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10 Articles in Volume 9, Issue #4
Application of Spinal Segmental Physiology to Evaluating Chronic Pain
Dental Consequences of Pain Management
Facility Profile: Casa Palmera
Intellectual and Moral Tasks in Intersection—Part 2
Milnacipran: A New Treatment Option for Fibromyalgia
Neuroma Pain of the Foot Successfully Managed with Laser Therapy
Opioid Treatment Longevity Study: Interim Report
Pain Management in a Palliative Care Setting
Precursor Amino Acid Therapy
Prolotherapy for Sacroiliac Joint Laxity

Milnacipran: A New Treatment Option for Fibromyalgia

On January 14, 2009, the Food and Drug Administration approved the use of SavellaTM (milnacipran) for the treatment of fibromyalgia. This third approved drug offers health care providers yet another treatment option for their fibromyaliga patients. Dr. Philip Mease’s detailed article covers the scientific specifics of Savella’s efficacy in a fibromyalgia treatment regimen and offers the promise of a better quality of life for people living with this chronic pain condition.

On January 14, 2009, milnacipran (SavellaTM, Forest Pharmaceuticals, Inc.) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of fibromyalgia (FM), a chronic disorder that affects an estimated 2%-4% of the US population and primarily occurs in women.1,2 The approval of milnacipran represents continued progress in the development of medications to manage this disorder. This approval was based on the results of several large clinical trials, using novel composite endpoints that demonstrated the benefits of milnacipran for not only pain, but also the patient’s overall fibromyalgia experience and function. The drug has been generally well tolerated. Detailed discussion of the drug’s pharmacology, efficacy, and safety data is provided. The FDA approval of milnacipran (SavellaTM) for the treatment of fibromyalgia is a welcome development. Milnacipran joins two other medications approved for the management of FM: pregabalin (Lyrica®, Pfizer, Inc.) and duloxetine (Cymbalta®, Eli Lilly & Co.).

In 1990, the American College of Rheumatology (ACR) published classification criteria for FM that were based on the symptom of chronic widespread pain.3 These criteria require the presence of pain for at least 3 months in all 4 quadrants of the body, as well as the presence of pain in 11 of 18 tender points upon digital palpation. Although the ACR criteria have been adapted by researchers and physicians, their usefulness in clinical practice may be limited.2,4 One major limitation is that the criteria focus on pain and do not address the other symptoms of FM, thereby failing to capture the complexity of this disorder. As reported in an internet survey of FM patients that was conducted in collaboration with the National Fibromyalgia Association (NFA),5 other common symptoms include stiffness, fatigue, sleep problems, cognitive dysfunction, anxiety, and depressed mood.

The importance of assessing the multiple symptoms of FM in clinical research is being addressed by the working group of Outcome Measures in Rheumatology (OMERACT). Patients and clinician-investigators achieved consensus on key domains to be assessed in clinical trials of FM, such as pain, fatigue, impaired multidimensional function, sleep disturbance, cognitive dysfunction, mood disorder, stiffness, and tenderness.6,7 In collaboration with the World Health Organization’s (WHO) International Classification of Functioning Disability and Health (ICF) and the US National Institutes of Health’s Patient Reported Outcome Measures Information System network (PROMIS), work is under way to develop more specific and sensitive instruments to measure these symptom domains and to demonstrate change with effective therapy. One method currently on the OMERACT agenda is the use of a composite responder index, which can simultaneously assess clinically-meaningful improvements in pain and other FM-associated symptoms in one outcome.6 In contrast to outcomes that only allow for comparisons among treatment groups in a single domain (e.g., pain scores, patient global changes, or function), composite responder rates identify the proportion of individual patients in a treatment group who experience simultaneous improvements in multiple domains.6,8 The phase three clinical trials of milnacipran used composite responder analyses as primary endpoints, pioneering this approach in FM.

Milnacipran is a dual norepinephrine and serotonin reuptake inhibitor and has an approximately three-fold greater potency for norepinephrine reuptake inhibition over that of serotonin.9 These neurotransmitters have been found to mediate endogenous analgesic mechanisms through descending pain inhibitory pathways in the brain and spinal cord.10 In animal models of pain, milnacipran and other dual reuptake inhibitors of norepinephrine and serotonin that augment the effects of these neurotransmitters have shown analgesic effects, whereas agents that augment just serotonin—such as selective serotonin reuptake inhibitors—exhibited little or no effect.11 Such results highlight the importance of norepinephrine in the modulation of pain.12 In clinical studies, patients with FM were found to have decreased cerebral spinal fluid (CSF) levels of norepinephrine and serotonin metabolites.13 Therefore, dysfunction of the norepinephrine and serotonin systems may be a potential mechanism for the pain experienced by FM patients.14-17

Milnacipran Clinical Studies

The first study of milnacipran was a Phase 2 dose escalation trial in which 125 patients meeting the 1990 ACR criteria for FM were randomized to receive placebo (n=28), milnacipran 200mg/day once-daily (n=46), or milnacipran 200mg/day in divided doses (n=51) for 12 weeks.18 Results showed that milnacipran 200mg/day—dosed twice daily—was more effective than once-daily dosing in improving pain and multiple other symptoms such as fatigue and physical function.

Results from two Phase 3 pivotal trials of milnacipran were the basis of US FDA approval.19,20 In both of these trials, 2-measure and 3-measure composite responder rates were used as primary efficacy endpoints. For the 2-measure composite responder, individual patients were required to have concurrent improvements in pain and global status, as defined by the following criteria: ≥30% improvement from baseline in 24-hour recall pain scores (recorded on electronic diaries) and a score of 1 (“very much improved”) or 2 (“much improved”) on the Patient Global Impression of Change (PGIC) (see Figure 1). For the more stringent 3-measure composite responder, patients were required to meet the above criteria for simultaneous improvements in pain and PGIC, as well as improvements in physical function, defined as a ≥6-point improvement from baseline in the Short Form-36 Health Survey (SF-36) Physical Component Summary (PCS) score. Secondary outcome measures in the milnacipran FM pivotal trials included assessments for weekly recall pain, real-time pain, physical and mental function (Fibromyalgia Impact Questionnaire [FIQ], SF-36), fatigue (Multidimensional Fatigue Inventory [MFI]), and cognition (Multiple Ability Self-report Questionnaire [MASQ]).

Figure 1. The 2-measure and 3-measure composite responder endpoints used in milnacipran clinical trials of FM. Composite responder analyses were conducted in each individual patient.

The first milnacipran pivotal trial was a 27-week study that enrolled 888 FM patients who were randomized to placebo (n=223), milnacipran 100mg/day (n=224), or milnacipran 200mg/day (n=441).19 Efficacy was evaluated at both 15 and 27 weeks in this study. Composite responder results from this trial demonstrated the benefits of milnacipran in treating the multiple symptoms of FM. In observed cases at the 15-week endpoint, a significantly higher proportion of patients in the milnacipran treatment groups met the 2-measure composite criteria than in the placebo group: placebo, 27.2%; milnacipran 100mg/day, 45.2% (P=0.003); milnacipran 200mg/day, 45.4% (P≤0.001). Significant differences between milnacipran and placebo-treated patients were also observed for the 3-measure composite responder analysis: placebo, 17.3%; milnacipran 100mg/day, 32.8% (P=0.003); milnacipran 200mg/ day, 32.8% (P<0.001).

At the 27-week endpoint, a significantly greater proportion of milnacipran-treated patients met the 2-measure composite responder criteria compared to those receiving placebo: placebo, 27.9%; milnacipran 100mg/day, 43.8% (P=0.021); milnacipran 200mg/day, 45.2% (P=0.001).19 For the 3-measure composite responder analysis, response rates were higher with both doses of milnacipran compared to placebo, with significantly greater improvements in the milnacipran 200mg/ day group compared to placebo: placebo, 19.4%; milnacipran 100mg/day, 33.3% (P=0.056); milnacipran 200mg/day, 31.9% (P=0.017). A significant reduction in 24-hour recall pain was found after 1 week of treatment with milnacipran (both doses, P<0.01 vs placebo). Significant results with milnacipran (P<0.05 vs placebo) were also observed in other outcome measures of pain, function, fatigue, and cognition.

The second milnacipran pivotal trial was a 15-week study that enrolled 1196 FM patients who were randomized to receive placebo (n=401), milnacipran 100mg/day (n=399), or milnacipran 200mg/day (n=396).20 At 15 weeks, the proportion of patients meeting the 2-measure and 3-measure composite responder criteria was significantly higher with both doses of milnacipran vs placebo (see Figure 2). The proportion of patients with ≥30% improvement in pain, a threshold that is commonly used to define clinical benefit,21 was significantly higher with milnacipran compared to placebo. In observed cases, clinically meaningful improvements in 24-hour recall pain were found in 52.3% and 54.8% of patients receiving milnacipran 100 and 200mg/day, respectively, compared to 38.4% of patients receiving placebo (both doses, P≤0.01 vs placebo). Significant decreases in 24-hour recall pain were observed as early as week one of treatment for both doses of milnacipran, with significant pain relief sustained through the end of this three-month study (all weeks for both doses, P<0.05).

Figure 2.Percentage of FM patients in a 15-week trial of milnacipran (N=1196)20 meeting 2-measure and 3-measure composite responder criteria at end of study, based on observed cases.

The proportion of patients with clinically meaningful global improvements (i.e., rating of “very much improved” or “much improved” on the PGIC) was also significantly higher with milnacipran vs placebo.20 In observed cases, these PGIC responder rates were 47.5% and 50.6% for milnacipran 100mg/day and 200mg/day, respectively, compared to 31.8% for placebo (both doses, P≤0.001). Significant results with milnacipran were found in other outcome measures, including: FIQ total score (both doses), SF-36 PCS (100mg/day) and SF-36 Mental Component Summary (200mg/day); fatigue (MFI total score, both doses), cognition (MASQ total score, 200mg/day), Beck Depression Inventory (200mg/day), and Multidimensional Health Assessment Questionnaire disability subscale score (both doses) (all measures, P<0.05).

Another Phase 3 study of milnacipran in FM patients was conducted in Europe.22 This study enrolled 884 patients who were randomized to placebo (n=449) or milnacipran 200mg/day (n=435). After 12 weeks of stable-dose treatment, significant differences between milnacipran 200mg/day and placebo were observed in two key primary endpoints: the 2-measure composite responder rate (P=0.0003) and FIQ total score (P=0.015). Improvements in pain, fatigue, mental and physical function, and cognition were also observed.

Preliminary results from a 6-month extension study23 of the 27-week pivotal trial19 have also been presented. This study included a total of 449 FM patients who successfully completed the 6-month lead-in study. Patients receiving milnacipran 200mg/day during the lead-in study were maintained at the same dose in the extension study; patients initially assigned to placebo or milnacipran 100mg/day were re-randomized to milnacipran 100mg/day or 200mg/day. Results showed that patients receiving 12 months of milnacipran treatment had persistent improvements in pain, FIQ, and PGIC scores. Further improvements were also observed in patients switched from placebo to milnacipran. These results confirm the efficacy of milnacipran in FM patients and indicate a durable therapeutic response for up to 1 year.

Milnacipran Safety and Tolerability

Treatment with milnacipran 100 or 200mg/day for up to one year was found to be well tolerated in patients with FM.18-20,23 In the three placebo-controlled US clinical trials (N=2209),18-20 the most frequently reported adverse event was nausea. The other most common adverse reactions occurring at an incidence >5% and greater than placebo were headache, constipation, insomnia, dizziness, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, migraine, dry mouth, and hypertension.24 Adverse events were generally mild to moderate in severity. Nausea tended to be dose-related and generally resolved within one to two weeks of continued therapy.19 Rates of discontinuation due to adverse reactions were 12%, 23%, and 26% for patients treated with placebo, milnacipran 100mg/day, and milnacipran 200mg/day, respectively.24 Discontinuation due to adverse events was generally more common in patients receiving the higher dose.

Similar to the clinical experience with other norepinephrine and serotonin reuptake inhibitors, some patients receiving milnacipran experienced increases in blood pressure and heart rate.25 In the US placebo-controlled trials, treatment with milnacipran was associated with mean increases in supine blood pressure (up to approximately 3 mm Hg) and heart rate (approximately 7-8 beats per minute).24 Patients receiving milnacipran 100 or 200mg/day for up to three months experienced a mean weight loss of approximately 0.8 kg (1.8 lbs), compared to a weight loss of approximately 0.2 kg (0.4 lbs) in patients receiving placebo.24

Pharmacology

Preclinical studies have shown milnacipran to be a potent inhibitor of norepinephrine and serotonin reuptake, resulting in the augmentation of the effects of these neurotransmitters at the neuronal synapse.9,24 In vitro, it has an approximately three-fold greater preference for inhibiting norepinephrine reuptake over serotonin reuptake, with minimal or no effect on the reuptake of dopamine or other neurotransmitters. Milnacipran has shown no significant affinity for adrenergic, serotonergic, muscarinic, histaminergic, dopaminergic, opiate, benzodiazepine, or gamma-aminobutyric acid (GABA) receptors in vitro.25

Milnacipran is rapidly absorbed after oral administration, reaching peak plasma concentrations within 2 to 4 hours post dose; steady-state levels are reached within 36 to 48 hours.24,26-28 The absolute bioavailability of milnacipran is high (85%-90%). The terminal elimination half-life is six to eight hours, which is compatible with the twice-daily dosing indicated for FM management. Milnacipran absorption is unaffected by food, and the drug is excreted primarily unchanged in urine (55%). The low protein binding (13%) of milnacipran, along with its low degree of hepatic metabolism27 and minimal effect on the cytochrome P450 system,29 suggest a low potential for pharmacokinetic drug interactions. Pharmacodynamic interactions with other drugs can occur.

Prescribing Information

The recommended dose of milnacipran for the management of FM in adults is 100mg/day (50 mg twice daily), although the dose may be increased to 200mg/day (100 mg twice daily) based on individual patient response.24 A seven-day dosing titration schedule is suggested, beginning with a single dose of 12.5 mg on day one. Patients with mild renal impairment or hepatic impairment do not require dose adjustment, although caution should be exercised in patients with severe hepatic impairment. It is recommended that milnacipran not be abruptly discontinued after extended use.

Milnacipran is contraindicated in patients with uncontrolled narrow angle glaucoma and those taking monoamine oxidase inhibitors (MAOIs). It is similar to some drugs used to treat depression and other psychiatric disorders, and it may increase the risk of suicidal ideation, thinking, and behavior in children, adolescents, and young adults. Milnacipran has not been approved for use in pediatric patients. Development of serotonin syndrome may occur with agents that inhibit serotonin reuptake, including milnacipran, particularly with concomitant use of serotonergic drugs (including triptans and tramadol) and with drugs that impair serotonin metabolism (including MAOIs). Concomitant use with centrally-acting medications, as well as cardiac or blood pressure medications, is also cautioned.

Increases in blood pressure and heart rate have been reported with milnacipran, and these vital signs should be monitored in patients starting and receiving treatment. Like other drugs that inhibit serotonin reuptake, milnacipran may increase the risk of abnormal bleeding. Patients should be cautioned about concomitant use of milnacipran with medications that affect coagulation, such as aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).

Conclusions

Clinical trials have shown that milnacipran treatment for up to one year is tolerable and effective in adult patients with FM. In some patients, improvements in pain were observed as early as week one of treatment, with pain relief sustained throughout the 15-week,20 27-week,19 and 6-month extension23 studies (one year total).

Although chronic pain is a key characteristic of FM, other symptoms that impact a patient’s every day life must be considered when prescribing medications to treat this disorder.

Important symptoms such as fatigue, cognitive difficulties, impaired physical function, and disturbed sleep can have a negative impact on a patient’s quality of life. Because many patients take concurrent medications to alleviate the multiple symptoms and comorbid disorders associated with FM, it is important that pharmacotherapies have a low potential for drug-drug interactions. Based on its pharmacokinetic profile, milnacipran appears unlikely to interact with several medications commonly used by FM patients, but pharmacodynamic interactions are still possible. In addition, clinical trial results indicate that milnacipran is not commonly associated with sedation, cognitive impairment, or weight gain, and that it does not adversely affect sleep. This safety profile suggests that milnacipran is unlikely to exacerbate common FM symptoms, such as fatigue, weight gain, and somnolence.

A therapeutic approach to FM would ideally address multiple symptom domains. In the milnacipran clinical studies, 2-measure and 3-measure composite responder endpoints were used to assess whether individual patients experienced simultaneous improvements in multiple symptom domains. Composite responder results from the two pivotal US studies and the European study demonstrate that a higher proportion of milnacipran-treated patients have concurrent improvements in pain and other symptoms, compared to those receiving placebo. These results, along with improvements in other efficacy outcomes such fatigue, cognition, and multidimensional functioning, indicate milnacipran’s beneficial effect. The approval of milnacipran for FM represents a welcome advance in the development of effective therapies.

Disclosure

Dr. Mease did not receive any financial support for this article. Editorial support was provided by Prescott Medical Communications Group, Inc.

Last updated on: December 13, 2011
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