Research approaches for evaluating opioid sparing in clinical trials of acute and chronic pain treatments: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations.

ABSTRACT: Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials.

AAAPT Diagnostic Criteria for Acute Pain Following Breast Surgery.

Acute pain after breast surgery decreases the quality of life of cancer survivors. Previous studies using a variety of definitions and methods report prevalence rates between 10% and 80%, which suggests the need for a comprehensive framework that can be used to guide assessment of acute pain and pain-related outcomes after breast surgery. A multidisciplinary task force with clinical and research expertise performed a focused review and synthesis and applied the 5 dimensional framework of the AAAPT (Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks [ACTTION], American Academy of Pain Medicine [AAPM], American Pain Society [APS] Pain Taxonomy) to acute pain after breast surgery. Application of the AAAPT taxonomy yielded the following: 1) Core Criteria: Location, timing, severity, and impact of breast surgery pain were defined; 2) Common Features: Character and expected trajectories were established in relevant surgical subgroups, and common pain assessment tools for acute breast surgery pain identified; 3) Modulating Factors: Biological, psychological, and social factors that modulate interindividual variability were delineated; 4) Impact/Functional Consequences: Domains of impact were outlined and defined; 5) Neurobiologic Mechanisms: Putative mechanisms were specified ranging from nerve injury, inflammation, peripheral and central sensitization, to affective and social processing of pain. PERSPECTIVE: The AAAPT provides a framework to define and guide improved assessment of acute pain after breast surgery, which will enhance generalizability of results across studies and facilitate meta-analyses and studies of interindividual variation, and underlying mechanism. It will allow researchers and clinicians to better compare between treatments, across institutions, and with other types of acute pain.

Unique aspects of clinical trials of invasive therapies for chronic pain.

Nearly all who review the literature conclude that the role of invasive procedures to treat chronic pain is poorly characterized because of the lack of "definitive" studies. The overt nature of invasive treatments, along with the risks, technical skills, and costs involved create challenges to study them. However, these challenges do not completely preclude evaluating invasive procedure effectiveness and safety using well-designed methods. This article reviews the challenges of studying outcomes of invasive therapies to treat pain and discuss possible solutions. Although the following discussion can apply to most invasive therapies to treat chronic pain, it is beyond the scope of the article to individually cover every invasive therapy used. Therefore, most of the examples focus on injection therapies to treat spine pain, spinal cord stimulation, and intrathecal drug therapies.

Characteristics of patients with neuropathic pain syndromes screened by the painDETECT questionnaire and diagnosed by physician exam.

BACKGROUND: The aim of this study was to identify the clinical characteristics, treatment usage, and health outcomes of US adults diagnosed with neuropathic pain (NeP) by experienced physicians. METHODS: Adults with scores exceeding the threshold for probable NeP (painDETECT ≥19) and diagnosed with NeP by a qualified physician completed a questionnaire that included comorbid conditions, pain symptoms and experiences, medication use, health status (3-level EuroQol 5 Dimensions (EQ-5D-3L]: health utilities index and visual analog scale), pain severity and interference with functioning (Brief Pain Inventory), and work and activity impairment (Work Productivity and Activity Impairment questionnaire). Descriptive analyses were performed for each NeP subtype. RESULTS: Participants (n=295) were predominantly female (64.4%), middle-aged (53.9%), and white (51.5%). Chronic low back pain was the most frequently diagnosed major NeP syndrome (n=166), followed by diabetic peripheral neuropathy (n=58), post-trauma neuropathy (n=47), post-surgical neuropathy (n=28), and central NeP (n=23). An additional 45 participants were diagnosed, but did not meet the criteria for the aforementioned subtypes. Participants could be diagnosed with multiple subtypes. Across each NeP subtype, patients reported high rates of comorbid disease, including arthritis (range: 39.1%-64.3%) and high blood pressure (range: 26.1%-69.0%), as well as symptomology that included numbness (range: 68.1%-91.4%) and changes in muscular strength (range: 24.1%-65.2%). The majority of patients reported back pain (range: 77.8%-95.7%) and arthritis/joint pain (range: 68.1%-78.6%). The most commonly reported types of NeP pain medication were non-steroidal anti-inflammatory drugs (range: 43.1%-70.2%), weak opioids (range: 22.2%-39.3%), and strong opioids (range: 8.7%-28.6%). All six NeP groups generally reported similar levels of dysfunction on all self-report measures. The most notable finding was that the EuroQol-5D-3L health utilities index scores for each of the six groups were lower than the US norms by a clinically important amount. CONCLUSION: These exploratory findings indicate that patients with NeP across different etiologies are medically complex and experience impaired function across multiple domains.

The prevalence of probable neuropathic pain in the US: results from a multimodal general-population health survey.

BACKGROUND: The prevalence of neuropathic pain (NeP) has been estimated within specific health conditions; however, there are no published data on its broad prevalence in the US. The current exploratory study addresses this gap using the validated PainDetect questionnaire as a screener for probable NeP in a general-population health survey conducted with a multimodal recruitment strategy to maximize demographic representativeness. MATERIALS AND METHODS: Adult respondents were recruited from a combination of Internet panels, telephone lists, address lists, mall-based interviews, and store-receipt invitations using a random stratified-sampling framework, with strata defined by age, sex, and race/ethnicity. Older persons and minorities were oversampled to improve prevalence estimates. Results were weighted to match the total adult US population using US Census data. Demographic information was collected, and respondents who experienced physical pain in the past 12 months completed the PainDetect and provided additional pain history. A cutoff score of 19 or greater on the PainDetect was used to define probable NeP. RESULTS: A total of 24,925 respondents (average response rate 2.5%) provided demographic data (52.2% female, mean age 51.5 years); 15,751 respondents reported pain (63.7%), of which 2,548 (15.7%, 95% confidence interval 14.9%-16.5%) had probable NeP based on the PainDetect, which was 10% (95% confidence interval 9.5%-10.5%) of all respondents. Among those reporting pain, the prevalence of probable NeP among Blacks and Hispanics was consistently higher than Whites in each age- and sex group. The highest prevalence among those with pain was among male Hispanics 35-44 years (32.4%) and 45-54 years (24.2%) old. The most commonly used medications reported by those with probable NeP were nonsteroidal anti-inflammatory drugs (44.2%), followed by weak opioids (31.7%), antiepileptics (10.9%), and strong opioids (10.9%). CONCLUSION: This is the first study to provide an estimate of the prevalence of probable NeP in the US, showing significant variation by age and ethnicity.

A systematic review of the effectiveness of policies restricting access to pregabalin.

BACKGROUND: Formularies often employ restriction policies to reduce pharmacy costs. Pregabalin, an alpha-2-delta ligand, is approved for treatment of fibromyalgia (FM); neuropathic pain (NeP) due to postherpetic neuralgia (PHN), diabetic peripheral neuropathy (pDPN), spinal cord injury; and as adjunct therapy for partial onset seizures. Pregabalin is endorsed as first-line therapy for these indications by several US and EU medical professional societies. However, restriction policies such as prior authorization (PA) and step therapy (ST) often favor less costly generic pain medications over pregabalin. METHODS: A structured literature search (PubMed, past 11 years) was conducted to evaluate whether restriction policies against pregabalin support real-world economic and healthcare utilization benefits. RESULTS: Search criteria identified three claims analyses and a modeling study that evaluated patients with NeP and/or FM with and without PA restrictions; three other studies included patients with FM and NeP in plans with ST requirements, and one evaluated a mail order requirement program. All studies evaluated outcomes during follow-up periods of 6 months or longer. Overall, PA, ST, and mail order restriction policies effectively reduced pregabalin usage, but the effects were inconsistent with reducing pharmacy costs and were non-significant for total disease-related medical costs. Two studies (one PA; one ST) reported significantly higher disease-related costs in restricted plans. The modeling study failed to demonstrate cost savings with PA. Opioid usage was higher in PA-restricted plans (two studies). The US Centers for Disease Control and Prevention and several professional NeP guidelines recommend opioid use only in cases when other non-opioid pain therapies have proven ineffective. New US Government taskforce guidelines now seek to reduce opioid exposure. Additionally, in both ST studies, gabapentin utilization (a common ST edit) was significantly increased. Both studies had substantial proportions of FM and pDPN patients and the only pain condition gabapentin is approved to treat in the United States is PHN. CONCLUSION: PA and ST restriction policies significantly decrease utilization of pregabalin, but do not consistently demonstrate cost savings for US health plans. More research is needed to evaluate whether these policies may lead to increased opioid usage as found in some studies. TRIAL REGISTRATION: N/A.

Burden of HIV-Related Neuropathic Pain in the United States.

BACKGROUND: HIV-related neuropathic pain (HIV-NeP) is common; however, the burden of HIV-NeP is not well-understood. METHODS: The cross-sectional study aimed to characterize the HIV-NeP burden. A total of 103 patients with HIV-NeP recruited during routine office visits completed a questionnaire to assess patient-reported outcomes, including pain severity, health status, sleep, mood, and lost productivity. Physicians completed a 6-month retrospective chart review. RESULTS: The sample was predominantly male and not employed for pay. A majority (75.7%) of patients experienced moderate or severe pain. Pain interference, general health, physical health, and depression were worse among patients with more severe pain (all Ps < .006). Most (87.4%) patients were prescribed at least 1 medication for NeP. HIV-related neuropathic pain was associated with 36.1% work impairment. Adjusted annualized costs increased with increasing pain severity (P < .0001). CONCLUSION: The impact of HIV-NeP on health status, physical function, and depression increases with severity, resulting in substantial clinical and economic burden.

Efficacy and Safety of Pregabalin in the Treatment of Patients With Painful Diabetic Peripheral Neuropathy and Pain on Walking.

OBJECTIVES: This randomized, double-blind, placebo-controlled, multicenter, 2-period crossover study (two 6-week treatment periods separated by a 2-week washout period) evaluated the efficacy and safety of pregabalin (150 to 300 mg/d) for treatment of pain and pain on walking in patients with painful diabetic peripheral neuropathy (DPN) who experienced pain while walking. METHODS: Co-primary efficacy endpoints were: (1) mean pain score (last 7 daily pain diary scores, 0 to 10 numeric rating scale at end of each treatment period) and (2) DPN pain on walking (0 to 10 numeric rating scale immediately after walking 50 feet [15.2 m] on flat surface). Secondary endpoints included other pain parameters, patient-reported sleep, health-related quality of life, and safety measures. RESULTS: Two hundred three patients were treated (pregabalin, n=198; placebo, n=186), with no statistically significant treatment difference for pregabalin versus placebo in the co-primary efficacy endpoints, mean DPN pain (P=0.0656) and mean DPN pain on walking (P=0.412). A carryover effect was observed. Analysis of co-primary endpoints for period 1 showed significant treatment difference for DPN pain (P=0.034) and DPN pain on walking (P=0.001). Treatment with pregabalin resulted in significant improvements versus placebo on prespecified patient global impression of change (end of period 1; P=0.002), and sleep interference rating scale (end of period 2; P=0.011). Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 13 (6.6%) pregabalin patients versus 5 (2.7%) placebo patients. DISCUSSION: Failure to meet the co-primary objectives may be related to carryover effect from period 1 to period 2, lower pregabalin dose (150 to 300 mg/d), and/or placebo response in painful DPN.

Pain severity and the economic burden of neuropathic pain in the United States: BEAT Neuropathic Pain Observational Study.

BACKGROUND: As with many chronic conditions, patients with neuropathic pain (NeP) are high consumers of health care resources. However, limited literature exists on the economic burden of NeP, including its impact on productivity. The aim of this study was to characterize health care resource utilization, productivity, and costs associated with NeP by pain severity level in US adults. METHODS: Subjects (n=624) with painful diabetic peripheral neuropathy, human immunodeficiency virus-related peripheral NeP, post-trauma/post-surgical NeP, spinal cord injury with NeP, chronic low back pain with NeP, and small fiber neuropathy were recruited during routine office visits to US community-based general practitioners and specialists. Clinicians captured clinical characteristics, NeP-related medications, and health care resource utilization based on 6-month retrospective medical chart review. Subjects completed questionnaires on demographics, pain/symptoms, costs, and productivity. Brief Pain Inventory pain severity scores were used to classify subjects by mild, moderate, or severe pain. Annualized NeP-related costs (adjusted for covariates) were estimated, and differences across pain severity groups were evaluated. RESULTS: In total, 624 subjects were recruited (mean age 55.5±13.7 years; 55.4% male), and 504/624 (80.8%) reported moderate or severe pain. Statistically significant differences were observed across pain severity levels for number of comorbidities, prescription medications, physician office visits, and lost productivity (all P≤0.0001). At all pain severity levels, indirect costs were the primary cost driver. After adjusting for demographic and clinical variables, total mean (95% confidence interval [CI]) annualized direct medical costs to payers, direct costs to subjects, and indirect costs per subject were US$6,016 (95% CI 5,316-6,716), US$2,219 (95% CI 1,919-2,519), and US$19,000 (95% CI 17,197-20,802), respectively, with significant differences across pain severity levels. CONCLUSION: Subjects with NeP, mainly those showing moderate or severe pain, had significant associations between pain severity and NeP-related health care resource utilization, productivity, and costs. The economic burden, particularly indirect costs, was highest among those with severe pain and higher than previously reported in studies of specific NeP conditions.

Burden of illness associated with peripheral and central neuropathic pain among adults seeking treatment in the United States: a patient-centered evaluation.

OBJECTIVE: The aim of this study was to evaluate patient-reported burden associated with peripheral and central neuropathic pain (NeP) by pain severity and NeP condition. DESIGN: Six hundred twenty-four subjects with one of six NeP conditions were recruited during routine office visits. Subjects consented to retrospective chart review and completed a one-time questionnaire (including EuroQol-5 dimensions, 12-item Short-Form Health Survey, Brief Pain Inventory-Short Form, Medical Outcomes Study Sleep Scale, Hospital Anxiety and Depression Scale, and demographic and clinical characteristics). Pain severity scores were used to stratify subjects by mild, moderate, and severe pain. Summary statistics and frequency distributions were calculated. Differences by severity level were compared using Kruskal-Wallis (continuous variables) and chi-square or Fisher's exact test (categorical variables). Effect size was computed with Cohen's d (mild vs severe). RESULTS: Subjects' mean age was 55.5. The majority (80.8%) had moderate or severe pain. Patient-reported outcomes (health status, physical and mental health, pain interference with function, sleep, anxiety, and depression) were significantly worse among subjects with greater pain severity (all P < 0.0001). Severe pain subjects were negatively impacted by ≥30% in each outcome compared with mild pain subjects; standardized effect size was moderate for anxiety (0.59) and large (>0.95) for all others. The observed burden was most substantial among chronic low back pain-NeP, although the pattern of disease burden was similar across the six NeP conditions. CONCLUSIONS: Subjects across NeP conditions exhibited high pain levels, which were significantly associated with poor function, compromised health status and sleep, and increased anxiety and depression. Results indicate substantial patient burden across broad NeP, particularly among subjects with severe pain.

Health status, function, productivity, and costs among individuals with idiopathic painful peripheral neuropathy with small fiber involvement in the United States: results from a retrospective chart review and cross-sectional survey.

OBJECTIVE: To characterize the burden of idiopathic painful peripheral neuropathy with small fiber involvement (idiopathic SFN) by pain severity in the US. METHODS: One hundred previously diagnosed idiopathic SFN subjects were enrolled during routine office visits. Subjects completed a one-time questionnaire, and investigators reported clinical characteristics and healthcare resource use, based on 6 month retrospective chart review. Annualized direct and indirect costs were estimated. Results were stratified across pain severity groups. RESULTS: Mean age was 63.5 years; 53.0% were female; 76.0% had moderate or severe pain. Most common comorbidities were sleep disturbance/insomnia (37.0%), anxiety (34.0%), and depressive symptoms (33.0%). Overall mean health status (0.59; -0.11-1.00 scale), physical and mental health (31.7 and 45.6, respectively, 0-100 scale), sleep index (45.1; 0-100 scale), and pain interference with function (5.0; 0-10 scale) differed by pain severity, with worse outcomes among those with greater pain (all p < 0.002). 84.0% were prescribed ≥1 SFN medication. 16.0% were employed; mean overall work impairment was 36.9%. Annualized average adjusted direct and indirect costs per subject ($8055 and $13,733, respectively) differed by pain severity. CONCLUSIONS: Idiopathic SFN subjects with pain experience moderate or severe pain, which negatively impacts health status, function, and productivity, and leads to substantial direct and indirect costs.

Economic and humanistic burden of post-trauma and post-surgical neuropathic pain among adults in the United States.

BACKGROUND: Neuropathic pain (NeP) can be chronic, debilitating, and can interfere with sleep, functioning, and emotional well being. While there are multiple causes of NeP, few studies have examined the disease burden and treatment patterns associated with post-traumatic/post-surgical (PTPS) NeP. OBJECTIVE: To characterize pain, health status, function, health care resource utilization, lost productivity, and costs among subjects with PTPS NeP in the United States. METHODS: This observational study enrolled 100 PTPS NeP subjects recruited during routine visits from general practitioner and specialist sites. Subjects completed a one-time questionnaire with validated measures of pain severity and pain interference, health status, sleep, anxiety and depression, productivity, and study-specific items on demographics, employment status, and out-of-pocket expenses. Investigators completed a case report form based on a 6-month retrospective chart review, recording subjects' clinical characteristics as well as current and previous medications/treatments for NeP. Subjects were stratified into mild, moderate, and severe pain groups. RESULTS: Subjects' demographic characteristics were: mean age of 54.9 years, 53% female, and 22% employed for pay. Mean pain severity score was 5.6 (0-10 scale), with 48% and 35% classified as having moderate and severe pain, respectively. The mean number of comorbidities increased with greater pain severity (P = 0.0009). Patient-reported outcomes were worse among PTPS NeP subjects with more severe pain, including pain interference with function, health state utility, sleep, and depression (P < 0.0001). Eighty-two percent of subjects were prescribed two or more NeP medications. The total mean annualized adjusted direct and indirect costs per subject were $11,846 and $29,617, respectively. Across pain severity levels, differences in annualized adjusted direct and indirect costs were significant (P < 0.0001). CONCLUSION: PTPS NeP subjects reported high pain scores, which were associated with poor health utility, sleep, mood, and function, as well as high health care resource utilization and costs. The quality of life impact and costs attributable to PTPS NeP suggest an unmet need for effective and comprehensive management.

Interventional management of neuropathic pain: NeuPSIG recommendations.

Neuropathic pain (NP) is often refractory to pharmacologic and noninterventional treatment. On behalf of the International Association for the Study of Pain Neuropathic Pain Special Interest Group, the authors evaluated systematic reviews, clinical trials, and existing guidelines for the interventional management of NP. Evidence is summarized and presented for neural blockade, spinal cord stimulation (SCS), intrathecal medication, and neurosurgical interventions in patients with the following peripheral and central NP conditions: herpes zoster and postherpetic neuralgia (PHN); painful diabetic and other peripheral neuropathies; spinal cord injury NP; central poststroke pain; radiculopathy and failed back surgery syndrome (FBSS); complex regional pain syndrome (CRPS); and trigeminal neuralgia and neuropathy. Due to the paucity of high-quality clinical trials, no strong recommendations can be made. Four weak recommendations based on the amount and consistency of evidence, including degree of efficacy and safety, are: 1) epidural injections for herpes zoster; 2) steroid injections for radiculopathy; 3) SCS for FBSS; and 4) SCS for CRPS type 1. Based on the available data, we recommend not to use sympathetic blocks for PHN nor radiofrequency lesions for radiculopathy. No other conclusive recommendations can be made due to the poor quality of available data. Whenever possible, these interventions should either be part of randomized clinical trials or documented in pain registries. Priorities for future research include randomized clinical trials, long-term studies, and head-to-head comparisons among different interventional and noninterventional treatments.

Burden of illness associated with painful diabetic peripheral neuropathy among adults seeking treatment in the US: results from a retrospective chart review and cross-sectional survey.

BACKGROUND: The purpose of this study was to characterize the burden of illness among adult subjects with painful diabetic peripheral neuropathy (pDPN) seeking treatment in the US. METHODS: This observational study recruited 112 subjects with pDPN during routine visits from general practitioner and specialist sites. Subjects completed a one-time questionnaire, which included demographics, symptom duration, health care resource use, out-of-pocket costs, employment status, and validated measures that assessed pain, functioning, sleep, anxiety and depression, health status, and productivity. Investigators completed a case report form based on a 6-month retrospective chart review to capture clinical information, pDPN-related treatments, and other pDPN-related health care resource use over the past 6 months. Annualized costs were extrapolated based on reported 6-month health care resource use. RESULTS: The mean age of the subjects was 61.1 years, 52.7% were female, and 17.9% were in paid employment. The most common comorbid conditions were sleep disturbance/insomnia (43.8%), depressive symptoms (41.1%), and anxiety (35.7%). The mean pain severity score was 5.2 (0-10 scale), and 79.5% reported moderate or severe pain. The mean pain interference with function score was 5.0 (0-10 scale) overall, with 2.0 among mild, 5.1 among moderate, and 7.0 among severe. The mean Medical Outcomes Study sleep problems index score was 48.5 (0-100 scale). The mean health state utility score was 0.61. Among subjects employed for pay, mean overall work impairment was 43.6%. Across all subjects, mean overall activity impairment was 52.3%. In total, 81.3% were prescribed at least one medication for their pDPN; 50.9% reported taking at least one nonprescription medication. Adjusted mean annualized total direct and indirect costs per subject were $4841 and $9730, respectively. Outcomes related to pain interference with function, sleep, health status, activity impairment, prescription medication use, and direct and indirect costs were significantly worse among subjects with more severe pain (P < 0.0020). CONCLUSION: Subjects with pDPN exhibited high pain levels, which were associated with poor sleep, function, and productivity. Health care resource utilization in pDPN was prevalent and costs increased with greater pain severity. The burden of pDPN was greater among subjects with greater pain severity.

Medical and psychological risks and consequences of long-term opioid therapy in women.

BACKGROUND: Long-term opioid use has increased substantially over the past decade for U.S. women. Women are more likely than men to have a chronic pain condition, to be treated with opioids, and may receive higher doses. Prescribing trends persist despite limited evidence to support the long-term benefit of this pain treatment approach. PURPOSE: To review the medical and psychological risks and consequences of long-term opioid therapy in women. METHOD: Scientific literature containing relevant keywords and content were reviewed. RESULTS AND CONCLUSIONS: Long-term opioid use exposes women to unique risks, including endocrinopathy, reduced fertility, neonatal risks, as well as greater risk for polypharmacy, cardiac risks, poisoning and unintentional overdose, among other risks. Risks for women appear to vary by age and psychosocial factors may be bidirectionally related to opioid use. Gaps in understanding and priorities for future research are highlighted.

Considerations for improving assay sensitivity in chronic pain clinical trials: IMMPACT recommendations.

A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo ("assay sensitivity"). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety.

Efficacy and safety of the α4ß2 neuronal nicotinic receptor agonist ABT-894 in patients with diabetic peripheral neuropathic pain.

Preclinical and clinical studies suggest that neuronal nicotinic receptor (NNR) agonists may be a novel and effective therapy for numerous painful conditions. Analgesic efficacy and safety of the highly selective α(4)ß(2) NNR agonist ABT-894 was evaluated in 2 separate randomized, double-blind, multicenter, placebo-controlled clinical trials in patients with diabetic peripheral neuropathic pain (DPNP). Study 1 (280 patients randomized) tested 1, 2, and 4 mg ABT-894 twice daily compared with placebo and 60 mg duloxetine once per day over 8 weeks of treatment. Study 2 (124 patients randomized) tested 6 mg ABT-894 twice daily vs placebo for 8 weeks. The primary efficacy outcome measure in both studies was the weekly mean of the 24-hour average pain score recorded in each patient's diary. In both trials, none of the ABT-894 dose groups showed efficacy compared with placebo, whereas duloxetine achieved a statistically significant improvement over placebo in Study 1. All dose levels of ABT-894 were well tolerated, and no significant safety issues were identified. These results are in contrast to the outcome of a previously reported study of DPNP using the less selective α(4)ß(2) NNR agonist ABT-594, which demonstrated efficacy compared with placebo, albeit with significant tolerability limitations. The failure of the highly selective α(4)ß(2) NNR agonist ABT-894 indicates that it may not be possible to define a therapeutic index for this mechanism or that selectively targeting α(4)ß(2) NNRs may not be a viable approach to treating neuropathic pain.