Short-term (2-week) effects of discontinuing milnacipran in patients with fibromyalgia

Abstract

Objective:

To examine the effects of abruptly withdrawing milnacipran during the 2-week discontinuation phase of a study in which FM patients had received 12 weeks of stable-dose treatment with milnacipran at 100 mg/day.

Research design and methods:

The effects of withdrawing milnacipran were evaluated prospectively over a 2-week period (Weeks 12 to 14) using a randomized, placebo-controlled withdrawal design. Patients who had originally received milnacipran 100 mg/d for 12 weeks were re-randomized to continue milnacipran (n = 178) or switch directly to placebo (n = 178); patients originally receiving placebo continued placebo (n = 359).

Clinical trial registration:

Clinicalstrials.gov (NCT00314249).

Main outcome measures:

Loss of efficacy was evaluated by mean changes in pain and functional measures and by percentage of composite responders, defined as patients with simultaneous improvements in pain, global status, and physical functioning. Newly emergent adverse events and changes in vital signs were also recorded.

Results:

Within 2 weeks,patients switched from milnacipran to placebo had greater mean worsening in pain, functioning, and global status measures when compared with patients continuing treatment. In addition, significantly fewer composite responders were found in patients who discontinued active treatment than in patients who continued receiving milnacipran (22.0% vs 32.3%, p < 0.05). Incidences of newly emergent adverse events were 16.3% and 18.0% in patients discontinuing and continuing treatment, respectively. Mean vital sign changes decreased or returned to baseline within 2 weeks of discontinuation.

Conclusions:

Patients discontinuing milnacipran experienced worsening in multiple efficacy parameters within 2 weeks. Vital sign changes observed with milnacipran during the 12-week stable-dose period decreased or returned to baseline values within 2 weeks after discontinuation of treatment. No new safety concerns were found during this discontinuation period with milnacipran.

Key words::

• Discontinuation
• Fibromyalgia
• Milnacipran
• Pain
• Physical function

Transparency

Declaration of funding

Supported by Forest Laboratories, Inc., New York, New York, and Cypress Bioscience, Inc., San Diego, California, USA.

Declaration of financial/other relationships

P.A.S. has received consulting fees from Forest Laboratories Inc. (<$15,000). L.M.A. has received consulting fees, and/or honoraria from Grünenthal, Forest Laboratories Inc., Daiichi Sankyo (<$10,000 each) and Pfizer Inc (>$10,000). She has received research support from Eli Lilly and Company, Cypress Bioscience Inc., Boehringer Ingelheim GmBH, Forest Laboratories Inc., Novartis AG, Takeda Pharmaceutical Company Ltd, and Pfizer Inc. R.H.P. and W.C. are full-time employees of Forest Research Institute Inc., a subsidiary of Forest Laboratories Inc. and own stock in that company. R.M.G. was formerly an officer and shareholder in Cypress Bioscience Inc.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgment

The authors thank Mildred Bahn at Prescott Medical Communications Group (Chicago, IL, USA) for medical writing assistance supported by Forest Laboratories Inc.

Previous presentation: these results were presented at the 73rd Annual Scientific Meeting of the American College of Rheumatology, Philadelphia, USA, 16–21 October 2009; the 62nd Annual Meeting of the American Academy of Neurology, Toronto, Canada, 10–17 April 2010); and the 13th World Congress on Pain, Montreal, Canada, 29 August – 2 September 2010.