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Intravesicular Treatment of Spastic Bladder

Capsaicin and Resiniferatoxin Therapy of Bladder Spasticity

Last updated 6 November 2001

Wise Young PhD MD, Professor II & Director
W M Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey
604 Allison Rd, Piscataway, NJ 08854-8082
tel: 732/445-2061, fax: 732/445-2063
email: wisey@pipeline.com, young@biology.rutgers.edu
web: http://carecure.rutgers.edu, http://sciwire.com

The overactive or spastic bladder is a significant problem for many people with spinal cord injury and other conditions where descending control of bladder function has been compromised. The spastic bladder contracts involuntarily while the sphincter is closed. This not only produces discomfort but also may lead to urine reflux into the ureters, increased kidney infections and damage. This is usually treated with anti-cholinergic drugs to relax the bladder but side-effects of such drugs may limit the useful of oral pharmaceutical approaches. While a number of surgical approaches are available to drain the bladder or to divert urine from the bladder, recent studies have suggested an interesting alternative approach to treating overactive bladders.

Many different pharmacological agents are currently under investigation for treating urinary incontinence due to overactive bladder (Wein, 2001). These include drugs aimed at blocking or enhancing a variety of neurotransmitters (GABA, opioids, serotonin, dopamine, glutamate, and norepinephrine). Anti-cholinergic drugs (such as Ditropan or oxybutinin chloride) are commonly used and increases bladder capacity and reduces bladder contractions. However, such drugs have typical anti-cholinergic side effects including dry mouth, blurred vision, constipation, somnolence, and impaired cognition. Instillation of oxybutinin directly into the bladder has been used to treat severe bladder spasticity that is refractory to oral oxybutinin, as described by Fowler (2000).

Capsaicin is a pepper compound that causes release and depletion of substance P, a neurotransmitter considered to be the sensory neurotransmitter that tells the spinal cord that the bladder is full (Kim & Chancellor, 2000). Resiniferatoxin (RTX) is potent toxin isolated from some species of Euphorbia, a cactus-like plant. Over 10 clinical trials (de Seze, et al. 1999a) indicate that intravesical administration of capsaicin or RTX effectively reduce bladder spasticity in over 200 patients with bladder spasticity from various causes. Long term histological safety and other factors appear to be reasonable although more long-term studies are needed. Two of the trials are placebo-controlled (deSeze, et al. 1999b). Capsaicin causes some initial transient increase in bladder contractions but this is followed by relaxation of the bladder that may last as long as a week in cats (Cheng, et al. 1999). The initial discomfort associated with the instillation of capsaicin, however, is a significant deterrent to more widespread use of the treatment (Chancellor & DeGroat, 1999). Peterson, et al. (1999) reported that capsaicin combined with lidocaine apparently was not effective.

Andersson (1999) describe a number of other pharmacological treatments of bladder spasticity. These include antimuscarinic drugs, beta-adrenoceptor agonists, alpha-adrenoceptor antagonists, drugs affecting membrane channels, prostaglandin synthetase inhibitors and several other agents. A number of new drugs are targeting acetylcholine release, including potassium channel openers. RTX appears to be the most promising of these. RTX is much more potent that capsaicin. Lazerri, et al. (1999) gave TRX to seven patients with detrusor hyperreflexia and were refractory to intravesical capsaicin. At 15 days after RTX treatment, the patients had no bladder spasticity and significantly higher bladder capacities. Several patients reported improvements in their symptoms. Cruz (1998) likewise found that resiniferatoxin did not evoked acute irritative urinary symptoms during bladder instillation.

Capsaicin is not very soluble in water and is therefore often administered in an alcohol solution. DeSeze, et al. (1998) showed that capsaicin's irritative effects do not differ from instillation of 30% ethanol. Wieart, et al. (1998) did a randomized, double-blind study comparing instillation of 30 mg capsaicin in 100 ml or 30% alcohol versus that received 200 ml of 30% alcohol alone in 12 people with various forms of spinal cord injury or multiple sclerosis. The capsaicin-treated group showed greater improvement than from the alcohol vehicle solution, extending up to a month after treatment. Dasgupta, et al. (1998) biopsied the bladders of 20 patients treated with intravesical capsaicin and did not find any pre- or malignant changes in the bladders of patients who have had repeated capsaicin instillations for up to five years.

Lazzeri, et al. (1997) compared the effects of intravesical capsaicin and RTX. They found that RTX does not produce warm or burning sensations at the suprapubic or urethral level during infusion and seems to have rapid desensitization but still had beneficial effects on bladders spastically. DeRidder, et al. (1997) reported capsaicin may have long-lasting effect, as long as 3-6 months after a single distillation. Kuo (1997), however, found that the effects of capsaicin on bladder response is limited to 6-12 hours. Lazzeri, et al. (1996) showed that intravesical capsaicin effective reduces severe bladder pain. Cruz, et al. (1996) found that capsaicin restored continence to 10 of 14 patients with bladder spasticity.

Capsaicin appears to work by depleting substance P and calcitonin-gene related peptide (CGRP) expressing neurons and terminals in the skin and administration of nerve growth factor (NGF) reverses the effects of capsaicin in rats (Donnerer, et al. 1996). Chandiramani, et al. (1996) carried out 90 intravesical instillations in 30 patients with a variety of traumatic and non-traumatic spinal disease, comparing these treatments against two patients that received ethanol-containing vehicle only. They found that people with spinal cord diseases tended to show increased bladder activity and discomfort during the instillation of the drug. To resolve this problem, they instilled local anesthetic agents into the bladder prior to capsaicin treatment and found that this did not alter the beneficial effects of the capsaicin.

Geirsso, et al. (1995) examined 10 patients with bladder spasticity associated with spinal cord injury. Capsaicin instillation improved bladder function in 9 of the 10 patients. The effects lasted 2 to 7 months. Immediately after the capsaicin administration, instillation of ice water (which normally strongly stimulates strong bladder contractions) had little effect. Barbanti, et al. (1993) gave the capsaicin every two weeks and suggest that the mechanism of action is not related to desensitization but rather due to counter-irritation of the bladder. Animal studies suggest that normal rats desensitize to repeated administration of capsaicin or RTX. Craft & Porreca (1994) gave rats RTX four times over 7-14 days and found nearly complete recovery of bladder function within 7-14 days.

In summary, capsaicin and resiniferatoxin are two promising therapies for bladder spasticity. Intravesical capsaicin and RTX both reduced bladders spasticity for weeks and even months in humans. Because capsaicin is not very soluble in water, it is usually mixed into a solution of 30% ethanol. The study data suggest that the effects of capsaicin cannot be attributed to ethanol alone. Resiniferatoxin has similar effects as capsaicin but has less side effects and may be working through mechanisms that we do not yet understand.

References

1. Wein AJ (2001). Pharmacological agents for the treatment of urinary incontinence due to overactive bladder. Expert Opin Investig Drugs. 10 (1): 65-83. Summary: Although the exact aetiology of overactive bladder is unknown to date, pharmacological therapy has been targeted to both the central and peripheral nervous systems. Potential CNS targets include GABA, opioid, serotonin (5-HT), dopamine and glutaminergic receptors as well as the alpha-adrenoceptors. Potential PNS targets include muscarinic receptors, calcium and potassium channels and alpha- and beta-adrenergic receptors. Since acetylcholine is the primary excitatory neurotransmitter involved in bladder (detrusor) contraction and emptying, anticholinergic agents are the primary compounds used clinically to decrease involuntary detrusor contractions. Anticholinergic therapy has a stabilising effect on the bladder (detrusor muscle); increases bladder capacity; decreases frequency of involuntary detrusor contractions; and delays the initial urge to void, but does not affect warning time. However, the clinical utility of antimuscarinic therapy is limited by the lack of receptor selectivity, resulting in the classic anticholinergic side effects of dry mouth, blurred vision, constipation and potentially, CNS effects such as somnolence and impaired cognitive function. These unwanted side effects often result in premature discontinuation of therapy and poor compliance. Previous attempts to develop uroselective alpha-adrenergic receptor antagonists have not been successful and although research continues, the hope that this class of agents would be viable alternatives to the anticholinergics remains to be proven in the clinical setting. The recent demise of several potassium channel openers does not augur well for the future of this class of agent. The reasons for the discontinuation of trials with these agents have not been fully elucidated, but one must assume that they were not uroselective and the cardiovascular side effects rendered them less than useful clinically. The serotonin re-uptake inhibitors appear to be promising novel therapeutic agents aimed at controlling bladder over-activity through specific CNS pathways. The sensory side of the micturition reflex is a potential therapeutic target. Agents to desensitise afferent nerve endings involved in C-fibre afferent reflexes include capsaicin and resiniferatoxin. Their clinical applicability is currently being evaluated. Finally, the recent findings related to the role of the P2X3 receptor in the sensory aspects of bladder filling have created new interest in the future development of agents that will improve the management of this prevalent and debilitating condition. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11116281> Division of Urology, University of Pennsylvania Health System, First Floor Rhoads Pavilion, 3400 Spruce Street, Philadelphia, PA 19104, USA. larmer@mail.med.upenn.edu

2. Fowler CJ (2000). Intravesical treatment of overactive bladder. Urology. 55 (5A Suppl): 60-4; discussion 66. Summary: Intravesical agents for overactive bladder have mostly been used in patients with neurogenic bladder disorders. The patients have usually had severe detrusor hyperreflexia (DH) plus a disorder of bladder emptying, and because of residual urine have been performing intermittent self-catheterization. Intravesical medication has therefore been appropriate. Strategies for treating DH have been either to lessen the parasympathetic efferent activity or to de-afferent the bladder. Two types of treatment have been used: intravesical medications that block pelvic nerve-detrusor smooth muscle cholinergic transmission, or agents that block the afferent arm of the reflex that causes detrusor contraction. Intravesical oxybutynin is thought to have some local anesthetic effect, although its main mode of action is to block cholinergic transmission. It has been demonstrated to be effective in resistant DH. Intravesical atropine has been demonstrated to increase bladder capacity but its usefulness in the clinical management of DH has yet to be demonstrated. Local anesthetics can increase bladder capacity, but the effect is short-lived. Longer-acting agents may have a selective neurotoxic effect on capsaicin-sensitive bladder afferents. Many patients worldwide have now been treated with intravesical capsaicin. Resiniferatoxin (RTX) is an ultrapotent capsaicin analog that has the significant advantage of being a nonirritant. Intravesical agents appear to be attractive alternatives to oral medication and hold the exciting possibility of selectively targeting end organs implicated in pathophysiologic responses. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10767456> Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, UCLH, Institute of Neurology, University College London, London, United Kingdom.

3. Kim DY and Chancellor MB (2000). Intravesical neuromodulatory drugs: capsaicin and resiniferatoxin to treat the overactive bladder. J Endourol. 14 (1): 97-103. Summary: Current pharmacologic treatment of the overactive bladder relies on anticholinergic drugs. However, these drugs often have troublesome side effects and frequently are given in doses insufficient to restore continence in patients with detrusor instability. We present the background and basic and clinical research dealing with intravesical instillation of capsaicin and resiniferatoxin as treatments for the overactive bladder. Capsaicin is the main pungent ingredient in "hot" peppers of the genus Capsicum. It is a specific neurotoxin that desensitizes C-fiber afferent neurons, which may be responsible for the signals that trigger detrusor overactivity. Studies with capsaicin over the past 8 years have demonstrated clinical efficacy with minimal long-term complications. Most of these studies have also shown that the acute pain and irritation associated with capsaicin are a major deterrent to widespread use. Resiniferatoxin (RTX), an ultrapotent analog of capsaicin that appears to have similar efficacy but with much less acute side effects may be more useful. Intravesical instillation of capsaicin or resiniferatoxin is a promising treatment for the overactive bladder. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10735579> Division of Urologic Surgery, University of Pittsburgh School of Medicine, Pennsylvania, USA.

4. De Seze M, Wiart L, Ferriere JM, de Seze MP, Joseph PA and Barat M (1999). [Intravesical instillations of capsaicin in urology: from pharmacological principles to therapeutic applications]. Prog Urol. 9 (4): 615-32. Summary: Capsaicin is a specific neurotoxin for type C nonmyelinated vesical afferent fibres involved in the transmission of nociceptive stimuli and reorganization of voiding reflexes in disease. The presence of afferents sensitive to vanilloid substances in the human bladder suggests the potential value of intravesical instillations of capsaicin in patients with symptoms of bladder hypersensitivity or bladder hyperactivity. Ten clinical trials document the efficacy and safety of vesical instillation of capsaicin in 200 patients with neurological or non-neurological lower urinary tract symptoms. The objective of this review is to analyse these various publications in order to define the indications and practical conditions of intravesical instillation of capsaicin. The value of intravesical capsaicin in neurogenic bladder hyperactivity has been clearly demonstrated. In non-neurological indications, the diversity of instillation protocols and the heterogeneity of the evaluation parameters complicate analysis of the results. Repeated low-dose capsaicin appears to be useful in bladder hyperactivity, but the value of capsaicin is uncertain in idiopathic detrusor instability. Transient adverse effects are almost systematically observed after intravesical capsaicin. The short-term and medium-term local histological safety appears to be satisfactory, but needs to be documented in the long-term. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10555213> Service de Reeducation Fonctionnelle Neurologique, Hopital Pellegrin Tastet-Girard, Bordeaux, France.

5. Cheng CL, Liu JC, Chang SY, Ma CP and de Groat WC (1999). Effect of capsaicin on the micturition reflex in normal and chronic spinal cord-injured cats. Am J Physiol. 277 (3 Pt 2): R786-94. Summary: The effect of capsaicin (10-80 mg/kg sc) on reflex activity of the urinary bladder was examined in anesthetized normal as well as anesthetized and awake chronic spinal cord-injured (SCI) cats. In normal cats, capsaicin elicited a transient increase in the frequency of isovolumetric bladder contractions and reduced the volume threshold for inducing micturition, but did not depress the amplitude of bladder contractions or the reflex firing on bladder nerves. In anesthetized SCI cats, capsaicin depressed reflex bladder activity and firing on bladder nerves. In awake SCI cats, capsaicin initially decreased the volume threshold for inducing micturition; however, after a delay of 3-6 h the volume threshold increased and intravesical voiding pressure decreased. This effect persisted for 4-12 days. It is concluded that capsaicin-sensitive C fiber bladder afferents are not involved in initiating reflex micturition in normal cats, but play an essential role in triggering automatic micturition in chronic SCI cats. The results are consistent with the clinical data indicating that C fiber bladder afferents contribute to bladder hyperactivity and incontinence in patients with neurogenic bladder dysfunction. <http://ajpregu.physiology.org/cgi/content/full/277/3/R786
http://ajpregu.physiology.org/cgi/content/abstract/277/3/R786
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10484496> Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung 407, Taiwan, Republic of China. clcheng@vghtc.vghtc.gov.tw

6. De Seze M, Wiart L, Ferriere J, de Seze MP, Joseph P and Barat M (1999). Intravesical instillation of capsaicin in urology: A review of the literature. Eur Urol. 36 (4): 267-77. Summary: OBJECTIVES: Interest in the intravesical instillation of capsaicin is growing among urologists. Its efficacy on detrusor hyperreflexia, hypersensitive bladder disorders and bladder pain has been reported in several studies. However, the lack of common evaluation parameters and the absence of consensus concerning a protocol of instillation hamper the interpretation of results. The purpose of this review is to better delineate the indications and optimum protocol for intravesical use of capsaicin. METHODS: Eight open and two placebo-controlled human clinical trials were analyzed. All 200 patients involved had lower urinary tract disorders. RESULTS: Clinical or urodynamic symptoms improved in 84.3% of the patients who received intravesical capsaicin for neurogenic hyperreflexic bladder, a significantly greater efficacy than that of placebo. Capsaicin may also be beneficial in patients who have non-neurogenic disorders. Whether or not the patients has a neurologic deficit, side effects appear during and in the period immediately following instillation. CONCLUSIONS: Intravesical capsaicin appears to be indicated in neurogenic hyperreflexic bladder, but is less effective against detrusor instability, hypersensitive bladder disorders or pelvic pain. The best instillation protocol and long-term tolerance remain to be established. <http://www.online.karger.com/library/karger/renderer/dataset.exe?jcode=EUR&action=render&rendertype=fulltext&uid=EUR.eur36267
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10473984> Service de Reeducation Fonctionnelle Neurologique, Centre Hospitalier Universitaire de Bordeaux, Hopital Pellegrin Tastet-Girard, Bordeaux, France. m.deseze@aol.fr

7. Chancellor MB and de Groat WC (1999). Intravesical capsaicin and resiniferatoxin therapy: spicing up the ways to treat the overactive bladder. J Urol. 162 (1): 3-11. Summary: PURPOSE: Pharmacological treatment of the overactive bladder relies on partially blocking the efferent parasympathetic innervation to the detrusor with anticholinergic drugs. However, often these drugs have troublesome side effects and doses are insufficient to restore continence in patients with detrusor instability. We present the background, basic and clinical research with intravesical instillation of capsaicin and resiniferatoxin as treatments for the overactive bladder. MATERIALS AND METHODS: Capsaicin, the main pungent ingredient in hot peppers of the genus Capsicum, is a specific neurotoxin that desensitizes C fiber afferent neurons which may be responsible for signals that trigger detrusor overactivity. RESULTS: In the last 6 years studies have demonstrated encouraging improvement in lower urinary tract symptoms with minimal long-term complications. Most of these studies have also demonstrated that the acute pain and irritation associated with capsaicin are major deterrents to widespread use. Therefore, resiniferatoxin, an ultra-potent analogue of capsaicin which appears to have similar efficacy but less acute side effects, may be more useful. CONCLUSIONS: Intravesical capsaicin and resiniferatoxin are novel and promising treatments for the overactive bladder, with profound basic and clinical implications. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10379728> Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania, USA.

8. Petersen T, Nielsen JB and Schroder HD (1999). Intravesical capsaicin in patients with detrusor hyper-reflexia--a placebo-controlled cross-over study. Scand J Urol Nephrol. 33 (2): 104-10. Summary: The aim of this study was to determine whether intravesical treatment with capsaicin could block detrusor hyper-reflexia (DH) and alter the substance P content, nerve fibres and mucosa of the bladder. Twelve patients with spinal cord disease with DH and urinary incontinence resistant to anticholinergic treatment underwent intravesical administration of 50 ml 2% lignocaine, followed by either 100 ml 1 mmol/l capsaicin or 100 ml physiological saline for 30 min. Cross-over to the alternative treatment took place after 4 weeks. Varying degrees of burning sensation were experienced by all but one patient during the capsaicin treatment and precluded the possibility of conducting studies of this type in a blind manner. No preference for capsaicin treatment was found, and micturition and VAS scores were unchanged after treatment with capsaicin. The mean volume of the contents of the bladder at which DH first appeared was 175 ml after saline and 195 ml after capsaicin (mean difference 20 ml with a 5% confidence interval from -25 to 65). Bladder biopsies taken 2 weeks after treatment with capsaicin showed more pronounced inflammation, superficial haemorrhage, squamous epithelial metaplasia and a more condensed bladder stroma. Immunohistochemical staining for substance P and neuronal cell adhesive molecule revealed the presence of small terminal axons and small nerve bundles in all of the biopsies. Intravesical treatment with capsaicin did not have a beneficial effect on DH or a destructive effect on nerve fibres. It did, however, produce significant reactive changes in the mucosa of the bladder. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10360450> Neurological Department, Aarhus University Hospital, Denmark.

9. Andersson KE (1999). Advances in the pharmacological control of the bladder. Exp Physiol. 84 (1): 195-213. Summary: To effectively control bladder activity, and to treat urinary incontinence caused by bladder overactivity, identification of suitable targets for pharmacological intervention is necessary. Such targets may be found in the central nervous system (CNS) or peripherally. The causes of bladder overactivity are not known, but theoretically increased afferent activity, decreased inhibitory control in the CNS and/or peripheral ganglia, and increased sensitivity of the detrusor to efferent stimulation may be involved. Several CNS transmitters may modulate voiding, but few drugs with a defined CNS site of action have been developed for treatment of voiding disorders. Potentially, drugs affecting GABA, opioid, 5-HT, noradrenaline, dopamine, or glutamatergic receptors and mechanisms can be developed, but a selective action on the lower urinary tract may be difficult to obtain. Traditionally, drugs used for treatment of bladder overactivity have had a peripheral site of action, mainly the efferent neurotransmission or the detrusor muscle itself. Antimuscarinic drugs, beta-adrenoceptor agonists, alpha-adrenoceptor antagonists, drugs affecting membrane channels, prostaglandin synthetase inhibitors and several other agents have been used. However, none of them has been developed specifically for treatment of bladder disorders, and their efficacy, as judged from controlled clinical trials (where performed), is often limited. Recent information on the alpha-adrenoceptor, beta-adrenoceptor (beta 3), and muscarinic receptor subtypes of the human detrusor and outflow region can be the basis for the development of compounds with effect on bladder overactivity and with improved tolerance. New ways of decreasing acetylcholine release may represent a promising way of controlling bladder contraction. Potassium channel (KATP) openers are theoretically attractive, but the drugs available so far have targeted vascular rather than bladder smooth muscle, which has limited their clinical use. However, new drugs belonging to these groups with an interesting profile of action have been developed. Drugs decreasing afferent activity represent an attractive therapeutic approach and transmitters of afferent nerves and their receptors are possible targets for pharmacological interventions. Tachykinins, such as substance P, neurokinins A and B, and other neuropeptides have been demonstrated in nerves of the lower urinary tract and have been shown to influence bladder function. Agents affecting these nerves by causing release of tachykinins, such as capsaicin and resiniferatoxin, given intravesically can be effective in some cases of bladder overactivity, and agents antagonizing tachykinin receptors may also be of therapeutic interest. New drugs specifically directed for control of bladder activity are under development and will hopefully lead to improved treatment of urinary incontinence. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10081718> Department of Clinical Pharmacology, Lund University Hospital, Sweden.

10. Lazzeri M, Spinelli M, Beneforti P, Zanollo A and Turini D (1998). Intravesical resiniferatoxin for the treatment of detrusor hyperreflexia refractory to capsaicin in patients with chronic spinal cord diseases. Scand J Urol Nephrol. 32 (5): 331-4. Summary: OBJECTIVE: Resiniferatoxin (RTX), a substance isolated from some species of Euphorbia, a cactus-like plant, shows pharmacological effects similar to those of capsaicin. We have studied the possibility of treating detrusor hyperreflexia refractory to intravesical capsaicin in patients with chronic spinal cord injuries, thereby providing insight into the mechanism of action of RTX on sensory neurons and its possible future pharmacological and clinical use. MATERIALS AND METHODS: RTX saline solution (30 ml at a concentration of 10(-5) M) was instilled into the bladder of 7 patients with detrusor hyperreflexia, refractory to intravesical capsaicin therapy, and left in place for 30 min. Effects on bladder function were monitored during the treatment and at follow-up (15 days and 4 weeks later). RESULTS: Fifteen days after RTX, the mean cystomanometric capacity increased significantly from 190 ml +/- 20 ml to 407.14 ml +/- 121.06 (p < 0.01), and it remained high four weeks later (421.66 +/- 74.40 p < 0.01). After 15 days, four patients had a pharmacologically induced detrusor areflexia. They emptied their bladders by clean intermittent catheterization. After four weeks, only two patients still had a pharmacologically induced detrusor areflexia. Clinically, three patients remained dry, and the other three reported a significant improvement in their incontinence and symptoms (frequency, urgency and nocturia). CONCLUSIONS: By interfering with sensory unmyelinated fibers, intravesical RTX seems to be a promising treatment option for selected cases of detrusor hyperreflexia. The ideal dosage and treatment interval have not yet been established, and further studies are necessary to confirm our preliminary results. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9825395> Department of Urology, University of Ferrara, Italy.

11. Cruz F (1998). Desensitization of bladder sensory fibers by intravesical capsaicin or capsaicin analogs. A new strategy for treatment of urge incontinence in patients with spinal detrusor hyperreflexia or bladder hypersensitivity disorders. Int Urogynecol J Pelvic Floor Dysfunct. 9 (4): 214-20. Summary: Recent experimental studies have identified a category of unmyelinated type C bladder afferent fibers in the pelvic nerves which are extremely sensitive to capsaicin. Sensory input conveyed by these fibers triggers a spinal reflex which, in chronic spinalized animals, facilitates and controls micturition. In addition, bladder C fibers were also shown to have a role in bladder pain perception. In humans capsaicin-sensitive afferent fibers also innervate the bladder and contribute to the reflexogenic control of the detrusor muscle and to bladder pain perception. Desensitization of such fibers by intravesical administration of capsaicin, presumably by blocking sensory transmission, has been shown to reduce involuntary micturition and to increase bladder capacity in patients with detrusor hyperreflexia of spinal origin, and to reduce the intensity of bladder pain in patients with bladder hypersensitivity. Very recently, resiniferatoxin, an ultrapotent capsaicin analog, was shown to have a similar clinical effect in this subset of patients. However, unlike capsaicin, resiniferatoxin did not evoke acute irritative urinary symptoms during bladder instillation. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9795827> Department of Urology, Hospital Sao Joao, Oporto, Portugal.

12. De Seze M, Wiart L, Joseph PA, Dosque JP, Mazaux JM and Barat M (1998). Capsaicin and neurogenic detrusor hyperreflexia: a double-blind placebo-controlled study in 20 patients with spinal cord lesions. Neurourol Urodyn. 17 (5): 513-23. Summary: The aim of this study was to investigate the efficacy and tolerance of capsaicin, a neurotoxin for C-fiber afferents, applied intravesically in the treatment of detrusor hyperreflexia. Eleven male and nine female patients who had spinal cord lesions caused by multiple sclerosis (12) or trauma (eight) resulting in detrusor hyperreflexia with urge incontinence and pollakiuria were randomized to receive one intravesical instillation of either 30 mg capsaicin in 100 ml 30% ethanol or 100 ml 30% ethanol alone. The patients were evaluated clinically (voiding diary) and urodynamically (maximum cystometric capacity, maximum detrusor pressure, first and normal desire to void) before and 30 days after the instillation. On day 30, the 10 patients who received capsaicin had significant decreases in 24-h voiding frequency from 9.3+/-6.1 to 6.7+/-3.8 (P=0.016) and leakages from 3.9+/-1.6 to 0.6+/-0.8 (P=0.0008); their maximum cystometric capacity increased from 169+/-68 to 299+/-96 ml (P=0.01) and maximum detrusor pressure decreased from 77+/-24 to 53+/-27 cm H2O. There were no significant changes in the control group. In seven subjects in each group, instillation triggered immediate side effects (suprapubic pain, sensory urgency, flushes, hematuria, autonomic hyperreflexia) that resolved within 2 weeks. Intravesical capsaicin significantly improves clinical and urodynamic parameters of detrusor hyperreflexia in spinal cord-injured patients. Side effects are frequent, tolerable, and identical to those induced by 30% ethanol alone. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9776014> Service de Reeducation Fonctionnelle Neurologique, Centre Hospitalier Universitaire de Bordeaux, Hopital Pellegrin Tastet-Girard, France.

13. Wiart L, Joseph PA, Petit H, Dosque JP, de Seze M, Brochet B, Deminiere C, Ferriere JM, Mazaux JM, N'Guyen P and Barat M (1998). The effects of capsaicin on the neurogenic hyperreflexic detrusor. A double blind placebo controlled study in patients with spinal cord disease. Preliminary results. Spinal Cord. 36 (2): 95-9. Summary: PURPOSE: Several recent open studies have provided encouraging results as to the efficacy of intravesical installations of capsaicin for neurogenic hyperreflectivity. The present trial was performed to verify these results under controlled conditions. Intravesical installation of capsaicin represents a new therapeutic hope for the treatment of the neurogenic hyperreflexic bladder. METHOD: This randomized, double-blind study compared the results of the intravesical installation of 30 mg capsaicin in 100 ml of 30% alcohol (experimental group) with those of installing 100 ml 30% alcohol alone (control group). On day 0 and day 30, urodynamic and biopsic examinations were performed in all subjects of each group. PATIENTS: All the subjects included in the study had a functionally disabling form of neurogenic hyperreflexic bladder resistant to the usual therapies. Cystoscopy and retrograde cystography were performed to exclude any patient who presented with a tumor-like lesion or had vesicoureteral reflux. RESULTS: Twelve paraplegic of tetraplegic subjects, seven women and five men whose average age was 46, were included. Eight had multiple sclerosis, and four had sustained a traumatic spinal cord injury. The patients were randomly separated into two groups of six. Initially, there was no clinical or urodynamic differences in these groups. Installation immediately triggered side effects and during the first 7 days (suprapubic burning sensation, sensory urgency, hot flushes, autonomic hyperreflexia, hematuria) in five of the six subjects in both groups. Bladder biopsy revealed no significant deterioration. On day 30, there was improvement in all of the experimental-group of patients with significant regression of leakage (P = 0.002) and of sensory urgency (P = 0.01). Only one control subject had amelioration. Urodynamic examination showed a rise in bladder capacity from 172.5 to 312.3 ml in the experimental group, significantly greater (P = 0.03) than the rise from 129 to 175.3 ml observed in the control group. CONCLUSION: This trial fully confirms the efficacy of intravesical installations of capsaicin, an efficacy obtained at the cost of nonnegligible side effects. An intermediate-term follow-up of this treatment will be necessary before considering more widespread use of this agent. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9494998> Neuro Rehabilitation Unit Center, Bruges, France.

14. Dasgupta P, Chandiramani V, Parkinson MC, Beckett A and Fowler CJ (1998). Treating the human bladder with capsaicin: is it safe? Eur Urol. 33 (1): 28-31. Summary: OBJECTIVES: Although human contact with capsaicin has occurred over thousands of years, some uncertainty surrounds its status as a possible carcinogen. This is the first report of bladder biopsies from patients who have been treated with capsaicin over a 5-year period. METHODS: Between 1991 and 1996, 20 patients (9 males, 11 females; mean age 52.5 years, range 40-70 years) with intractable detrusor hyperreflexia have had repeated instillations of intravesical capsaicin (1-2 mmol/l). The number of treatments per patient varied between 1 and 17 (total = 82; average 6/patient). The surveillance programme involved repeated flexible cystoscopy and bladder biopsies before and after capsaicin. Cryostat sections were stained with haematoxylin-eosin and examined by light microscopy. RESULTS: None of the bladder biopsies have shown metaplasia, dysplasia, flat carcinoma in situ, papillary or solid invasive cancer. CONCLUSIONS: No pre-malignant of malignant change has been found in biopsies of patients who had repeated capsaicin instillations for up to 5 years. However, as the morphological effects of chemical carcinogens may not be apparent for 10 years, further surveillance is being continued. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9471038> Uro-Neurology Department, Institute of Neurology, UCL Hospitals Trust, London, UK.

15. Lazzeri M, Beneforti P and Turini D (1997). Urodynamic effects of intravesical resiniferatoxin in humans: preliminary results in stable and unstable detrusor. J Urol. 158 (6): 2093-6. Summary: PURPOSE: Resiniferatoxin, a substance isolated from some species of euphorbia, a cactus-like plant, presents pharmacological effects similar to those of capsaicin. We studied the urodynamic effects of intravesical resiniferatoxin* in normal subjects and patients with unstable detrusor contraction to provide insight into the action mechanism of the molecule on sensory neurons and possible future pharmacological and clinical use. MATERIALS AND METHODS: A total of 15 subjects with normal (8 patients) or unstable detrusor muscle (1 with detrusor instability and 6 with detrusor hyperreflexia) underwent urodynamic assessment during and after intravesical instillation of resiniferatoxin. Volume required to elicit the first desire to void, maximum bladder capacity and maximum bladder pressure were recorded during instillation of resiniferatoxin at a flow rate of 20 ml. per minute (normal subjects) or 15 minutes after instillation of 30 cc of a saline solution containing 10(-8) M. of resiniferatoxin and kept for 30 minutes in patients with unstable detrusor. The experiment was examined by the analysis of variance for repeated measures and post hoc comparisons were performed by Tukey-Kramer procedure. A p value <0.05 was accepted as significant. RESULTS: Resiniferatoxin did not decrease the volume required to elicit the first desire to void and did not produce warm or burning sensations at the suprapubic/urethral level during infusion in subjects with normal detrusor function. In patients with bladder hyperactivity mean bladder capacity increased from 175.28 ml. plus or minus standard deviation 36.05 to 280.85 ml. plus or minus standard deviation 93.33 (p <0.01) immediately after treatment, and no significant modification of bladder pressure was recorded. Four weeks after treatment, bladder capacity remained increased in 2 patients but mean capacity did not increase significantly from 175.28 ml. plus or minus standard deviation 36.053 to 216.71 plus or minus standard deviation 86.91. The 2 patients with stable increase of bladder capacity reported significant clinical improvement of frequency, nocturia and incontinence 4 weeks later. CONCLUSIONS: Our results suggest that in humans there may be substantial differences in urodynamic effects between resiniferatoxin and capsaicin when the drugs are instilled into the bladder. Further studies, in vitro and in vivo, are necessary to define the pharmacological and clinical effects of resiniferatoxin. Because resiniferatoxin did not produce warm or burning sensations at the suprapubic/urethral level during infusion and seems to have rapid desensitization, it could be an interesting alternative to intravesical capsaicin in the treatment of select cases of bladder hyperactivity. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9366319> Department of Urology, University of Ferrara, Firenze, Italy.

16. De Ridder D, Chandiramani V, Dasgupta P, Van Poppel H, Baert L and Fowler CJ (1997). Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: a dual center study with long-term followup. J Urol. 158 (6): 2087-92. Summary: PURPOSE: We described the long-term outcome of intravesical capsaicin instillations in patients with urinary incontinence and compared its efficacy in 2 similar populations of patients with multiple sclerosis in a dual center study. MATERIALS AND METHODS: During 5 years 79 patients with intractable urinary incontinence have been treated with intravesical capsaicin. The majority of patients had spinal cord disease due to multiple sclerosis but 4 were neurologically normal. Cystometry was performed before and 4 to 6 weeks after intravesical instillation of 1 to 2 mmol./l. of capsaicin in 30% ethanol in saline. Instillations of vehicle (30% ethanol in saline) alone were carried out in 5 patients. RESULTS: In patients with phasic detrusor hyperreflexia complete continence was achieved in 44%, satisfactory improvement occurred in 36% and treatment failed in 20%. Clinical benefit from a single instillation lasted 3 to 6 months and was repeated in some patients with similar improvement. Capsaicin was ineffective in patients with poor bladder compliance and in neurologically normal patients with sensory urgency and detrusor instability. There was no clinical or urodynamic improvement in patients treated with vehicle alone. There have been no long-term complications. CONCLUSIONS: Our study shows that repeated instillations of intravesical capsaicin are effective in treatment of patients with detrusor hyperreflexia due to spinal cord disease and that effectiveness of the treatment persists at least 3 to 5 years. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9366318> Department of Uro-Neurology, National Hospital for Neurology and Neurosurgery, London, United Kingdom.

17. Kuo HC (1997). Reversibility of the inhibitory effect of intravesical capsaicin on the micturition reflex in rats. J Formos Med Assoc. 96 (10): 819-24. Summary: The reversibility of the inhibitory effect of capsaicin on the micturition reflex was investigated in adult rats. The experimental group (n = 38) were given 0.5 mL of 1 mmol/L intravesical capsaicin. After 30 minutes the bladder was evacuated, then the rats were allowed to recover for various times from 0 to 24 hours before cystometrography. Control rats (n = 6) were injected with saline. Immediately after capsaicin treatment, the bladders showed detrusor hyperactivity and high intravesical pressure during cystometrography. All capsaicin-treated bladders showed final urinary retention and hematuria developed in 32 of 38. At 6 hours after intravesical instillation of capsaicin, detrusor hyperactivity was reduced and the micturition reflex gradually reappeared. By 12 hours, micturition reflexes were noted in seven of eight bladders with a volume threshold equal to that of the control group. At 24 hours, the volume threshold for the micturition reflex was significantly greater in the capsaicin-treated group than in the control group. The amplitude of detrusor contractions at 6, 12, and 24 hours showed no significant difference from that in the controls. In vitro whole bladder contractility in response to electrical field stimulation, bethanechol, and KCl also showed no significant difference between the control and the experimental groups. The bladder weight increased as the recovery period increased, indicating the presence of neurogenic inflammation. From this study we conclude that capsaicin-induced micturition reflex inhibition in rats is reversible at 12 hours and the volume threshold for eliciting the micturition reflex continues to increase up to 24 hours after capsaicin treatment. These results may provide insight into the clinical application of capsaicin in the treatment of various voiding disorders in humans. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9343982> Department of Urology, Buddhist Tzu-Chi General Hospital, Hualien, Taiwan, ROC.

18. Lazzeri M, Beneforti P, Benaim G, Maggi CA, Lecci A and Turini D (1996). Intravesical capsaicin for treatment of severe bladder pain: a randomized placebo controlled study. J Urol. 156 (3): 947-52. Summary: PURPOSE: Present therapeutic approaches to control bladder pain are clinically and scientifically unsatisfactory, and pain in the lower urinary tract remains a challenge even to the skilled urologist. A randomized placebo controlled study was done to evaluate intravesical capsaicin for severe bladder pain. Followup was 6 months. MATERIALS AND METHODS: A total of 36 patients was prospectively randomized into those receiving 10 microM. intravesical capsaicin twice weekly for 1 month (group 1) or placebo (group 2). All patients had pelvic pain for at least 6 months, and had 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 immediately at the end of treatment (primary end point) and 6 months later (secondary end point). RESULTS: Both groups were adequately homogeneous with regard to age, sex ratio, duration of disease, voiding pattern and pain score. At both end points group 1 had significant improvement in frequency and nocturia but no improvement in urgency. No change was noted in group 2. A significant decrease in pain score was found in group 1 at the primary (mean plus or minus standard deviation 3.22 +/- 0.42, p < 0.01) and secondary (3.83 +/- 0.47, p < 0.01) end points compared to before treatment (5.61 +/- 0.40, chi-square with 2 degrees of freedom 29.25, p < 0.0001). A significant improvement was also observed in the placebo group, in which the pretreatment pain score (5.47 +/- 0.37) was decreased at the primary (4.47 +/- 0.36, p < 0.01) and secondary (4.48 +/- 0.34, p < 0.01, chi-square with 2 degrees of freedom 12.71, p < 0.002) end points. There were no statistically significant differences between the 2 groups. CONCLUSIONS: We confirmed the beneficial effect of intravesical instillation of capsaicin on voiding pattern in patients with hypersensitive disorders (frequency and nocturia). We could not confirm improvement in pain score after capsaicin treatment compared to placebo. Possibly a larger dose of capsaicin would be more effective in controlling pain and neurological disease of the bladder. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8709370> Department of Urology, University of Ferrara, Florence, Italy.

19. Cruz F, Guimaraes M, Silva C, Rio ME, Coimbra A and Reis M (1997). Desensitization of bladder sensory fibers by intravesical capsaicin has long lasting clinical and urodynamic effects in patients with hyperactive or hypersensitive bladder dysfunction. J Urol. 157 (2): 585-9. Summary: PURPOSE: Capsaicin was used to treat symptomatic patients with hyperactive or hypersensitive bladders. MATERIALS AND METHODS: Capsaicin solution (1 mM.) was instilled into the bladder of 16 patients with spinal hyperreflexia, bladder instability or hypersensibility. RESULTS: Frequency decreased in 14 patients and continence was achieved in 10 of 14 incontinent cases. Mean first desire to void and maximal cystometric capacity increased significantly. These effects lasted for 6 to 12 months and were renewed following repeat treatment. CONCLUSIONS: Bladder afferent desensitization with capsaicin is promising in patients with motor or sensory bladder dysfunction, although initial pungency might limit its use. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8996364> Department of Urology, Hospital S. Joao, Porto, Portugal.

20. Donnerer J, Amann R, Schuligoi R and Skofitsch G (1996). Complete recovery by nerve growth factor of neuropeptide content and function in capsaicin-impaired sensory neurons. Brain Res. 741 (1-2): 103-8. Summary: In the present study the ability of nerve growth factor (NGF) to facilitate the recovery of peptidergic primary sensory C-fibers after an acute capsaicin treatment (50 mg/kg s.c.) was investigated in adult rats. NGF (4 micrograms 1/day for 3 days) was injected into the plantar of one hind paw starting 24 h after the capsaicin treatment. Without NGF, there was a significant reduction of calcitonin gene-related peptide (CGRP) and substance P content of the paw skin and the sciatic nerve. CGRP and substance P levels were completely replenished in the NGF-treated paw skin and in the innervating sciatic nerve they even increased over control levels as determined 40 h after the last injection of NGF. CGRP levels also recovered in the contralateral paw and sciatic nerve, but no recovery was observed in other tissues such as the front paw, the auricle, or the urinary bladder. Mustard oil-induced neurogenic plasma extravasation, taken as a functional parameter for peptidergic primary sensory C-fibers, was significantly decreased after the capsaicin treatment and showed a complete recovery by NGF in the injected paw as well as in the contralateral paw skin. These results show that NGF not only was able to reverse the decrease of transmitter content caused by capsaicin but also restored the peripheral function of primary afferent neurons. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9001711> Department of Experimental and Clinical Pharmacology, University of Graz, Austria. josef.donnerer@kfunigraz.ac.at

21. Chandiramani VA, Peterson T, Duthie GS and Fowler CJ (1996). Urodynamic changes during therapeutic intravesical instillations of capsaicin. Br J Urol. 77 (6): 792-7. Summary: OBJECTIVE: To describe the technique for and urodynamic changes during therapeutic instillations of intravesical capsaicin in patients with detrusor hyper-reflexia. PATIENTS AND METHODS: Ninety intravesical instillations of capsaicin were performed as a therapeutic procedure in 30 patients; 21 patients had various causes of non-traumatic spinal cord disease, five patients were very severely neurologically impaired and were bed-bound with an indwelling catheter, and four were neurologically normal. Simultaneous cystometry was performed in 25 patients during the instillation of capsaicin; 100 mL of 1 or 2 mmol/L capsaicin in 30% ethanol/saline was instilled into the bladder for 30 min and two patients received 30% ethanol/saline only. The last 56 capsaicin treatments were preceded by the instillation of 40 mL of 2% lignocaine for 20 min. Detrusor hyper-reflexia was decreased and urinary continence improved for 3-6 months after a single instillation; the instillation was then repeated. Two patients who received only ethanol/saline showed no clinical or urodynamic improvement. RESULTS: The treatment was not abandoned in any patient due to discomfort and there were no short- or medium-term complications. All patients with spinal cord disease and phasic detrusor hyper-reflexia had similar, frequent and repetitive detrusor contractions during the instillation of capsaicin. These acute reactive contractions did not occur in the neurologically normal patients. Similarly, the instillation of intravesical lignocaine only caused no phasic detrusor contractions. Intravesical lignocaine instillation before capsaicin markedly reduced and sometimes abolished the detrusor overactivity and lessened the discomfort for the patients. The instillation of lignocaine before capsaicin did not alter the benefit from each instillation of intravesical capsaicin. CONCLUSION: A method has been developed for administering capsaicin intravesically which diminishes discomfort for the patient and in the short- and medium-term is free of complications. The study also provides functional evidence of the role of capsaicin-sensitive afferents in phasic detrusor hyper-reflexia due to spinal cord disease. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8705210> Department of Uro-neurology, National Hospital for Neurology and Neurosurgery, London, UK.

22. Geirsson G, Fall M and Sullivan L (1995). Clinical and urodynamic effects of intravesical capsaicin treatment in patients with chronic traumatic spinal detrusor hyperreflexia. J Urol. 154 (5): 1825-9. Summary: PURPOSE: We administered capsaicin, a neurotoxic substance causing a reversible suppression of C fiber afferent neuronal activity, in an attempt to decrease bladder hyperreflexia. MATERIALS AND METHODS: Capsaicin solution (2 mM.) dissolved in 30% alcohol was instilled into the bladders of 10 men with traumatic chronic spinal lesions and left in place for 30 minutes. Effects on bladder function, including response to cold stimulation, were recorded during treatment, immediately after instillation and at followup. RESULTS: Bladder function improved in all but 1 patient, which was expressed as an increase in cystometric capacity and/or a decrease in maximal detrusor pressure. The effects lasted for 2 to 7 months. Immediately after capsaicin administration the ice water test was negative in half of the patients. CONCLUSIONS: The positive effects on bladder function of capsaicin treatment can be explained by the blocking of C fiber afferents. The optimum dose and treatment interval are presently not established. The ice water test might possibly be used as an instrument to monitor the ideal dosage. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7563356> Department of Urology, Reykjavik City Hospital, Iceland.

23. Barbanti G, Maggi CA, Beneforti P, Baroldi P and Turini D (1993). Relief of pain following intravesical capsaicin in patients with hypersensitive disorders of the lower urinary tract. Br J Urol. 71 (6): 686-91. Summary: We have extended our earlier observations on pain relief produced by intravesical instillation of capsaicin (10 microM in saline) in patients with hypersensitive disorders of the lower urinary tract. Patients in group A (n = 15) received intravesical capsaicin on days 0, 14 and 28: on each occasion the drug produced a warm or burning sensation, reduction in bladder capacity and a delayed, transient improvement or disappearance of symptoms. Patients in group B (n = 5) received intravesical capsaicin (10 microM at cystometry) 3 times on day 0. The initial sensation of warmth was experienced on each occasion, indicating that no significant desensitisation has been produced by the first instillation. Clinical improvement similar to that found in group A was observed. Three patients (group C) received warm saline (42 degrees C) at cystometry. This produced a pricking sensation, no change at cystometry and no subjective clinical improvement. Apart from the initial sensation of warmth, no patient in group A or B experienced side effects, either local or systemic. These findings confirm that intravesical instillation of capsaicin has a beneficial effect on patients with hypersensitive bladder disorders. Counter-irritation rather than desensitisation of primary afferents could be a possible mechanism of action. Further studies are needed to establish whether the intravesical administration of capsaicin or capsaicin-like agents represents a new form of treatment for relief of bladder pain. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8343895> Department of Pharmacology, A. Menarini Pharmaceuticals, Florence, Italy.

24. Craft RM and Porreca F (1994). Temporal parameters of desensitization to intravesical resiniferatoxin in the rat. Physiol Behav. 56 (3): 479-85. Summary: Temporal factors affecting desensitization of bladder sensory afferents to the capsaicin-like irritant resiniferatoxin (RTX) were studied, to determine optimal treatment parameters for clinical application of such substances. Four days after implantation of a chronic cannula into the bladder dome, vehicle or RTX (0.1-10 nmol) was injected into the bladders of awake, freely moving rats four times at 60-min intervals for exposure durations of 5, 15, or 45 min, or at intervals of 15, 60, or 120 min (duration 5 min). The first RTX injection dose-dependently increased time spent engaged in abdominal licking. Regardless of exposure interval and duration, time spent licking increased to a lesser extent with each subsequent injection, indicating desensitization of sensory afferents. Magnitude and duration of desensitization were dose dependent for all exposure regimens, and there were few differences between groups. Desensitization at 24 h was also greater in rats exposed four times compared to rats exposed once. Following four exposures to RTX, nearly complete recovery occurred within 7-14 days, in a dose-dependent manner. Thus, magnitude and duration of desensitization to locally administered RTX depend primarily on dose and number of exposures to RTX; duration of exposure and interval between exposures within the ranges studied were less important determinants. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7972397> Department of Pharmacology, University of Arizona Health Sciences Center, Tucson 85724.

25. Lazzeri M, Barbanti G, Beneforti P, Maggi CA, Taddei I, Andrea U, Cantini C, Castellani S and Turini D (1995). Vesical-renal reflex: diuresis and natriuresis activated by intravesical capsaicin. Scand J Urol Nephrol. 29 (1): 39-43. Summary: In the last years the role of capsaicin sensitive innervation, in the activation of the micturition reflex, has been reported in many papers. In our experience, upon the intravesical administration of capsaicin in humans, we noticed an increase of diuresis. No interaction is known about the sensory innervation of the bladder and renal function, so we studied the possibility of the existence of a vesical-renal reflex arc. Twenty-one patients (9 men and 12 women) were randomised to receive intravesical infusion of saline solution containing 10 microM capsaicin. Urine output, glomerular renal filtrate (GRF) and effective plasma renal flow (EPRF), measured by Technetium-99m diethylenetetramine-penta-acetic acid (DTPA) renal scintigraphy, were recorded over twenty minutes before and after the intravesical administration of capsaicin. Urine density, [Na+] and [K+] concentration, and prostaglandin E2 excretion were also determined before and after intravesical administration of capsaicin or vehicle. Installation of saline solution containing 10 microM capsaicin produced a significant increase of mean urine output, an increase of GRF, of EPRF and of [Na+] and [K+] urine concentration. An increase, not statistically significant, was observed of PgE2 excretion. None of the patients treated with vehicle showed any modification of parameters examined. The present findings demonstrate a hitherto unrecognized effect: increased diuresis following selective chemical stimulation of bladder efferents with capsaicin. The renal diuretic response to intravesical capsaicin represents a working hypothesis about the possible involvement of a vesical-renal reflex arc organized at spinal or supraspinal level. <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7618049> Department of Urology, University of Ferrara, Italy.



©Wise Young PhD, MD


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