BACKGROUND: Neuromodulation, as a therapeutic modality for pain treatment, is an alternative to opioid therapies and therefore receiving increased interest and use. Neuromodulation at a peripheral nerve target, in the form of bilateral electrical pudendal nerve stimulation (bPNS), has been shown to reduce bladder hypersensitivity in rats and anecdotally reduces pain in humans with pelvic pain of urological origin. Recent studies have identified a role for spinal γ-aminobutyric acid (GABA) receptors in this effect. Concomitant medication use, such as benzodiazepines, could alter responses to neuromodulation, and so before the development of a clinical trial to confirm translation of this potential therapy, the potential interactions between acute and chronic use of benzodiazepines and bPNS were examined in a preclinical model. METHODS: Bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Diazepam (1–5 mg/kg intraperitoneal [i.p.]) or vehicle was administered acutely (with or without bPNS) and chronically (5 mg/kg subcutaneous [s.c.] daily for 2 weeks before the final experiment). bPNS was delivered as bilateral biphasic electrical stimulation of the mixed motor/sensory component of the pudendal nerves. Visceromotor responses (VMRs; abdominal muscle contractile responses to urinary bladder distension [UBD]) were used as nociceptive end points. Due to the profound effects of diazepam, the effect of midazolam (0.5–1.0 mg/kg i.p.) on VMRs and bPNS effects was also studied. RESULTS: Diazepam and midazolam both produced a dose-dependent, flumazenil-reversible inhibition of VMRs to UBD. bPNS resulted in statistically significant inhibition of VMRs to UBD in hypersensitive rats that had received vehicle injections. Select doses of diazepam and midazolam suppressed the inhibitory effect of bPNS on VMRs. CONCLUSIONS: This study suggests that inhibitory effects of bPNS on bladder pain could be suppressed in subjects receiving benzodiazepine therapy, suggesting that potential clinical testing of pudendal nerve stimulation for the treatment of painful bladder syndromes may be confounded by the use of benzodiazepines. Clinical assessment of other forms of neuromodulation should also be screened for impacts of benzodiazepines.

Neuromodulation (nerve stimulation) can produce analgesia. One form, bilateral pudendal nerve stimulation (bPNS), suppresses responses to urinary bladder distension (UBD) in hypersensitive rats. Drugs can modify this effect (eg, benzodiazepines, but not opioids, suppress bPNS effects). Prior to a clinical trial of bPNS effects on bladder pain, we felt it was prudent to survey the effects of medications commonly used in patients with bladder disorders.

Bilateral electrical pudendal nerve stimulation (bPNS) reduces bladder hypersensitivity in rat models of bladder pain and anecdotally reduces pain in humans with pelvic pain of urologic origin. The spinal neurochemical mechanisms of this antinociception are unknown. In the present study, bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Visceromotor responses (VMRs; abdominal muscle contractions) to urinary bladder distension (UBD) were used as a nociceptive endpoint under urethane-isoflurane anesthesia. bPNS consisted of bilateral biphasic electrical stimulation of the mixed motor/sensory component of the pudendal nerves. Following determination of the inhibitory effect of bPNS on VMRs, pharmacological antagonists were administered via an intrathecal catheter onto the lumbosacral spinal cord and bPNS effects on VMRs redetermined. bPNS resulted in statistically significant inhibition of VMRs to UBD in hypersensitive rats that was statistically reduced by the intrathecal administration of methysergide, WAY100636, CGP35348 and strychnine but was unaffected by naloxone, bicuculline, phentolamine, ondansetron and normal saline. This study suggests that inhibitory effects of bPNS may include serotonergic, GABA-B-ergic and glycinergic mechanisms suggesting the potential for interaction of the neuromodulatory effect with concommitant drug therapies.

OBJECTIVES:The present study compared the effectiveness of patterned frequency of spinal nerve stimulation (SNS) with continuous, fixed-frequency nerve stimulation in an animal model of the bladder reflex contraction (BRC). MATERIALS AND METHODS:In anesthetized female rats, wire electrodes were placed under each of the L6 spinal nerve to produce bilateral SNS. A cannula was placed into the bladder via the urethra, and the urethra was ligated to ensure an isovolumetric bladder. RESULTS:Using motor threshold intensity, continuous stimulation at fixed frequencies of 4 Hz (n = 5) and 10 Hz (n = 7) decreased the frequency of BRC of 71 ± 24% (mean, SEM) and 85 ± 18% of controls, respectively (vs. no stimulation, n = 10, p < 0.05, two-way analysis of variance [ANOVA]). Fixed-frequency stimulation at 0.01, 0.1, 1, 40, and 100 Hz, did not demonstrate a trend change on BRC. When stimulation frequency is delivered with a 4-6 pulse/burst pattern every 1-100 sec, neuromodulation has demonstrated a trend toward effectiveness, with a four-pulse 40 Hz burst stimulation per second showing the most difference, reducing the BRC frequency of 74 ± 8% of control (n = 8, p < 0.05, two-way ANOVA). However, it is not more effective than continuous neuromodulation at a fixed frequency of 4 Hz or 10 Hz at BRC inhibition. CONCLUSIONS:Burst stimulations may inhibit bladder contractions; however, they are not more effective than continuous neuromodulation. Without further knowledge regarding mechanisms and potential benefit of burst stimulation on bladder control in patients with neuropathological conditions, applications should utilize continuous fixed 10 Hz stimulation for maximal clinical outcomes.

Objective Sacral neuromodulation (SNM) is a clinically used therapy for refractory urge frequency and incontinent patients. Using a recently developed sheep model, this preclinical study retrospectively evaluated the relationship between implanted sacral lead locations, motor threshold (MT) values, motor mapping, and acute urological efficacy to determine if acute location and physiological measurements are correlated. Methods Twelve female polypay sheep were implanted with bilateral InterStim® devices (Model 3058) connected to quadripolar leads (model 3889) placed in the S2-4 foramina with S3 as the ideal target. CT scans at post-op and ≥12 months later were used for 3D rendering using MedCAD points placed on the sacrum and lead contacts to compare coordinates across animals. Acute cystometry was performed to test responses to SNM (0.21 ms PW, 10 Hz) at maximum tolerable amplitude (MTA). MT values were obtained by visual identification of the first motor response and the motor reflex was mapped to an anatomical map. Results Sheep were categorized as responders (n=6; 50%) or non-responders (n=6; 50%) based on ≥50% increase in bladder capacity to acute SNM. There was a significant difference in motor mapping areas between responders (peri-anal contacts) and non-responders (activation of leg) (chi-square; P<0.05). Higher MTA values correlated with larger bladder capacity increases (Pearson correlation; P<0.05). Contact position correlated with urological response (ANOVA; P<0.05). A generalized Procrustes analysis on the 17 leads in S3 (remainder in S2 or S4) showed variability of distributions was higher in distal contacts (0 & 1, mean distance to center 7.3±1.8 mm, left & 6.8±1.3 mm, right) than proximal (2 & 3, mean distance to center 5.8±0.86 mm, left & 4.3±0.35 mm, right (ANOVA; alpha =0.05; F(3,64) =20.55; P<0.0001). Conclusions (I) Responder sheep showed motor responses in peri-anal areas significantly more often than non-responders; (II) MTA weakly correlated with increased bladder capacity; (III) activation of lead contacts proximal to the sacral foramen produced more reliable urological results than did activation of distal contacts. These results suggest well-positioned leads will elicit specific responses that could be essential to effective SNM therapy. Future work will characterize changes over time to provide a temporal correlation of this relationship. Funding Source(s) Medtronic

Bilateral electrical pudendal nerve stimulation (bPNS) anecdotally reduces pain in humans with pain due to interstitial cystitis (IC) and we have reported that it reduces bladder hypersensitivity in rat models. Concomitant medication use can alter responses to neuromodulation and so prior to the development of a clinical trial, the interaction between opioid medication use and acute bPNS was examined. Bladder hypersensitivity was produced by neonatal bladder inflammation in rats pups coupled with a second inflammatory insult as an adult. Morphine was administered acutely (1 or 2 mg/kg s.c.) or chronically (5 mg/kg s.c. daily for 2 weeks prior to the final experiment). Acute bPNS consisted of bilateral biphasic electrical stimulation (10 Hz, 100 msec biphasic pulses for 10 min) of the mixed motor/sensory component of the pudendal nerves using embedded hook electrodes. Visceromotor responses (VMRs; abdominal muscle contractile responses to urinary bladder distension, UBD) were used a nociceptive endpoints. Morphine produced a dose-dependent inhibition of VMRs to UBD that was naloxone-reversible. bPNS resulted in statistically significant inhibition of VMRs to UBD in hypersensitive rats that had received acute or chronic s.c. morphine injections. Rats which received chronic doses of morphine were tolerant to acute effects of morphine. Morphine preadministration did not appear to alter strength-duration effects of acute bPNS. This study suggests that inhibitory effects of bPNS can be evoked in subjects who are receiving opioid therapy, thus giving guidance to potential clinical trials for treating episodic pain in IC. This research performed as contract work for Medtronics, Inc.

Hypothesis / aims of study Exploratory testing in cats and dogs established early evidence for the use of sacral neuromodulation (SNM) for detrusor overactivity (1). However translational value of preclinical models has not been fully evaluated and the optimal stimulation of SNM therapy has not been studied in detail. Only recently have significant advances been made for acute parameter optimization in the rat isovolumetric bladder contraction model. Results from this work suggest similar stimulation parameters optimally attenuate bladder contractions in both rodent testing and in human clinical use (2, 3). In this study we link the work of isovolumetric bladder contraction model with cystometric quantification in acute anesthetized rats as well as in conscious unanesthetized sheep. The hypothesis tested in this study was that stimulation parameters differentially modify bladder capacity in the rat model of aceticacid induced cystitis as well as in normal conscious sheep.

Clinical reports suggest painful bladder disorders (PBD; e.g. interstitial cystitis) may benefit from neuromodulation of the pudendal nerve (PN). However, a systematic evaluation of this has not been carried out. Here we investigated the effect of PN stimulation on visceromotor reflex (VMR) responses to urinary bladder distension (UBD) in rat models of bladder hypersensitivity1-3 due to 1) early-in-life bladder inflammation, 2) acute bladder inflammation, or 3) footshock-induced stress. Electrodes were placed under the PN bilaterally to deliver biphasic pulses (100 μs) at 3x motor threshold. PN stimulation for 10 min significantly attenuated the VMR to UBD (n=10, P<0.05) in rats which had received intravesical zymosan treatments early-in-life at all three frequencies tested (10 Hz, 50 Hz, 100 Hz). Inhibition was also observed using 10 Hz PN stimulation in rats receiving acute intravesical zymosan treatment as adults (n=8, p<0.05). Overall ANOVA revealed no significant effects of PN stimulation in the chronic stress or control groups. The presence of inhibitory effects of PN stimulation within the early-in-life inflammation group and smaller-but-significant effects in the acute bladder inflammation group suggest potential utility of PN stimulation in the treatment of PBD with inflammatory mechanisms. These findings suggest PN stimulation may be less efficacious for PBD when caused by psychological stress mechanisms. Clinical follow will better direct our understanding of this potentially useful therapy. (1. DeBerry J et al. J Pain, 11: 247-255, 2010. 2. DeBerry J et al. J Pain, 8: 914-923, 2007. 3. Robbins MT and Ness TJ. J. Pain 9: 991-998, 2008.) Supported by a grant from Medtronic, Inc.

Hypothesis / aims of study Electrical stimulation of one side of the S3 sacral nerve using Interstim® Therapy produces an effective therapy in 40 to 80% of patients with overactive bladder. Bilateral stimulation has been reported to increase efficacy of neuromodulation therapy. In a preclinical porcine model, bilateral stimulation was found to be more effective for attenuating hyperactive detrusor contractions induced by formalin infusion (1). Using the rat bladder rhythmic contraction (BRC) model, we have demonstrated that bilateral electrical stimulation of the L6 spinal nerve (SN), through which most mechanosensitive bladder afferent fibers pass in the rat, at 10 Hz for 10 min inhibits bladder contractions (2, 3). In this study, we compare the relative effectiveness of unilateral vs bilateral neuromodulation by stimulating the L6 SN.