Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity. A randomized, double-blind, placebo-controlled trial of trazodone hydrochloride in chronic low back pain syndrome. Controlled trial of imipramine for chronic low back pain. Efficacy of noradrenergic and serotonergic antidepressants in chronic back pain: a preliminary concentration-controlled trial. Amitriptyline and chronic low-back pain. A randomized double-blind crossover study. Tofranil in the treatment of low back pain. A placebo-controlled randomized clinical trial of nortriptyline for chronic low back pain. [Prospective study of the analgesic action of clomipramine versus placebo in refractory lumbosciatica (68 cases)]. The relationship between pain and depression in a trial using paroxetine in sufferers of chronic low back pain. A randomized, placebo-controlled trial of bupropion sustained release in 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 Of these 74 completed the trial; of the 29 who did not complete, 19 were withdrawn because of adverse effects.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. A 6-week placebo-controlled trial evaluated the efficacy of trazodone hydrochloride for the relief of chronic low back pain. Forty-two subjects (22 trazodone, 20 placebo) with a 20.3-year average history of back pain were titrated to an average dose of trazodone 201 mg or placebo 238 mg and evaluated daily on a Visual Analogue Scale of pain intensity, at 2-week intervals on an observer rating of pain behavior while walking, and before and after the trial on the Beck Depression Inventory, the Sickness Impact Profile, and a solid state microcomputer (Vitalog) that measured physical activity. Trazodone blood levels and urine toxicology screens were also obtained. There were no significant differences between groups in treatment effect. The results of this study require confirmation by longer trials with larger, less chronic, more homogeneous samples at higher doses with follow-up assessments. 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. Although antidepressants are widely prescribed as analgesics in chronic back pain, their clinical pharmacology is not well established. Norepinephrine transporter blockade seems to be essential for analgesia, but optimal concentrations are unknown. Fixed-dose studies of serotonin reuptake inhibitors are generally negative, but such studies cannot be interpreted clearly because efficacy might be detected if concentration-response relationships were known. We evaluated (1) the feasibility of conducting a controlled-concentration study of a norepinephrine (desipramine) and a serotonin reuptake (fluoxetine) inhibitor and (2) the relationship between achieved concentrations and analgesic response.
                This single-center, 12-week, double-blind, prospective, controlled-concentration study randomized 121 chronic back pain patients without major depression to active placebo (benztropine mesylate) or to predetermined low, medium, or high concentrations of desipramine (targets were 50, 110, and 150 ng/mL, respectively) or fluoxetine (targets were 100, 200, and 400 ng/mL, respectively). Of these, 83 completed the trial: 38 withdrew primarily due to side effects.
                Manipulation check revealed significant overlap of assigned and achieved concentrations related to drug intolerability. Completers' analysis of achieved concentrations revealed reduction in pain intensity was significantly greater for low-concentration desipramine (<60 ng/mL, mean Descriptor Differential Scale [DDS], 4.5) compared with placebo (DDS 6.2), higher concentrations of desipramine (>60 ng/mL, DDS 7.9), and all concentrations of fluoxetine (P < 0.05, DDS 7.1). Significant improvement in everyday function mirrored findings for pain intensity.
                Preliminary evidence for a low-concentration "therapeutic window" for noradrenergic analgesia may warrant additional study. 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. This report describes a double-blind between-group comparison of Tofranil and placebo in fifty-nine patients admitted to the Joint Service Medical Rehabilitation Unit suffering from low back pain. Patients were given 25 mg of either Tofranil or placebo three times a day for four weeks. Fifteen patients were not included in the analysis, nine dropping out for non-trial related reasons, two dropping out complaining of lost libido and four not taking the tablets, or taking additional drugs. One of the patients complaining of lost libido was taking Tofranil and the other was taking placebo. Over the whole sample there was no significant benefit for Tofranil over placebo as regards physical measurements. Both Tofranil and placebo groups showed a significant improvement during the trial on straight leg raise and backward flexion. For lateral flexion the Tofranil group was significantly worse than the placebo group on entering the trial, and during the trial the Tofranil group improved to match the placebo group. The clinician's pain and stiffness assessments and the patients' pain and stiffness assessments show a significant improvement for both the Tofranil and placebo groups during the trial. However, no difference is shown between Tofranil and placebo. The psychological tests show no difference between Tofranil and placebo and only a marinal improvenmet over initial condition. Further analysis according to initial diagnosis showed nothing conclusive. Numerically, the use of Tofranil produced a marked improvement in pain and stiffness in patients with 'disc lesion only' diagnoses, whereas placebo did not produce an improvement. However, this observation was far from reaching statistical significance. Side-effects were not severe for either drug. Additional medication was rarely used. 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. The authors sought to determine the analgesic activity of clomipramine (CMP) versus placebo, efficacy and side-effects according to the time of administration, long term clinical results and the relationship between plasma levels and analgesic effect. This double-blind randomised trial involved the infusion of 250 ml of glucose solution morning and evening versus placebo. CMP was administered at progressive doses for 8 days (maximum dosage 75 mg), either in the morning at 8 a.m. or in the evening at 6 p.m. Sixty eight patients accepted to be treated, all suffering from low back pain with or without sciatica. Maintenance treatment at the dose of 75 mg/day was then administered. CMP had a statistically significant analgesic action independent (rapidity of action) of its antidepressant activity. CMP was more effective and better tolerated (sedative and tranquilizer effect) in the evening. Long term results were poor (75% of cases). There was no link between plasma levels and clinical response. The authors noted that the analgesic activity of CMP was rapid, but for a duration limited to the short term and that this efficacy compared with the quite good results obtained with the placebo could be explained by a possible methodological bias (patients hospitalised and treated by intravenous infusions). The finding that CMP was better tolerated in the evening, without any loss of efficacy, is a positive feature (chronotherapeutic trial). Poor long term results could be partially explained by side-effects (66%). There was no relationship between analgesic effect and plasma levels. 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. 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.
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.