Milnacipran/Ultram/Elavil and norepinephrine

[bshaw99]

Does anyone have any experience with Milnacipran? It's an anti-depressant available in Europe that is also prescribed for chronic pain. It may seem like an oxymoron but one of it's possible side-effects is dysuria.

[kevin]

Milnacipran seems to be an SNRI (serotonin-norepinephrine reuptake inhibitor). It should have similar actions to those of Cymbalta, which is in the same class of drugs. Although I personally experienced relief taking Cymbalta, I don't think this generalizes to most people with CPPS/IC. The below study showed that Cymbalta (duloxetine) was not effective for IC. It might be worth a try, though.

The dual serotonin and noradrenaline reuptake inhibitor duloxetine for the treatment of interstitial cystitis: results of an observational study.

van Ophoven A, Hertle L.

Department of Urology, Universitatsklinikum Munster, Germany. [email protected]

PURPOSE: We report an observational study to evaluate the efficacy and tolerability of duloxetine for interstitial cystitis. MATERIALS AND METHODS: A total of 48 women were prospectively treated for 2 months following an uptitration protocol to the target dose of 2 x 40 mg duloxetine per day. Patients received the target dose for 5 weeks. The efficacy of duloxetine treatment was assessed at week 8. The primary end point was a change in the overall well-being evaluated by a patient reported global response assessment. Secondary end points were changes in pain and urgency (visual analog scales), frequency and functional bladder capacity (48-hour voiding log), and changes in overall symptom severity (O'Leary-Sant index). RESULTS: There were 5 patients (10.4%) who were identified as responders and 17 patients (35.4%) who dropped out of the study exclusively due to side effects, with nausea present in all dropouts. No severe adverse events were reported. All 5 responders reported onset of symptom improvement but not until they had reached the target dose. Regarding secondary outcome parameters, duloxetine treatment did not result in statistically significant improvement of symptoms. Maximum urinary flow rate and residual volume were influenced more prominently in patients at the target dose, however, the changes did not appear to be clinically meaningful. CONCLUSIONS: Treatment of interstitial cystitis with duloxetine did not result in significant improvement of symptoms. The drug administration was safe but the tolerability of the drug was poor mainly due to nausea occurring with the starting dose of 20 mg per day. Based on the preliminary data of this observational trial we currently cannot recommend duloxetine as a therapeutic approach for interstitial cystitis.

[bshaw99]

Yes, the Cymbalta and Milnacipran are similar however, unlike Cymbalta, Milnacipran works equally on noradrenaline and serotonin thereby reducing many undesirable side-effects of Cymbalta. But I had the same urinary hesitation and pain that I've had with other antidepressants that effect noradrenaline.

Oddly enough, Ultram also effects noradrenaline and yet it's considered the primary pain-killer for prostatitis. Any experience in that regard?

I guess I'm supposed to say I AM NOT A DOCTOR.

[kevin]

Excellent question, bshaw.

Lots of anti-depressants that people use for chronic prostatitis / chronic pelvic pain syndrome act on norepinephrine reuptake, increasing the amount of norepinephrine in the nervous system. Elavil and Ultram are two examples. In addition to their other various effects, they are thought to relieve pain by acting on spinal alpha2 receptors.

(Begin jargon)
Here's the thing: people with CPPS/IC are thought to have down-regulated (desensitized) alpha2 receptors [1]. Because spinal alpha2 receptors have an analgesic effect, a loss in alpha2 receptor sensitivity can cause increased pain. So taking a drug such as Elavil or Ultram will stimulate those alpha2 receptors, and reduce pain. However, use of these drugs over the long term will desensitize alpha2 receptors, which in theory could make the problem worse. Moreover, these antidepressants will stimulate alpha1 receptors in the bladder, possibly resulting in urinary hesitancy (for extra credit, look up the role of presynaptic alpha2 receptors in peripheral nerves for further explanation of urinary hesitancy caused by norepinephrine-active drugs).
(End jargon)

I took Elavil for several weeks, and looking back on that time period, it was then that my symptoms got worse. I believe I am more sensitive to adrenergic drugs than most people with CPPS, as described in the study, but most people with chronic prostatitis / chronic pelvic pain syndrome do have a bad reaction to these drugs. Just note how both this site and the IC Network warn patients to stay away from decongestants, for fear of urinary hesitancy/retention, when those are not big concerns for the population at whole. Also, chronic prostatitis / chronic pelvic pain syndrome patients are advised to use alpha blockers.

I wonder if people might be adversely affecting their chronic prostatitis / chronic pelvic pain syndrome symptoms in the long run by using norepinephrine-active drugs. I'm interested to hear if other people on this forum have noted any long-term effects of using Elavil/Ultram, such as hesitancy and frequency. It's important to remember that those drugs, unlike decongestants such as Sudafed, also have several other forms of action (serotonin, opioids), so in the end the norepinephrine effect might not be that significant. But you raise a good point, which I've been thinking about myself recently.

[1]
In vivo evaluation of alpha(2)-adrenoceptors in cats with idiopathic cystitis.
Jodi Westropp, Philip Kass, and C A Buffington
American journal of veterinary research 68 (2), 203-7 (Feb 2007)

[bshaw99]

Thanks for the compliment, Kevin

I, too, have wondered if I hung in there long enough with the Milnacipran or Ultram (both of which I started in very low doses as I always do), the effect of the serotonin or opiod would make the pain go away. But it was so intense even at the low dose that I was reluctant to exacerbate things even further.

So I guess I'm also curious as to whether any others in this forum have had INITIAL pain from any of these drugs which decreased over time.

[/b]

[scotsman]

I'm interested to hear if other people on this forum have noted any long-term effects of using Elavil/Ultram, such as hesitancy and frequency.

I've been taking Ultram (tramadol) now for over 2 years and I've no urinary symptoms these days (they were resolved via physiotherapy). I used to be on 250mg at one point but now I only take 50mg a day. The drug has been a blessing for me.

Richard.

[bshaw99]

I'm a little confused. If the urinary symptoms have been resolved why are you still taking the Ultram at all?

[scotsman]

I'm a little confused. If the urinary symptoms have been resolved why are you still taking the Ultram at all?

Ultram is a pain medication - it didn't make any difference to my urinary symptoms when I had them - but it was excellent for pain control and I take it as I still have pain.

Richard.

[carld]

Thanks for the compliment, Kevin

I, too, have wondered if I hung in there long enough with the Milnacipran or Ultram (both of which I started in very low doses as I always do), the effect of the serotonin or opiod would make the pain go away. But it was so intense even at the low dose that I was reluctant to exacerbate things even further.

So I guess I'm also curious as to whether any others in this forum have had INITIAL pain from any of these drugs which decreased over time.

I have been taking Elavil 10mg for about 5 months and in my case, I have more LUTS associated with my condition and some discomfort in my perineum. So as far as PAIN, I have had very little if any. Maybe a bout here or there with proctalgia fugax like symptoms shooting through my perineum.

As far as Elavil, I think it has helped with some of the discomfort and LUTS by quieting down the nerves so I can focus away from the condition, there for relaxing the muscles more and step further away from anxiety, thus further relaxing the muscles and creating a cycle of healing and not the vicious cycle we have experienced with this condition. Elavil, I think is very helpful at low dosages like 5-10mg. I have even titrated down to 5mg and stopped for 3 days with no side effects, until the discomfort in my perineum started to creep back. I also throw in some antihistamines to help as well like OTC loratadine (antihistamine). It then really occurred to me that Elavil is the right option for me with very little if any side effects right now in the long term until I can fully learn to relax the mind and body on a regular basis. Just have to keep pushing through...