response curve, which indicates that the analgesic effect is independent of the antidepressant effect and vice versa.
Milnacipran14 and venlafaxine23 also appear to have an analgesic effect independent of the antidepressant effect, but evidence from large controlled trials for venlafaxine is lacking.
The treatment plan for patients with depression associated with pain should be aggressive, with the goal of remission. Evidence suggests that some antidepressants have analgesic properties, such as dual-action antidepressants, and these agents may be the best treatment for many patients with depression and co-occurring pain.
citalopram (Celexa and others), duloxetine (Cymbalta), fluoxetine (Prozac and others), venlafaxine (Effexor and others)
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