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The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.

Supplemental Digital Content is Available in the Text., Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

Food intake can alter the pharmacokinetics of certain medications, including changes in their oral bioavailability, which is of particular concern for extended-release (ER) opioids because of the high drug loads. Two randomized, open-label studies assessed the effect of food on the pharmacokinetics of single and multiple doses of hydrocodone ER formulated with CIMA® Abuse-Deterrence Technology. Healthy subjects in fed and fasted states received single 90-mg doses of hydrocodone ER (Studies 1 and 2) or multiple doses of hydrocodone ER (45 mg twice daily on days 2–3, 60 mg twice daily on days 4–5, 90 mg twice daily on days 6–10, and 90 mg once in the morning on day 11) (Study 2). Naltrexone was administered to minimize opioid-related adverse events. Pharmacokinetic parameters included maximum hydrocodone plasma concentration (C max) and area under the concentration-versus-time curve from time 0 to infinity (AUC0–∞) in Study 1 (day 1) and for one dosing interval at steady state (AUCτ,ss) in Study 2 (day 11). Before conducting the multiple-dose study, single-dose data were fitted with a population pharmacokinetic methodology. In total, 40 subjects were randomized to Study 1 and 43 subjects were randomized to Study 2. While overall exposure (AUC0–∞) was relatively similar (least squares mean ratio [90% CI]: 1.11 [1.06–1.16]), results indicated that the single-dose C max was 40% higher under fed versus fasted conditions (least squares mean ratio [90% CI]: 1.40 [1.31–1.51]; Study 1). Modeling of single-dose data predicted that the effect of food would be much less at steady state [predicted fed:fasted C max at steady state (C max,ss) and AUCτ,ss ratios of 1.18 and 1.09, respectively]. The multiple-dose study results validated these predicted ratios and indicated that the steady-state 90% CIs were within 0.80–1.25 for the fed:fasted C max,ss (1.14 [1.07–1.21]) and AUCτ,ss (1.11 [1.04–1.17]) parameters, indicating that clinically meaningful food effects at steady state are not expected. No evidence of an effect of food was found on the pharmacokinetics of hydrocodone ER after multiple days of twice-daily dosing.

Objective The objective was to evaluate the safety and efficacy of TV-45070 ointment, as a treatment for postherpetic neuralgia, and to explore the response in patients with the Nav1.7 R1150W gain-of-function polymorphism. Materials and methods This was a randomized, placebo-controlled, 2-period, 2-treatment crossover trial. Patients with postherpetic neuralgia with moderate or greater pain received TV-45070 and placebo ointments, each applied twice daily for 3 weeks. The primary efficacy measure was the difference in change in mean daily pain score from baseline compared with the last week of placebo and active treatment. Secondary endpoints included responder rate analyses and a further exploratory analysis of response in carriers of the Nav1.7 R1150W polymorphism was conducted. Results Seventy patients were enrolled and 54 completed the study. TV-45070 was safe and well tolerated. No statistical difference was observed between treatments for the primary endpoint. However, the proportion of patients with ≥50% reduction in mean pain scores at week 3 was greater on TV-45070 than on placebo (26.8% vs. 10.7%, P=0.0039). Similarly, a greater proportion of patients on TV-45070 had a ≥30% reduction in mean pain scores at week 3 (39.3% on TV-45070 vs. 23.2% on placebo, P=0.0784). Of note, 63% of patients with the R1150W polymorphism versus 35% of wild-type carriers had a ≥30% reduction in mean pain score on TV-45070 at week 3 (no inferential analysis performed). Conclusions The 50% responder analysis suggests a subpopulation may exist with a more marked analgesic response to TV-45070.The trend toward a larger proportion of responders within Nav1.7 R1150W carriers warrants further investigation.

Misuse, abuse and diversion of prescription opioid analgesics represent a global public health concern. The development of abuse-deterrent formulations (ADFs) of prescription opioid analgesics is an important step toward reducing abuse and diversion of these medications, as well as potentially limiting medical consequences when misused or administered in error. ADFs aim to hinder extraction of the active ingredient, prevent administration through alternative routes and/or make abuse of the manipulated product less attractive, less rewarding or aversive. However, opioid ADFs may still be abused via the intended route of administration by increasing the dose and/or dosing frequency. The science of abuse deterrence and the regulatory landscape are still relatively new and evolving. This paper reviews the current status of opioid ADFs, with particular focus on different approaches that can be used to deter abuse, regulatory considerations and implications for clinical management.

Objective: To evaluate long-term safety, maintenance of analgesia, and aberrant drug-related behaviors of hydrocodone extended release (ER) formulated with CIMA ® Abuse-Deterrence Technology. Design: Phase 3, multicenter, open-label extension. Setting: Fifty-six US centers. Patients: Adults with chronic low back pain completing a 12-week placebo-controlled study of abuse-deterrent hydrocodone ER were eligible. One hundred eighty-two patients enrolled and received ≥ 1 dose of study drug, 170 entered open-label treatment, and 136 completed the study. Interventions: Patients receiving hydrocodone ER in the 12-week, placebo-controlled study continued their previous dose unless adjustment was needed; those previously receiving placebo (n = 78) underwent dose titration/adjustment to an analgesic dose (15-90 mg every 12 hours). Patients received 22 weeks of open-label treatment. Main outcome measures: Safety: adverse events (AEs). Maintenance of analgesia: worst pain intensity (WPI) and average pain intensity (API) at each study visit. Aberrant drug behavior: study drug loss and diversion. Results: AEs were reported for 65/182 (36 percent) patients during dose titration/adjustment and 88/170 (52 percent) during open-label treatment. No treatment-related serious AEs were reported. There were no clinically meaningful trends in other safety assessments, including physical examinations and pure tone audiometry. One patient receiving hydrocodone ER 30 mg twice daily experienced a severe AE of neurosensory deafness that was considered treatment related. Mean WPI and API remained steady throughout open-label treatment. Six (3 percent) patients reported medication loss, and 5 (3 percent) reported diversion. Conclusions: Abuse-deterrent hydrocodone ER was generally well tolerated in patients with chronic low back pain, maintained efficacy, and was associated with low rates of loss and diversion.

Background This phase 3 study evaluated quality of life, functioning, and productivity after treatment with extended-release (ER) hydrocodone formulated with CIMA® Abuse-Deterrence Technology platform. Methods Patients with chronic pain were rolled over from a 12-week placebo-controlled hydrocodone ER study or were newly enrolled. Hydrocodone ER doses were titrated (15 to 90 mg every 12 hours) to an analgesic dose, and patients received up to 52 weeks of open-label treatment. Assessments included Clinician Assessment of Patient Function (CAPF), Patient Assessment of Function (PAF), Brief Pain Inventory–Short Form (BPI–SF), 36-item Short-Form Health Survey (SF-36), Sheehan Disability Scale (SDS), and World Health Organization Health and Work Performance Questionnaire–Short Form (HPQ–SF). Results Of 330 enrolled patients, 291 composed the full analysis population. By week 4, ≥ 50% of patients showed improvement from baseline in all 5 CAPF domains (general activities, walking, work/daily living, relationships, and enjoyment of life) and 6 of 7 PAF domains (work attendance, work performance, walking, exercise, socializing, and enjoying life). Mean decreases from baseline of 2 to 3 points were noted for BPI–SF pain interference questions from week 4 through endpoint. Mean improvements from baseline to endpoint in SF-36 subscales ranged from 3.3 to 22.3, and SDS scores improved from moderate (4.8 to 5.1) to mild (2.5 to 2.8) disruptions in work/school, social life, and family life. At endpoint, mean HPQ–SF absolute absenteeism scores decreased from 13.6 to 10.0 hours lost/month and absolute presenteeism scores improved from 67.0 to 77.1. Conclusions Patients receiving hydrocodone ER showed early numeric improvements in functioning that continued throughout this 12-month study.

Barriers to clinical trial recruitment can delay study completion, potentially resulting in increased costs and an unrepresentative sample. In the current study of 150 participants with chronic pain, we used a computerized adaptive choice-based conjoint survey that included 8 characteristics that may affect enrollment in pharmacologic pain treatment trials (ie, treatment allocation, frequency of pain ratings, treatment administration method, current medications, number of study visits, availability of evening and weekend visits, invasiveness of laboratory procedures, payment). These data were analyzed using Sawtooth Software ver. 8.4.8 (Sawtooth Software, Inc, Orem, UT), which identifies the characteristics that dominate participants' decisions across multiple sets of potential trials. Three characteristics had the largest relative importance in participants’ trial preferences: 1) invasiveness of required laboratory procedures (ie, 22%), with no procedures or blood tests preferred over ice-water sensory testing or skin biopsy; 2) ability to continue current pain medications (21%); and 3) payment for study participation (21%), with higher payment preferred. The fourth most important characteristic was number of study visits (13%), with participants preferring fewer in-person visits and more phone contacts. Understanding the preferences of potential participants is an important step toward enhancing enrollment in pain treatment trials. Perspective This article presents the preferences of individuals with chronic pain conditions regarding modifiable pain treatment trial characteristics (eg, number of study visits, payment, treatment allocation). These findings may help to improve enrollment into analgesic clinical trials and in turn accelerate the development of new pain treatments.

Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.

Objective: To evaluate efficacy and safety of hydrocodone bitartrate extended-release (ER) tablets developed with CIMA® Abuse-Deterrence Technology (ADT) versus placebo in alleviating moderate-to-severe pain in patients with chronic low back pain . Design: Phase 3, randomized, double-blind study consisting of a screening period (7-14 days), open-label titration period ( ≤ 6 weeks), and double-blind treatment period ( ≤ 12 weeks) . Setting: Seventy-eight US centers . Main outcome measures: Changes from baseline at week 12 in weekly average of daily worst pain intensity (WPI; primary efficacy measure), weekly average pain intensity (API; secondary efficacy measure), adverse events (AEs), and study drug loss and diversion . Results: Patients (N = 625) who entered open-label dose titration and identified the analgesic hydrocodone ER dose (30-90 mg every 12 h) providing optimal pain relief with minimal AEs were randomized to hydrocodone ER (n = 191) or placebo (n = 180) for double-blind treatment at the identified dose; 297 patients completed the study. Least squares means [SE] changes from baseline were significantly greater (worsening pain; 11-point scale) with placebo than hydrocodone ER in weekly average of daily WPI (0.74 [0.15] vs 0.11 [0.14]; p < 0.001) and weekly API (0.55 [0.14] vs − 0.03 [0.12]; p < 0.001). The most common AEs with hydrocodone ER were constipation (14 percent) and nausea (10 percent). Study drug loss ( ≤ 4 percent) and diversion ( ≤ 2 percent) rates were low . Conclusions: Hydrocodone ER formulated with ADT was significantly more effective than placebo in alleviating chronic low back pain and demonstrated a safety profile consistent with that of opioids, with a low occurrence of study drug loss and diversion .

This meeting report highlights the main topics presented at the conference "Chronic Inflammatory and Neuropathic Pain," convened jointly by the New York Academy of Sciences, MedImmune, and Grunenthal GmbH, on June 2-3, 2011, with the goal of providing a conducive environment for lively, informed, and synergistic conversation among participants from academia, industry, clinical practice, and government to explore new frontiers in our understanding and treatment of chronic and neuropathic pain. The program included leading and emerging investigators studying the pathophysiological mechanisms underlying neuropathic and chronic pain, and experts in the clinical development of pain therapies. Discussion included novel issues, current challenges, and future directions of basic research in pain and preclinical and clinical development of new therapies for chronic pain.

There is no widely accepted validated scale to assess the comprehensive symptom burden and severity of neurogenic orthostatic hypotension (NOH). The Orthostatic Hypotension Questionnaire (OHQ) was developed, with two components: the six-item symptoms assessment scale and a four-item daily activity scale to assess the burden of symptoms. Validation analyses were then performed on the two scales and a composite score of the OHQ. The validation analyses of the OHQ were performed using data from patients with NOH participating in a phase IV, double blind, randomized, cross over, placebo-controlled trial of the alpha agonist midodrine. Convergent validity was assessed by correlating OHQ scores with clinician global impression scores of severity as well as with generic health questionnaire scores. Test–retest reliability was evaluated using intraclass correlation coefficients at baseline and crossover in a subgroup of patients who reported no change in symptoms across visits on a patient global impression scores of change. Responsiveness was examined by determining whether worsening or improvement in the patients’ underlying disease status produced an appropriate change in OHQ scores. Baseline data were collected in 137 enrolled patients, follow-up data were collected in 104 patients randomized to treatment arm. Analyses were conducted using all available data. The floor and ceiling effects were minimal. OHQ scores were highly correlated with other patient reported outcome measures, indicating excellent convergent validity. Test–retest reliability was good. OHQ scores could distinguish between patients with severe and patients with less severe symptoms and responded appropriately to midodrine, a pressor agent commonly used to treat NOH. These findings provide empirical evidence that the OHQ can accurately evaluate the severity of symptoms and the functional impact of NOH as well as assess the efficacy of treatment.

Prescription opioid analgesics are an important treatment option for patients with chronic pain; however, misuse, abuse and diversion of these medications are a major global public health concern. Prescription opioid analgesics can be abused via intended and non-intended routes of administration, both intact or after manipulation of the original formulation to alter the drug-delivery characteristics. Available data indicate that ingestion (with or without manipulation of the prescribed formulation) is the most prevalent route of abuse, followed by inhalation (snorting, smoking and vaping) and injection. However, reported routes of abuse vary considerably between different formulations. A number of factors have been identified that appear to be associated with non-oral routes of abuse, including a longer duration of abuse, younger age, male sex and a rural or socially deprived location. The development of abuse-deterrent formulations of prescription opioid analgesics is an important step toward reducing abuse of these medications. Available abuse-deterrent formulations aim to hinder extraction of the active ingredient, prevent administration through alternative routes and/or make abuse of the manipulated product less attractive, less rewarding or even aversive. There are currently five opioid analgesics with a Food and Drug Administration abuse-deterrent label, and a number of other products are under review. A growing body of evidence suggests that introduction of abuse-deterrent opioid analgesics in the USA has been associated with decreased rates of abuse of these formulations. The availability of abuse-deterrent formulations therefore appears to represent an important step toward curbing the epidemic of abuse of prescription opioid analgesics, while ensuring the availability of effective pain medications for patients with legitimate medical need.

Objective: To evaluate long-term safety of hydrocodone extended-release (ER) formulated with CIMA ® Abuse-Deterrence Technology platform. Design: Phase 3, open-label study. Setting: Sixty-one US study centers. Patients: Patients with chronic pain newly enrolled or rolled over from a 12-week, placebo-controlled hydrocodone ER study; 330 patients enrolled, 329 patients received study drug, and 189 completed the study. Intervention: After titrating to an analgesic dose (15-90 mg every 12 hours), patients received ≤ 52 weeks of open-label treatment. Main outcome measures: Safety: adverse events (AEs), vital signs, laboratory values, electrocardiograms, and audiometry. Abuse potential: drug loss and diversion, Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), Addiction Behaviors Checklist (ABC), Current Opioid Misuse Measure (COMM) questionnaires, and Patient Global Assessment (PGA) of pain control. Results: Of 329 patients who received ≥ 1 hydrocodone ER dose, 284 (86 percent) reported ≥ 1 AE and 27 (8 percent) experienced ≥ 1 serious AE. Sixty-two (19 percent) patients withdrew because of AEs, and two AEs leading to death were reported. No serious AEs or AEs leading to death were considered treatment related by the investigator. There were no clinically meaningful trends in other safety assessments. SOAPP-R, ABC, and COMM scores demonstrated low risk of aberrant drug-related behavior. Good/excellent PGA responses were reported by 20 percent of patients at baseline and 75 percent at endpoint. The incidence of drug loss (11 percent) and diversion (2 percent) was low. Conclusions: Hydrocodone ER demonstrated acceptable safety when administered for ≤ 12 months in patients with chronic pain. Low occurrence of aberrant drug-related behavior may support the abuse-deterrence properties of hydrocodone ER.

Martin E Hale,1 Charles Laudadio,2 Ronghua Yang,2 Arvind Narayana,2 Richard Malamut2 1Gold Coast Research, LLC, Plantation, FL, 2Teva Branded Pharmaceutical Products R & D, Inc., Frazer, PA, USA Abstract: This double-blind, placebo-controlled study evaluated the efficacy and safety of hydrocodone extended release (ER) developed with abuse-deterrence technology to provide sustained pain relief and limit effects of alcohol and tablet manipulation on drug release. Eligible patients with chronic moderate-to-severe low back or osteoarthritis pain were titrated to an analgesic dose of hydrocodone ER (15–90 mg) and randomized to placebo or hydrocodone ER every 12 hours. The primary efficacy measure was change from baseline to week 12 in weekly average pain intensity (API; 0=no pain, 10=worst pain imaginable). Secondary measures included percentage of patients with >33% and >50% increases from baseline in weekly API, change from baseline in weekly worst pain intensity, supplemental opioid usage, aberrant drug-use behaviors, and adverse events. Overall, 294 patients were randomized and received ≥1 dose of placebo (n=148) or hydrocodone ER (n=146). Weekly API did not differ significantly between hydrocodone ER and placebo at week 12 (P=0.134); although, in post hoc analyses, the change in weekly API was significantly lower with hydrocodone ER when excluding the lowest dose (15 mg; least squares mean, –0.20 vs 0.40; P=0.032). Significantly more patients had .33% and .50% increase in weekly API with placebo (P

To control diabetic retinopathy, we need not only to detect it promptly, but also to manage common systemic comorbid conditions such as hypertension, hyperlipidemia, anemia, obstructive sleep apnea, and smoking--all of which tend to accelerate its course and increase its severity.

Opioids are essential to the management of pain in many patients, but they also are associated with potential risks for abuse, overdose, and diversion. A number of efforts have been devoted to the development of abuse-deterrent formulations of opioids to reduce these risks. This article summarizes a consensus meeting that was organized to propose recommendations for the types of clinical studies that can be used to assess the abuse deterrence of different opioid formulations. Due to the many types of individuals who may be exposed to opioids, an opioid formulation will need to be studied in several populations using various study designs in order to determine its abuse-deterrent capabilities. It is recommended that the research conducted to evaluate abuse deterrence should include studies assessing: (1) abuse liability; (2) the likelihood that opioid abusers will find methods to circumvent the deterrent properties of the formulation; (3) measures of misuse and abuse in randomized clinical trials involving pain patients with both low risk and high risk of abuse; and (4) post-marketing epidemiological studies.

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.

This evidence-based review was performed to evaluate the utility of nerve conduction studies (NCSs) and needle electromyography (EMG) in the diagnosis of tibial neuropathy at the ankle (tarsal tunnel syndrome, TTS). A total of 317 articles on TTS were identified that were published in English from 1965 through April 2002, from the National Library of Medicine MEDLINE database. All articles were reviewed on the basis of six selection criteria. The results of this search revealed that four articles met five or more criteria. All four articles examined the use of electrodiagnostic (EDX) techniques for the evaluation of patients with clinically suspected TTS, and were included in this practice parameter. Each of these four studies was considered to meet Class III level of evidence. NCSs were abnormal in some patients with suspected TTS. Sensory NCSs were more likely to be abnormal than motor NCSs but the actual sensitivity and specificity could not be determined. The sensitivity of needle EMG abnormalities could not be determined. NCSs may be useful for confirming the diagnosis of tibial neuropathy at the ankle, recommendation Level C. Well-designed studies are needed to evaluate more definitively EDX techniques in TTS.

This 12-month, phase 3, open-label study evaluated long-term safety of an extended-release (ER) hydrocodone tablet developed with OraGuard technology. Eligible patients (aged 18-80 years) were rolled over from a previous 12-week, randomized, placebo-controlled study of ER hydrocodone or were newly enrolledwith chronic ($3months) noncancer pain. After titrating ER hydrocodone (15-90 mg every 12 hours) to a successful dose, patients received up to 52 weeks of open-label treatment. Safety assessments included adverse events (AEs), serious AEs, withdrawals, and deaths. Patient global assessment (PGA) of pain control was also evaluated (assessments collected before the first titration dose in the previous study were considered baseline for rollover patients). In total, 329 patients received$1 ER hydrocodone dose andwere evaluable for safety; mean age was 54.4 years, 79% were white, and 65% had back/ low back pain. A total of 284 patients (86%) reported $1 AE, most commonly (>5%) constipation (26%), nausea (19%), headache (12%), somnolence (11%), vomiting (9%), and upper respiratory tract infection (8%). Twenty-seven (8%) patients experienced$1 serious AE (SAE); SAEs (>1 patient) included dehydration (n=2), deep vein thrombosis (n=2), renal failure (n=3), and pneumonia (n=3); nonewere considered treatment-related. Sixty-two (19%) patients withdrew because of treatment-emergent AEs, most commonly nausea (5%) and constipation (3%). Two deaths were reported (cause unknown, n=1; cardiac arrest and hyperkalemia, n=1); neither was considered treatment-related. Good/ excellent PGA responses were reported by 20% of patients at baseline, 81% at the beginning of open-label treatment, and 75% at endpoint (last observed postbaseline data). ER hydrocodone demonstrated a safety profile consistent with the known safety profile of hydrocodone and was well-tolerated up to 12 months in patients with chronic pain, with improvements in pain control observed early and maintained through the end of the study. Sponsored by Cephalon, now a subsidiary of Teva Pharmaceuticals.