Association between ACE inhibitors and CRPS, New Study sugests inflamatory patho..
 

The association between ACE inhibitors and the complex regional pain syndrome:
Suggestions for a neuro-inflammatory pathogenesis of CRPS.


http://www.rsds.org/2/library/articl...rickerBHCh.pdf


I think it's a given that a neuro inflamitory process is involved.
Page one (1) Calcium Channel Blockers, can't praise em enouph.
Lidocaine infusions, lidocaine cream.
Epsome Salts, lots of soaks.. sory getting distracted.. read the study

:grouphug:
Sandra

This is good news!
Thank You, Sandel!

It brings a single thought to my mind, that's been rattlin' around in there for some time.

Is there Any Single Medication that has been produced, that's aimed specifically for,
CRPS / RSD ?
Have we grown to that size of the population yet? (sad, if so).

And, if not, do we (Doowee) spend enough, for ta be anything but a "blip" on the drug companies radar?

Just wondering.....


Pete

Thanks for the article. I found it interesting.

ACE inhibitors are getting alot of press lately.
As certain ones cross the blood brain barrier...and are showing
as useful to prevent Alzheimer's progression and now usefulness in multiple sclerosis.

The bradykinin connection is interesting. Certain people develop a cough on ACE drugs...I wonder if they are the ones more prone to the RSD connection?

I have seen papers about using calcium channel blockers to treat RSD... nifedipine specifically. I've posted them here a few times already. ;)

MrsD's comment motivates me to post an older abstract from the following study:

"Complex regional pain syndrome (reflex sympathetic dystrophy and causalgia): management with the calcium channel blocker nifedipine and/or the alpha-sympathetic blocker phenoxybenzamine in 59 patients," Muizelaar JP, Kleyer M, Hertogs IA, DeLange DC, Clin Neurol Neurosurg. 1997 Feb;99(1):26-30.

Department of Neurosurgery, University of California, Davis, Sacramento 95817, USA.

Complex Regional Pain Syndrome (CRPS) is the new name for entities formerly known mostly as Reflex Sympathetic Dystrophy and Causalgia. Treatment of CRPS with either the calcium channel blocker nifedipine or the alpha-sympathetic blocker phenoxybenzamine was assessed in 59 patients, 12 with early stages of CRPS, 47 with chronic stage CRPS. In the early stage CRPS patients, 3 of 5 were cured with nifedipine and 8 of 9 (2 of whom had earlier received nifedipine) with phenoxybenzamine, for a cure rate of 92% (11 out of 12). In the chronic stage CRPS patients, 10 of 30 were cured with nifedipine; phenoxybenzamine cured 7 of 17 patients when administered as a first choice and another 2 of 7 patients who received nifedipine earlier, for a total late stage success rate of 40% (19 out of 47). The most common side effects necessitating discontinuing the drug were headaches for nifedipine and orthostatic dizziness, nausea and diarrhoea for phenoxybenzamine. All male patients on phenoxybenzamine experienced impotence, but this did not lead to discontinuing this agent and immediately disappeared after stopping the drug. These results once again stress the importance of early recognition of CRPS, and treatment with either of these drugs could be considered as a first choice for early CRPS, especially because in this series this treatment was not combined with physical therapy making it very cost-effective. In the chronic stage of CRPS, treatment with these drugs was much less successful (40%), even though it was always combined with physical therapy, but it can still be considered, either as a first choice or when other types of treatment have failed. [Emphasis added.]

PMID: 9107464 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/sites/entrez

What's inclear from the abstract alone is how long a patient with chronic CRPS must remain on the drug(s) once a successful result has been established. But even a 40% success rate looks pretty good, all things consider: assuming you can avoid the contraindications of the two drugs. Wonder what happened to the treatment? I'll try to pull the article.

Mike


PS Okay. Here we go. The problem was that iv phenoxybenzamine was pulled by the FDA a while back, and that's was was being used in at least one of these studies. See, "Intravenous Regional Phenoxybenzamine in the Treatment of Reflex Sympathetic Dystrophy," Malik, Vinod K, et al, Anesthesiology March 1998 - Volume 88 - Issue 3 - pp 823-827, html full text at http://journals.lww.com/anesthesiolo...he.36.aspx#P24 Nevertheless, an oral tablet is on the market, marketed under the name of Dibenzyline.

Last year, some promising results with the oral tablet were reported in chronic CRPS patients using the drug on a long term basis. "Treatment of complex regional pain syndrome type I with oral phenoxybenzamine: rationale and case reports," Inchiosa MA Jr, Kizelshteyn G.Pain Pract. 2008 Mar-Apr;8(2):125-32. Epub 2008 Jan 7 full text at http://www.rsds.org/2/library/articl...izelshteyn.pdf

Department of Pharmacology, New York Medical College, Valhalla, New York 10595, USA. mario_inchiosa@nymc.edu

The nonselective alpha-adrenergic antagonist, phenoxybenzamine, has been used in the treatment of neuropathic pain syndromes, specifically, complex regional pain syndrome (CRPS) types I and II. This agent has also previously been used in intravenous regional peripheral blocks for treatment of CRPS I; however, an intravenous preparation of phenoxybenzamine is not currently available in the U.S.A. In this case series, systemic administration was more appropriate for three of the four patients, as their syndromes had spread beyond the initial area of surgery or trauma. We report an apparent clinical benefit in three of the four patients following oral administration. We postulate that this may be due to the noncompetitive (irreversible) blockade of alpha(1)- and alpha(2)-adrenergic receptors. We further hypothesize that this blockade could reduce stimulation of an increased population of adrenergic receptors in hyperalgesic skin, blunt the stimulation by norepinephrine of alpha(2)-adrenergic receptors on macrophages, and ultimately reduce the release of proinflammatory cytokines from cellular elements.

PMID: 18194348 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum

BUT, in April, 2008, the FDA required that a product warning be placed on the (physician's) product information sheet, which reads in part as follows:

PRECAUTIONS

Carcinogenesis and Mutagenesis

Case reports of carcinoma in humans after long-term treatment with phenoxybenzamine have been reported. Hence long-term use of phenoxybenzamine is not recommended. Carefully weigh the benefits and risks before prescribing this drug... [Emphasis added.]

http://www.fda.gov/Safety/MedWatch/S.../ucm117801.htm Unfortunately, I can't seem to pull a complete copy either a full copy of the new warning language or the prescribing information sheet (which is odd) and in fact that new warning doesn't even appear in the patient friendly Medline Plus page for phenoxybenzamine, last revised September 1, 2008, http://www.nlm.nih.gov/medlineplus/d...s/a682059.html but the foregoing warning language from an official FDA site is enough for me, when it comes to considering the long-term use of the drug. No thank you.

So the question is, can the use of nifedipine, combined with the short-term use of oral phenoxybenzamine, be effective in the treatment of CRPS? And for that one, the jury may still be out.

Thanks, fmichael.

A little history:
Phenoxybenzamine (Dibenzyline oral) has been on the market for decades. It was originally for hard to control blood pressure in the 70' and 80's. Then it was reduced to use in people with a rare adrenergic tumor of the adrenals called pheochromocytoma.
It was only used for a short time until the surgery removed the tumor.
Here is the RXlist.com monograph
http://www.rxlist.com/dibenzyline-drug.htm

It is very rarely used today. I hadn't dispensed it in 20 yrs easily.

There is another paper on PubMed from Japan, that only used
nifedipine in a patient who developed RSD following renal surgery. So nifedipine might be useful alone, if done correctly at the right dose for the right time frame, and perhaps earlier in the course of the RSD presentation.

I have seen since I did those searches a while back last spring that Dr. H....does list calcium channel blockers in his book..it was a Google book reference I believe, but I didn't save it.

Nifedipine is a fast acting calcium channel blocker and is also used to block premature labor now for pregnant women. It is less used for long term blood pressure control because it can cause gum overgrowth and has significant side effects. Its brand name was ProCardia. Some ERs still use it for toxic hypertension, where a liquid capsule is opened and put under the tongue. That is an emergency use. It is also used, as well as its cousin to treat migraine, in refractory cases.

Here is a wiki article with a list of the family:
http://en.wikipedia.org/wiki/Calcium_channel_blocker

I'll share this with you. If I had RSD and was suffering like the posters I read here, I'd be very aggressive and seek this treatment. I think it is just that not many doctors even know about RSD...and waiting is critical for success with calcium channel blockers. But even a 40% success rate...that is pretty good. We don't have that number at all on Peripheral Neuropathy!

I did have a doctor early on in my RSD recommend this treatment (Calcium Channel Blockers). Unfortunately we could not get it approved... Insurance said no as it was seen as experimental for RSD. (my thought was/is---DUH, EVERYTHING with RSD is experimental!!)

Now I am 5+ years, full body, with each day intensifying.

I wish, hope, and pray for something to come along... I'm tired of the pain.

If I was at the beginning of this, I would definitely check it out... most likely give it a try... It can't be any worse than the constant increasing pain.

That is terrible Abbie.

Nifedipine is not expensive...it is a generic and has been for a long time orally.

IV yes, that would cost much more.

mrsD -

Thank you, thank you. Turns out, in the 1997 study by Muizelaar et al, cited above, they only got a 40% success rate in chronic CRPS cases with the sequential administration of what turns out to have been oral phenoxybenzamine: I just had to read the description of the earlier study in Inchiosa and Kizelshteyn, 2008, more carefully. Without phenoxybenzamine the "cure rate" with nifedipine alone was still a respectable 33%.

Which again raises the question of why at those odds aren't more doctors at least trying nifedipine, even if they have good reason to avoid Dibenzyline?

And what's really off is that when I just ran a PubMed search of "CRPS nifedipine," it came back with only result: the Muizelaar study. But then, searching under "RSD nifedipine" I got one relevant hit, a case report in Japanese. See, [A case report of reflex sympathetic dystrophy treated with nifedipine][Article in Japanese], Ohta S, Tanahashi T, Iida H, Asano T, Ueda N, Tani T, Suzuki A, Uematsu H, Yamamoto M, Masui 1989 May;38(5):679-83:

Reflex sympathetic dystrophy (RSD) refers to a symptom complex observed after nerve injury and consists primarily of severe burning pain associated with sensory, vasomotor and trophic phenomena. A 54-year-old male had undergone nephrectomy. At surgery left XIth intercostal nerve had been injured by cautery. After a few weeks following surgery, the patient developed progressive deep burning pain, stabbing sensation and dysesthesia in the left abdominal region. Analgesics and narcotics were ineffective. We diagnosed his case as RSD. He received nifedipine 10mg sublingually. Pain relief was obtained within 10min and lasted for 6hs. Consequently, nifedipine therapy was started at a daily dose of 30 to 60mg. His symptoms were markedly improved within 4 weeks. After 3 months his pain resolved. At the present, some pain often returns, but nifedipine is effective. Nifedipine may be useful as a drug for the management of reflex sympathetic dystrophy.

PMID: 2778955 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/2...ubmed_RVDocSum

The apparent lack of academic curiousity on the subject is amazing!

Mike

Yes, I agree.. confusing, sad, and infuriating.

This parallels the ignorant doctors who fail to recognize, test, and treat properly B12 deficiency. There are millions out there
with this problem, who go to doctor after doctor with no result.
For 10 yrs I have read countless posts from people who have been ignored in the PN area in this way.

So the RSD patients are seeing the same.

There is a post on Forum Feedback from a neurologist wanting input. You might want to read it and contribute:

http://neurotalk.psychcentral.com/thread97228.html

and on second (or third) thought . . .
 

:deadhorsebeat: :deadhorsebeat: :deadhorsebeat: :deadhorsebeat: :deadhorsebeat: :deadhorsebeat: :deadhorsebeat: :deadhorsebeat: :deadhorsebeat: :deadhorsebeat: :deadhorsebeat: :deadhorsebeat:

After all that, it occured to me that Procardia (nifedipine) was very likely what my internist/cardiologist put me on - very briefly - last summer in an attempt to control what we believed were vascular spasms in my chest. In short order, a little edema blew up to the point where, two months and 60 mg./day of Lasix later - along with a prescription potassium supplement - he told me that I looked like I had come in with "Elephantiasis" in the calves, ankles and feet of both legs, mud-like edema under the skin, couldn't even fit into flip flops, etc.

It took about three months for it to come down, most, but not quite all of the way. I was reminded of this tonight when I looked at the prescribing information sheet for Procardia and found this on pp. 5 - 6:

Peripheral Edema: Mild to moderate peripheral edema, typically associated with arterial vasodilation and not due to left ventricular dysfunction, occurs in about one in ten patients 6 treated with PROCARDIA (nifedipine). This edema occurs primarily in the lower extremities and usually responds to diuretic therapy. With patients whose angina is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.

http://www.pfizer.com/files/products/uspi_procardia.pdf

For folks with CRPS, this may have been in fly in the ointment with nifedipine. In any event, rest assured the folks at Pfizer have been on it. See, "The T- and L-Type Calcium Channel Blocker (CCB) Mibefradil Attenuates Leg Edema Induced by the L-Type CCB Nifedipine in the Spontaneously Hypertensive Rat: A Novel Differentiating Assay," Terry C. Major, et al., Journal of Pharmacology And Experimental Therapeutics, 2008 325:723–731, full text at http://jpet.aspetjournals.org/cgi/reprint/325/3/723.pdf at 723-24:

Calcium channel blockers comprise a class of powerful, well tolerated, and safe antihypertensive agents that are widely used either alone or as a key component of combination therapy for hypertension. It is unfortunate that a common adverse effect of calcium channel blockers (CCBs) is vasodilatory edema, which results in peripheral leg edema. Vasodilatory edema is related to several mechanisms, including arteriolar dilation (Hayashi et al., 2005), stimulation of the renin-angiotensin-aldosterone system (Schiffrin, 2003; He et al., 2005), and fluid volume retention (Messerli, 2002). The most widely held theoretical mechanism for this edema is a disproportionate decrease in arteriolar versus venular resistance, which increases hydrostatic pressure in the capillary circulation and drives fluid shifts into the interstitial compartment. Vasodilatory edema is common and dose-dependent with first generation CCBs such as verapamil and nifedipine (Messerli, 2002; Safak and Simsek, 2006). Once edema is present, it can be slow to resolve without intervention. A number of strategies exist to treat CCB-related edema, including switching CCB classes, reducing the dosage, adding known venodilators such as nitrates, or adding renin-angiotensin-aldosterone system inhibitors such as angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers to the treatment regimen (Messerli, 2001; Weir et al., 2001). Diuretics may remediate the edema state somewhat, but at the expense of further reducing plasma volume. Traditional measures such as limiting the amount of time that a patient is upright and/or considering use of graduated compression stockings are useful adjunctive therapies.

Unfortunately, Mibefradil (Posicor), the alternative suggested in the article, appears to have been withdrawn from the US market by Roche on June 8, 1998, due to the potential for drug interactions, some of them serious, which could occur when taken together with certain medications. http://en.wikipedia.org/wiki/Mibefradil

Perhaps Pfizer is not yet ready to concede defeat. (To be continued?)

Mike

The peripheral edema issue is strange.
I got that with Norvasc (another calcium channel blocker), and had to discontinue it.(it became so bad I couldn't bend my knees). But many people take this too and have no problem with it. (everyone is different)

But then I can tolerate Cardizem with no problem.
So I guess each person is different.

I used to work at an HMO that served a large African American patient base, and very high doses of ProCardia cause NO edema for them. So there may be genetic reasons for that peripheral edema side effect. African American hypertension patients typically tolerate drugs that other groups use less. For example Bidil was developed for them.( caused quite a stir when it came out...was even a story line on the TV show HOUSE.)

There has been a movement away from nifedipine for long term blood pressure control, and this parallels the introduction of ARBs...like Cozaar etc.

Lidocaine is a calcium channel blocker too.
 

My continuous subcutanious Lidocaine infusions are also calcium channel blockers, I havent realy noticed alot more edema in my legs since starting my infusions over a year ago, though it's hard to tell they've always swelled up and down alot.
I do get alot of relief from alot of the RSD symptoms though and I think it (calcium channel blocker combo's) are our best safest chance that I have seen so far. I am no longer the bed case that I was a couple years ago..

So I think that if there was a drug just for RSD it would be a calcium channel blocker CCB/NAC/VC combination if I have that right.. in sandra's world lol

Hi Sandel -

I'm not sure if all calcium channel blockers exacerbate edema, but I would absolutely make a point of checking the FDA (or Canadian) approved prescribing information for the specific drug, to be sure that it's not associated with edema in any significant fashion.

And for what it's worth, it's my understanding that lidocaine is a sodium channel blocker, a broad class of drugs that may soon offer incredible results, once developed into "voltage-gated sodium channel blockers." (Although I've been told by one of my doctors that the FDA has not yet approved them for use in the U.S., I haven't been able to independantly confirm it.) On Liodcaine's use as a sodium channel blocker, see, e.g., "Sodium channel blockers in neuropathic pain," Kalso E, Curr Pharm Des. 2005;11(23):3005-11.

[Abstract]
Subtypes of tetrodotoxin resistant voltage-gated sodium channels are involved in the development of certain types of neuropathic pains. After nerve injury hyperexcitability and spontaneous firing develop at the site of injury and also in the dorsal root ganglion cell bodies. This hyperexcitability results at least partly from accumulation of sodium channels at the site of injury. The facts that these sodium channels seem to exist in peripheral nerves only and that they can be blocked at the resting state (use-dependent block) offer the possibility to develop drugs, which selectively block these damaged, overexcited nerves. At the moment no such drugs are available. However, some of the most potent drugs that are currently used to manage neuropathic pain e.g. amitriptyline and other tricyclic antidepressants, also block these channels in addition to having several other mechanisms of action. Also most anticonvulsants that are used to alleviate neuropathic pain are sodium channel blockers. Lidocaine, the prototype drug, has been shown to be effective in peripheral neuropathic pain. Its use is limited by the fact that it cannot be administered orally. An oral local anesthetic type sodium channel blocker, mexiletine is an antiarrhythmic agent that is effective in neuropathic pain. However, effective doses may be difficult to achieve because of adverse effects. [Emphasis added.]

PMID: 16178759 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/16178759

And specifically as to voltage-gated sodium channel blockers, check out, "The pharmacology of voltage-gated sodium channels in sensory neurones," Docherty RJ, Farmer CE, Handbook of Experimental Pharmacology 2009;(194):519-61.

[Abstract]
Voltage-gated sodium channels (VGSCs) are vital for the normal functioning of most excitable cells. At least nine distinct functional subtypes of VGSCs are recognized, corresponding to nine genes for their pore-forming alpha-subunits. These have different developmental expression patterns, different tissue distributions in the adult and are differentially regulated at the cellular level by receptor-coupled cell signalling systems. Unsurprisingly, VGSC blockers are found to be useful as drugs in diverse clinical applications where excessive excitability of tissue leads to pathological dysfunction, e.g. epilepsy or cardiac tachyarrhythmias. The effects of most clinically useful VGSC blockers are use-dependent, i.e. their efficacy depends on channel activity. In addition, many natural toxins have been discovered that interact with VGSCs in complex ways and they have been used as experimental probes to study the structure and function of the channels and to better understand how drugs interact with the channels. Here we have attempted to summarize the properties of VGSCs in sensory neurones, discuss how they are regulated by cell signalling systems and we have considered briefly current concepts of their physiological function. We discuss in detail how drugs and toxins interact with archetypal VGSCs and where possible consider how they act on VGSCs in peripheral sensory neurones. Increasingly, drugs that block VGSCs are being used as systemic analgesic agents in chronic pain syndromes, but the full potential for VGSC blockers in this indication is yet to be realized and other applications in sensory dysfunction are also possible. Drugs targeting VGSC subtypes in sensory neurones are likely to provide novel systemic analgesics that are tissue-specific and perhaps even disease-specific, providing much-needed novel therapeutic approaches for the relief of chronic pain.

PMID: 19655117 [PubMed - in process]
http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum

Mike

Thanks Mike,

I have not found anyone from the USA who has had the 12 hour subcutanious lidocaine infusions that alot of us in Canada get, we can get them every 3-4 weeks depending on the dose and persons need.
My dosage was just increased by 10% to 1300mg the dosage is determined by body weight and has to be infused over a long time in order for it to work over a long time.. well that and so as not to be too toxic in concentrated form (this is a little over my regular %'s but my doc says he knows my tolerances well enouph and I was in more pain than usual from our rain)

I will take pictures of myself all set up next infusion and post them in neurotalk I keep forgetting.

I met a man in the clinic on friday when I got my infusion who had triginominal nuralgia in his face and eye and he said the lidocaine infusions make his life worth living.. I kinda feel that way too, I felt like there was no way out for me before these treatments, now at least I get a partial repreve from some symptoms for a while... and that is huge believe me, I realy notice when my regular apointmets are delayed.

Thanks for the links bud.

And thank you Sandra. Wonder if there is any literature out there that addresses whether there are different results between the 12 hour subcutanious lidocaine infusions you received and the 5-day iv infusion that appears to be the standard in Philadelphia? The one that was a complete bust for me, even though I was told by a nurse in the hospital that it appeared to give immediate relief to most and perhaps 2/3 of the people who were on it.

As to voltage-gated sodium channels, the most accessible piece I've found is a beautifully constructed Wikipedia article at http://en.wikipedia.org/wiki/Sodium_channel

And for the language of a recent patent application on such a potential drug, which lays out the concept of voltage-gated sodium channels in some detail (the online version omitting the formulas and the numerical data from test results to date, which don't show up under the "Images" link either), see, "Benzaepinones as sodium channel blockers, description/claims" from USPTO Patent Application 20090181946, December 8, 2008 (Inventors: Scott B. Hoyt, et al, Agent, MERCK AND CO., Inc.), which reads in part:

Description:

FIELD OF THE INVENTION

[0001]The present invention is directed to a series of benzazepinone compounds. In particular, this invention is directed to benzazepinones that are sodium channel blockers useful for the treatment of chronic and neuropathic pain. The compounds of the present invention are also useful for the treatment of other conditions, including pruritis, itchiness, allergic dermatitis, and disorders of the nervous system such as postherpetic neuralgia, diabetic neuropathy, epilepsy, manic depression, bipolar disorder, depression, anxiety and urinary incontinence.

BACKGROUND OF THE INVENTION

[0002]Voltage-gated ion channels allow electrically excitable cells to generate and propagate action potentials and therefore are crucial for nerve and muscle function. Sodium channels play a special role by mediating rapid depolarization, which constitutes the rising phase of the action potential and in turn activates voltage-gated calcium and potassium channels. Voltage-gated sodium channels represent a multigene family. Nine sodium channel subtypes have been cloned and functionally expressed to date. [Clare, J. J., Tate, S. N., Nobbs, M. & Romanos, M. A. Voltage-gated sodium channels as therapeutic targets. Drug Discovery Today 5, 506-520 (2000)]. They are differentially expressed throughout muscle and nerve tissues and show distinct biophysical properties. All voltage-gated sodium channels are characterized by a high degree of selectivity for sodium over other ions and by their voltage-dependent gating. [Catterall, W. A. Structure and function of voltage-gated sodium and calcium channels. Current Opinion in Neurobiology 1, 5-13 (1991)]. At negative or hyperpolarized membrane potentials, sodium channels are closed. Following membrane depolarization, sodium channels open rapidly and then inactivate. Sodium channels only conduct currents in the open state and, once inactivated, have to return to the resting state, favored by membrane hyperpolarization, before they can reopen. Different sodium channel subtypes vary in the voltage range over which they activate and inactivate as well as in their activation and inactivation kinetics.

[0003]Sodium channels are the target of a diverse array of pharmacological agents, including neurotoxins, antiarrhythmics, anticonvulsants and local anesthetics. [Clare, J. J., Tate, S. N., Nobbs, M. & Romanos, M. A. Voltage-gated sodium channels as therapeutic targets. Drug Discovery Today 5, 506-520 (2000)]. Several regions in the sodium channel secondary structure are involved in interactions with these blockers and most are highly conserved. Indeed, most sodium channel blockers known to date interact with similar potency with all channel subtypes. Nevertheless, it has been possible to produce sodium channel blockers with therapeutic selectivity and a sufficient therapeutic window for the treatment of epilepsy (e.g. lamotrigine, phenyloin and carbamazepine) and certain cardiac arrhythmias (e.g. lignocaine, tocainide and mexiletine).

[0004]It is well known that the voltage-gated Na.sup.+ channels in nerves play a critical role in neuropathic pain. Injuries of the peripheral nervous system often result in neuropathic pain persisting long after the initial injury resolves. Examples of neuropathic pain include, but are not limited to, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias. It has been shown in human patients as well as in animal models of neuropathic pain, that damage to primary afferent sensory neurons can lead to neuroma formation and spontaneous activity, as well as evoked activity in response to normally innocuous stimuli. [Carter, G. T. and B. S. Galer, Advances in the management of neuropathic pain. Physical Medicine and Rehabilitation Clinics of North America, 2001. 12 (2): p. 447-459]. The ectopic activity of normally silent sensory neurons is thought to contribute to the generation and maintenance of neuropathic pain. Neuropathic pain is generally assumed to be associated with an increase in sodium channel activity in the injured nerve. [Baker, M. D. and J. N. Wood, Involvement of Na channels in pain pathways. TRENDS in Pharmacological Sciences, 2001. 22 (1): p. 27-31].

[0005]Indeed, in rat models of peripheral nerve injury, ectopic activity in the injured nerve corresponds to the behavioral signs of pain. In these models, intravenous application of the sodium channel blocker and local anesthetic lidocaine can suppress the ectopic activity and reverse the tactile allodynia at concentrations that do not affect general behavior and motor function. [Mao, J. and L. L. Chen, Systemic lidocaine for neuropathic pain relief. Pain, 2000. 87: p. 7-17]. These effective concentrations were similar to concentrations shown to be clinically efficacious in humans. [Tanelian, D. L. and W. G. Brose, Neuropathic pain can be relieved by drugs that are use-dependent sodium channel blockers: lidocaine, carbamazepine and mexiletine. Anesthesiology, 1991. 74 (5): p. 949-951]. In a placebo-controlled study, continuous infusion of lidocaine caused reduced pain scores in patients with peripheral nerve injury, and in a separate study, intravenous lidocaine reduced pain intensity associated with postherpetic neuralgia (PHN). [Mao, J. and L. L. Chen, Systemic lidocaine for neuropathic pain relief. Pain, 2000. 87: p. 7-17. Anger, T., et al., Medicinal chemistry of neuronal voltage-gated sodium channel blockers. Journal of Medicinal Chemistry, 2001. 44 (2): p. 115-137]. Lidoderm.RTM., lidocaine applied in the form of a dermal patch, is currently the only FDA approved treatment for PHN. [Devers, A. and B. S. Galer, Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-label study. Clinical Journal of Pain, 2000. 16 (3): p. 205-208].

[0006]In addition to neuropathic pain, sodium channel blockers have clinical uses in the treatment of epilepsy and cardiac arrhythmias. Recent evidence from animal models suggests that sodium channel blockers may also be useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis (MS). [Clare, J. J., et al. And Anger, T., et al].

SUMMARY OF THE INVENTION

[0007]The present invention is directed to benzazepinone compounds which are sodium channel blockers useful for the treatment of chronic and neuropathic pain. The compounds of the present invention are also useful for the treatment of other conditions, including urinary incontinence, pruritis, itchiness, allergic dermatitis, and disorders of the CNS such as anxiety, depression, epilepsy, manic depression and bipolar disorder. This invention also provides pharmaceutical compositions comprising a compound of the present invention, either alone, or in combination with one or more therapeutically active compounds, and a pharmaceutically acceptable carrier.

[0008]This invention further comprises methods for the treatment of acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain and disorders of the CNS including, but not limited to, epilepsy, manic depression, depression, anxiety and bipolar disorder comprising administering the compounds and pharmaceutical compositions of the present invention. . . .

(Public record not subject to copyright.)

http://appft.uspto.gov/netacgi/nph-P...DN/20090181946

Mike