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. 2014 Nov 21:7:679-87.
doi: 10.2147/JPR.S70200. eCollection 2014.

Efficacy of long-term milnacipran treatment in patients meeting different thresholds of clinically relevant pain relief: subgroup analysis of a randomized, double-blind, placebo-controlled withdrawal study

Philip J Mease  1 , Daniel J Clauw  2 , Joel M Trugman  3 , Robert H Palmer  3 , Yong Wang  3
Affiliations

Efficacy of long-term milnacipran treatment in patients meeting different thresholds of clinically relevant pain relief: subgroup analysis of a randomized, double-blind, placebo-controlled withdrawal study

Philip J Mease et al. J Pain Res. .

Abstract

Background: Fibromyalgia patients from a long-term, open-label study of milnacipran (50-200 mg/day) were eligible to participate in a 12-week, randomized, placebo-controlled withdrawal study. The withdrawal study evaluated loss of therapeutic response in patients who achieved ≥50% pain improvements after receiving up to 3.25 years of milnacipran. This post-hoc analysis investigated whether patients who met lower thresholds of pain improvement also experienced worsening of fibromyalgia symptoms upon treatment withdrawal.

Method: Among patients who received milnacipran ≥100 mg/day during the long-term study, three subgroups were identified based on percentage of pain reduction at randomization: ≥50% (protocol-defined "responders"; n=150); ≥30% to <50% (patients with clinically meaningful pain improvement; n=61); and <30% (n=110). Efficacy assessments included the visual analog scale (VAS) for pain, Fibromyalgia Impact Questionnaire-Revised (FIQR), 36-Item Short-Form Health Survey Physical Component Summary (SF-36 PCS), and Beck Depression Inventory (BDI).

Results: In the ≥30 to <50% subgroup, significant worsening in pain was detected after treatment withdrawal. The difference between placebo and milnacipran in mean VAS score changes for this subgroup (+9.0, P<0.05) was similar to the difference in protocol-defined responders (+9.4, P<0.05). In the <30% subgroup, no worsening in pain was observed in either treatment arm. However, patients in this subgroup experienced significant worsening in FIQR scores after treatment withdrawal (placebo, +6.9; milnacipran, -2.8; P<0.001), as well as worsening in SF-36 PCS and BDI scores.

Conclusion: Patients who experienced ≥30% to <50% pain reduction with long-term milnacipran had significant worsening of fibromyalgia symptoms after treatment withdrawal. These results suggest that the conventional ≥30% pain responder cutoff may be adequate to demonstrate efficacy in randomized withdrawal studies of fibromyalgia. Patients in the <30% pain reduction subgroup had worsening scores on the FIQR and other multidimensional measures after treatment withdrawal, indicating the importance of identifying and managing the multiple symptoms of fibromyalgia.

Keywords: fibromyalgia; post-hoc analysis; responders; symptoms.

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Figures

Figure 1
Figure 1
Overview of milnacipran studies. Abbreviations: DB, double-blind; MLN, milnacipran; OL, open-label.
Figure 2
Figure 2
Distribution of pain response at randomization in patients who received milnacipran ≥100 mg/day during the prior long-term, open-label study.
Figure 3
Figure 3
Mean changes from pre-milnacipran exposure in VAS pain scores. Notes: The group with ≥50% pain reduction at randomization represents the protocol-defined responder population of the randomized withdrawal study; *P<0.05 versus milnacipran; **P<0.01; ***P<0.001. Abbreviations: MLN, milnacipran; VAS, visual analog scale.
Figure 4
Figure 4
Mean change from randomization in Fibromyalgia Impact Questionnaire-Revised total scores in (A) ≥30% to <50% pain reduction subgroup and (B) <30% pain reduction subgroup. Notes: *P<0.05 versus milnacipran; **P<0.01; ***P<0.001.
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