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Fibromyalgia Basics

Savella for Fibromyalgia
Input from Doctors & Patients

Approved by the Food and Drug Administration (FDA) for treating fibromyalgia in 2009, Savella (milnacipran) does not go off patent until 2029. Out of all your medication options, this drug is likely the most expensive, so you may ask: Is it worth the money to give it a try? Also, is there any way to determine if you might be a good candidate for trying Savella?

Like the other two FDA-approved drugs for fibromyalgia, Savella reduces pain in a minority of patients, but it has the potential to aid with fatigue. According to a 2021 report, the most likely candidates to reap benefits from this medication are fibromyalgia patients who do not have anxiety or problems sleeping.1 These two factors help determine who might be candidates for trying the drug, but they don’t predict if you will respond favorably to it.

The FDA trials enrolled people with mild cases of fibromyalgia who did not have any other painful medical condition, so the results may not apply to you. That’s why a survey of 503 “typical” patients who tried Savella might offer useful insight on how well it is tolerated. In addition, several doctors with experience using the drug offer advice.

How it Works

Savella works in the central nervous system to increase norepinephrine (NE) and serotonin at the nerve junction. It’s in the same class as duloxetine, a selective serotonin and NE reuptake inhibitor or SNRI. Basically, these drugs allow NE and serotonin to remain available at the nerve junction to be reused. Savella is believed to exert three times the amount of action on NE compared to serotonin (duloxetine is thought to affect these two transmitters equally). The increased action on NE may lead to relief of fatigue (and will prevent weight gain), but it also has the potential for more side effects.

When impulse signals from painful muscles enter the spinal cord, various centers in the brain release NE, serotonin, and opioids to tone down or filter out the pain inputs. These brain centers are not as active as they should be in fibromyalgia, so in theory patients may be helped by drugs that increase the action of NE and serotonin.

One study measured how well the pain inhibitory system worked in patients before and after taking Savella for one month, compared to patients taking a placebo.2 Twelve percent of the fibromyalgia patients on 100 mg/day of Savella showed a measurable improvement in the function of their pain inhibitory system. Perhaps more patients would have responded favorably to the drug if the trial had been longer, but this doesn’t explain why the drug fails to benefit most patients.

What You Should Know

The clinical trials supporting Savella’s FDA approval for fibromyalgia tested two daily doses: 100 mg and 200 mg. Due to the drug’s quick elimination from the body (half of it is gone in 6-8 hours), Savella must be taken in two equally divided portions a day.

In the trials, roughly 20 percent of the patients taking Savella (either dose) were deemed responders, compared to 12 percent in the placebo group.3 This is a small margin of difference. Fatigue, cognition (fibrofog), and mood also improved for those taking the drug.

The idea of titrating from the lowest dose of 12.5 mg is to allow the body to build up tolerance to the drug’s side effects. Robert Ettlinger, M.D., of Tacoma, WA, says, “I find the ‛start low, go slow’ approach to dose increases is a good idea, although the studies ramped up the medication quite quickly. By titrating slowly, I have discovered that many patients do well on 25 mg twice a day. Why push the dose up over days or weeks and possibly get into side-effect trouble when most patients have had the disease for years and can gradually adjust to the medication over months?”

What are the most common side effects of Savella? “The nausea is the biggest problem with this drug,” says Daniel Clauw, M.D., of the University of Michigan at Ann Arbor, and adds: “This is a class effect, as duloxetine has the same issues. The nausea is better if people take it with plenty of food, and it often resolves within a few weeks.”

Can it Help You?

Roughly one-fourth of the 503 patients surveyed who had tried Savella rated the drug as beneficial for treating both pain and fatigue. Eighty percent of the survey participants were at a dose of 100 mg/day or less.

The greatest factor predicting a person’s response to Savella had to do with the severity of side effects to the drug. Patients who experienced either mild or no side effects were four times more likely to benefit from Savella than those patients who felt they had to quit the drug due to intolerable side effects.

Many of the patients surveyed said that the titration recommendations to increase to the target dose were too aggressive, and in hindsight, this could lead to more side effects. So, for anyone who wishes to try Savella, the advice that follows ought to make it a smoother experience.

Minimizing the Side Effects

“In my experience, about 75 percent of patients tolerate the drug with little or no nausea,” says Kevin Hackshaw, M.D., now at University of Texas in Austin, who treats lots of fibromyalgia patients. “When patients encounter this side effect, it can be severe (surpassing that of duloxetine).”

“If tolerated, a three-week titration period is required as a minimum and may need to be expanded to six weeks to build tolerance to the side effects. Major symptom improvement may be seen as soon as one week in most cases. In a smaller subgroup (10-25 percent), patients may need to go through the entire titration period, and even dose up further to 100 mg twice daily to reap the desired efficacy.”

Many of the side effects caused by Savella might be manageable by altering the way you take this drug, but not always.

Nausea – Savella is best taken on a full stomach (not just milk and cookies) and the nausea may still persist. “Some patients have found that they get benefit from the drug at 25 mg twice daily with less nausea,” says Hackshaw. “Although these patients may get more efficacy at 50 mg or 100 mg twice daily, they are unable to tolerate the degree of nausea.”

Kenneth Miller, M.D., a clinical trial expert in Danbury, CT, has patients with similar experiences. “Patients may get to the 25 mg twice daily for a few days but encounter more GI symptoms. They should stay at this dose until the GI symptoms improve, then increase the evening dose to 50 mg for one week and then 50 mg twice daily.”

Another approach is offered by Kim Jones, Ph.D., FNP, now at Emory University in Atlanta. “Start by taking a 12.5 mg tablet with the evening meal, only once daily.” There is no reason why you can’t titrate up in smaller increments to improve tolerability.

Sweating and Hot Flush – “These symptoms are not unique to Savella, they occur with duloxetine as well,” says Luis Torregrosa, M.D., who treats lots of fibromyalgia patients in Dearborn, MI. “There are no effective therapies for the sweating side effect.”

Lawrence Robbins, M.D., a neurologist in Northbrook, IL, agrees with Torregrosa and adds, “Sweating is one of the side effects that may not reduce with continued use.”

Dizziness – “This symptom tends to get better over three months of continued use,” says Ettlinger. To get through this acclimation period, Hackshaw suggests omitting the morning dose and only take Savella in the evening for a week before trying it twice daily again. You can even get creative with dosing (off label), taking the bulk of the drug in the evening because when you go to bed, this symptom is usually not an issue.

Headaches – “This symptom appears to be dosage-related, and reducing the dose in the morning may minimize headaches,” says Hackshaw. He also suggests that omitting the morning dose for a week sometimes helps. “If headaches increase,” says Robbins, “Savella usually has to be discontinued. It is not a good idea to treat the side effects of one drug with another drug unless we can’t help it.”

Nervousness/Anxiety – “The anxiety initially experienced on Savella often lessens with continued use,” says Robbins. However, he adds that if a person already has moderate anxiety or serious insomnia problems, this drug may not be a great choice. Ettlinger suggests lowering the dose for a period of time to see if tolerance develops.

Palpitations (pounding heart) – “This symptom can occur with any medication that increases NE,” says Robbins. “It depends upon how annoying or severe the palpitations are, but in general it may signal the need to discontinue the drug.” Hackshaw agrees, especially if the symptom persists at the 12.5 mg dosing. “Palpitations are usually dosage-related and don’t go away unless the dosage is decreased or the drug is stopped.”

Worsening of Sleep – Jones suggests that you cut your evening dose in half (off label). “If this still doesn’t work, add Lyrica at bedtime. If you still aren’t sleeping, add a sleep medication.” A strategy endorsed by the fibromyalgia patients surveyed (most of whom were already on a sleep med) was to take the evening dose at least six hours before bedtime.

Signs of Trouble

Savella should probably be discontinued when the following symptoms persist at the lowest dose beyond two weeks: nausea, headaches, palpitations, and sweating. If the nausea leads to regular vomiting, Miller recommends discontinuing the drug. He also says that tachycardia (rapid heartbeat) and hypertension (significantly elevated blood pressure) are also signs that this drug is not for you.

Depression/Irritability – “Although Savella was not approved by the FDA for the treatment of depression in the U.S., it is an antidepressant and carries a black box warning about suicidal thoughts that is the same for other antidepressants,” says Lesley Arnold, M.D., a psychiatrist and clinical trial expert at the University of Cincinnati in Ohio. “A worsening of mood or suicidal thoughts while taking Savella should prompt patients to contact their doctor immediately and they will probably have to discontinue the drug.” Arnold also brings up an important but delicate subject: bipolar mood disorder.

If a person experiences worsening of mood on an antidepressant, especially agitation or severe irritability, Arnold says that these may be signs that a patient may need to be evaluated for bipolar disorder. The recommended medications for this illness are different, and patients should be aware of the possibilities, says Arnold, so that “alternatives to antidepressants can be considered for both pain and mood treatment.”

Robbins suggests that some people with bipolar may be able to tolerate Savella as long as they are also on a mood stabilizer such as lamotrigine (Lamictal).

Drug Interactions

Most medications you take are broken down by enzymes in your liver so that your body can eliminate them. Only a small portion of Savella is processed through the liver and it has no effect on your liver enzymes.4 So even if you are taking multiple medications, you need not worry about Savella causing serious drug interaction. You do, however, have to limit your exposure to medications that increase serotonin because too much of this transmitter leads to a toxic condition called serotonin syndrome.

Before you begin taking Savella, you will probably have to discontinue or at least start lowering the dose of selective serotonin reuptake inhibitors (SSRIs) and other potent serotonin boosting drugs. If you are on duloxetine, Arnold says it is possible to taper off the dose of duloxetine while slowly titrating up the dose of Savella. Robbins says the triptan class of drugs used to treat migraines could produce a serious reaction. The point is, you only need to discontinue (or taper) serotonin enhancing drugs, but you can stay on other medications that do not alter this chemical.

1. Gupta H, et al. Health Psychol Res 9(1), 2021.
2. Pickerin G, et al. Drug Des Dev Ther 12:2485-2496, 2018.
3. Mease PJ, et al. J Rheumatol 36:398-409, 2009.
4. Puozzo C, et al. Clin Pharmacokinet 44:977-88, 2005.