inkblot - It seems weird that NSRI can help with pain, like Cymbalta™ (duloxetine) and some of the older tricyclic antidepressants (TCA). I have noticed that the TCAs with both serotonin (5-HT) and norepinephrine (NE) reuptake blockade activity (eg. Elavil™ - amitriptyline) seem (to me ) to work far better than the TCAs that preferentially block reuptake of either 5-HT (eg. Aventyl™ - clomipramine) or NE (eg. Norpramin™ -desipramine).

But (in science there's always a "but") the antimigraine drugs called triptans [eg. Imitrex™ (sumatriptan), Maxalt™ (rizatriptan), Amerge™ (naratriptan), and Zomig™ (zolmitriptan)] seem to relieve pain by enhancing activity at a serotonin receptor subtypes 5-HT1B and 5-HT1D, with (seemingly) no NE involvement. These receptors are located on the intracranial blood vessels and vasoconstriction (ie. spasm) of these vessels in certain brain areas are thought to be involved in the production of the symptoms of migraines. One theory how the triptans alleviate migraines is by stimulating these serotonin receptor-subtypes, thus causing the overly dilated blood vessels to contrict, relieving the pain. Although, other researchers think that the relief of migraine pain may be due to the activation 5-HT1 receptors on nerve terminals surrounding blood vessels in the branches of the trigeminal nerve (aka TGN or 5th cranial nerve). This is thought to result in an inhibition of release of pain-causing neuropeptides and decreased transmission of pain signals along the trigeminal nerve.

This is not to say that global increases of 5-HT and NE in the brain are actually responsible for alleviating the pain of syndromes like diabetic neuropathy, fibromyalgia, chronic fatigue syndrome, phantom limb pain, and other varieties of neuropathic pain. I can't believe that the mechanism is that simple, but it hurts my brain when I try to figure it through.

Cymbalta and Elavil may actually be binding to a different type of receptor and enhancing or blocking it's normal activity, resulting in analgesia. It has been shown that Elavil binds to the adenosine-A2A receptor in the spinal cord (? - I think) and this may be responsible for at least of of Elavil's pain killing activity.

Another thing is is that, in my experience, the drugs being used in the treatment of neuropathic pain seem to work very well .... or they don't work at all. I see this This sort of all-or-nothing effect bugs me. Aside from Elavil, I see this all-or-none pain relieving effects with Neurontin™ (gabapentin), Effexor™ (venlafaxine), Tegretol™ (carbamazepine), and others.

I guess what I am trying to say is that I am not sure how Cymbalta works for neuropathic pain. It should help with emotional problems, but since the drug works for neuropathic pain syndromes, I'm not sure it will be effective for arthritis. Arthritis pain and neuropathic pain have different causes, and are essentially different kinds of pain. Then again, I have never had any clinical experience with Cymbalta, so I may be wrong.

- Cam
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