Milnacipran (brand names: Savella, Ixel) is the third and last drug the FDA approved for the treatment of fibromyalgia in the United States. The fourth serotonin–norepinephrine reuptake inhibitor (SNRI), to be introduced in the U.S., Savella stops the reuptake of serotonin and norepinephrine in the nerves synapses – making more of those neurotransmitters available to the central nervous system. Savella is the most “balanced” SNRI in that it increases serotonin and norepinephrine equally. Unlike other SNRI’s it does not affect dopamine levels.
SNRI’s are usually considered antidepressants (although they are also often used to treat anxiety, obsessive compulsive disorder and ADHD) but two SNRI’s, Savella and Cymbalta (Duloexetine) have also been shown to be effective in treating chronic pain in some patients without mood disorders.
Several kinds of antidepressants (including TCA’s), in fact, are now commonly used to treat many kinds of pain including arthritis, central pain syndrome, fibromyalgia, low back pain, migraines, nerve damage from diabetes (diabetic neuropathy), and nerve damage from shingles (postherpetic neuralgia). Lower doses than used in depression are usually sufficient.
Different nerve pathways in the central nervous system can promote or inhibit pain. Reduced activity of the pain inhibition circuits appears to be the major problem in FM. The pain reducing circuits originating in the brainstem are loaded with neurons that respond to serotonin and norepinephrine. By increasing serotonin or norepinephrine levels, antidepressants may be reinvigorating the pain inhibiting circuits in the brainstem – thus lowering pain levels.
Antidepressants may also block receptors (histamine, NMDA, a-adrenergic) involved in pain processing, effect ion channel activity, (weakly) stimulate opioid receptors and may even affect immune regulation. Some recent animal model evidence suggests that Savella and similar drugs may enhance the effectiveness of microglial inhibitors such as minocycline.
It’s possible, even likely, that nerve pain and depression have an overlapping pathophysiology. Similar neurotransmitters, HPA axis, autonomic nervous system and immune alterations can be found in each.
The Savella Fibromyalgia Story
Savella has been the least of the big three drugs for FM. Cymbalta has been FDA approved for six conditions in the U.S., Lyrica for four and Savella for only one. Cymbalta is expected to challenge Lyrica for the top FM drug in sales, with Savella far, far behind.
Savella’s approval record is rather mixed, as well. Savella is FDA approved for treating fibromyalgia but not depression. Rather confusingly, it is not approved for fibromyalgia in Europe but is widely used for depression. It is approved for treating FM in Australia.
One of the advantages of getting FDA approval for a drug is that the drug tends to get more study. Since 2009, Savella has sparked numerous studies, with increasing studies in the last couple of years.
A 2010 review indicated that Savella can be effective in managing pain and improving fatigue and cognitive dysfunction as well as depression.
Side effects were limiting, however, with almost 25% of patients dropping out of clinical trials because of them. (Twelve percent of patients taking the placebo dropped out.)
One milnacipran review noted that most side effects vanish after a week or two and that slowly uptitrating the drug helps. The doctors recommended starting with 12.5 mg once daily in the morning for one week, then increasing to 25 mg once daily in the morning for 2 weeks, and then 50 mg once daily in the morning. In some patients they may add a evening dose.
Because milnacipran is the only FDA approved FM treatment shown to improve symptoms of fatigue and cognitive dysfunction in phase 3 clinical trials, they recommended using it in patients with brain-fog problems. They also noted that “many patients who have previously failed to respond to either of the other two indicated medications can have an excellent therapeutic response to milnacipran.”
A 2012 Cochrane Review, however, was not quite as enthusiastic. It stated that the drug does provide moderate pain relief (30% reduction) in about 40% of patients, but that placebo provided about a similar reduction to about 30% of patients. (The placebo response rate in chronic pain tends to be high. A later analysis found that almost 20% of FM patients on placebo in 18 studies experienced a 50% in reduction in pain.) In contrast to placebo, though, studies indicate that milnacipran (or Savella or Ibex) does appear to maintain its effectiveness long term.
A 2012 study found that the presence or absence of depression had little effect on milnacipran’s effectiveness in FM; i.e., the drug was effective or not independent of whether a patient was suffering from depression. Milnacipran was also associated with some weight loss (in a rather overweight FM population) over two years of treatment.
A long term analysis of 3,000 FM patients over 11 years, however, found that the FDA approved drugs for FM provided little extra benefit compared to past treatments (NSAID’s and opioids). Interestingly, as the FDA drugs came on line, opioid use in FM continued to increase; almost 50% of FM patients were using mild to strong opioids (mostly mild) by the end of the study. As the use of tricyclic antidepressants such as amitriptyline dropped (27-15%), the proportion of patients who were using Lyrica or the FDA approved antidepressants by the end of the study rose dramatically (about 40%). The new drugs increased costs for the patients, but study found that the clinical benefits of the new drugs were limited with 2-5% reductions in pain and no increases in functionality.
A large three-year study, however, found that 70% of FM patients on milnacipran reported themselves “”much improved” or “very much improved”.
Meanwhile a quite small study found no significant differences in pain reduction or cognitive improvement between milnacipran and placebo. The home of the NIH institute for FM, the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) got into the act by funding a CBT/milnacipran study that found “moderate benefits” to combining the two therapies.
Doctors had earlier reported that milnacipran was often effective in some FM patients who didn’t do well on other FM drugs. That report was largely borne out in a 2013 study that found that 33% of patients who did not respond to duloxetine (Cymbalta) were classified as responders to Savella.
By 2013 the drug industry was clearly tiring of meta-analyses finding rather low clinical benefits to their drugs. Researchers associated with major drug companies penned a review suggesting that these analyses “do not always tell the full story” and that some benefits had been missed.
A large 2013 study continued the push-back from the drug industry. A large study lead by an Eli Lily researcher found that patients using FDA approved drugs or tricyclic antidepressants reported “satisfaction with overall treatment and their fibromyalgia medication (46.0% and 42.8%, respectively)”. They also reported “modest improvements” and high rates of medication use.
Attempts to broaden the reach of milnacipran ensued. It proved to be helpful in reducing the frequency of migraine and headache, two common issues in FM, in a 2014 study. A 2014 analysis of three studies found that milnacipran did indeed improve fatigue significantly (30% reduction in fatigue) in about 15-20% of patients. A meta-analysis, however, suggested Savella was no better than placebo at reducing neuropathic pain.
Finally, the first pediatric study of milnacipran in FM had mixed results. The trial – co-authored by Lucinda Bateman – suggested the drug may improve symptoms of FM in kids at about the same rate as it does in adults, but the authors had so much difficulty enrolling pediatric patients that the trial was halted early.
Targeting Patients That Benefit – the Next Step
People with FM have had mixed results on Savella. That’s true for all FDA approved drugs for FM (and probably for all the recommended treatments for it). Lyrica, in particular, has a bad reputation for side effects – including the dreaded weight gain. (For Savella nausea seems to be the biggest problem.)
Realizing they have a PR problem, drug companies are trying to fine-tune who they are giving their drugs to. A recent study “Is the efficacy of Milnacipran predictable?” may be a harbinger of what’s to come. An analysis of three large trials revealed that one subset of FM patient benefited the most from Savella. It found that FM patients with
- high pain intensity
- low anxiety or catastrophizing
- absence of major sleeping problems’
- and significant physical limitations in the daily life
did best. It suggested that if you have significant levels of anxiety (or catastrophizing), relatively low levels of pain and major sleeping issues you’re probably not going to benefit much from Savella. On the other hand, if you can get your anxiety and sleep under control – you might.
There are no magic bullets for FM but a 30-40% reduction in pain is nothing to sneeze at. People with fibromyalgia trying Savella might want to do two things
- consider whether you fit the above group
- if you don’t, take steps to alleviate any of the above factors that might keep you from benefiting from Savella
- use the very slow ramp up period suggested by the doctors (see above)
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