Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity. A randomized, placebo-controlled trial of bupropion sustained release in chronic low back pain. A randomized, within-patient, cross-over, placebo-controlled trial on the efficacy and tolerability of the tricyclic antidepressants chlorimipramine and nortriptyline in central pain. The relationship between pain and depression in a trial using paroxetine in sufferers of chronic low back pain. A randomized, placebo-controlled trial of exercise therapy in patients with acute low back pain. Amitriptyline and chronic low-back pain. A randomized double-blind crossover study. Acupuncture treatment of chronic back pain. A double-blind placebo-controlled trial. A placebo-controlled randomized clinical trial of nortriptyline for chronic low back pain. Controlled trial of imipramine for chronic low back pain.
To understand the relative efficacy of noradrenergic and serotonergic antidepressants as analgesics in chronic back pain without depression, we conducted a randomized, double-blind, placebo-control head-to-head comparison of maprotiline (a norepinephrine reuptake blocker) and paroxetine (a serotonin reuptake blocker) in 103 patients with chronic low back pain. Of these 74 completed the trial; of the 29 who did not complete, 19 were withdrawn because of adverse effects. The intervention consisted of an 8-week course of maprotiline (up to 150 mg daily) or paroxetine (up to 30 mg daily) or an active placebo, diphenhydramine hydrochloride (up to 37.5 mg daily). Patients were excluded for current major depression. Reduction in pain intensity (Descriptor Differential Scale scores) was significantly greater for study completers randomized to maprotiline compared to placebo (P=0.023), and to paroxetine (P=0.013), with a reduction of pain by 45% compared to 27% on placebo and 26% on paroxetine. These results suggest that at standard dosages noradrenergic agents may provide more effective analgesia in back pain than do selective serotonergic reuptake inhibitors. Clinical trials of the efficacy of antidepressant drugs in patients with chronic low back pain have had mixed results, possibly because of the different mechanisms of action of the drugs that have been studied. Because bupropion has a mechanism of action that differs from other antidepressants and has shown efficacy in neuropathic pain, a randomized, placebo-controlled, 2-period crossover trial was conducted to evaluate its efficacy in subjects with chronic low back pain. The primary efficacy variable was mean daily diary pain intensity ratings, and secondary pain intensity and relief outcomes included weekly pain intensity ratings, the McGill Pain Questionnaire (MPQ) Present Pain Intensity scale, pain relief ratings, and satisfaction with pain relief ratings. Adverse events were also assessed throughout the trial. Analyses were performed of an intention-to-treat sample of 44 patients, only 3 of whom met criteria for neuropathic low back pain. Daily and weekly pain intensity ratings, the MPQ Present Pain Intensity scale, and pain relief ratings were not significantly different following treatment with bupropion sustained release (SR) vs. placebo. These results suggest that bupropion SR was not significantly better than placebo in the treatment of patients with non-neuropathic chronic low back pain.
                Antidepressant medications that have both noradrenergic and serotonergic effects appear to have greater efficacy in patients with chronic low back pain than those with only serotonergic activity. We studied bupropion because it inhibits the reuptake of both norepinephrine and dopamine, but found no evidence of efficacy in patients with non-neuropathic chronic low back pain. Antidepressant drugs are increasingly used in the management of chronic pain. They are mainly prescribed for cancer-related pain and central pain, e.g. phantom or stump pain, post-herpetic neuropathy. However, no controlled clinical trials have validated their in either pathology. Thus, physicians still do not know whether antidepressants are really effective and which might be best. It is still debated whether the effect of antidepressants in the management of chronic pain is limited to the amelioration of frequently concomitant depression or extends to pain itself. To verify both the analgesic effect of tricyclic antidepressants, and the possible relationship between their antidepressant effect and the relief of central pain, we carried out a randomized, within-patient (cross-over) placebo-controlled study in patients suffering from central pain. The results clearly indicate the better analgesic effect of tricyclic antidepressants over placebo (p less than 0.0001). Within the antidepressants tested, chlorimipramine, a blocker of serotonin reuptake, is significantly more effective (p less than 0.0001) than notriptyline, a blocker of noradrenaline reuptake. Finally, the antinociceptive effect is independent of the effects of the two drugs on the symptoms of depression. Previous studies have shown a positive association between pain and depression, though evidence supporting a direct link between these two variables is less robust. Using a placebo-controlled trial, the authors examined the analgesic and antidepressant efficacy of paroxetine (20 mg) in chronic low back pain sufferers. The authors examined the associations among pain, depression, disability, and illness attitudes. Paroxetine showed no effects on pain or depression compared with placebo; however, subjects randomized to paroxetine were more likely to reduce concomitant analgesic medication. The cross-sectional association of depression and pain at baseline (r = 0.2, P = 0.02) was weaker than the association between depression and disability (r = 0.3, P = 0.004). Similarly, the association of change in depression scores with change in pain (r = 0.25, P = 0.016) was weaker than change between depression and disability (r = 0.49, P<0.0005). Whereas the relationship between pain and depression became nonsignificant when disability and illness attitudes were controlled, the relationship between depression and disability remained highly significant when pain and illness attitudes were controlled. These data are consistent with the association between pain and depression being wholly modulated by disability and illness attitudes, with no direct relationship between pain and depression. To assess the efficacy of exercise therapy for acute low back pain, a randomized, placebo-controlled trial was performed in 40 Dutch general practices. Patients received either exercise instruction with advice for daily life by a physiotherapist; placebo ultrasound therapy by a physiotherapist; or usual care by the general practitioner. All patients received analgesic agents and information on low back pain before randomization. Four hundred seventy-three patients were included. No differences in number of recurrences, functional health status, or medical care usage could be found among the three groups. In the exercise group, duration of recurrences was shorter and patients were less tired during the first 3 months than in the usual care group, but no differences were found between the exercise and placebo groups. It was concluded that exercise therapy for patients with acute low back pain has no advantage over usual care from the general practitioner. The effect of antidepressant medication on chronic low-back pain patients was studied in a randomized blind crossover study. Among those patients who completed the study, there was a 46% decrease in the use of analgesics while on amitriptyline when compared to placebo (P less than 0.005). There was also improvement in affect, but no measurable change in activity level. The MMPI profile of those patients who were unable to comply with the study protocol differed from that of patients who completed the study. The noncompliers demonstrated an elevation of the F, Pd, Pt (P less than 0.05) and Mf (P less than 0.01) scales. Although the interpretation of such a profile is left open to speculation, it may serve as an indicator of noncompliant individuals. Acupuncture treatment of chronic low back pain was studied in a placebo-controlled double-blind crossover trial completed by 77 patients. The patients had significantly increased depression, neuroticism, and hypochondriasis scores. Initial pain levels correlated with state-anxiety, depression, pain duration, and abnormal illness behavior measures, as well as with the intake of psychotropic but not analgesic medication. Overall reduction in pain score was 26 percent for acupuncture and 22 percent for placebo treatment; the difference was not significant (p greater than 0.6). Analgesic drug intake was reduced to a similar extent in both groups. During the first phase of treatment, patients receiving acupuncture had a greater but not significantly different reduction in pain rating scores compared with those receiving placebo (t = 0.52; p greater than 0.6). This group showed significantly lower pain scores (p less than 0.05) in the second phase of the trial while receiving placebo treatment. Overall reduction in individual patient's pain score was best predicted by initial pain severity (r = 0.43; p less than 0.001) and psychotropic drug intake (r = 0.37; p less than 0.001). None of the variables tested predicted which patients would specifically respond to acupuncture or placebo. To assess the efficacy of nortriptyline, a tricyclic antidepressant, as an analgesic in chronic back pain without depression, we conducted a randomized, double-blind, placebo-controlled, 8-week trial in 78 men recruited from primary care and general orthopedic settings, who had chronic low back pain (pain at T-6 or below on a daily basis for 6 months or longer). Of these 57 completed the trial; of the 21 who did not complete, four were withdrawn because of adverse effects. The intervention consisted of inert placebo or nortriptyline titrated to within the therapeutic range for treating major depression (50-150 ng/ml). The main outcome endpoints were pain (Descriptor Differential Scale), disability (Sickness Impact Profile), health-related quality of life (Quality of Well-Being Scale), mood (Beck Depression Inventory, Spielberger State Anxiety Inventory, Hamilton Anxiety/Depression Rating Scales), and physician rated outcome (Clinical Global Impression). Reduction in pain intensity scores was significantly greater for participants randomized to nortriptyline (difference in mean change 1.68, 95%-0.001, CI -3.36, P = 0.050), with a reduction of pain by 22% compared to 9% on placebo. Reduction in disability marginally favored nortriptyline (P = 0.055), but health-related quality of life, mood, and physician ratings of overall outcome did not differ significantly between treatments. Subgroup analyses of study completers supported the intent-to-treat analysis. Also, completers with radicular pain on nortriptyline (n = 5) had significantly (P < 0.05) better analgesia and overall outcome than did those on placebo (n = 6). The results suggest noradrenergic mechanisms are relevant to analgesia in back pain. This modest reduction in pain intensity suggests that physicians should carefully weigh the risks and benefits of nortriptyline in chronic back pain without depression. Chronic low back pain is a common problem that has been noted in several studies to exist as a component of masked depression. To determine the usefulness of imipramine in the treatment of chronic low back pain, either by a direct action or indirectly via resolution of a depressive equivalent, 50 consecutive patients were entered into a controlled trail that employed serum imipramine and desipramine levels and Beck depression questionnaires. Forty-one patients completed the study, and 48 were used in the statistical analysis. Imipramine had a statistically significant effect over placebo in most, but not all, of the clinical parameters that were measured. A linear relationship between serum drug levels and reported symptoms was not noted. Only 10 of the 50 patients entered into the study were judged clinically depressed and, of these, 7 were depressed according to standard criteria. There was no statistically significant difference noted in either the initial or the change in Beck depression scores between those on imipramine and those on placebo. However, among those on the active drug, the patients with a greater symptomatic response had a simultaneous change in the total Beck depression scores (toward less depression) that approached statistical significance when compared with those with a less symptomatic response. Although the results are not conclusive, imipramine may possibly be useful in the treatment of chronic low back pain, especially so when it exists as a component of masked depression.
There is no clear evidence that antidepressants are more effective than placebo in the management of patients with chronic low-back pain. These findings do not imply that severely depressed patients with back pain should not be treated with antidepressants; furthermore, there is evidence for their use in other forms of chronic pain.