Estimating health related quality of life effects in vitiligo. Mapping EQ-5D-5 L utilities from vitiligo specific scales: VNS, VitiQoL and re-pigmentation measures using data from the HI-Light trial.

BACKGROUND: Vitiligo is reported to affect 2% of the world's population and has a significant impact on health related quality of life (HRQoL). The relationship between HRQoL and clinical outcomes used in vitiligo require further examination. Mapping condition specific measures of HRQoL: vitiligo specific quality of life instrument (VitiQoL), vitiligo noticeability scale (VNS) and vitiligo re-pigmentation scores (RPS) to the EQ-5D have not yet been reported. METHODS: Data collected from a randomised clinical trial (HI-Light) in vitiligo was used to develop mapping algorithms for the EQ-5D-5 L and the relationship between HRQoL, clinical outcomes and EQ-5D were investigated. Two EQ-5D-5 L value sets (Van Hout and Alava) using linear and non-linear models were considered. Logistic regression models were used to model the probability of vitiligo noticeability (VNS) in terms of RPS, EQ-5D and VitiQoL scores. RESULTS: Mapping from RPS appeared to perform better followed by VNS for the Alava crosswalks using polynomial models: Mean observed vs. predicted utilities of 0.9008 (0.005) vs. 0.8984 (0.0004) were observed for RPS. For VNS, mean observed vs. predicted utilities of 0.9008 (0.005) vs. 0.8939 (0.0003) were observed. For VitiQoL, mean observed vs. predicted utilities of 0.9008 (0.005) vs. 0.8912 (0.0002) were observed. For patients with the least re-pigmentation (RPS < 25%), a Total VitiQoL score of about 20 points gives around an 18% chance of vitiligo being no longer or a lot less noticeable. CONCLUSION: The algorithm based on RPS followed by VNS performed best. The relationship between effects from vitiligo specific HRQoL instruments and clinical RPS was established allowing for plausible clinically relevant differences to be identified, although further work is required in this area.

Bridging disconnected networks of first and second lines of biologic therapies in rheumatoid arthritis with registry data: bayesian evidence synthesis with target trial emulation.

OBJECTIVES: We aim to use real-world data in evidence synthesis to optimize an evidence base for the effectiveness of biologic therapies in rheumatoid arthritis to allow for evidence on first-line therapies to inform second-line effectiveness estimates. STUDY DESIGN AND SETTING: We use data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis to supplement randomized controlled trials evidence obtained from the literature, by emulating target trials of treatment sequences to estimate treatment effects in each line of therapy. Treatment effects estimates from the target trials inform a bivariate network meta-analysis (NMA) of first-line and second-line treatments. RESULTS: Summary data were obtained from 21 trials of biologic therapies including two for second-line treatment and results from six emulated target trials of both treatment lines. Bivariate NMA resulted in a decrease in uncertainty around the effectiveness estimates of the second-line therapies, when compared to the results of univariate NMA, and allowed for predictions of treatment effects not evaluated in second-line randomized controlled trials. CONCLUSION: Bivariate NMA provides effectiveness estimates for all treatments in first and second line, including predicted effects in second line where these estimates did not exist in the data. This novel methodology may have further applications; for example, for bridging networks of trials in children and adults.

Stress Hyperglycemia Is Independently Associated with Persistent Organ Failure in Acute Pancreatitis.

BACKGROUND/AIMS: Stress hyperglycemia is common in critical illness but it has not been clearly studied in patients with acute pancreatitis (AP). This study aimed to investigate the specific blood glucose (BG) level that defines stress hyperglycemia and to determine the impact of stress hyperglycemia on clinical outcomes in AP patients. METHODS: AP patients admitted ≤ 48 h after abdominal pain onset were retrospectively analyzed. Patients were stratified by pre-existing diabetes and stress hyperglycemia was defined using stratified BG levels for non-diabetes and diabetes with clinical outcomes compared. RESULTS: There were 967 non-diabetic and 114 diabetic (10.5%) patients met the inclusion criteria and the clinical outcomes between these two groups were not significantly different. In non-diabetes, the cut-off BG level of ≥ 180 mg/dl was selected to define stress hyperglycemia with an 8.8-fold higher odds ratio for persistent organ failure (POF) (95% CI 5.4-14.3; P < 0.001). For diabetes, ≥ 300 mg/dl was selected with a 7.5-fold higher odds ratio for POF (95% CI 1.7-34.3; P = 0.009). In multivariable logistic regression, stress hyperglycemia was independently associated with POF, acute necrotic collection, major infection and mortality. The combination of BG and systemic inflammatory response syndrome (SIRS) score in predicting POF was better than SIRS or Glasgow score alone. CONCLUSIONS: This study identifies a cut-off BG level of ≥ 180 mg/dl and ≥ 300 mg/dl was optimal to define stress hyperglycemia for non-diabetic and diabetic AP patients, respectively. There was a significant relationship between stress hyperglycemia and adverse clinical outcomes.

Methods for the inclusion of real-world evidence in network meta-analysis.

BACKGROUND: Network Meta-Analysis (NMA) is a key component of submissions to reimbursement agencies world-wide, especially when there is limited direct head-to-head evidence for multiple technologies from randomised controlled trials (RCTs). Many NMAs include only data from RCTs. However, real-world evidence (RWE) is also becoming widely recognised as a valuable source of clinical data. This study aims to investigate methods for the inclusion of RWE in NMA and its impact on the level of uncertainty around the effectiveness estimates, with particular interest in effectiveness of fingolimod. METHODS: A range of methods for inclusion of RWE in evidence synthesis were investigated by applying them to an illustrative example in relapsing remitting multiple sclerosis (RRMS). A literature search to identify RCTs and RWE evaluating treatments in RRMS was conducted. To assess the impact of inclusion of RWE on the effectiveness estimates, Bayesian hierarchical and adapted power prior models were applied. The effect of the inclusion of RWE was investigated by varying the degree of down weighting of this part of evidence by the use of a power prior. RESULTS: Whilst the inclusion of the RWE led to an increase in the level of uncertainty surrounding effect estimates in this example, this depended on the method of inclusion adopted for the RWE. 'Power prior' NMA model resulted in stable effect estimates for fingolimod yet increasing the width of the credible intervals with increasing weight given to RWE data. The hierarchical NMA models were effective in allowing for heterogeneity between study designs, however, this also increased the level of uncertainty. CONCLUSION: The 'power prior' method for the inclusion of RWE in NMAs indicates that the degree to which RWE is taken into account can have a significant impact on the overall level of uncertainty. The hierarchical modelling approach further allowed for accommodating differences between study types. Consequently, further work investigating both empirical evidence for biases associated with individual RWE studies and methods of elicitation from experts on the extent of such biases is warranted.

Comparative effectiveness analysis between entrectinib clinical trial and crizotinib real-world data in ROS1+ NSCLC.

Aim: Generating direct comparative evidence in prospective randomized trials is difficult for rare diseases. Real-world cohorts may supplement control populations. Methods: Entrectinib-treated adults with advanced ROS1 fusion-positive NSCLC (n = 94) from Phase I/II trials (ALKA-372-001 [EudraCT2012-00148-88], STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]) were compared with a real-world crizotinib-treated cohort (n = 65). Primary end point, time-to-treatment discontinuation (TTD); secondary end points, PFS and OS. Results: Median (95% CI) weighted TTD: 12.9 (9.9-17.4) months for entrectinib; 8.8 (6.2-9.9) months for crizotinib (weighted hazard ratio: 0.72 [0.51-1.02]). Median OS with entrectinib was not reached, weighted median OS with crizotinib was 18.5 (15.1-19.9) months. Conclusion: Entrectinib administered in clinical trials may be associated with longer TTD than a real-world crizotinib population.

An adaptive randomized clinical trial in interstitial cystitis/bladder pain syndrome evaluating efficacy of ASP3652 and the relationship between disease characteristics and Hunner's lesions.

PURPOSE: The primary purpose of this study was to evaluate the effect of the fatty acid amide hydrolase (FAAH) inhibitor ASP3652 on efficacy and safety in patients with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). The secondary purpose was to evaluate phenotyping based on Hunner's lesions (HL). METHODS: In this randomized trial, adult female patients with moderate/severe IC/BPS received 12 weeks of treatment with an oral dose of ASP3652 (50, 150, or 300 mg twice daily) or placebo. A Bayesian model was employed using accumulating data to adjust the randomization probability and to analyze the primary efficacy variable (change from baseline to end of treatment in Mean Daily Pain [MDP; range 0-10]). Study outcomes and patient characteristics of patients with and without HL (HL+ and HL-) were compared. RESULTS: In total, 287 patients were randomized. The 300 mg dose group (n = 97) showed the largest effect, i.e., a mean change from baseline to end of treatment of -1.73 in MDP. However, the mean difference from placebo was 0.02. The probability that this dose was better than placebo was 13.5%. Adverse event incidence was low and similar between study groups. HL+ patients were older and had more severe symptoms than HL-. An association was suggested in HL+ patients between changes in micturition frequency and MDP (R = 0.41 [95% CI 0.18, 0.63]), which was not observed in HL- (R = 0.04 [95% CI -0.16, 0.29]). CONCLUSION: ASP3652 was safe and well tolerated, but did not show efficacy in IC/BPS. The observed differences between HL+ and HL- suggest that IC/BPS diagnosis and treatment may be approached differently in these two phenotypes. TRIAL REGISTRATION: EudraCT number 2011-004555-39, date of registration: 2012-05-07.

A combined proof of concept and dose finding study with multiple endpoints: A Bayesian adaptive design in chronic prostatitis/chronic pelvic pain syndrome.

There is a need for identifying effective drugs or terminating ineffective drugs as early as possible to optimize efficient and cost effective drug development. The aim of the proposed trial was to simultaneously establish Proof of Concept (PoC) and dose finding (DF) for a new drug with a novel mode of action in a new indication. We simulated and executed an adaptive allocation design to investigate the effects of a drug on male patients suffering from chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). This manuscript describes the clinical trial simulations and primary analysis results. A Bayesian adaptive allocation procedure was employed to allocate patients to treatment using a normal dynamic linear model. The study was to stop early for efficacy if the probability of a clinically significant difference between an experimental arm and placebo was at least 90%. The study was to stop for futility if the probability that the maximum effective dose was better than placebo by at least the futility difference was less than 20%. During the execution phase the study was stopped early, that is 32% less than planned maximum sample size, due to futility. The final results confirmed that the predefined stopping rules were met. In conclusion, the simulations showed that, if the drug was effective, this adaptive design could accomplish both the goals of PoC and DF. However, the study stopped early for futility in line with the simulation predictions for stopping. This resulted in the early stopping of a trial recruiting patients on ineffective treatment.

The inclusion of real world evidence in clinical development planning.

BACKGROUND: When designing studies it is common to search the literature to investigate variability estimates to use in sample size calculations. Proprietary data of previously designed trials in a particular indication are also used to obtain estimates of variability. Estimates of treatment effects are typically obtained from randomised controlled clinical trials (RCTs). Based on the observed estimates of treatment effect, variability and the minimum clinical relevant difference to detect, the sample size for a subsequent trial is estimated. However, data from real world evidence (RWE) studies, such as observational studies and other interventional studies in patients in routine clinical practice, are not widely used in a systematic manner when designing studies. In this paper, we propose a framework for inclusion of RWE in planning of a clinical development programme. METHODS: In our proposed approach, all evidence, from both RCTs and RWE (i.e. from studies in routine clinical practice), available at the time of designing of a new clinical trial is combined in a Bayesian network meta-analysis (NMA). The results can be used to inform the design of the next clinical trial in the programme. The NMA was performed at key milestones, such as at the end of the phase II trial and prior to the design of key phase III studies. To illustrate the methods, we designed an alternative clinical development programme in multiple sclerosis using RWE through clinical trial simulations. RESULTS: Inclusion of RWE in the NMA and the resulting trial simulations demonstrated that 284 patients per arm were needed to achieve 90% power to detect effects of predetermined size in the TRANSFORMS study. For the FREEDOMS and FREEDOMS II clinical trials, 189 patients per arm were required. Overall there was a reduction in sample size of at least 40% across the three phase III studies, which translated to a time savings of at least 6 months for the undertaking of the fingolimod phase III programme. CONCLUSION: The use of RWE resulted in a reduced sample size of the pivotal phase III studies, which led to substantial time savings compared to the approach of sample size calculations without RWE.

Comparative effectiveness from a single-arm trial and real-world data: alectinib versus ceritinib.

AIM: To compare the overall survival of anaplastic lymphoma kinase-positive non-small-cell lung cancer patients who received alectinib with those who received ceritinib. MATERIALS & METHODS: Two treatment arms (alectinib [n = 183] and ceritinib [n = 67]) were extracted from clinical trials and an electronic health record database, respectively. Propensity scores were applied to balance baseline characteristics. Kaplan-Meier and multivariate Cox regression were conducted. RESULTS: After propensity score adjustment, baseline characteristics were balanced. Alectinib had a prolonged median overall survival (alectinib = 24.3 months and ceritinib = 15.6 months) and lower risk of death (hazard ratio: 0.65; 95% CI: 0.48-0.88). CONCLUSION: Alectinib was associated with prolonged overall survival versus ceritinib, which is consistent with efficacy evidence from clinical trials.

qSOFA, SIRS and NEWS for predicting inhospital mortality and ICU admission in emergency admissions treated as sepsis.

BACKGROUND: The third international consensus definition for sepsis recommended use of a new prognostic tool, the quick Sequential Organ Failure Assessment (qSOFA), based on its ability to predict inhospital mortality and prolonged intensive care unit (ICU) stay in patients with suspected infection. While several studies have compared the prognostic accuracy of qSOFA to the Systemic Inflammatory Response Syndrome (SIRS) criteria in suspected sepsis, few have compared qSOFA and SIRS to the widely used National Early Warning Score (NEWS). METHODS: This was a retrospective cohort study carried out in a UK tertiary centre. The study population comprised emergency admissions in whom sepsis was suspected and treated. The accuracy for predicting inhospital mortality and ICU admission was calculated and compared for qSOFA, SIRS and NEWS. RESULTS: Among 1818 patients, 53 were admitted to ICU (3%) and 265 died in hospital (15%). For predicting inhospital mortality, the area under the receiver operating characteristics curve for NEWS (0.65, 95% CI 0.61 to 0.68) was similar to qSOFA (0.62, 95% CI 0.59 to 0.66) (test for difference, P=0.18) and superior to SIRS (P<0.001), which was not predictive. The sensitivity of NEWS≥5 (74%, 95% CI 68% to 79%) was similar to SIRS≥2 (80%, 95% CI 74% to 84%) and higher than qSOFA≥2 (37%, 95% CI 31% to 43%). The specificity of NEWS≥5 (43%, 95% CI 41% to 46%) was higher than SIRS≥2 (21%, 95% CI 19% to 23%) and lower than qSOFA≥2 (79%, 95% CI 77% to 81%). The negative predictive value was 88% (86%-90%) for qSOFA, 86% (82%-89%) for SIRS and 91% (88%-93%) for NEWS. Results were similar for the secondary outcome of ICU admission. CONCLUSION: NEWS has equivalent or superior value for most test characteristics relative to SIRS and qSOFA, calling into question the rationale of adopting qSOFA in institutions where NEWS is already in use.

Fatty Acid Amide Hydrolase Inhibitor Treatment in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome: An Adaptive Double-blind, Randomized Controlled Trial.

OBJECTIVE: To examine the effect of a peripherally active fatty acid amide hydrolase (FAAH) inhibitor ASP3652 on safety and efficacy outcomes in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Inhibition of FAAH is hypothesized to reduce the excitability of urinary tract afferents including nociceptors. MATERIALS AND METHODS: In this adaptive, randomized, double-blind, placebo-controlled study, adult male patients with moderate to severe CP/CPPS were treated for 12 weeks with an oral dose of ASP3652 (25, 75, 150, or 300 mg twice daily, or 300 mg once daily), or placebo. A Bayesian model was used for adaptive prospective modeling of randomization, study continuation decisions, and analysis of the efficacy variables. RESULTS: The study was stopped for futility at preplanned interim analysis when 239 patients were randomized (226 were included in the intention-to-treat set): the 25 mg group showed the largest reduction of the primary end point National Institutes of Health Chronic Prostatitis Symptom Index total score (7.0 points), but the placebo group showed a mean reduction of 7.3 points (difference: 0.3 [95% confidence interval: -1.9, 2.6]). Micturition outcomes improved compared with placebo in all ASP3652 groups; for example, in the 300 mg twice daily group, voiding frequency decreased by -1.10 (95% CI: -2.0, -0.2) voids/24 hours vs placebo. Safety outcomes were comparable across the treatment groups. CONCLUSION: ASP3652 was generally safe and well-tolerated. It did not show efficacy on pain symptoms in patients with CP/CPPS. However, the results indicate that FAAH inhibition may attenuate lower urinary tract symptoms. Dedicated studies in patients with lower urinary tract dysfunction are needed to confirm this.

Electronic bladder diaries of differing duration versus a paper diary for data collection in overactive bladder.

AIMS: This observational study compared data values, reliability, consistency and compliance collected by electronic and paper diaries of differing durations. METHODS: Subjects ≥18 years with overactive bladder (OAB) on stable antimuscarinic treatment for ≥12 weeks were assigned to one of five, 15-week diary schedules in this randomized, parallel-group observational study. Sample size was sufficient to assess reliability and consistency of diary data with adequate precision. Reliability was assessed via intraclass correlation coefficients, variability with ANCOVAs, and consistency using Cronbach's alpha. RESULTS: Demographic characteristics of randomized subjects were representative of OAB trial populations. For mean volume voided, reliability was comparable across diary groups. For incontinence, reliability improved with increasing diary duration. For micturition frequency, electronic 7-day diary results had highest reliability and lowest variability. Lowest overall reliability was observed in the 3-day paper diary. Consistency was highest in the electronic continuous groups; Cont A (daily measurements throughout the study period [fully Continuous]) and Cont B (daily measurements for some but not all endpoints of interest [Partially Continuous]). Compliance was generally high; across groups ≥90% of diaries had at least one entry per day. There was no significant change in average micturition frequency with diary duration, suggesting no diary fatigue. One-third of subjects in the electronic Cont B group also reported micturitions as incontinence when they only needed to report incontinence; they also reported lowest satisfaction with the study. The electronic 7-day and electronic Cont A schedules (who reported incontinence and micturitions throughout the study) had lowest residual errors. CONCLUSIONS: For future OAB trials, 7-day or continuous electronic diaries may improve accuracy and reliability of micturition and incontinence frequency data compared with shorter collection periods and paper diaries. Neurourol. Urodynam. 35:743-749, 2016. © 2015 Wiley Periodicals, Inc.

A clinical perspective on the analysis and presentation of the number of incontinence episodes following treatment for OAB.

AIMS: To provide a clinical view and interpretation on the methods for analysis of incontinence in patients with overactive bladder. METHODS: Results are analyzed using the total number of incontinence episodes in a 3-day diary period, using fixed and random effect Poisson regression models to calculate ratio of event rates and 95% confidence interval (CI) together with P-values and are compared with the analysis of the mean number of incontinence episodes/24 hr using analysis of covariance models to calculate P-values and 95% CI for the difference between treatments. RESULTS: Using random effects Poisson regression models demonstrated that the number of incontinence episodes was reduced by 26% more with mirabegron 50 mg than with placebo. For solifenacin 5 and 10 mg, treatment resulted in a 43% (41%) greater decrease in the number of incontinence episodes compared with placebo. CONCLUSION: Instead of providing a fixed number of incontinence episodes/24 hr that reflects the mean effect, the estimate using Poisson methodology provides an efficacy estimate that can be interpreted in the context of, and relative to, the patient's baseline (severity). Using the total number of incontinence episodes in the diary period, and expressing this as percent decrease in the number of episodes, may be easier to interpret; for example, because this results in a relative measure of effect that provides an alternative understanding of a patient's improvement at end of treatment compared with the comparator arm. Also, it is based on statistical methods that are more suitable for the analysis of count data. Neurourol. Urodynam. 35:728-732, 2016. © 2015 Wiley Periodicals, Inc.

Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony).

BACKGROUND: Combining the ß3-adrenoceptor agonist mirabegron and the antimuscarinic (AM) agent solifenacin may improve efficacy in the treatment of overactive bladder (OAB) while reducing the AM side effects. OBJECTIVE: The primary objective was to evaluate the efficacy of combinations of solifenacin/mirabegron compared with solifenacin 5mg monotherapy. The secondary objective was to explore the dose-response relationship and the safety/tolerability compared with placebo and monotherapy. DESIGN, SETTING, AND PARTICIPANTS: A phase 2, factorial design, randomised, double-blind, parallel-group, placebo- and monotherapy-controlled trial, conducted at 141 sites in 20 European countries. Male and female patients were aged ≥18 yr with symptoms of OAB for ≥3 mo. INTERVENTION: A total of 1306 patients (66.4% female) were randomised to 12 wk of treatment in 1 of 12 groups: 6 combination groups (solifenacin 2.5, 5, or 10 mg plus mirabegron 25 or 50 mg), 5 monotherapy groups (solifenacin 2.5, 5, or 10 mg, or mirabegron 25 or 50 mg), or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Change from baseline to end of treatment in mean volume voided per micturition (MVV) (primary end point) and mean numbers of micturitions per 24 h, incontinence episodes per 24 h, and urgency episodes per 24 h were analysed using an analysis of covariance model. Safety assessments included treatment-emergent adverse events (TEAEs), blood pressure, pulse rate, postvoid residual (PVR) volume, and laboratory and electrocardiography (ECG) parameters. RESULTS AND LIMITATIONS: Compared with solifenacin 5 mg monotherapy, all combinations with solifenacin 5 or 10 mg significantly improved MVV, with adjusted differences ranging from 18.0 ml (95% confidence interval [CI], 5.4-30.0) to 26.3 ml (95% CI, 12.0-41.0). Three combination groups significantly reduced micturition frequency compared with solifenacin 5 mg, ranging from -0.80 (95% CI, -1.39 to -0.22) to -0.98 (95% CI, -1.68 to -0.27). Five of six combinations significantly reduced urgency episodes compared with solifenacin 5 mg, ranging from -0.98 (95% CI, -1.78, to -0.18) to -1.37 (95% CI, -2.03 to -0.70). No dose-related trends in TEAEs, blood pressure, pulse rate, PVR volume, or laboratory or ECG parameters were observed between combination and monotherapy groups, although the incidence of constipation was slightly increased with combination therapy. CONCLUSIONS: Combination therapy with solifenacin/mirabegron significantly improved MVV, micturition frequency, and urgency compared with solifenacin 5 mg monotherapy. All combinations were well tolerated, with no important additional safety findings compared with monotherapy or placebo. PATIENT SUMMARY: To improve treatment of overactive bladder (OAB), mirabegron/solifenacin in combination was compared with each drug alone and placebo. Combination therapy improved OAB symptoms and had similar safety and acceptability. TRIAL REGISTRATION: Clinical trials.gov: NCT01340027.

The effect of intravenous infusion of adenosine on electrically evoked hyperalgesia in a healthy volunteer model of central sensitization.

Human pain models invoking central sensitization, one of the key mechanisms of chronic pain, may be useful for characterizing new analgesics. A new model of electrical hyperalgesia can detect the efficacy of several analgesic mechanisms. Because IV adenosine can alleviate neuropathic pain, we investigated its effect on experimental sensitization. This was a double-blinded, randomized, two-period crossover study in 20 healthy volunteers. Current pulses (0.5 ms; 1 Hz) were applied intracutaneously to achieve pain rating of approximately 5 on a 0-10 numeric rating scale. Pain, areas of pinprick hyperalgesia, and tactile allodynia were assessed during the 2.5-h stimulation period. Adenosine (50 microg. kg(-1). min(-1)) and placebo were infused IV over 60 min. Additional testing was performed 24 h after each treatment. Adenosine reduced the area of pinprick hyperalgesia during the infusion compared with placebo; there was no significant effect on tactile allodynia or pain rating. The effect on hyperalgesia developed over 15 min and was significant (P < or = 0.05) for the rest of the infusion period. There was no difference between treatments at 24 h. Thus, in accordance with reports on neuropathic pain, adenosine reduced central sensitization in the human model of electrical hyperalgesia. However, adenosine did not have the long-term effects seen in patients. The model can investigate mechanisms of drugs for the treatment of chronic pain.