Milnacipran is a chemically novel, dual acting reuptake inhibitor, distinguished from other SNRIs (Serotonin Norepinephrin Reuptake Inhibitors) by its preference for norepinephrine (NE) reuptake inhibition over serotonin (5-HT). This profile most closely mimics that seen with tricyclic antidepressants (TCAs) such as amitriptyline. While mimicking the NE preference seen with TCAs, milnacipran lacks the other receptor interactions that underlie the side effects of the TCAs, and limit their use. While new antidepressants have displaced TCAs for most psychiatric indications, the TCAs remain in clinical use in chronic pain states, where they have consistently demonstrated superior efficacy to SSRIs, NSAIDs and non-opiate pain medications. Such applications include the so-called Functional Somatic Syndromes (FSS), such as fibromyalgia syndrome (FMS), irritable bowel syndrome (IBS),and tension headaches (TH), which share a similar spectrum of symptoms, including pain, disturbed sleep, fatigue, and depressed mood; b) a level of distress, as reported by the patient, that can not be readily explained by the physical and laboratory findings of the physician; and c) high levels of comorbidity. These syndromes are common, accounting for up to 60% of all primary care visits in the United States, by some estimates. We hypothesize that the NE reuptake inhibition preference of agents such as amitriptyline may account for their superior efficacy relative to SSRIs in chronic pain states, and set out to test this hypothesis by studying the efficacy of milnacipran in FMS, a prototypical FSS. A rigorous Phase II randomized, double-blind, placebo-controlled, flexible dose escalation monotherapy trial was conducted to evaluate milnacipran in patients with a diagnosis of FMS. Following washout of any centrally-acting agents including antidepressants, patients began a two week baseline period, followed by dosing at 25 mg daily (active or placebo pill), provided either QD or BID in a blinded fashion. Patients were then escalated weekly to 50, 100 and finally 200mg daily, or until dose-limiting toxicity became evident. The four weeks of dose escalation was followed by eight weeks of stable dosing. During the 14-week study, participants were asked to carry an electronic diary and record pain, fatigue, sleep and quality of life information. The custom designed diary captured spontaneous pain data in several ways including: (a) random daily prompts (the device notified the patient to record their current level of pain 4-5 times per day), (b) a daily prompt in the morning querying about the previous 24-hours’ pain and (c) a weekly report asking about the patient’s average pain for the past seven days. The electronic assessments were supplemented with traditional recording of weekly average pain during clinic visits at baseline and weeks 10 and 14. Since pain amplification as a result of “central sensitization” has been reported in FMS, as well as in other FSS a novel Applied Pain Threshold Tester (APT2) apparatus was developed, and patients’ evoked pain to pressure stimuli were monitored at baseline, and after 4 and 8 weeks of treatment. This study of milnacipran as a new therapy for the treatment of the pain associated with FMS represents the first in a series of studies within the FSS spectrum of disorders. Additional studies are planned to assess the efficacy of milnacipran on depressed mood within the context of FMS and related chronic pain states.

National Fibromyalgia Research Association
Neurology and New Treatment Modalities in Fibromyalgia
Sympossium – Portland, Oregon – October 2002