resiniferatoxin and Pelvic-Pain

Recent years have brought dramatic advances in the clinician's ability to offer effective pharmacotherapy to patients who have interstitial cystitis. Medical treatments have been developed and applied to reduce the interstitial cystitis symptoms of pelvic pain and urinary urgency/frequency, and to address underlying causes of the disorder. In addition, advances in the understanding of the natural history of interstitial cystitis have revealed that it is insidiously progressive and the classical definition--rare, severe and difficult to treat--is in fact the relatively uncommon, advanced stage of a disorder that affects most individuals in a mild-to-moderate and readily treatable form. This recognition has led to the identification of large numbers of previously unsuspected cases of interstitial cystitis, and the successful treatment of many individuals in the early stages of interstitial cystitis when it is far more responsive to therapy. A heparinoid-based multimodal medical regimen can effectively control symptoms and address disease pathophysiology in the majority of cases. Intravesical therapeutic solutions are new and promising adjunctive therapies that can offer immediate symptom relief during symptom flares, and for patients who are just beginning medical therapy.

Topics: Administration, Intravesical; Analgesics, Non-Narcotic; Anesthetics, Local; Anti-Inflammatory Agents; Clinical Trials as Topic; Cystitis, Interstitial; Dimethyl Sulfoxide; Diterpenes; Drug Administration Schedule; Drug Therapy, Combination; Heparinoids; Humans; Lidocaine; Neurotoxins; Pelvic Pain; Pentosan Sulfuric Polyester; Sodium Bicarbonate

Present therapeutic approaches to control hypersensitive disorder of the lower urinary tract and bladder pain are clinically and scientifically unsatisfactory. We performed a randomized placebo controlled study with followup after 1 and 3 months using intravesical resiniferatoxin to treat hypersensitive disorder and bladder pain.. We prospectively randomized 18 patients into 2 groups to receive a single dose of 10 nM. resiniferatoxin intravesically (group 1) or a placebo saline solution only (group 2). All patients had at least a 6-month history of frequency, nocturia, urgency and symptoms of pelvic pain as well as no urinary tract infection within the last 3 months, functional disorders of the lower urinary tract, or other vesical or urethral pathology. Pretreatment voiding pattern and pain score were recorded. Patients were evaluated after 30 days (primary end point) and 3 months (secondary end point).. The 2 groups were adequately homogeneous in regard to patient age, sex ratio, disease duration, voiding pattern and pain score. At the primary end point mean frequency plus or minus standard error of mean was decreased from 12. 444 +/- 0.70 voids to 7.111 +/- 0.67 and nocturia from 3.777 +/- 0. 27 to 1.666 +/- 0.16 (p <0.01). We observed a lesser significant improvement in mean frequency in group 1 at the secondary end point to 10.444 +/- 0.94 voids (p <0.05). No significant modification was noted in patients assigned to placebo. Mean pain score significantly decreased in group 1 at the primary end point from 5.555 +/- 0.29 to 2.666 +/- 0.23 (p <0.01) but not at the secondary end point (4.777 +/- 0.66, p >0.05). No statistically significant improvement in mean pain score was observed in placebo group 2. During resiniferatoxin infusion 4 group 1 patients noticed a light warm or burning sensation at the suprapubic and/or urethral level.. Intravesical resiniferatoxin may significantly improve the voiding pattern and pain score in patients with hypersensitive disorder and bladder pain. Because resiniferatoxin did not cause a significant warm or burning sensation at the suprapubic and/or urethral level, it may be considered a new strategy for treating hypersensitive disorder and bladder pain. However, further studies are necessary to confirm our results and define the resiniferatoxin mechanism of action, dose and necessary treatment schedule.

Topics: Administration, Intravesical; Adult; Analysis of Variance; Diterpenes; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neurotoxins; Pain Measurement; Pelvic Pain; Placebos; Prospective Studies; Urinary Bladder Diseases; Urinary Catheterization; Urination; Urination Disorders; Urodynamics

Chronic pelvic pain of unknown etiology is a common clinical condition and may develop as a result of cross-sensitization in the pelvis when pathological changes in one of the pelvic organs result in functional alterations in an adjacent structure. The aim of the current study was to compare transient receptor potential vanilloid 1 (TRPV1) activated pathways on detrusor contractility in vivo and in vitro using a rat model of pelvic organ cross-sensitization. Four groups of male Sprague-Dawley rats (N = 56) were included in the study. Animals received intracolonic saline (control), resiniferatoxin (RTX, TRPV1 agonist, 10(-7) M), 2,4,6-trinitrobenzene sulfonic acid (TNBS, colonic irritant), or double treatment (RTX followed by TNBS). Detrusor muscle contractility was assessed under in vitro and in vivo conditions. Intracolonic RTX increased the contractility of the isolated detrusor in response to electric field stimulation (EFS) by twofold (P ≤ 0.001) and enhanced the contractile response of the bladder smooth muscle to carbachol (CCh). Acute colonic inflammation reduced detrusor contractility upon application of CCh in vitro, decreased bladder capacity by 28.1% (P ≤ 0.001), and reduced micturition volume by 60% (P ≤ 0.001). These changes were accompanied by an increased number of nonmicturition contractions from 3.7 ± 0.7 to 15 ± 2.7 (N = 6 in both groups, P ≤ 0.001 vs. control). Desensitization of intracolonic TRPV1 receptors before the induction of acute colitis restored the response of isolated detrusor strips to CCh but not to EFS stimulation. Cystometric parameters were significantly improved in animals with double treatment and approximated the control values. Our data suggest that acute colonic inflammation triggers the occurrence of detrusor instability via activation of TRPV1-related pathways. Comparison of the results obtained under in vitro vs. in vivo conditions provides evidence that intact neural pathways are critical for the development of an overactive bladder resulting from pelvic organ cross talk.

Topics: Acute Disease; Animals; Carbachol; Cholinergic Agents; Colitis; Diterpenes; Electric Stimulation; Male; Models, Animal; Muscle Contraction; Pelvic Pain; Rats; Rats, Sprague-Dawley; Signal Transduction; Trinitrobenzenesulfonic Acid; TRPV Cation Channels; Urinary Bladder; Urinary Bladder, Overactive