A systematic review of the effectiveness of policies restricting access to pregabalin.
ABSTRACT: 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.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.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.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.N/A.
Project description:OBJECTIVES:The US opioid medication epidemic has resulted in serious health consequences for patients. Formulary management tools adopted by payers, specifically prior authorization (PA) policies, may lower the rates of opioid medication abuse and overdose. We compared rates of opioid abuse and overdose among enrollees in plans that varied in their use of PA from "High PA" (ie, required PA for 17 to 74 opioids), with "Low PA" (ie, required PA for 1 opioid), and "No PA" policies for opioid medications. STUDY DESIGN:Retrospective cohort study of patients initiating opioid treatment in Pennsylvania Medicaid from 2010 to 2012. METHODS:Generalized linear models with generalized estimating equations were employed to assess the relationships between the presence of PA policies and opioid medication abuse and overdose, as measured in Medicaid claims data, adjusting for demographics, comorbid health conditions, benzodiazepine/muscle relaxant use, and emergency department use. RESULTS:The study cohort included 297,634 enrollees with a total of 382,828 opioid treatment episodes. Compared with plans with No PA, enrollees in High PA (adjusted rate ratio [ARR], 0.89; 95% confidence interval [CI], 0.85-0.93; P <.001) and Low PA plans (ARR, 0.93; 95% CI, 0.87-1.00; P = .04) had lower rates of abuse. Enrollees in the Low PA plan had a lower rate of overdose than those within plans with No PA (ARR, 0.75; 95% CI, 0.59-0.95; P = .02). High PA plan enrollees were also less likely than No PA enrollees to experience an overdose, but this association was not statistically significant (ARR, 0.88; 95% CI, 0.76-1.02; P = .08). CONCLUSIONS:Enrollees within Medicaid plans that utilize PA policies appear to have lower rates of abuse and overdose following initiation of opioid medication treatment.
Project description:BACKGROUND:Fibromyalgia (FM) is an idiopathic, functional syndrome characterized by chronic, widespread pain and diffuse tenderness. This disorder affects more than 6 million patients in the United States and is associated with significant clinical and economic burdens. OBJECTIVES:The objectives of this study were to: 1) estimate the costs associated with a FM diagnosis; and 2) estimate the impact of chronic opioid use on the costs of FM patients. RESEARCH DESIGN:Case-control study. METHODS:Subjects were identified in a large nationally representative database of commercially insured patients. Propensity score-matched analyses included 445,912 FM-control pairs in the first analysis, while the second analysis included 48,333 chronic opioid users with the FM-control pairs. Primary outcomes of interest were the medical and prescription costs compared between matched pairs, based on propensity for being a case as evidenced by coefficients obtained from a first-stage logistic regression. Patient characteristics considered include: state of residence, diagnosing provider type, comorbid conditions, and concurrent medication use. RESULTS:When controlling for propensity to receive a FM diagnosis, the actual diagnosis has a small effect on medical (-$83.54 [95% CI, -152.55 to -16.53]) and prescription ($120.31 [95% CI, 109.98-130.62]) costs. However, the effect of chronic opioid use in FM patients on medical ($9094.05 [95% CI, 8924.79-9263.31]) and prescription ($3391.81 [95% CI, 3368.84-3414.79]) costs is much more substantial. CONCLUSIONS:While the differences seen in FM patients and controls are marginal, those attributed to chronic opioid use in these patients are significantly higher. Chronic opioid therapy to treat FM is a practice based not on evidence available to practitioners, but on other variables.
Project description:Although pregabalin therapy is beneficial for neuropathic pain (NeP) by targeting the CaV?2?-1 subunit, its site of action is uncertain. Direct targeting of the central nervous system may be beneficial for the avoidance of systemic side effects.We used intranasal, intrathecal, and near-nerve chamber forms of delivery of varying concentrations of pregabalin or saline delivered over 14 days in rat models of experimental diabetic peripheral neuropathy and spinal nerve ligation. As well, radiolabelled pregabalin was administered to determine localization with different deliveries. We evaluated tactile allodynia and thermal hyperalgesia at multiple time points, and then analyzed harvested nervous system tissues for molecular and immunohistochemical changes in CaV?2?-1 protein expression. Both intrathecal and intranasal pregabalin administration at high concentrations relieved NeP behaviors, while near-nerve pregabalin delivery had no effect. NeP was associated with upregulation of CACNA2D1 mRNA and CaV?2?-1 protein within peripheral nerve, dorsal root ganglia (DRG), and dorsal spinal cord, but not brain. Pregabalin's effect was limited to suppression of CaV?2?-1 protein (but not CACNA2D1 mRNA) expression at the spinal dorsal horn in neuropathic pain states. Dorsal root ligation prevented CaV?2?-1 protein trafficking anterograde from the dorsal root ganglia to the dorsal horn after neuropathic pain initiation.Either intranasal or intrathecal pregabalin relieves neuropathic pain behaviours, perhaps due to pregabalin's effect upon anterograde CaV?2?-1 protein trafficking from the DRG to the dorsal horn. Intranasal delivery of agents such as pregabalin may be an attractive alternative to systemic therapy for management of neuropathic pain states.
Project description:Purpose:Although analyses of pooled clinical trial data have reported how international populations respond to pregabalin by baseline neuropathic pain (NeP) severity, no studies have evaluated this specifically in patients from Japan. Thus, this post hoc pooled analysis evaluated the efficacy of pregabalin in Japanese subjects for treating moderate or severe baseline NeP. Patients and methods:Data were pooled from three placebo-controlled trials enrolling Japanese subjects with postherpetic neuralgia (PHN), diabetic peripheral neuropathy (DPN), and spinal cord injury (SCI). The efficacy of pregabalin was evaluated by baseline pain severity (moderate or severe NeP). The trials on PHN and DPN included a 1-week titration of pregabalin from 150 mg/day to 300 or 600 mg/day; the SCI trial included a 4-week dose optimization phase (150 mg/day, titrated up to 600 mg/day). Treatment durations were 13-16 weeks (excluding 1-week taper periods), and pregabalin was administered in two divided doses per day. Results:Mean baseline pain scores and demographic characteristics were comparable between treatment cohorts. Pregabalin treatment significantly reduced pain scores from baseline to endpoint compared with placebo in subjects with both moderate (P<0.001) and severe (P<0.05) baseline pain. Significant improvements in mean sleep scores from baseline to endpoint were associated with pregabalin compared with placebo in subjects with both moderate and severe baseline pain (both P<0.0001). A greater proportion of subjects in both pain cohorts achieved a ≥30% reduction in pain from baseline with pregabalin vs placebo (P<0.05). Higher proportions of pregabalin-treated vs placebo-treated subjects shifted to a less severe pain category at endpoint. Consistent with the known safety profile of pregabalin, common adverse events included dizziness, somnolence, weight gain, and peripheral edema. Conclusion:Pregabalin demonstrated efficacy for pain relief and sleep improvement with a consistent safety profile in Japanese subjects with either moderate or severe baseline pain severity. ClinicalTrialsgov identifiers:NCT0039490130, NCT0055347522, NCT0040774524.
Project description:BACKGROUND: Subjects with diabetes mellitus (DM) develop gait dysfunction contributing to falls, reluctance to perform activities and injuries. Neuropathic pain (NeP) related to diabetic peripheral neuropathy (DPN) is associated with increased gait variability that may contribute to gait dysfunction. We used a portable device (GaitMeter™) and related gait and balance measures to measure gait parameters in painful DPN (PDPN) subjects prior to and during analgesia. Our hypothesis was that PDPN subjects would have decreased gait step variability when receiving pharmacological relief of NeP. METHODS: DPN subjects with at least moderate NeP were assessed in a randomized, double-blind crossover study of pregabalin versus placebo. The outcome measure was variability in step length and step velocity. Testing for Timed Get-Up-and-Go Test, Tinetti Mobility Scales, Sway Testing, a Physiological Profile Approach, and fall-related surveys were also performed. DPN severity was quantified using the Utah Early Neuropathy Score. RESULTS: PDPN subjects developed increased, rather than decreased, step length and step velocity variability during pregabalin treatment. There were no significant differences between cohorts for other physiological gait and balance testing. Non-significant NeP relief occurred in the pregabalin phase of study as compared with placebo. There was a negative relationship for step length with pain severity. CONCLUSION: Analgesia did not decrease gait variability in PDPN patients, and in fact, increased gait variability was seen during pregabalin treatment. Other important relationships of gait dysfunction with PDPN should be sought.
Project description:OBJECTIVE:To evaluate the impact of pregabalin on sleep, pain, function, and health status in patients with chronic low back pain with accompanying neuropathic pain (CLBP-NeP) under routine clinical practice. METHODS:This prospective, non-interventional, observational study enrolled Japanese adults (?18 years) with CLBP-NeP of duration ?3 months and severity ?5 on a numerical rating scale (0= no pain, 10= worst possible pain). Treatment was 8 weeks with pregabalin (n=157) or usual care alone (n=174); choice of treatment was determined by the physician. The primary efficacy outcome was change from baseline to 8 weeks in pain-related interference with sleep, assessed using the Pain-Related Sleep Interference Scale (PRSIS; 0= did not interfere with sleep, 10= completely interferes with sleep). Secondary endpoints were changes in PRSIS at week 4, and changes at weeks 4 and 8 in pain (numerical rating scale), function (Roland-Morris Disability Questionnaire), and quality of life (EuroQol 5D-5L); global assessments of change were evaluated from the clinician and patient perspectives at the final visit. RESULTS:Demographic characteristics were similar between cohorts, but clinical characteristics suggested greater disease severity in the pregabalin group including a higher mean (standard deviation) pain score, 6.3 (1.2) versus 5.8 (1.1) (P<0.001). For the primary endpoint, pregabalin resulted in significantly greater improvements in PRSIS at week 8, least-squares mean changes of -1.3 versus -0.4 for usual care (P<0.001); pregabalin also resulted in greater PRSIS improvement at week 4 (P=0.012). Relative to usual care at week 8, pregabalin improved pain and function (both P<0.001), and showed global improvements since beginning study medication (P<0.001). Pregabalin was well tolerated. CONCLUSION:In clinical practice in patients with CLBP-NeP, pregabalin showed significantly greater improvements in pain-related interference with sleep relative to usual care. In addition, pregabalin significantly improved pain, function, and health status, suggesting the benefits of pregabalin for overall health and well-being relative to usual care in these patients. (Clinicaltrials. gov identifier NCT02273908).
Project description:Pregabalin is approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM), diabetic peripheral neuropathy (DPN), postherpetic neuralgia (PHN), and neuropathic pain due to spinal cord injury (SCI). Approval was based on clinical trial data demonstrating statistically significant differences in pain scores versus placebo. However, statistically significant pain relief may not always equate to clinically meaningful pain relief. To further characterize the clinical benefit of pregabalin, this analysis examined shifts in pain severity categories in patients with FM, DPN/PHN (pooled in this analysis), and SCI treated with pregabalin.Data were pooled from 23 placebo-controlled trials in patients with FM (1,623 treated with pregabalin, 937 placebo), DPN/PHN (2,867 pregabalin, 1,532 placebo), or SCI (181 pregabalin, 175 placebo). Pain scores were assessed on an 11-point numeric rating scale and categorized as mild (0 to <4), moderate (4 to <7), or severe (7 to 10). Only patients with mean score ≥4 at baseline were randomized to treatment. The percentage of patients shifting pain category from baseline to endpoint for pregabalin and placebo was analyzed using a modified ridit transformation with the Cochran-Mantel-Haenszel procedure.A higher proportion of patients shifted to a less severe pain category at endpoint with pregabalin compared with placebo. With flexible-dose pregabalin, the percentage of patients improving from: severe to mild (pregabalin versus placebo) was 15.8 versus 13.4 in FM patients, 36.0 versus 16.6 in DPN/PHN patients, 14.3 versus 7.7 in SCI patients; severe to moderate was 28.7 versus 28.2 in FM patients, 32.5 versus 28.2 in DPN/PHN patients, 35.7 versus 28.2 in SCI patients; and moderate to mild was 38.3 versus 26.4 in FM patients, 59.5 versus 41.4 in DPN/PHN patients, 38.6 versus 27.2 in SCI patients.Compared with placebo, pregabalin is more often associated with clinically meaningful improvements in pain category in patients with FM, DPN, PHN, or SCI.
Project description:Background: Despite high prevalence of chronic neck pain in Japan and the negative impact pain has on patient's quality of life (QoL), the therapeutic value of pregabalin for chronic neck pain with a neuropathic pain (NeP) component has not been assessed in a typical Japanese health care setting. Methods: An 8-week, non-interventional, multicenter, observational study of Japanese adults (?20 years) with chronic refractory cervical pain including a NeP element (for ?12 weeks) and sleep disturbance on the Pain-Related Sleep-Interference Scale (PRSIS) ?1 (from 0 "does not interfere with sleep" to 10 "completely interferes"). Patients received either usual care with conventional analgesics or pregabalin (150-600 mg/day) for 8 weeks. "Usual care" with analgesics or other treatment(s) was determined based on physician's best clinical judgment. Primary endpoint was change from baseline to week 8 in PRSIS. Secondary endpoints included: change from baseline to week 4 in PRSIS, and to week 4 and 8 in pain Numerical Rating Scale (NRS; from 0 "no pain" to 10 "worst possible pain"), and on the Neck Disability Index (NDI). Other assessments of QoL were undertaken. Safety was monitored. Results: Overall, 369 patients received pregabalin (n=145) or usual care (n=224). The median (range) dose of pregabalin was 49.6 (25.0-251.5) mg/day. Least-squares mean change in PRSIS from baseline to week 8 favored pregabalin (-1.167 vs -0.269; treatment difference -0.898 [95% CI -1.262, -0.535], P<0.001). Similar observations were seen at week 4 in favor of pregabalin versus usual care (P<0.001). Pregabalin significantly improved pain NRS and NDI scores at weeks 4 and 8 (all P<0.001). Improvements in QoL versus usual care were also observed. Pregabalin was generally well tolerated. Conclusion: In this open-label study, pregabalin improved PRSIS and resulted in clinically meaningful reductions in pain in Japanese patients with NeP associated with chronic cervical pain. ClinicalTrials.gov identifier: NCT02868359.
Project description:Fibromyalgia (FM) is a common pain condition characterized by widespread musculoskeletal pain and tenderness. Pregabalin is an approved treatment for adults in the United States, but there are no approved treatments for adolescents with FM.This was a 15-week, randomized, double-blind, placebo-controlled study and 6-month open-label safety trial of flexible-dose pregabalin (75-450 mg/day) for the treatment of adolescents (12-17 years) with FM. Primary outcome was change in mean pain score at endpoint (scored from 0-10, with 24-h recall). Secondary outcomes included global assessments and measures of pain, sleep, and FM impact.A total of 107 subjects were randomized to treatment (54 pregabalin, 53 placebo) and 80 completed the study (44 pregabalin, 36 placebo). Improvement in mean pain score at endpoint with pregabalin versus placebo was not statistically significant, treatment difference (95 % CI), -0.66 (-1.51, 0.18), P?=?0.121. There were significant improvements with pregabalin versus placebo in secondary outcomes of change in pain score by week (P?<?0.05 for 10 of 15 weeks); change in pain score at week 15 (1-week recall), treatment difference (95 % CI), -0.87 (-1.68, -0.05), P?=?0.037; and patient global impression of change, 53.1 % versus 29.5 % very much or much improved (P?=?0.013). Trends toward improvement with pregabalin in other secondary outcomes measuring pain, sleep, and FM impact were not significant. Safety was consistent with the known profile of pregabalin in adults with FM.Pregabalin did not significantly improve the mean pain score in adolescents with FM. There were significant improvements in secondary outcomes measuring pain and impression of change.NCT01020474 ; NCT01020526 .
Project description:<h4>Background</h4>Neuropathic pain (NeP) is a common symptom of a group of a variety of conditions, including diabetic neuropathy, trigeminal neuralgia, or postherpetic neuralgia. Prevalence of NeP has been estimated to range between 5-7.5%, and produces up to 25% of pain clinics consultations. Due to its severity, chronic evolution, and associated co-morbidities, NeP has an important individual and social impact. The objective was to analyze the effect of pregabalin (PGB) on pain alleviation and longitudinal health and non-health resources utilization and derived costs in peripheral refractory NeP in routine medical practice in primary care settings (PCS) in Spain.<h4>Methods</h4>Subjects from PCS were older than 18 years, with peripheral NeP (diabetic neuropathy, post-herpetic neuralgia or trigeminal neuralgia), refractory to at least one previous analgesic, and included in a prospective, real world, and 12-week two-visit cost-of-illness study. Measurement of resources utilization included both direct healthcare and indirect expenditures. Pain severity was measured by the Short Form-McGill Pain Questionnaire (SF-MPQ).<h4>Results</h4>One-thousand-three-hundred-fifty-four PGB-naive patients [58.8% women, 59.5 (12.7) years old] were found eligible for this secondary analysis: 598 (44%) switched from previous therapy to PGB given in monotherapy (PGBm), 589 (44%) received PGB as add-on therapy (PGB add-on), and 167 (12%) patients changed previous treatments to others different than PGB (non-PGB). Reductions of pain severity were higher in both PGBm and PGB add-on groups (54% and 51%, respectively) than in non-PGB group (34%), p < 0.001. Incremental drug costs, particularly in PGB subgroups [€ 34.6 (80.3), € 160.7 (123.9) and € 154.5 (133.0), for non-PGB, PGBm and PGBadd-on, respectively (p < 0.001)], were off-set by higher significant reductions in all other components of health costs yielding to a greater total cost reductions: -€ 1,045.3 (1,989.6),-€ 1,312.9 (1,543.0), and -€ 1,565.5 (2,004.1), for the three groups respectively (p = 0.03).<h4>Conclusion</h4>In Spanish primary care settings, PGB given either add-on or in monotherapy in routine medical practice was associated with pain alleviation leading to significant longitudinal reductions in resource use and total costs during the 12-week period of the study compared with non-PGB-therapy of patients with chronic NeP of peripheral origin. The use of non-appropriate analgesic therapies for neuropathic pain in a portion of subjects in non-PGB group could explain partially such findings.