Daily Worst Pain Research Articles

Prospective Study of Preoperative Negative Affect and Postoperative Pain in Patients Undergoing Thoracic Surgery: The Moderating Role of Sex.

Objective: Preoperative negative affect is a risk factor for worse postoperative pain, but research investigating this association among patients undergoing thoracic surgery is inconsistent. Additionally, female patients often report greater negative affect and postoperative pain than males. This prospective observational study investigated the association between preoperative negative affect and postoperative pain after thoracic surgery and whether this association differed by sex. Methods: Patients (n = 105) undergoing thoracic surgery completed preoperative assessments of pain and negative affect (PROMIS anxiety and depression short forms). Patients reported their daily worst pain over the first 7 postoperative days, and an index score of acute postoperative pain was created. Six months after surgery, a subsample of patients (n = 60) reported their worst pain. Results: Higher levels of preoperative anxiety (r = 0.25, p = 0.011) and depression (r = 0.20, p = 0.042) were associated with greater acute postoperative pain, but preoperative negative affect was not related to chronic postsurgical pain (anxiety: r = 0.19, p = 0.16; depression: r = -0.01, p = 0.94). Moderation analyses revealed that the associations between both preoperative anxiety (b = 0.12, 95% CI [0.04, 0.21], p = 0.004) and depression (b = 0.15, 95% CI [0.04, 0.26], p = 0.008) with acute postoperative pain were stronger among females than males. Similarly, the association between preoperative anxiety and chronic postsurgical pain was stronger among females (b = 0.11, 95% CI [0.02, 0.20], p = 0.022), but the association between preoperative depression and chronic pain did not differ based on sex (b = 0.13, 95% CI [-0.07, 0.34], p = 0.201]). Conclusions: Our findings suggest that negative affect may be especially important to the experience of pain following thoracic surgery among female patients, whose degree of preoperative anxiety may indicate vulnerability to progress to a chronic pain state. Preoperative interventions aimed at reducing negative affect and pain may be particularly useful among females with high negative affect before thoracic surgery.

S1063 Disease Burden in Patients With Acute Hepatic Porphyria: Experience From the Phase 3 ENVISION Study

Introduction: Acute hepatic porphyria (AHP) is a family of rare genetic diseases caused by defects in hepatic heme biosynthesis. Intravenous (IV) hemin is the standard of care for acute attacks and is at times used off label prophylactically, but can have acute (e.g. phlebitis) and chronic (e.g. iron overload) complications. The phase 3 ENVISION study (NCT03338816) showed givosiran reduced annualized attack rate (AAR) by 73% versus placebo in the double-blind (DB) period. Open-label extension data showed 85% of patients continuing givosiran were attack free at >15–18 months. Here we summarize data from ENVISION to assess the spectrum of disease burden associated with AHP. Methods: Patients (N=94) enrolled in ENVISION had experienced ≥2 attacks requiring hospitalization, urgent care, or IV hemin at home in the 6 months before the study. This analysis assessed AAR, daily worst pain (eDiary), comorbidity, concomitant medication, and quality of life (12-Item Short Form Health Survey [SF-12]). Results: Patients had severe disease burden at study entry, consistent with AHP burden shown in natural history studies. Patients reported a median of 4 (range, 0–46) attacks during the previous 6 months, despite 40% being on prophylactic hemin. Of all patients, 34% did not have attacks requiring hospitalization. Chronic symptoms, including pain, were experienced by 52% of patients daily or on most days between attacks. Baseline median SF-12 bodily pain score was 40 (scale 0–100), suggesting interference with normal functioning. Overall, 29% of patients used opioids daily or on most days between attacks. Most patients had comorbidities at baseline (47% had psychiatric disorders) (Table 1) and were taking concomitant medications. The median (Q1–Q3) ferritin level was 209 (48–719) µg/L (normal: female, 13–150 µg/L; male, 30–400 µg/L). A moderate linear correlation between longer time since AHP diagnosis and higher AAR with placebo during the 6-month DB period (r=0.403) suggests patients may experience worsening disease and complications over time. Givosiran provided clinical benefit, including reduction of daily worst pain and analgesics use. Conclusion: AHP disease burden, including the number of attacks, comorbidities, and concomitant medication use, has negative impacts on daily functioning. Earlier initiation of treatments, such as givosiran, that prevent attacks and reduce chronic manifestations of AHP may lead to improved prognosis for patients.Table 1.: Comorbidities at baseline of patients in the ENVISION trial. eGFR, estimated glomerular filtration rate

Conditioned open-label placebo for opioid reduction after spine surgery: a randomized controlled trial.

Placebo effects have traditionally involved concealment or deception. However, recent evidence suggests that placebo effects can also be elicited when prescribed transparently as "open-label placebos" (OLPs), and that the pairing of an unconditioned stimulus (eg, opioid analgesic) with a conditioned stimulus (eg, placebo pill) can lead to the conditioned stimulus alone reducing pain. In this randomized control trial, we investigated whether combining conditioning with an OLP (COLP) in the immediate postoperative period could reduce daily opioid use and postsurgical pain among patients recovering from spine surgery. Patients were randomized to COLP or treatment as usual, with both groups receiving unrestricted access to a typical opioid-based postoperative analgesic regimen. The generalized estimating equations method was used to assess the treatment effect of COLP on daily opioid consumption and pain during postoperative period from postoperative day (POD) 1 to POD 17. Patients in the COLP group consumed approximately 30% less daily morphine milligram equivalents compared with patients in the treatment as usual group during POD 1 to 17 (-14.5 daily morphine milligram equivalents; 95% CI: [-26.8, -2.2]). Daily worst pain scores were also lower in the COLP group (-1.0 point on the 10-point scale; 95% CI: [-2.0, -0.1]), although a significant difference was not detected in average daily pain between the groups (-0.8 point; 95% CI: [-1.7, 0.2]). These findings suggest that COLP may serve as a potential adjuvant analgesic therapy to decrease opioid consumption in the early postoperative period, without increasing pain.

S1169 Twelve-Month Interim Analysis of Efficacy and Safety of Givosiran, an Investigational RNAi Therapeutic for Acute Hepatic Porphyria, in the ENVISION Open Label Extension

INTRODUCTION: Acute hepatic porphyria (AHP) is a family of rare genetic diseases due to enzyme defects in hepatic heme biosynthesis. Induction of 5-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting step in heme biosynthesis, can lead to accumulation of toxic heme intermediates 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), causing neurovisceral attacks and chronic manifestations. Givosiran, an investigational RNAi therapeutic, targets liver ALAS1 to reduce ALA/PBG and ameliorate attacks and clinical manifestations. METHODS: ENVISION (NCT03338816) is an ongoing Phase 3 global, multicenter, randomized, placebo-controlled trial, evaluating the efficacy and safety of subcutaneous monthly doses of 2.5 mg/kg givosiran in AHP patients in a 6-month double-blind (DB) period and an open label extension (OLE) period (up to 30 months). During the OLE, patients received either 2.5 mg/kg or 1.25 mg/kg monthly givosiran. Outcome measures included composite annualized attack rate (AAR) requiring hospitalization, urgent care, or IV-hemin at home, ALA/PBG levels, hemin use, daily worst symptoms, and quality of life (QoL). Analyses were descriptive. RESULTS: As of July 23, 2019, 93 patients entered the OLE: 56 (placebo/givosiran = 29; givosiran/givosiran = 27) received 2.5 mg/kg monthly givosiran, and 37 (placebo/givosiran = 17; givosiran/givosiran = 20) received 1.25 mg/kg. In givosiran patients (both doses), median AAR was 1.1 (range: 0–20.5) through Month 12. In placebo patients who crossed over to givosiran in the OLE, median AAR (DB = 10.65; OLE = 1.81) and proportion of attack-free patients (DB = 17.4%; OLE = 42.2%) were similar to the givosiran group in the DB period (median AAR = 1.04; attack free patients = 48.9%). In addition, sustained lowering of ALA/PBG in the OLE was accompanied by reductions in hemin use, daily worst pain and analgesic use, and improvements in QoL. Among patients on givosiran through Month 12, 62% had ≥1 drug-related adverse event (AE) and 3% had ≥1 drug-related serious AE. There were no new AEs leading to discontinuation and no deaths. No new safety concerns occurred in the OLE. There was a trend toward increased efficacy with the 2.5 mg/kg dose compared to 1.25 mg/kg dose, and safety was acceptable at both doses. CONCLUSION: In an ongoing Phase 3 study, givosiran 2.5 mg/kg monthly demonstrated maintenance or enhancement of clinical efficacy and an acceptable safety profile consistent with that observed in the 6-month DB period.

Bimodal Release Ondansetron Improves Stool Consistency and Symptomatology in Diarrhea-Predominant Irritable Bowel Syndrome: A Randomized, Double-Blind, Trial

Previous, small studies have suggested that ondansetron has beneficial effects in diarrhea-predominant irritable bowel syndrome (IBS-D). This randomized, double-blind study evaluated the efficacy and safety of daily 12 mg RHB-102, an investigational bimodal release ondansetron tablet, in IBS-D. Men and women with IBS-D by the Rome III criteria, Bristol Stool Scale ≥6 on 2 or more days weekly, and average daily worst pain intensity ≥3/10 were randomized 60:40 to RHB-102 or placebo once daily for 8 weeks. The primary end point was overall stool consistency response for at least 4 of 8 weeks. Secondary end points included overall worst abdominal pain and overall composite response, defined as response on both abdominal pain and stool consistency end points. Overall stool consistency response rates were 56.0% and 35.3% (RHB-102 vs placebo, P = 0.036) and similar among male and female patients. Overall pain response (50.7% vs 39.2%) and composite response rates (40.0% vs 25.5%) favored RHB-102, although these differences were not statistically significant. Stool consistency response rates were enhanced in patients with baseline C-reactive protein above the median (2.09 mg/L), 59.5%, vs 23.1% (P = 0.009). Overall rates of adverse events were similar, with a higher rate of constipation in RHB-102 patients (13.3% vs 3.9%) that resolved rapidly on withholding treatment. RHB-102 was effective and safe in the treatment of men and women with IBS-D. Baseline C-reactive protein seemed to be predictive of response.

Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria

BackgroundUp-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression.MethodsIn this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria.ResultsA total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions.ConclusionsAmong patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.)

Efficacy and safety of mirogabalin for the treatment of fibromyalgia: results from three 13-week randomized, double-blind, placebo- and active-controlled, parallel-group studies and a 52-week open-label extension study

Objective: To investigate the efficacy and safety of mirogabalin, an α2δ ligand, in patients with fibromyalgia (FM).Methods: In three 13-week, multicenter, double-blind, phase 3 studies (studies A, B, and C), patients with FM (n = 1293, 1270, and 1301, respectively) were randomized (1:1:1:1) to placebo, pregabalin 150 mg twice daily, mirogabalin 15 mg once daily or mirogabalin 15 mg twice daily. The primary endpoint was the change in weekly average daily worst pain score (ADPS) at week 13. Key secondary endpoints included Patient Global Impression of Change and change in the Fibromyalgia Impact Questionnaire total score. Long-term safety of mirogabalin was assessed in a 52-week extension study.Results: Neither mirogabalin dose demonstrated a significant ADPS reduction from baseline vs. placebo at week 13 in any of the three studies. Pregabalin significantly reduced ADPS from baseline vs. placebo in studies B and C (p = .0008 and .0001, respectively). The effect of mirogabalin compared with placebo on key secondary endpoints was variable across the studies. Mirogabalin was well tolerated by most patients in the phase 3 studies; no unexpected adverse events occurring during the 52-week extension study.Conclusion: While both mirogabalin doses were well tolerated by most patients and showed potential for reducing pain associated with FM, the primary endpoint of significant pain reduction in patients on mirogabalin compared with placebo was not achieved in any of the three randomized controlled studies.Clinical trial registration: NCT02146430; NCT02187159; NCT02187471; and NCT02234583 (extension study).

Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 3 Trial with a Primary Pain Endpoint

BackgroundBone metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) are associated with debilitating pain and functional compromise. ObjectiveTo compare pain palliation as the primary endpoint for cabozantinib versus mitoxantrone-prednisone in men with mCRPC and symptomatic bone metastases using patient-reported outcome measures. Design, setting, and participantsA randomized, double-blind phase 3 trial (COMET-2; NCT01522443) in men with mCRPC and narcotic-dependent pain from bone metastases who had progressed after treatment with docetaxel and either abiraterone or enzalutamide. InterventionCabozantinib 60mg once daily orally versus mitoxantrone 12mg/m2 every 3wk plus prednisone 5mg twice daily orally. Outcome measurements and statistical analysisThe primary endpoint was pain response at week 6 confirmed at week 12 (≥30% decrease from baseline in patient-reported average daily worst pain score via the Brief Pain Inventory without increased narcotic use). The planned sample size was 246 to achieve ≥90% power. Results and limitationsEnrollment was terminated early because cabozantinib did not demonstrate a survival benefit in the companion COMET-1 trial. At study closure, 119 participants were randomized (cabozantinib: N=61; mitoxantrone-prednisone: N=58). Complete pain and narcotic use data were available at baseline, week 6, and week 12 for 73/106 (69%) patients. There was no significant difference in the pain response with cabozantinib versus mitoxantrone-prednisone: the proportions of responders were 15% versus 17%, a −2% difference (95% confidence interval: −16% to 11%, p=0.8). Barriers to accrual included pretreatment requirements for a washout period of prior anticancer therapy and a narcotic optimization period to maximize analgesic dosing. ConclusionsCabozantinib treatment did not demonstrate better pain palliation than mitoxantrone-prednisone in heavily pretreated patients with mCRPC and symptomatic bone metastases. Future pain-palliation trials should incorporate briefer timelines from enrollment to treatment initiation. Patient summaryCabozantinib was not better than mitoxantrone-prednisone for pain relief in patients with castration-resistant prostate cancer and debilitating pain from bone metastases.

Daily factors driving daily substance use and chronic pain among older adults with HIV: An exploratory study using ecological momentary assessment.

Adults 50 and older make up approximately 50% of persons living with HIV. Multiple co-morbidities are common among this group, including chronic pain and substance abuse, yet little is known about the daily factors that either enhance or inhibit these experiences or behaviors. This study explored daily drivers of substance use, pain, and relief from pain among older adults living with HIV utilizing ecological momentary assessment (EMA). Participants (N=55), ages 49-71, completed seven consecutive days of daily EMA online surveys prior to treatment initiation within a randomized controlled trial. Multilevel modeling tested predictors of pain, substance use, and relief from pain by examining within- and between-person relationships. Results revealed an associational, reciprocal relationship between daily worst pain and daily drinking, where greater worst pain ratings predicted heavier drinking and heavier drinking predicted greater daily and overall pain. Greater happiness and poorer quality of sleep predicted greater daily worst pain. Exercising and overall confidence to cope with pain without medication were associated with lower levels of daily worst pain. Finally, spending less time with a loved one over time and reporting any coping behavior were associated with relief from pain. Investigation of daily factors that drive pain and substance use behaviors among this unique population help inform which daily factors are most risky to their health and well-being. Alcohol use emerged as the only substance associated with both driving pain and responding to pain. Findings suggest key points for prevention and intervention.

Patterns of recovery from pain after cesarean delivery.

We know very little about the change in pain in the first 2 months after surgery. To address this gap, we studied 530 women scheduled for elective cesarean delivery who completed daily pain diaries for 2 months after surgery through text messaging. Over 82% of subjects missed fewer than 10 diary entries and were included in the analysis. Completers were more likely to be Caucasian, nonsmokers, and with fewer previous pregnancies than noncompleters. Daily worst pain intensity ratings for the previous 24 hours were fit to a log(time) function and allowed to change to a different function up to 3 times according to a Bayesian criterion. All women had at least one change point, occurring 22 ± 9 days postoperatively, and 81% of women had only one change, most commonly to a linear function at 0 pain. Approximately 9% of women were predicted to have pain 2 months after surgery, similar to previous observations. Cluster analysis revealed 6 trajectories of recovery from pain. Predictors of cluster membership included severity of acute pain, perceived stress, surgical factors, and smoking status. These data demonstrate feasibility but considerable challenges to this approach to data acquisition. The form of the initial process of recovery from pain is common to all women, with divergence of patterns at 2 to 4 weeks after cesarean delivery. The change-point model accurately predicts recovery from pain; its parameters can be used to assess predictors of speed of recovery; and it may be useful for future observational, forecasting, and interventional trials.

A pilot trial of intravenous pamidronate for chronic low back pain

Intravenous (i.v.) bisphosphonates relieve pain in conditions such as Paget’s disease of bone, metastatic bone disease, and multiple myeloma. Based on positive findings from a prior case series, we conducted a randomized placebo-controlled study to assess the analgesic effect of i.v. pamidronate in subjects with chronic low back pain (CLBP) and evidence of degenerative disease of the spine. Four groups of 11 subjects (7 active, 4 placebo) were enrolled at escalating dose levels of 30, 60, 90, and 180mg pamidronate (the latter administered as two 90mg infusions). Primary outcomes were safety and change from baseline in average daily pain scores, recorded at 1, 2, 3, and 6months postinfusion using electronic diaries. Secondary outcomes included responder rate, daily worst pain, and pain-related interference with daily function. There were no pamidronate-related serious adverse events or other significant safety findings. A statistically significant overall treatment difference in pain scores was observed, with clinically meaningful effects persisting for 6months in the 180mg pamidronate group. Least squares mean changes in daily average pain score were −1.39 (SE=0.43) for placebo, and −1.53 (0.71), −1.26 (0.81), −1.42 (0.65), and −4.13 (0.65) for pamidronate 30, 60, 90, and 180mg, respectively (P=0.012 for pamidronate 180mg vs placebo). The proportion of responders, changes in worst pain, and pain interference with daily function were also significantly improved for pamidronate 180mg compared with placebo. In conclusion, i.v. pamidronate, administered as two 90mg infusions, decreased pain intensity for 6months in subjects with CLBP.

Randomized study of pregabalin in patients with cancer-induced bone pain.

IntroductionImprovements are needed in the management of cancer-induced bone pain (CIBP). The objective of this study was to assess the efficacy and safety of pregabalin compared with placebo in the adjunctive treatment of patients with moderate to severe CIBP who were receiving opioids.MethodsIn this randomized, double-blind, placebo-controlled, parallel-group, multicenter trial, 152 adults diagnosed with a malignant, solid tumor with metastases to bone were randomized to flexible-dose pregabalin (100, 150, 300, or 600 mg/day) or placebo, as add-on to stable opioid analgesic therapy, which was optimized prior to the start of the study. The primary efficacy endpoint was the duration-adjusted average change (DAAC) from baseline in the daily worst pain at the reference site (measured by 11-point numeric rating scale [NRS]) during the fixed-dosage phase. The study was terminated early following an interim analysis that indicated an increase in sample size would be needed to satisfy statistical assumptions for the primary endpoint. Given the early termination of the study, only descriptive analyses were performed.ResultsThe mean (standard deviation) DAAC from baseline in NRS score for the primary endpoint favored pregabalin treatment: −1.53 (1.81) in the pregabalin group and −1.23 (1.74) in the placebo group. Mean DAAC for average pain and sleep interference (NRS) also favored pregabalin. More patients treated with pregabalin reported improvement (“very much improved,” “much improved,” or “minimally improved”) based on Patient Global Impression of Change: 81.4% compared with 70.0% in the placebo group.ConclusionData from this study indicate that pregabalin use may reduce metastatic bone pain. Due to the incomplete analysis, further study of pregabalin in the management of CIBP is required.

Investigation of a Ca2+ Channel α2δ Ligand for the Treatment of Interstitial Cystitis: Results of a Randomized, Double-Blind, Placebo Controlled Phase II Trial

We investigated PD-0299685, a Ca(2+) channel α2δ ligand, for interstitial cystitis pain in a randomized, double-blind, placebo controlled phase IIa study. Patients with interstitial cystitis/bladder pain syndrome received 30 or 60 mg PD-0299685 daily or placebo for 12 weeks. Primary end points were change in average daily worst pain severity score (on an 11-point numerical rating scale) and change in Interstitial Cystitis Symptom Index score from baseline to week 12. Secondary end points included global response assessment, micturition and urgency episode frequency per 24 hours and mean voided volume per micturition. Incidence of adverse events was also assessed. Of 161 patients 54 received 30 mg PD-0299685 daily, 55 received 60 mg PD-0299685 daily and 52 received placebo. At week 12 the 60 mg dose produced a clinically significant reduction in daily worst pain severity score from baseline compared to placebo (treatment difference [90% CI] -0.82 [-1.72, 0.08]). A greater proportion of patients taking 60 mg PD-0299685 daily demonstrated improvement in global response assessment. PD-0299685 had no clinically significant effect on the Interstitial Cystitis Symptom Index score or urinary end points. More patients discontinued due to treatment related adverse events with 30 or 60 mg PD-0299685 daily than with the placebo. PD-0299685 failed to demonstrate positive proof of concept for the treatment of pain and other urinary end points associated with interstitial cystitis/bladder pain syndrome.

821 A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE IIA TRIAL OF A CA2+ CHANNEL α2Δ LIGAND, PD-0299685, FOR THE TREATMENT OF INTERSTITIAL CYSTITIS/BLADDER PAIN SYNDROME

You have accessJournal of UrologyInfections/Inflammation of the Genitourinary Tract: Interstitial Cystitis1 Apr 2012821 A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE IIA TRIAL OF A CA2+ CHANNEL α2Δ LIGAND, PD-0299685, FOR THE TREATMENT OF INTERSTITIAL CYSTITIS/BLADDER PAIN SYNDROME J. Curtis Nickel, Anna Crossland, Edward Davis, Francois Haab, Ian Mills, Eric Rovner, David Scholfield, and Tim Crook J. Curtis NickelJ. Curtis Nickel Kingston, Canada More articles by this author , Anna CrosslandAnna Crossland Sandwich, United Kingdom More articles by this author , Edward DavisEdward Davis Glendora, CA More articles by this author , Francois HaabFrancois Haab Paris, France More articles by this author , Ian MillsIan Mills Sandwich, United Kingdom More articles by this author , Eric RovnerEric Rovner Glendora, CA More articles by this author , David ScholfieldDavid Scholfield Sandwich, United Kingdom More articles by this author , and Tim CrookTim Crook Sandwich, United Kingdom More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.911AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The α2Δ subunit of ligand-gated calcium ion channels mediates afferent pain fibers and is implicated in chronic pain. There are a small number of uncontrolled reports suggesting that an α2Δ ligand (eg gabapentin and pregabalin) may have efficacy in refractory genito-urinary pain and interstitial cystitis/bladder pain syndrome (IC/BPS). The objective of this study was to investigate the efficacy, tolerability and safety of PD-0299685, a potent Ca2+ channel α2Δ ligand, for pain and symptoms associated with IC/BPS. METHODS Following a 2 week single blind placebo run-in, patients with IC/BPS were randomized to placebo, 15 mg or 30 mg PD-0299685 BID for 12 weeks, with stratification by cystoscopic features of IC and baseline worst pain severity score. Patients assigned to 30 mg were initially treated with 15 mg bid for 2 weeks, prior to up-titrating to 30 mg BID. Primary endpoints were change in mean daily worst pain severity score on an 11-point numerical rating scale and change in Interstitial Cystitis Symptom Index from baseline to week 12. Secondary endpoints included global response assessment, micturition and urgency episode frequency per 24 hours, and mean voided volume per micturition. Vital signs, weight, physical exams, concomitant medications, PVR volume, adverse events, laboratory assessments were recorded through the study. RESULTS 54 patients received 15 mg, 55 patients received 30 mg PD-0299685 BID and 52 patients received placebo. At week 12, PD-0299685 30 mg BID PD-0299685 produced a reduction of worst daily pain severity score from baseline compared with placebo (treatment difference [90% CI]: -0.82 [–1.72, 0.08]). At week 12, the difference in ICSI score reduction from baseline for PD-0299685 30 mg BID compared with placebo was –1.58 (90% CI –3.24, 0.09). The 15 mg group differences over placebo for the primary endpoints were minimal. A higher proportion of patients taking PD-0299685 30 mg BID reported improved global response assessment. More patients discontinued due to treatment-related adverse events with PD-0299685 15 mg BID and 30 mg BID than with placebo. CONCLUSIONS PD-0299685 did not demonstrate proof-of-concept for the treatment of pain and other urinary endpoints associated with IC/BPS by showing unfavorable benefit-tolerability profile in this patient population at both doses tested. Clinical and biomarker phenotyping is required to improve our therapeutic results for IC/BPS patients with neuropathic pain. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e335 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information J. Curtis Nickel Kingston, Canada More articles by this author Anna Crossland Sandwich, United Kingdom More articles by this author Edward Davis Glendora, CA More articles by this author Francois Haab Paris, France More articles by this author Ian Mills Sandwich, United Kingdom More articles by this author Eric Rovner Glendora, CA More articles by this author David Scholfield Sandwich, United Kingdom More articles by this author Tim Crook Sandwich, United Kingdom More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...