Friday, February 5, 2010

Initial Clinical Trial data suggest that lower-dose Savella improves chronic pain, physical function

Written By Charles Bankhead, Staff Writer, MedPage Today; Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

Action Points 

  • Explain to patients that a fibromyalgia drug proved superior to a placebo throughout two large clinical trials.
  • Note that the drug affected several outcomes and demonstrated efficacy at two different doses.
  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

( - SAN ANTONIO) -- The fibromyalgia drug milnacipran (Savella) achieved clinically meaningful reductions in pain throughout almost four months of randomized therapy, a post-hoc analysis of daily pain control showed.

Half of patients treated with the serotonin/norepinephrine reuptake inhibitor had at least a 30% improvement in pain scores at 15 weeks, and 35% to 40% had at least a 50% improvement, according to analyses reported here at the American Academy of Pain Medicine meeting.

Two different doses of milnacipran led to at least 30% improvement in pain on almost half of the days during the randomized trial. Patients treated with milnacipran had at least 50% improvement during 30% of the days.

"A 30% improvement in pain is clinically significant, and half the patients treated with milnacipran attained that level of pain relief," Aroon Datta, MD, of Forest Laboratories in Jersey City, N.J., said in an interview. "Even when the more stringent criteria of 50% improvement were applied, significantly more patients in the milnacipran groups achieved that threshold compared with placebo."

"By any measure, it is fair to say that patients treated with milnacipran had significantly better pain control," he added.

Milnacipran is chemically similar to the antidepressant venlafaxine (Effexor). However, milnacipran has three times the power to inhibit norepinephrine reuptake. The drug was approved in 2009 for treatment of fibromyalgia.

Datta reported results of a post-hoc analysis of data from two randomized, placebo-controlled clinical trials. One lasted 27 weeks, and the other had a 15-week follow-up.

In the 27-week trial, approximately 900 patients were randomized 1:1:2 to placebo, milnacipran 100 mg/d (50 mg BID), or milnacipran 200 mg/d (100 mg BID). In the 15-week trial, 1,200 patients were randomized in equal proportion to placebo and the two doses of milnacipran.

Patients recorded their pain level several times a day by means of an electronic diary. They rated their pain according to a visual analog scale (VAS) with a range of 0 to 100.

The post-hoc analysis centered on outcomes at 15 weeks in both trials. The primary outcomes were change from baseline in weekly 24-hour VAS pain score, the proportion of patients who achieved ≥30% and ≥50% improvement in the VAS pain score, and the proportion of days with ≥30% and ≥50% improvement in pain.

In the longer trial, the change in the weekly average of 24-hour recall of VAS scores differed significantly in both milnacipran groups within two weeks, and the difference was maintained through 15 weeks (P<0.05 to P<0.001).

Significant differences emerged within the first week in the second trial and persisted through week 15 (P<0.05 to P<0.001).

In both trials, 52% of patients assigned to 100 mg of milnacipran and 56% of those assigned to 200 mg had ≥30% improvement in pain scores, compared with 40% to 42% of placebo-treated patients (P<0.05 to P<0.001).

When the more stringent criterion of ≥50% improvement was used, 31% to 35% of the 100-mg milnacipran patients achieved that goal, as did 36% to 37% of patients treated with 200 mg.

About 25% of placebo patients had ≥50% improvement. Only the 200-mg dose differed significantly from placebo (P<0.05 to P<0.01).

A similar pattern emerged in evaluation of the proportion of days with threshold pain reductions. Milnacipran-treated patients had ≥30% improvement on 44% to 47% of days in the trial and ≥50% improvement on 25% to 30% of days.

For both thresholds, milnacipran was significantly better than placebo, whose patients had ≥30% pain improvement on about a third of days and ≥50% improvement on fewer than 20% of days (P<0.01 to P<0.001).

Datta also reported findings from a randomized, placebo-controlled clinical trial evaluating the pain relief afforded by the 100-mg daily dose of milnacipran. The study involved 1,025 patients with fibromyalgia randomized to placebo or active therapy.

The trial had two principal 12-week efficacy outcomes: the composite of ≥30% improvement in pain and the Patient Global Impression of Change (PGIC), and the composite of the same two outcomes plus improvement ≥6 points on the physical function component of the SF-36 health assessment survey.

The principal efficacy analysis used baseline observation carried forward (BOCF) for patients with missing data. By that statistical method, 29% of milnacipran patients were responders compared with 18% of the placebo group (P<0.001).

An analysis that employed last observation carried forward (LOCF) showed response rates of 33% with milnacipran and 19% with placebo (P<0.001).

An analysis of observed cases resulted in response rates of 42% versus 26% (P<0.001).

Similar results emerged from analyses of the three-measure outcome. Milnacipran led to significantly higher (P<0.001) response rates by BOCF (20% versus 11%), by LOCF (28% versus 12%), and by observed cases (30% versus 16%).

Milnacipran therapy also led to significantly higher (P<0.001) response rates for each component of the composite outcomes: ≥30% improvement in pain (45% versus 31%), PGIC (42% versus 26%), and ≥6-point improvement in physical function (40% versus 31%).

The results indicate that milnacipran 100 mg (50 mg BID) could offer an alternative for patients who cannot tolerate the FDA-approved 200-mg dose, said Datta. If physicians choose to start patients on 100 mg and then titrate up to the approved dose, that also would appear feasible, he said.

The studies were supported by Forest Laboratories and Cypress Bioscience.

All but two of the authors are employees of the study sponsors.

Primary source: American Academy of Pain Medicine
Source reference:
Mease P, et al "A day-to-day analysis of the analgesic efficacy of milnacipran in the management of fibromyalgia" AAPM 2010; Abstract 110.

Additional source: American Academy of Pain Medicine
Source reference:
Arnold LM, et al "Milnacipran 100 m/day in the management of fibromyalgia: a randomized, double-blind placebo-controlled trial" AAPM 2010; Abstract 109.

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