January, 2008, the US FDA href="http://www.frx.com/news/PressRelease.aspx?ID=1244788">approved
milnacipran for use in treatment of href="http://www.med.umich.edu/painresearch/pro/fibromyalgia.htm">fibromyalgia.
It is ( or soon will be) available in tablets of 12.5, 25, 50, and
100mg. It has been marketed as an antidepressant in Europe for
years, but has not been available in the USA until now.
Milnacipran is a drug that inhibits reuptake of serotonin and
norepinephrine. The effect on norepinephrine is stronger than the
effect on serotonin. It can be thought of as an SNRI, is the same
family as venlafaxine (Effexor), duloxetine (Cymbalta) and
From the Savella package
insert (PDF), I’ve copied the dosing guidelines below. Note
that the initial dosing guidelines often are not quite right; it takes
experience in a larger population to figure out the best dosing.
The titration schedule, as proposed, has the potential to be
troublesome. It is likely that they will distribute dose-packs to
make the titration easier to follow.
• Administer Savella in two divided doses per day
• Begin dosing at 12.5 mg on the first day and increase to 100 mg/day
over a 1-week period (2.1): Day 1: 12.5 mg once Days 2-3: 25 mg/day
(12.5 mg twice daily) Days 4-7: 50 mg/day (25 mg twice daily) After Day
7: 100 mg/day (50 mg twice daily)
• Recommended dose is 100 mg/day
• May be increased to 200 mg/day based on individual patient response
For milnacipran, the kinetics are as follows: oral bioavailability is
85-90%; the extent of absorption is not affected by food; half-life is
6-8 hours; 55% percent is excreted unchanged in the urine. Note
that the active enantiomer, d-milnacipran, has a longer elimination
half-life (8-10 hours) than the l-enantiomer (4-6 hours). Small
percentages of the parent drug are metabolized by desethylation
(N-desethyl milnacipran, 8%) and glucuronidation (d- and l-milnacipran
carbamoyl-O-glucuronide, 2% and 17%, respectively). Plasma
protein binding is 13%. No dosage adjustment is needed for mild
renal impairment, or for mild to moderate hepatic impairment.
Cmax and area-under-the-curve are 30% higher for persons over 65, and
20% higher for women, but no dosage adjustment is necessary.
Milnacipran did not inhibit or induce any of the cytochrome P450
enzymes listed in the PI.
Savella carries a black-box warning about suicidality, based upon its
similarity to other SNRI. This is addressed in href="http://www.savella.com/SavellaMedicationGuide.pdf">this
Medication Guide (PDF).
What role will milnacipran have in the armamentarium of available
treatments? As it happens, a meta-analysis was published in JAMA
a couple of weeks ago: href="http://jama.ama-assn.org/cgi/content/abstract/301/2/198">Treatment
of Fibromyalgia Syndrome With Antidepressants: A Meta-analysis (JAMA.
2009;301(2):198-209) Only the abstract is openly
accessible. There’s a href="http://cme.medscape.com/viewarticle/587044">summary
available on Medscape (free registration) that contains more detail
than the abstract:
The researchers found that amitriptyline had a large effect
on reducing pain, fatigue, and sleep disturbances, a small effect on
HRQOL, and no significant effect on mood.
In addition, they found that the SSRIs fluoxetine and paroxetine had a
small effect on reducing pain and improving HRQOL but had no effect on
fatigue or sleep.
SNRIs duloxetine and milnacipran had a small effect on reducing pain
and sleep disturbances, and duloxetine had a small effect on improving
mood and HRQOL, but no effect on fatigue.
The MAOIs moclobemide and pirlindole had a small effect on pain
reduction. Moclobemide had no effect on sleep or fatigue, and
pirlindole did not affect depressed mood.
HRQOL=health-related quality of life.
Only one study of milnacipran was included in the analysis, so there is
a lot of information that was not included. Plus, the
meta-analysis isn’t ideally suited to compare one drug against the
others. The bottom line, though, is that amitriptyline appeared
to have the biggest effect. Unfortunately, amitriptyline is more likely than
the others to have burdensome adverse effects. Amitriptyline is
inexpensive, $4/month in some places. I don’t know what
milnacipran will cost, but it will be a lot more than $4/month.
Some additional perspective can be gained from
interview with a fibromyalgia expert, href="http://www2.med.umich.edu/departments/internalmedicine/index.cfm?fuseaction=intmed.facultyBio&individual_id=107925">Daniel
J. Clauw, MD:
Q: Do you have a standardized treatment protocol for your
Dr. Clauw: I use a combination of low-impact aerobic exercise,
symptom-based pharmacologic therapy, and cognitive behavioral therapy.
Not all patients need all three.
I usually begin by prescribing medications to target the two or three
most prominent symptoms that a patient has. In most cases pain is one,
but poor sleep, fatigue, memory problems, or other symptoms sometimes
interfere more with function than pain.
I only use one treatment at a time, and see if it works before deciding
whether to continue with the treatment, or discard it. One of the
biggest problems I see in practice is that doctors and patients try too
many things at once, and then they have limited ability to tell if
something is working, or whether a new symptom is a side effect of a
After I find the correct one or two medications to reasonably control
many of the symptoms, then I will add aerobic exercise, and sometimes
cognitive behavioral therapy (CBT). Both exercise and CBT can either be
done simply (with simple instructions for exercise or a workbook or
Arthritis Foundation course for CBT) or with more professional guidance
(e.g., with a physical therapist, personal trainer, social worker, or
These treatments take many months to work (in contrast to medications,
which usually work within a month or so if they are going to work at
all), but the benefits are more durable than the benefits obtained from
Clauw goes on to discuss specific drugs, but milnacipran is not
included, since the interview is from 2007.
The main points from the interview: patients often have to try several
different medications or combinations, and the medication is only part
of the overall treatment. There is no single treatment that
stands out as clearly superior, and there is no single treatment that
eliminates the need for multimodal intervention. In such a
situation, it is always nice to have another option. In my view,
milnacipran is exactly that: another option. Probably it will be
a great thing for some people, pretty good for others, so-so for some,
and worthless for others.