Fibromyalgia is a complex disorder characterized by chronic widespread pain, fatigue, stiffness, poor sleep, depressed mood and cognitive difficulties [1–3]. On the basis of the 1990 American College of Rheumatology (ACR) classification criteria, which focus on pain and tenderness [4], it has been estimated that fibromyalgia affects 2% to 4% of the general population [5, 6]. However, in a recent population-based study that used modified ACR 2010 diagnostic criteria [7], which incorporate many of the other hallmark symptoms of fibromyalgia [8], the estimated prevalence was 6.4%. Because ongoing therapy is often required to manage the chronic symptoms of fibromyalgia, demonstration of a medicine's long-term efficacy is of great interest to both clinicians and patients.

Centrally acting analgesics, such as the tricyclic compounds, were investigated once it became clear that the diffuse pain and other symptoms of fibromyalgia were likely due to aberrations in the central nervous system. Preliminary studies with amitriptyline and cyclobenzaprine showed efficacy in patients receiving one to three months of treatment [9, 10]. These initially promising results were not replicated in subsequent longer-term studies, and tolerability is always an issue when using tricyclic compounds. Tramadol, another centrally acting analgesic that likely acts by largely augmenting serotonergic and noradrenergic activity (along with some weak μ-opioid effects) has also been shown to have short-term efficacy in patients with fibromyalgia [11–13].

As the pathophysiology of fibromyalgia became better understood, research focused on other centrally acting analgesics that would likely improve this condition [14]. This led to the approval of three medications by the US Food and Drug Administration (FDA) for the management of fibromyalgia: pregabalin, duloxetine and milnacipran. FDA approval of these drugs was based on results from large, randomized, placebo-controlled trials ranging from three to six months in duration [15–17]. In addition to each compound demonstrating efficacy in at least two of these pivotal trials, all three compounds were evaluated in extension studies that ranged from three months to one year in duration [18–21]. The longest fibromyalgia study to date was an open-label trial in which patients received up to 3.25 years of milnacipran after having participated in prior placebo-controlled trials or extension studies [22].

Although treatment benefits were found in the extension studies and the open-label milnacipran study, none included a placebo control group, because placebo-controlled, parallel-group clinical trials are ethically and practically difficult to conduct over long periods of time in patients with chronic pain. Therefore, this randomized withdrawal study was conducted to investigate the effects of discontinuing treatment of fibromyalgia patients who had completed participation in the long-term, open-label milnacipran study [22]. This design provided the opportunity to use a randomized, double-blind, placebo-controlled method to evaluate the long-term efficacy of milnacipran in patients with fibromyalgia.

Because it can be difficult to conduct long-term, placebo-controlled, parallel-arm studies to assess the efficacy of chronic pain medications, we used a randomized, placebo-controlled, withdrawal design in this trial to evaluate the loss of therapeutic response in patients with fibromyalgia who discontinued long-term treatment with milnacipran. As in other withdrawal studies [34], including the Future Revascularization Evaluation in patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) study of pregabalin in fibromyalgia [35], the present study focused on a subset of patients who responded to treatment. Although there are differences in design between the present study and FREEDOM, and though it would be improper to make any formal comparison between the two studies, it is of interest that both showed a loss of response in almost two-thirds of patients who were taken off therapy. It is also true that both studies showed a loss of response in almost one-third of patients continuing on therapy-attesting, perhaps, to the underlying variability in the pain of fibromyalgia. The fact that approximately one-third of patients switched to placebo in each study did not lose their therapeutic response is also of interest. Again, this may reflect the natural variability in the disease; in either case, there is sufficient evidence to suggest that these medications had a pharmacologic effect on the fundamental disturbances in pain processing that are characteristic of fibromyalgia [36].

In the current study, we analyzed data from patients who achieved ≥50% pain improvement after receiving 1.5 to 4.5 years (mean, 3 years) of milnacipran treatment in one or more prior clinical trials. Milnacipran dosages had been optimized for each patient entering the withdrawal study (50 mg/day to 200 mg/day), although the present analyses were limited to patients receiving at least the minimum recommended dosage of 100 mg/day [17]. The results of these analyses indicate that the patients classified as responders had experienced clinical benefits during long-term treatment with milnacipran, as evidenced by a shorter time to LTR and greater worsening in symptom severity postrandomization among the patients who were switched to placebo (that is, discontinued treatment) as compared to those who continued milnacipran. For the prespecified primary endpoint, significantly more patients in the placebo group experienced an LTR by the end of study compared to the milnacipran group (64% vs. 35%, P < 0.001).

The primary endpoint, as well as two of the three sensitivity analyses, included either worsening of fibromyalgia or discontinuation from the study as a definition of LTR. Sensitivity analysis II, however, was based solely on the pain criterion (that is, <30% reduction in VAS pain score from pre-milnacipran exposure). The results of this analysis, in conjunction with analyses of mean pain scores at various time points (that is, pre-milnacipran exposure, study randomization and end of study), may provide some important insights about pain responses in patients who had received up to 4.5 years of prior milnacipran treatment. First, notable pain improvements were found in patients who received long-term milnacipran treatment, as indicated by the 73% decrease in mean VAS pain score from pre-milnacipran exposure (65.7%) to randomization (17.5%) (Table 1). Of course, this result was derived from a selected group of responders who elected to continue treatment for an extended period of time, and the large mean decrease in pain does not necessarily imply that long-term treatment increases response to milnacipran. Nonetheless, the results from sensitivity analysis II indicate that, after randomization, the percentage of patients maintaining clinically meaningful pain improvement (that is, >30% decrease in pain from pre-milnacipran exposure) was higher in the group continuing milnacipran (81%) than in the group switched to placebo (58%) (Table 2). Although mean increases in VAS and BPI pain scores from randomization to the end of the study were observed in both treatment groups, worsening was greater in patients who discontinued milnacipran. There is no definitive explanation for the slight increase in mean pain scores in patients continuing milnacipran, but because randomization was based on achieving a certain level of pain reduction (≥50%), it is likely that some regression to the mean in pain severity occurred in this group. It is also possible that the results reflect some patients' assumptions that they had been discontinued from active treatment (for example, a "reverse placebo" or nocebo effect) [37].

This study also demonstrated that improvements in global status (PGIC), fibromyalgia severity (FIQR) and physical functioning (SF-36 PCS) occurred in patients receiving long-term milnacipran treatment. A higher percentage of patients discontinuing milnacipran reported feeling "much worse" or "very much worse" since randomization as compared with patients who continued treatment (50% vs. 22%, P < 0.001). These findings were supported by mean worsening from randomization in FIQR and SF-36 PCS scores, which were significantly worse with placebo than milnacipran at every study visit.

In patients who discontinued treatment, the greatest worsening in mean SF-36 PCS scores occurred between randomization and week 2, whereas mean VAS pain scores worsened steadily from randomization to week 8 (Figure 3). These results are consistent with findings in an earlier milnacipran study that included 12 weeks of double-blind treatment followed by a 2-week placebo-controlled discontinuation period [38]. The results from the short discontinuation period in that study also seem to indicate that physical functioning worsens more rapidly than pain after withdrawal of treatment. The reasons for these findings are unknown, but one possible explanation is that the function measures used in previous milnacipran studies were more sensitive than pain measures for detecting loss of response. It is also possible that when fibromyalgia patients experience a decline in physical function after discontinuing treatment, they decrease their activity levels, which in turn prevents them from experiencing increased pain severity. Alternatively, the results may simply indicate that the effects of milnacipran on pain are more persistent than its effects on functioning.

In addition to demonstrating the continuing efficacy of milnacipran, the worsening of pain and other symptoms observed in this withdrawal study confirms the benefit of ongoing treatment in patients with fibromyalgia. Moreover, these results suggest that the underlying pathophysiology of fibromyalgia was been reversed by long-term treatment, which has important implications for our understanding of this disorder-namely, that even a reasonably successful treatment, as demonstrated in this study by the ≥50% pain improvement from pre-milnacipran exposure at randomization, is not sufficient to "cure" individuals with this disorder by somehow resetting pain processing. This finding, combined with the fact that spontaneous remission is very uncommon, suggests that individuals with fibromyalgia who experience significant benefit with initial therapy (at least with this compound) should expect to continue to require long-term treatment.

No unexpected safety issues were observed in this study. Nausea and headache, the most commonly reported treatment emergent adverse events with milnacipran in placebo-controlled trials [25, 26, 39] and the long-term lead-in study [22], were each observed in 4% of patients continuing milnacipran in this study. In patients discontinuing treatment, the most common treatment emergent adverse events were sinusitis, peripheral edema and irritability (6% each with none rated as severe). Of those symptoms, only irritability is commonly associated with the abrupt discontinuation of serotonin and norepinephrine reuptake inhibitors [16, 17, 40]. However, patients in this study were not specifically evaluated for a discontinuation syndrome. Mean increases in blood pressure and heart rate have been reported in milnacipran-treated patients during placebo-controlled trials [17]. The results in the present study suggest that the effects of milnacipran on blood pressure and heart rate do not persist after patients discontinue treatment.

A few limitations should be noted. First, on the basis of the results reported above, no conclusions can be drawn about the effects of discontinuing milnacipran in patients who did not meet the stringent ≥50% pain responder criterion. However, subsequent analyses of this study indicate that patients who had 30% to <50% pain improvement from pre-milnacipran exposure, which indicates clinically meaningful improvement, also experienced loss of therapeutic effect after milnacipran was discontinued [41]. Second, although milnacipran dosages were optimized for each patient entering this withdrawal study (50 mg/day to 200 mg/day), the analyses were designed to evaluate only those patients who received at least 100 mg/day, the recommended minimum dosage [17]. Thus, no conclusions can be drawn regarding the effects of any specific dosage. Third, as has been discussed in other randomized withdrawal studies [34, 35], some patients may have suspected that they were on placebo if they experienced a clear worsening of symptoms during the 12-week discontinuation period. Any such unblinding effect may have influenced how patients assessed their pain and other symptoms in this study. Nonetheless, significant differences between milnacipran and placebo were observed.

In patients who received milnacipran for an average of three years (range, 1.5 to 4.5 years), loss of therapeutic response upon discontinuation of treatment provides evidence of long-term efficacy of this medication for the management of fibromyalgia.