The Corpus Callosum

i-22e6238bf526fb40e50fcb7425d97c62-150px-Milnacipran.svg.pngOn 14
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
desvenlafaxine (Pristiq). 

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 href="http://www.prohealth.com/library/showarticle.cfm?id=3854&t=CFIDS_FM">this
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
FM patients?

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
treatment.

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
psychologist).

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
medications.

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. 

Comments

  1. #1 Dave Gill
    January 26, 2009

    How does this new drug fit into the mix with Cymbalta and Lyrica? My wife currently takes both. The Lyrica helped immediately – though there is still room for improvement. Does this replace Cymbalta or supplement it?

    Thanks!
    Dave

  2. #2 Joseph j7uy5
    January 26, 2009

    It would not be added to Cymbalta; it would be a replacement. I can’t comment on any one persons specific situation. In general, it is a real judgment call as to whether it would make sense to replace a existing drug, if there have been positive results. The new drug could be better, could be worse, could be the same. So you would want to know ahead of time how you are going to compare the two. Presumably, this would be with diaries and rating scales of some sort. Also, you would also want to make sure that the Cymbalta had been given for a long enough time, at a high enough dose, to be sure that the maximum response has been observed, before considering a trial of something else.

  3. #3 Neuroskeptic
    January 27, 2009

    So it’s basically me-too-Venlafaxine?

  4. #4 Joseph j7uy5
    January 27, 2009

    Venlafaxine has a greater effect on serotonin than on norepinephrine; it gains the norepi effect only at higher doses. Duloxetine is somewhere in the middle. Milnacipran has a greater effect on norepi across the dosage range. Atomoxetine, for what it’s worth, affects only norepi.

    Do we really need milnacipran? Probably not. I always appreciate having another option, but this drug was not high on my wish list. I suspect that the only reason it was submitted to the FDA is to eke out a bit more profit from a drug that already had been developed.

  5. #5 Derf115
    February 18, 2009

    Can you tell me the Ki Values for Savella for both Serotonin and Norepi?

  6. #6 Linda
    March 18, 2009

    How much will Savella (generic) cost?

  7. #7 Dr. Miguel Alejandro De León
    March 24, 2009

    I am psychiatrist at the National Hospital for Mental Health in Guatemala, besides teach at the postgrade of psychiatry, and I am very interested in your articles.

  8. #8 PAT BAKER
    May 5, 2009

    WHERE CAN I PURCHASE MILNACIPRAN/SAVELLA? I HAVE A PRESECRIPTION FOR THE MEDICINE BUT, MY PHARMACY HAS BEEN UNABLE TO LOCATE THE DRUG. IT WAS MY UNDERSTANDING THAT IT WAS TO BE AVAIABLE IN LOCAL DRUG STORES THE FIRST PART OF MARCH, 2009. ANY HELP WILL BE APPRECIATED. PAT BAKER

  9. #9 Joseph j7uy5
    May 5, 2009

    It does not appear to be available anywhere, yet. I think all you can do is wait.

  10. #10 Dawn Carnes
    June 6, 2009

    I am currently being weaned off of Lyrica and have a script for Savella. I have read information that this drug is also helpful in Lupus as well as Fibromylagia. I was diagnosed with dysautonomia as well and I am really hesitant to start another drug regimen. I am also concerned about using this medication in light of other medications that I currently take, namely digoxin,and Inderal to control tachycardia. Is the precaution due to possible low heart rate? And what about hypertensive medications? Will the potential taking of Savella cause my hypertension to be out of control? My Rheumatologist is the one prescribing the Savella. My heart doctor prescribes the others. Both have a constant update on medications that I take. Is there reason to be concerned? I also read the study that was promoting the use of Savella but had not read any other studies as to the effeciency of this med over the others. I would appreciate any help you can give me. Sincerely, Dawn Carnes

  11. #11 Bonnie Bellmer
    June 21, 2009

    Hello, I have had Fibromyalgia for 63 years. I have had deep muscle pain for years, also IBS, migraine headaches, & many more symptoms. I have tried many prescription drugs over the years & found nothings really helped the FM. I have been taking Savella for 22 days, these are some of the side effects I’m experiencing. Hot flushes, faintness,& nausea. To my surprise I have no muscle pain at all. How much longer do I have to ut up with the hot flushes? They are terrible. I’m having them all day & nigh long.My clothes get drenched with sweat. I wonder if anyone know if this will go away. Thank you, Bonnie

  12. #12 Joseph j7uy5
    June 21, 2009

    It is not a good idea to give or get specific medical advice in a forum such as this. I will make some general comments, though, that may or may not apply to anyone’s particular situation.

    Elderly persons tend to be more susceptible to adverse effects, so may need much lower doses than everyone else. Also, drug interactions become more likely as older persons tend to have slower metabolism and tend to be on multiple medications. Obviously there are many exceptions to this.

    Sometimes, problems with adverse effects can be managed with either smaller single doses, or smaller but more frequent doses.

    Assessing drug interactions requires expert attention. It would be foolish for me to attempt to help someone with that in an Internet comment thread. A geriatric psychopharmacologist would be in a good position to help with something like that, but they are hard to find.

    Some pharmacists can be very helpful too, but often they will simply look on the computer and give vague information based upon general principles, which may or may not apply to a specific individual with a specific combination of drugs. The warnings tend to be overly broad.

  13. #13 pierrette fradette
    August 21, 2009

    my husband is going true cancer we lived on social security we are full of medical bill i have fybromealgia for over 20 years it is getting worse they came up with savella insurance will not cover it when the generic pills will come up please help

  14. #14 Joseph j7uy5
    August 23, 2009

    Insurance may or may not cover it. If it does, it may require “prior authorization,” which is a pain in the neck, but may be manageable. Or, your doctor may be able to get samples. But the patent will run for many years. Don’t know what the retail price would be, I would guess around $100/month.

  15. #15 Patty
    October 15, 2009

    Had been tapered off my Cymbalta from 120mg to 60mg then 30mg and then started the graduating dose of Savella the tapering of the Cymbalta was a nightmare with pain and depression I hit rock bottom. Have started the 50mg twice daily this week and feel like it may possibly be helping. Went to pharmacy to get prescription and found out my good insurance will not cover it due to it is to new and it is over $120.00 per month. Can’t afford with all my other meds and would hate to go off it and start back on Cymbalta.I have not found any coupons on the internet to help with cost.

  16. #16 Billie
    October 22, 2009

    My doctor took me off Cymbalta and put me immediately on Savella. The only side effects I can see is that I have cried continuously since I started this medication. I asked my doctor did I need to wean off Cymbalta but he didn’t seem to think I did. I have neurapathy not fibromyalgia but just hoping this would help. I really don’t think it is going to help much. I don’t have insurance anymore as I have lost my job due to my health issues. I do understand from my pharmacist that it is pretty expensive.

  17. #17 Phil
    January 25, 2010

    Is Savella helpful for sleep? I have not seen information indicating it is helpful for that purpose ( I have chronic fatigue, but only little or no fibromygalia).

  18. #18 Joseph j7uy5
    January 26, 2010

    Savella is not likely to be very helpful for sleep, but everyone is gong to be different, so it is possible. It would not be my first choice if one is going to try something specifically for that purpose.

  19. #19 Michael
    January 29, 2010

    I switched from Cymbalta to Savella a couple of months ago. I see very, very little difference. I have a bit more nauseau with Savella at 100 mg. Basically I would not bother to make the switch again.

    If you look closely at the Savella FDA tests, the 6 month results for pain **were not** statistically better than placebo!! Even at 3 months it was something like 19% to 16%, barely significant.

    They did the justification on the HRQOL in a second attempt, and even that was **weak**! I had one rheumatologist tell me not to switch from Cymbalta to Savella, it was just marketing. For me – he was right!

    I do admire the work of Dr Clauw though, the Chronic Pain research group at U of M is doing fantastic work! They just published a while ago on Mu Receptors and Acupuncture.

    Hint: I think meditation has the same positive effect on pain receptors as acupuncture! Just a guess, but as a meditator for 28 years (with hard core fibro, pain, fatigue, insmonia, etc.) that is the 1 thing that helps me the most! Second is ever elusive sleep, 3rd is opiates …

    Cheers! Good luck all!

    Michael T.

  20. #20 Fibromyalgia treatment
    March 4, 2010

    Recently I was going through a particularly bad few weeks with my fibro pain so I was looking online for a support group. Instead I found something about fibro and gluten intolerance. I cut gluten out of my diet and it has only been a week, but but my pain has improved a lot. There were pages of people with stories like mine which convinced me to try it. I shouldn’t have need convincing. My sister is gluten intolerant (she does not have fibro). I have learned online that people with fibro commonly have sleep disorders (which I do) and now apparently gluten intolerance? I hope that it is can be this simple for many of us. Some people had other food allergies to contend with, but even that would be worth it if you had hope for a pain-free future. I hopeful.

  21. #21 Cathy Ann McCartney
    May 15, 2010

    Cannot find any directions re taking this med. Take it early a.m. on empty stomach or eat first? Take it with water or milk? Could someone shed any light?

  22. #22 Sylvia D
    June 2, 2010

    I have sever fibromyalgia. my doctor prescribed Savella…I have been on Wellbutron for depression for years. I would like to know if I could take them both!? or should I stop the Wellbutron? just like others I have been having heart palp. and hot flushes since I started the savella. Are these permanent?

  23. #23 Joseph j7uy5
    June 6, 2010

    Sorry, as a matter of prudence I never give specific recommendations to individuals, nor comment on specific clinical situations.

  24. #24 L Chebbi
    July 5, 2010

    The problem that I have had with both Cymbalta and Savella is the intense gas pains 24/7. I was trying to find a way to counteract this side effect. I read that cleansing your liver would be helpful but I haven’t found anything more to substantiate that. I do take gas-x and similar products but have not found those to be helpful. Does any one have a suggestion on dealing with this awful sife effect as I do want to continue the Cymbalta because it has helped with the pain.

  25. #25 C Barendregt
    August 3, 2010

    My doctor started me on a Titration Pack of Savella. I had a couple of bad flares with Fibro. I am still taking the Lyrica as well. He also changed my muscle relaxer which has helped some with the muscle spasms I have at night. I am also taking the Elavil 100 mg at night so I can sleep. He also put me on mobic since I was having osteoarthritis pain in my hands and elbows. I feel like a walking drug store. But the pain has improved alot and I am able to function so I can work at least 2 12 hour shifts per week. My concern is should I be taking the Savella with the Elavil?

  26. #26 Pepper Assafi
    August 12, 2010

    I am concerned as my Dr. told me to just stop taking the Cymbalta 60mg twice a day and start on the Savella Titration pack. I always thought one was supposed to taper off. True, Dr.s SHOULD know what is best, but anyone can make a mistake. I also know that not everyone has symptoms or the same symptoms, but I am concerned about whether or not anyone has experienced weight loss or gain on Savella?
    Thanx and I sincerely hope that anyone having to take this medicine gets relief!

  27. #27 J Pecora
    September 11, 2010

    I take 90mg Cymbalta everyday. Recently, my physical pain doctor gave me a starter pack for Savella and told me to take it along with my Cymbalta. If it helps, I continue to take it; if not I am to let him know so he can RX a starter pack to taper off Savella. It’s been 3 weeks since I saw him & I still haven’t started it yet because I am leary about taking both Savella and Cymbalta (60mg & 30mg) (plus the Savella) together as well as the high cost for both drugs. I can’t take Lyrica. I’m on mobic, 2 thyroid meds, a cholesterol med, baclofen & flexeril as well. I am also afraid of the side affects of going off Cymbalta unless I’m tapered off, but like I said, the doctor told me to stay on it. I’m already in the donut hole with my drugs. Has anyone tried Savella along with the Cymbalta, and did it make a remarkable difference with FM pain?

  28. #28 Frank
    November 20, 2010

    Hi all. 
    I have had FM and CFS for years, and have found out recently that these are included in the Gulf War Illness from being stationed in areas of Southwest Asia. If you are a Vet, and were in those areas from 1990 to present, and have these symptoms, contact your nearest VA office. You maybe entitled to compensation. I’m just starting to check into it myself after being overseas in 1990 and have had these symptoms for over ten years! 
    I have just started the trial pack. Was wonderful at the initial 12.5 dose. As I have moved up to the 50mg twice a day, it seems slightly less effective, but also work stress and my long commute to work in the car aggravates the neck pain.
    I haven’t taken anything in the past, and wouldn’t have taken this if the trial pack had mentioned it was an SNRI. My doctor over the years would say it was depression, and try to prescribe many SSRIs over the ten years. I’m still in a military status that medication of that type will cause me to lose my civilian job. I’m not sure about Savella. So far when I’m not at work, it seems to be really helpful, but as the work week continues, it looses it’s edge. Worries me that the whole thing IS in my head!
     I really avoid medications; hardly take Aleve or Tylenol for a headache. 
    I have change my mind and tried for the two reasons: Seeing the acceptance of the Gulf War condition made me realize it’s not ‘in my head’ (up to now I wasn’t aware they added FM and CFS), and the way they wrote the sale tactic brochure for Savella.
    Surprisingly, the monkey that has been sitting on my neck and shoulders for ten years, finally took a bathroom break! After his relief, he’s lighter, but not completely gone. 
    I was skeptical, as after my first couple pills I researched the meds. To my surprise, it has helped some. I’d have to say for side effects, the most noticeable was a tingle that would spread when touching the skin. Kind of a chill like sensation. Clothing or even rubbing your own head would send this wave from head to toe. Odd, but not unpleasant. There have also been some sexual oddities, such as, genitial constriction, and a miss timing of arousal? Kind of he is set to a different time zone than where you are! Varies. Haven’t notice a decrease in desire, that is still there! The tingle thing has diminished as the dosage has increased, might be a symptom of just getting used to the drug, but as mentioned, work seems to bring the monkey’s lighter kid to the neck shoulders. Better than it was. I should say I’d at least recommend a trial. Good luck to all at removing there own monkey! 

  29. #29 Liz
    December 8, 2010

    Very interesting article, thank you for it. I have just recently been diagnosed with FM and my doctor started me on Savella. I had taken Cymbalta for years due to depression but recently “graduated” from needing antidepressants. I always had pain, even on Cymbalta so when my doctor suggested it first, I asked if there was something else we could try. He gave me a titration pack of the Savella. Now, I haven’t noticed much of a difference with pain (yet) but I have noticed a HUGE improvement in my sleep. Typically I wake up 5 – 7 times a night and have tried everything under the sun to help but nothing has. Since starting the Savella, I’ve slept great. A full 7 hours last night without waking up once. I’m hopeful that it will also help with the pain, and that it will continue to help me sleep. I’m not sure why it’s helping with sleep for me but it certainly seems to be. I am hopeful that this medication will help more as I continue taking it.

  30. #30 GAIL
    July 25, 2011

    I JUST BEGAN TO TAKE SAVELLA ON JULY 15, 2011. I BEGAN WITH THE TWO WEEK TITRATION PACK. AS OF JULY 25, 2011 I JUST BEGAN TO FEEL A LITTLE RELIEF. MY SIDE EFFECTS ARE NAUSEA AND HEADACHES. I HAVE TRIED LYRICA NAD CYMBALTA. THE LYRICA DID NO GOOD AT ALL. THE CYMBALTA WAS GREAT THE THE SIDE EFFECTS WERE HORRIBLE.

  31. #31 Jenna
    February 2, 2012

    Amitriptyline used to give so many side effects when I used it. I guess it helped me some but the side effects were totally awful.

  32. #32 Ashley
    March 27, 2012

    I have been on cymbalta for over a year now. It was amazing when I started taking it. It helped my mental status improve and definitely brought me to a better level in the respects of depression. I have been diagnosed with GAD, MDD, OCD, ADHD, and PTSD. I take a regiment of meds. Cymbalta, klonopins, remeron, and Ativan. I see a therapist as well as my medications. I have had horrible sexual side affects with cymbalta though. I lost all want and interest to engage in the activity. Being a woman I find it hard to find methods that bring my desire back. I have been searching on the internet and found the drug Savella. I am considering asking my psychiatrist about changing my medication over to it. My question: Is Savella a replacement for Cymbalta? Or is it found to be clinically unequal to it. I have been on everything under the sun and Cymbalta is the first medication that worked for me. SO I am leery and just want to know if it is a replacement or if I should look for another alternative drug. Thank you for your time.

    Ashley

  33. #33 Joni
    May 16, 2012

    I started on Savella two weeks ago. I had to stop taking it after 5 days. I had so many side effects with this drug I cannot say anything good about it. I have had a cluster migraine attack since day 3 of taking the drug and I am still dealing with it more than a week after. Twelve side effects in all and still not feeling well. I spoke with a woman today that was hospitalized after taking this drug. Pay attention to the side effects with this and all drugs!

  34. #34 Tammy
    May 17, 2012

    I have been on Savella for my Fibro for 2 months. I am taking 2 / 50 mg pills a day. It has helped tremendously. I can actually move around , where as before , I wanted to lay in a fetal position all day, I do have the hot flashes from this & my nose stays so cold. But , hey , I can deal with this better than the rest. I just have to remember to stay hydrated. This stuff is so expensive…I have no insurance. It is costing me $ 174.68 a month. Is there a generic comiong very soon. PLEASE.

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