Psychosomatics 46:379-384, October 2005
doi: 10.1176/appi.psy.46.5.379
© 2005 Academy of Psychosomatic Medicine
Evaluation of Reboxetine, a Noradrenergic Antidepressant, for the Treatment of Fibromyalgia and Chronic Low Back Pain
Heather V. Krell, M.D., M.P.H.,
Andrew F. Leuchter, M.D.,
Ian A. Cook, M.D., and
Michelle Abrams, R.N.
Received Dec. 4, 2003; revision received Oct. 27, 2004; accepted Nov. 15, 2004. From the Laboratory of Behavioral Pharmacology, UCLA Neuropsychiatric Institute. Address correspondence and reprint requests to Dr. Krell, UCLA Neuropsychiatric Institute, 37-452 NPI, 760 Westwood Plaza, Los Angeles, CA 90024; hkrell{at}mednet.ucla.edu (e-mail).
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ABSTRACT
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Clinical experience supports the use of antidepressant medications to treat chronic pain syndromes, such as low back pain and fibromyalgia. Although this use of antidepressants is common in clinical practice, the literature supporting this off-label use has some limitations. In this report, the authors review the body of clinical data on the use of antidepressants in treating pain and present a case series of depressed patients with these syndromes who experienced relief of pain symptoms while being treated with the noradrenergic antidepressant reboxetine. These subjects experienced significant relief of pain before any significant improvement in actual mood symptoms. Our experience with reboxetine suggests that this noradrenergic antidepressant may have efficacy in the treatment of chronic pain in patients with depression.
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INTRODUCTION
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Pain is a complex neurobiological phenomenon and implicates several neuromodulatory pathways. Both the serotonergic and noradrenergic pathways have been identified as significant in both central and peripheral pain signaling mechanisms.1 Administration of serotonin receptor antagonists, alpha-adrenoreceptor antagonists, as well as the depletion of central serotonergic and noradrenergic stores have all demonstrated antinociceptive properties. Both of these neurochemical pathways also interact peripherally, with activation of both noradrenergic and serotonergic receptors producing analgesia, mediated by the alpha-1 and alpha-2 adrenoreceptors as well as the serotonin 5-HT1-4 receptors on the nerve terminals.2,3
Development of therapies for pain is complicated by the different types of pain and heterogeneity of nociceptive mechanisms. An increased understanding of the mechanisms of action have led to particular interest in the treatment of chronic pain with antidepressant medications. Based on their actions in blocking the reuptake of both 5-HT and norepinephrine, tricyclic antidepressants are currently ranked among the most commonly prescribed medications for the relief of chronic pain.4
Studies examining treatment of pain with antidepressants generally have focused on specific subtypes of pain. In particular, a significant body of literature indicates the usefulness of antidepressants in treating neuropathic pain. This literature demonstrates significant relief of pain using antidepressants as monotherapy for painful diabetic neuropathy and for postherpetic neuralgias.4 Antidepressants have also been shown to reduce pain complaints of some patients with rheumatoid arthritis and fibromyalgia and may potentiate the effects of other analgesics in these conditions.5–7 The effectiveness of antidepressants in painful conditions is in part dependent upon specific classes of medication. The literature in each of the major classes is reviewed briefly in the next section.
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TRICYCLIC ANTIDEPRESSANTS
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Despite the widespread use of tricyclic antidepressants for the treatment of chronic back pain, the evidence of their efficacy is based on few studies. Chronic back pain, which has a lifetime prevalence of 60%–80%, is one of the leading causes of medical visits and work disability in the United States.8 Fewer than a dozen placebo-controlled studies have addressed the efficacy of tricyclic antidepressants on diminution of back pain, decreased disability, or improved perception of well being.4,9–19 Half of these studies include individuals with depression, complicating measures of pain complaints with the presence of depression.4,9,10,12,17,19 The six randomized placebo-controlled trials that excluded individuals with a major depressive disorder provided mixed although generally positive results.17
Tricyclic antidepressants are also commonly used as a first line of treatment for fibromyalgia, although the literature supporting this application includes few well-controlled studies.6,20–39 Fibromyalgia is a musculoskeletal pain disorder of unknown etiology with an estimated lifetime prevalence of 2% in community samples.40 It is an illness characterized by pain, muscle tenderness, fatigue, and sleep disturbance and is diagnosed in 2% to 6% of adults and more commonly in women (estimated at 3.4% to 10.5%).41 Most individuals with this disorder consistently demonstrate abnormalities in alpha-delta non-REM sleep in polysomnographic studies.42 This sleep abnormality had been hypothesized to be related to biogenic amine reuptake abnormalities, particularly in central 5-HT mechanisms, supporting the conjecture that biogenic reuptake inhibitors may be helpful in treating this condition.5 This line of reasoning has been further supported by the experimental production of a condition similar to fibromyalgia after the administration of a centrally-acting serotonin synthesis inhibitor, p-chlorophenylalanine, as well as the large comorbidity of depression and the unusually high incidence of depression in first-degree relatives.43,44 Although cyclobenzaprine is not classified as an antidepressant, it has an effect similar to tricyclic antidepressants on both noradrenergic and serotonergic neurotransmission in the CNS. In a meta-analysis of nine studies examining the treatment of fibromyalgia with tricyclic antidepressants or cyclobenzaprine, the results were modestly favorable, with the largest overall improvement in sleep quality and modest improvement overall in pain and stiffness.5 It should be noted, however, that significant methodological concerns may limit the interpretation of these studies, including a lack of systematic screening for depression, modest sample sizes, and varying, nonstandardized dosing and duration of treatment with antidepressants.
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SEROTONERGIC AND OTHER NEWER AGENTS
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Because tricyclic antidepressants have significant side effect profiles, patient adherence has consistently been a challenge to their clinical use. The superior safety and tolerability profiles of the serotonergic agents raised hopes for their use in the treatment of chronic pain. Studies indicating the benefits of serotonergic agents for chronic back pain, however, remain limited. For instance, in a head-to-head randomized clinical trial by Atkinson et al.,17 paroxetine was compared with maprotiline, a noradrenergic antidepressant. This study found that maprotiline, but not paroxetine, reduced the intensity of chronic lower back pain in nondepressed individuals. One study found moderate but statistically significant improvement in pain and mood in fibromyalgia patients treated with fluoxetine.6 Overall results from treatment studies of fibromyalgia with selective serotonin reuptake inhibitors (SSRIs), however, do not offer compelling support for the efficacy of these agents, with little consistent efficacy demonstrated and similar methodological limitations. Of interest, a small study by Goldenberg et al.28 suggested an increased effectiveness related to the blockade of both norepinephrine and 5-HT by treatment with a combination of fluoxetine and amitriptyline rather than with either medication alone, possibly indicating a weak analgesic effect in the presence of tricyclic antidepressants.28 This theory is further supported by the small open trial of Dwight et al.,40 which also suggested efficacy in alleviating the pain and stiffness of this syndrome with the antidepressant venlafaxine, an antidepressant that inhibits the reuptake of both serotonin and norepinephrine. As with chronic back pain, the findings suggest differential efficacy related to antidepressant mechanism of action, with more promising results to date involving mixed rather than more selectively serotonergic medications. In both chronic back pain and fibromyalgia, antidepressant analgesic activity appears related to noradrenergic antidepressant activities, with SSRIs appearing to be of limited use and perhaps effective only at very high serum levels or as adjunctive treatment.17
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NORADRENERGIC SELECTIVE REUPTAKE INHIBITORS
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Because agents that affect norephinephrine and 5-HT appear superior to 5-HT-selective agents in pain management, some recent research in this area has explored the use of purely noradrenergic reuptake inhibitors as analgesic treatment. Animal research suggests that noradrenergic antidepressants may have antinociceptive effects comparable to mixed tricyclic antidepressants.45 The recent introduction of reboxetine, a selective norepinephrine reuptake inhibitor, has resulted in an increase of interest in the catecholamine pathway for the treatment of chronic pain. Double-blind, placebo-controlled studies indicate that as an antidepressant, reboxetine is more effective than placebo and similar in efficacy to SSRIs and tricyclic antidepressants in reducing depressive symptoms, with a relatively benign side effect profile.46 Because of its comparatively low affinity for muscarinic acetylcholine receptors, it causes less dry mouth, constipation, and other side effects often found problematic with tricyclic antidepressant treatment. Because reboxetine does not block alpha-1 receptors or the 5-HT transporter, side effects of nausea, diarrhea, and hypotension appear to be less common. In addition, reboxetine is nonsedating and, in fact, may be somewhat stimulating with regard to physical activity and vitality.47 The clinical implications of the potential role of norepinephrine reuptake blockers in the treatment of chronic pain, both related to and independent of depression, appear promising, as demonstrated by the series of cases we report.
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CASE REPORTS
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Case 1
Ms. A was a 44-year-old woman who was seen with a history of major depressive disorder for a clinical trial with the experimental antidepressant reboxetine. The trial was performed according to a protocol approved by the institutional review board at the University of California at Los Angeles, and all subjects provided informed consent. Ms. A’s current episode coincided with a diagnosis of fibromyalgia, made according to American College of Rheumatology criteria in 1997.48 Ms. A had a history of four previous major depressive episodes and was refractory to treatment with multiple antidepressants, at least three of which were trials of adequate duration with SSRI compounds (fluoxetine, paroxetine, and sertraline). Her presenting symptoms included a depressed mood with anhedonia, decreased energy, psychomotor retardation, and chronic pain, leading to a large decrease in her perceived quality of life.49 Ms. A reported a significant loss in her level of functioning both at home and at work, noting that she had consistently missed 1 to 2 days of work per week because of mood and pain symptoms. She also reported symptoms consistent with generalized anxiety disorder at the time of her presentation. Ms. A had a history of Graves’ disease treated with excision and radiation therapy in 1995, but she had consistently stable thyroid function tests while taking low doses of levothyroxine replacement therapy since that time. The results of laboratory tests at entry into our study were unremarkable, including thyroid studies. Ms. A’s physical examination was notable for musculoskeletal tenderness, with multiple tender points in her neck and shoulders. At her presentation, her score on the 17-item Hamilton Rating Scale for Depression50 was 23; her score on the 36-item Short Form Health Survey,51 which was performed as part of the protocol, was significant for Ms. A’s rating of herself as in generally poor health, worsening over the past year, with significant limitations on a variety of activities. Her rating on the pain scale was 3. Her score on the 36-item Short Form Health Survey also reflected a perception that her "very severe" bodily pain had notably decreased her feelings of accomplishment and her ability to do normal work in and outside of the home.
After 10 weeks of treatment with 8 mg/day of reboxetine, her score on the 36-item Short Form Health Survey demonstrated a considerable improvement from baseline, most notably with Ms. A reporting pain as moderate and only slightly limiting her work, home, and social activities. Her rating on the pain scale was improved, with a score of 6.1. Ms. A’s mood continued to be depressed at this time, with a score on the Hamilton depression scale of 14 and high scores on mood and anxiety items, in spite of the improvement of her chronic pain and the reduction in number and intensity of tender points noted during a physical examination. Her complaints of fatigue and loss of energy also improved. An asymptomatic moderate increase in blood pressure was observed on day 10 that resolved within 1 week. Ms. A reported, however, that she developed transient moderate diaphoresis and a maculopapular rash on her trunk. Based on her mood symptoms, Ms. A’s reboxetine dosage was increased to 10 mg/day at week 10. By week 18, she subjectively reported herself as having greatly reduced pain and reported no limitations in her activities or level of functioning, with a Hamilton depression scale score of 4.
Case 2
Mr. B was a 60-year-old man who was seen with a major depressive episode reported to be "continuous over the past 50 years." He described consistent symptoms of depressed mood, marked anhedonia, insomnia, psychomotor retardation, and low energy, with no period of remission lasting longer than 1 week. His baseline Hamilton depression scale score was 25. Mr. B reported three antidepressant trials in the 1970s but stated that all were discontinued because of side effects early in their courses, without improvement in mood. He described a history of lower back pain after an automobile accident over 20 years ago, and although no specific injury had been documented, he reported that this pain interfered significantly with all facets of his life. His physical examination showed significant limitation in his range of motion in his cervical and lumbar spine. Mr. B’s score on the 36-item Short Form Health Survey at the time of admission into the study was significant for moderate limitations on all assessed activities relating to his physical health. He reported that his level of pain disrupted both his work and social activities on a regular basis, which led to diminished feelings of accomplishment. Mr. B reported a robust improvement in mood, energy, productivity, and pain as early as his 6th week of taking reboxetine. His 6-week Hamilton depression scale score was 8, with a report of increasing energy and significant improvement in anhedonia. His 6-week 36-item Short Form Health Survey score showed change in the rating of daily pain and interference at work from severe to mild, with an overall improvement in feelings of vitality. By his 10th week of reboxetine treatment, Ms. A had a Hamilton depression scale score of 3, and his score on the 36-item Short Form Health Survey reflected a great improvement, with his health rated as "very good" and "much better." No changes in his baseline dose of reboxetine, 8 mg/day, were made. Overall, he felt that his health/pain affected his activities little or not at all, causing only slight interference with his work, home, and social life.
Case 3
Mr. C was a 51-year-old man who was seen during his fifth major depressive episode, with symptoms including severe psychomotor retardation and anorexia, with a weight loss of 40 lb. He reported that this episode was precipitated by an automobile accident, which had resulted in chronic cervical and lumbar back pain. This injury consisted of soft tissue injury, without any vertebral damage and no reports of disk protrusion. At his presentation, Mr. C was unemployed because of his incapacitating pain and a depressed mood. He reported adequate trials (i.e., an acceptable duration at the maximum tolerated dose) of several antidepressant medications, including fluoxetine, paroxetine, nortriptyline, and amitryptyline, with only minimal improvement in mood symptoms and no change in his level of pain. He stated that he had self-discontinued all medications over the 2 years before his presentation. Mr. C’s mental status examination was significant for a depressed mood, an extremely restricted affect, severe psychomotor retardation, and a notable paucity of spontaneous speech. His physical examination revealed right-sided stiffness and pain on palpation in both the cervical and lumbar regions, with severely limited torsional range. On his initial 36-item Short Form Health Survey, Mr. C reported that his physical pain significantly interfered with his daily performance in home, work, and social activities. By week 10, Mr. C had demonstrated consistent improvement in symptoms of both depression and pain, with a reduction in his Hamilton depression scale score from 24 to 6 and his score on the 36-item Short Form Health Survey showing a pronounced decrease in physical limitations because of pain by the conclusion of the study period. His improvement was maintained with 8 mg/day of reboxetine throughout the course of the study.
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DISCUSSION
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Chronic pain is one of the most common medical illnesses affecting the population and a significant cause of disability for patients. It is a major public health problem that, unfortunately, is often underrecognized and undertreated. The social and physical impairment and psychiatric comorbidity associated with chronic pain indicate a need for continued progress in developing optimal treatment strategies. Although chronic pain is commonly treated with antidepressants, few controlled studies are available to help in clinical decision making. From the limited data available, it appears that the noradrenergic system may be a cornerstone of antidepressant efficacy in the treatment of chronic pain. Our own experience in treating a series of patients with reboxetine bears out this principle, with relief of chronic back pain and fibromyalgia pain in advance of any significant improvement in actual mood symptoms. Several of the studies of antidepressants in chronic pain have examined the possible confounding issue of comorbidity with psychiatric illness in general and depression in particular. In his review, Fishbain52 concluded that depressed mood is significantly more common in patients with chronic pain than in the general population, with a prevalence of major depressive disorder of 54.5%. It has been reported in several trials of varied pain syndromes that the analgesic effect of tricyclic antidepressants may occur in the absence of any antidepressant effect, often at much lower doses and with a more rapid onset of action then an antidepressant effect requires.53 In a randomized controlled clinical trial comparing paroxetine and maprotiline in chronic lower back pain, Atkinson et al.17 excluded all patients with abnormal mood ratings and found an analgesic effect on chronic lower back pain, suggesting improvement in pain independent of any effect on mood symptoms.
Similarly, in clinical trials examining the efficacy of tricyclic antidepressants in fibromyalgia, one study found only a weak correlation between the improvement in depression and fibromyalgia symptoms. The remaining studies reported improvement on the psychiatric rating scales, even though they did not find a correlation between improvement of symptoms of fibromyalgia and those specific to depression.54 Further research is needed to determine whether our case reports indicate a specific effect of antidepressants independent of the treatment of depressive symptom profiles. Placebo-controlled studies with reboxetine for pain indications seem warranted. The related issues of comorbidity and heterogeneity among subtypes of chronic pain must be addressed in these studies as well.
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ACKNOWLEDGMENTS
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The authors thank Pharmacia & Upjohn for providing the reboxetine used in this study.
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ABSTRACT
INTRODUCTION
