Three recent meta-analyses of fibromyalgia pharmacological trials assessed the efficacy of medications that inhibit the reuptake of serotonin and/or norepinephrine. The first meta-analysis [16
] assessed nine placebo-controlled trials of the cyclic drugs that inhibit the reuptake of both serotonin and norepinephrine, including the tricyclics amitriptyline [17
], dothiepin, which is structurally similar to amitriptyline and doxepin [21
], cyclobenzaprine [18
], which possesses structural and pharmacological properties of other tricyclics [25
], clomipramine [26
], and the tetracyclic maprotiline [26
]. Seven outcome measures were assessed, including: the patients' self-ratings of pain, stiffness, fatigue and sleep; the patient and the physician global assessment of improvement; and tender points. The largest effect was found in measures of sleep quality, with more modest changes in tender point measures and stiffness. Thus, the most consistent improvement could be attributed to the sedative properties of these medications.
The results of another meta-analysis of randomized, placebo-controlled studies of cyclobenzaprine was consistent with the Arnold and colleagues [16
] meta-analysis. Cyclobenzaprine treatment resulted in moderate improvement in sleep, modest improvement in pain, and no improvement in fatigue or tender points [27
A third meta-analysis of antidepressants in the treatment of fibromyalgia [28
] evaluated 13 trials of antidepressants, most of which studied the cyclic drugs amitriptyline [17
], clomipramine [26
], and maprotiline [26
]. The meta-analysis also included trials of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine [20
] and citalopram [34
], as well as a reversible inhibitor of the monoamine oxidase-A enzyme, moclobemide [29
], and the dietary supplement S-adenosylmethionine [35
]. Outcome measures included the number of tender points, and patients' self-ratings of pain, sleep, fatigue, and overall well being. The pooled results showed a significant symptomatic benefit of antidepressants that was moderate for sleep, overall well being, and pain severity, and mild for fatigue and number of tender points. The magnitude of benefit was similar to that found in the Arnold and colleagues [16
] meta-analysis. Because only three trials of SSRIs were included in the meta-analysis, it was not possible to assess the relative efficacy of SSRIs.
The trials of SSRIs in fibromyalgia have shown mixed results, suggesting that medications with selective serotonin effects are less consistent than those with dual effects on norepinephrine and serotonin in the relief of pain associated with fibromyalgia. Citalopram, which has the highest selectivity for the serotonin reuptake transporters among the SSRIs, was not effective for the treatment of fibromyalgia in two small controlled studies [33
]. On the other hand, the SSRIs fluoxetine and paroxetine CR, which may have additional effects on norepinephrine at adequate doses [38
], have been shown to be effective for fibromyalgia in recent studies [40
Although the meta-analyses indicated that the overall effect of the cyclic drugs on most symptoms of fibromyalgia was modest, possibly related to the low doses that were typically studied, tricyclics continue to be frequently recommended for the treatment of patients with fibromyalgia [42
]. Furthermore, even at low doses, many patients experience problems with the safety and tolerability of these medications related to their anticholinergic, antiadrenergic, antihistaminergic, and quinidine-like effects [43
Recently, fibromyalgia trials have focused on new selective serotonin and norepinephrine reuptake inhibitors (SNRIs), which are potent dual reuptake inhibitors but, unlike the tricyclics, do not interact with adrenergic, cholinergic or histaminergic receptors, or sodium channels, and, therefore, lack many side effects of tricyclics. Preliminary, open trials of the SNRI venlafaxine were promising [44
], but one study, a six-week, randomized, placebo-controlled, double-blind trial of a fixed, low dose of venlafaxine (75 mg/day) [46
], found that venlafaxine improved some but not all measures of pain. The short duration of this trial and low dose of venlafaxine may explain the discrepant results. To date, two randomized, placebo-controlled studies of the SNRI duloxetine and one study of the SNRI milnacipran in the treatment of fibromyalgia have been published, and are described below.
Duloxetine, a new, potent SNRI with dual reuptake inhibition of serotonin and norepinephrine over the entire clinically relevant dose range [47
], is a safe, tolerable, and effective antidepressant [48
] that also significantly reduces painful physical symptoms associated with major depressive disorder [51
]. In non-depressed patients with diabetes, duloxetine effectively reduces diabetic peripheral neuropathic pain [52
], supporting an analgesic effect of duloxetine that is independent of its effects on mood. Duloxetine is currently indicated by the FDA for the treatment of major depressive disorder in adults and diabetic peripheral neuropathic pain in adults [54
The first study of duloxetine in fibromyalgia was a randomized, placebo-controlled, double-blind, parallel-group, multi-site, 12-week monotherapy study of duloxetine titrated to 60 mg twice a day (BID) that included 207 patients with fibromyalgia with or without current major depressive disorder [55
]. Co-primary outcome measures were the Fibromyalgia Impact questionnaire (FIQ) total score and pain score [56
]. The FIQ is a self-report instrument in which patients rate their overall symptoms and function over the previous week. Duloxetine-treated patients compared with placebo-treated patients improved significantly more on the FIQ total score, but not on the FIQ pain score. However, duloxetine-treated patients had significantly greater improvement in secondary measures of pain, including the Brief Pain Inventory (short form) [57
] average pain severity score, which measured pain over the past 24 hours from 0 (no pain) to 10 (pain as bad as you can imagine), and the average pain interference score, which assessed interference from 0 (does not interfere) to 10 (completely interferes) with general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Duloxetine-treated patients compared with patients on placebo also experienced significant improvement in tender point number and mean tender point pain thresholds that were assessed using a Fischer dolorimeter [58
] applied to the 18 tender point sites defined by the American College of Rheumatology criteria. Other secondary measures that significantly improved in the duloxetine-treated group compared with the placebo group included the FIQ stiffness score, Clinical Global Impression of Severity scale [59
], and the Patient Global Assessment of Improvement scale. Quality of life measures that significantly improved in the duloxetine group compared with the placebo group included the Quality of Life in Depression Scale total score [60
], the Sheehan Disability Scale total score [61
], and the Medical Outcomes Study Short Form 36 (SF-36) physical subscore and scores for bodily pain, general health perception, mental health, physical functioning, and vitality [62
Significantly more duloxetine-treated female patients (30.3%) had a clinically meaningful (≥50%) decrease in the FIQ pain score compared with placebo-treated female patients (16.5%). In addition, the Brief Pain Inventory average pain severity score decreased by ≥50% in significantly more duloxetine-treated women (30%) than women on placebo (16%). However, duloxetine-treated male patients failed to significantly improve on any efficacy measure. The reasons for the sex differences in response to duloxetine are unclear, but may be related to the small male subgroup (23 (11%) of 207 patients), or to possible sex differences in fibromyalgia that affect treatment response.
The duloxetine trial was one of the first fibromyalgia clinical trials to assess baseline psychiatric comorbidity using a structured psychiatric clinical interview and to include patients with and without current major depressive disorder in order to evaluate the impact of major depressive disorder on the response to treatment with duloxetine. Of importance is that duloxetine reduced pain severity regardless of the presence or absence of major depressive disorder. In addition, the treatment effect of duloxetine on significant pain reduction in female patients was independent of the effect on depressive or anxiety symptoms. Therefore, the effect of duloxetine on the reduction of pain associated with fibromyalgia appears to be independent of its effect on mood.
Duloxetine was well tolerated, and there was no significant difference in the number of patients who discontinued due to adverse events. Duloxetine-treated patients reported insomnia, dry mouth, and constipation significantly more frequently than placebo-treated patients. Most treatment-emergent adverse events were of mild or moderate severity.
The second, randomized, placebo-controlled, double-blind, parallel-group, multi-site, 12-week study of duloxetine monotherapy in fibromyalgia tested the safety and efficacy of both 60 mg BID and a lower dose of 60 mg once a day (QD) in 354 women with fibromyalgia with or without current major depressive disorder [63
]. This study included only women to confirm the results of the first duloxetine trial in which women, but not men, responded significantly to duloxetine compared with the same sex placebo-treated patients on efficacy measures. The primary outcome measure was pain severity as measured by the Brief Pain Inventory (short form) average pain severity score (score range 0 to 10). Compared with the placebo group, the duloxetine 60 mg QD group and the duloxetine 60 mg BID group experienced significantly greater improvement in the Brief Pain Inventory average pain severity score, beginning at week 1 and continuing through week 12. Significantly more patients treated with duloxetine 60 mg QD (41%) and duloxetine 60 mg BID (41%) compared with placebo (23%) had a ≥50% reduction in the Brief Pain Inventory average pain severity score. Compared with placebo, duloxetine 60 mg QD or duloxetine 60 mg BID resulted in significantly greater improvement in the remaining Brief Pain Inventory pain severity and interference scores, and other secondary outcomes, including the FIQ, Clinical Global Impression of Severity, and the Patient Global Impression of Improvement. Consistent with the first duloxetine study, several quality of life measures significantly improved in both duloxetine groups compared with the placebo group, including the Quality of Life in Depression Scale total score, the Sheehan Disability Scale total score, and the SF-36 mental subscore, bodily pain, mental health, role limit emotional, role limit physical, and vitality. There were no significant differences between duloxetine 60 mg QD and duloxetine 60 mg BID treatment groups in efficacy outcomes. However, only the duloxetine 60 mg BID dose, compared with placebo, significantly improved the tender point assessments. This suggests that the higher dose may be necessary to improve pressure pain thresholds, which have been found to be less responsive to treatment in previous fibromyalgia trials using tricyclics [16
]. As in the first study of duloxetine, the treatment effect of duloxetine on pain reduction was independent of the effect on mood and the presence of major depressive disorder.
The most frequent side effect in patients in the duloxetine 60 mg QD and 60 mg BID groups was nausea, and side effects were generally mild to moderate in severity for most patients. Significantly more patients in the duloxetine 60 mg BID group than the placebo group discontinued treatment due to adverse events. This finding differs from the previous duloxetine trial of 60 mg BID in which there were no differences between treatment groups in discontinuation due to treatment-emergent adverse events. The difference between the studies might be explained by the slower titration of duloxetine in the first study, in which duloxetine was titrated from a starting dose of 20 mg QD to 60 mg BID over 2 weeks. In the second study, patients were started on 60 mg QD and titrated to 60 mg BID over just three days. This suggests that some patients would benefit from a lower duloxetine starting dose and slower titration.
The results of both duloxetine studies in fibromyalgia provide evidence that duloxetine 60 mg QD and 60 mg BID for up to 12 weeks are safe and effective in the treatment of fibromyalgia in women with or without major depressive disorder.
Milnacipran is another selective SNRI that has been approved for treatment of depression since 1997 in parts of Europe, Asia, and elsewhere, but is currently unavailable in the US. Milnacipran is a dual serotonin and norepinephrine reuptake inhibitor within its therapeutic dose range and also exerts mild N-methyl-D-aspartate (NMDA) inhibition [64
In a double-blind, placebo-controlled, multicenter trial, 125 patients (98% women) with fibromyalgia were randomized to receive placebo or milnacipran monotherapy for 4 weeks of dose escalation to the maximally tolerated dose followed by 8 weeks of stable dose (25 to 200 mg/day) [65
]. The study evaluated the efficacy and safety of two different dosing regimens of milnacipran (QD versus BID) for the treatment of fibromyalgia. The primary outcome measure was based on change of average daily pain scores recorded on an electronic diary (e-diary), comparing the two-week baseline period to endpoint (last two weeks on treatment). The majority of milnacipran-treated patients, 92% of completers on the BID regimen and 81% on the QD regimen, titrated to the highest daily dose (200 mg). Although the primary outcome measure of daily e-diary pain scores did not significantly improve in either patients on BID milnacipran or those on the QD regime compared to placebo, patients treated with milnacipran on a BID schedule experienced significant improvement in the weekly e-diary pain scores, paper pain scores, and the McGill Pain Questionnaire present pain intensity score [66
] compared to those on placebo. Furthermore, significantly more patients receiving milnacipran BID (37%) reported a reduction in the weekly average pain scores by 50% or more, compared with 14% of patients in the placebo group. Milnacipran-treated patients on the QD schedule did not exhibit the same degree of improvement in pain, suggesting that dosing frequency is important in the use of milnacipran for pain associated with fibromyalgia. The QD regime may have resulted in inadequate drug levels of milnacipran and less effective pain relief by the end of the day because of milnacipran's short half-life of 6 to 8 hours. Both milnacipran groups (QD and BID dosing), compared with the placebo-treated patients, had significantly greater improvement in other secondary measures, including the patient global impression of change score, and the physical function and 'days felt good' subscales of the FIQ. The BID milnacipran-treated group, compared to patients on placebo, also had significant improvement in the FIQ scores for pain, fatigue, and morning stiffness.
Milnacipran was generally well tolerated and most adverse events were rated as mild or moderate in severity. Overall, 14.4% of patients discontinued the study due to adverse events, including 7 (13.7%) from the milnacipran BID group, 10 (21.7%) from the milnacipran QD group, and 1 (3.6%) from the placebo-treated group. Headache and gastrointestinal complaints (nausea, abdominal pain, gastrointestinal upset, and constipation) were the most frequent reasons for early discontinuation. Other reasons included orthostatic dizziness, exacerbation of hypertension, depression, lethargy, increased sweating, and hot flashes. The QD group experienced a higher incidence of adverse events than the BID group, suggesting that the QD dose was not as well tolerated as BID dosing.
As in the duloxetine trials, patients were evaluated for psychiatric comorbidity and those with and without current major depressive disorder were included. Unlike the results of the duloxetine trials in which both depressed and non-depressed patients responded similarly to duloxetine, statistically greater improvement in pain reduction was seen in non-depressed patients versus depressed patients treated with milnacipran. Although this finding needs to be replicated in a larger clinical trial, the positive response in non-depressed patients suggests that, like duloxetine, the pain relieving effects of milnacipran do not occur only through improvement in mood.