Randomized controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in adults with complex regional pain syndrome.

OBJECTIVE: The objective was to investigate the efficacy and safety of soticlestat as adjunctive therapy in participants with complex regional pain syndrome (CRPS). DESIGN: A proof-of-concept phase 2a study, comprising a 15-week randomized, double-blind, placebo-controlled, parallel-group study (part A), and an optional 14-week open-label extension (part B). METHODS: Twenty-four participants (median age 44.5 years [range, 18-62 years]; 70.8% female) with chronic CRPS were randomized (2:1) to receive oral soticlestat or placebo. Soticlestat dosing started at 100 mg twice daily and was titrated up to 300 mg twice daily. In part B, soticlestat dosing started at 200 mg twice daily and was titrated up or down at the investigator's discretion. Pain intensity scores using the 11-point Numeric Pain Scale (NPS) were collected daily. The Patient-Reported Outcomes Measurement Information System (PROMIS)-29, Patients' Global Impression of Change (PGI-C), and CRPS Severity Score (CSS) were completed at screening and weeks 15 and 29. RESULTS: From baseline to week 15, soticlestat treatment was associated with a mean change in 24-hour pain intensity NPS score (95% confidence interval) of -0.75 (-1.55, 0.05) vs -0.41 (-1.41, 0.59) in the placebo group, resulting in a non-significant placebo-adjusted difference of -0.34 (-1.55, 0.88; P = .570). Statistically non-significant numerical changes were observed for the PROMIS-29, PGI-C, and CSS at weeks 15 and 29. CONCLUSIONS: Adjunctive soticlestat treatment did not significantly reduce pain intensity in participants with chronic CRPS.

Complex Regional Pain Syndrome: Practical Diagnostic and Treatment Guidelines, 5th Edition.

There have been some modest recent advancements in the research of Complex Regional Pain Syndrome, yet the amount and quality of the work in this complicated multifactorial disease remains low (with some notable exceptions; e.g., the recent work on the dorsal root ganglion stimulation). The semi-systematic (though in some cases narrative) approach to review is necessary so that we might treat our patients while waiting for "better research." This semi-systematic review was conducted by experts in the field, (deliberately) some of whom are promising young researchers supplemented by the experience of "elder statesman" researchers, who all mention the system they have used to examine the literature. What we found is generally low- to medium-quality research with small numbers of subjects; however, there are some recent exceptions to this. The primary reason for this paucity of research is the fact that this is a rare disease, and it is very difficult to acquire a sufficient sample size for statistical significance using traditional statistical approaches. Several larger trials have failed, probably due to using the broad general diagnostic criteria (the "Budapest" criteria) in a multifactorial/multi-mechanism disease. Responsive subsets can often be identified in these larger trials, but not sufficient to achieve statistically significant results in the general diagnostic grouping. This being the case the authors have necessarily included data from less compelling protocols, including trials such as case series and even in some instances case reports/empirical information. In the humanitarian spirit of treating our often desperate patients with this rare syndrome, without great evidence, we must take what data we can find (as in this work) and tailor a treatment regime for each patient.

Measurement Properties of the SF-MPQ-2 Neuropathic Qualities Subscale in Persons with CRPS: Validity, Responsiveness, and Rasch Analysis.

OBJECTIVES: The purpose of this study was to conduct classical psychometric evaluation and Rasch analysis on the Neuropathic Qualities subscale of the Short-Form McGill Pain Questionnaire-2 utilizing scores from persons with complex regional pain syndrome to consider reliability and person separation, validity (including unidimensionality), and responsiveness in this population. METHODS: Secondary analysis of longitudinal data from persons with acute complex regional pain syndrome was utilized for analysis of the psychometric properties and fit to the Rasch model of the Neuropathic Qualities subscale. We followed an iterative process of Rasch analysis to evaluate and address data fitting challenges. RESULTS: Repeated measures from 59 persons meeting the Budapest criteria were used for analysis. Both item-total correlations and unidimensionality analyses supported theoretical construct validity; all convergent construct validity hypotheses were also supported. Responsiveness was demonstrated comparing baseline and one-year data at d = 0.92, with a standardized response mean of 0.97. Data were able to fit the Rasch model, but all Neuropathic Qualities items had disordered thresholds that required rescoring. Additionally, local dependency and differential item function were addressed by "bundling," suggesting that no further item reduction would be possible. CONCLUSIONS: This study provided preliminary support for the validity and responsiveness of the Neuropathic Qualities subscale in persons with complex regional pain syndrome. Rasch analysis further endorses use of the Neuropathic Qualities subscale as a "stand-alone" measure for neuropathic features, but with substantial background data transformations. Replication with larger samples is recommended to increase confidence in these findings.

"Managing" the Placebo Effect: The Single-Blind Placebo Lead-in Response in Two Pain Models.

OBJECTIVE: "Placebo effects" in analgesic medication trials for chronic pain are pervasive; however, little is known regarding mechanisms or factors that may influence the presence or magnitude of these effects. Our objective is to consider elements of the placebo response in the context of two pain models using a "single-blind placebo lead-in" design (SBPLI). METHODS: As part of two pilot drug trials using knee osteoarthritis (KOA) and non-radicular low back pain (LBP) subjects, SBPLI protocols were conducted. We examined whether gender and/or diagnosis affected placebo responses as observed in changes in patient self-reported pain, depressive and pain anxiety symptoms. We also evaluated the placebo response on performance-based tests (stair climbing, range of motion (ROM), sit to stand repetitions, and 6-minute treadmill distance). RESULTS: VAS Pain Intensity (Now) values decreased significantly during the SBPLI for the sample as a whole, but the effects appeared stronger among LBP subjects. CES-D short form values (depressive symptoms) did not decrease significantly during the SBPLI for the sample as a whole, but some placebo effects appeared to emerge for women in the KOA group. PASS values (pain anxiety symptoms) decreased significantly, albeit mildly, during the SBPLI for the sample as a whole.Stair Climb (time) revealed no significant SBPLI effects. Bend Forward to Floor (ROM) increased significantly at the end of the SBPLI period for the sample as a whole, but the effects appeared stronger among KOA subjects. Sit to Stand Repetitions increased during the SBPLI for the sample as a whole. Treadmill Distance did not change significantly from Visit 1 to Visit 2; however, a significant Sex difference for the KOA group was found such that women showed greater Treadmill Distance at Visit 2. CONCLUSION: Placebo effects emerged across psychometric and performance-based measures, indicating the pervasiveness of this phenomenon. In this design, diagnostic and (to a lesser extent) gender categories differentials were observed during the placebo period. The SBPLI design may prove not only a robust method in studying the placebo phenomena, but also as a design element to mitigate some aspects of the placebo response in clinical trials.

A systematic review of ketamine for complex regional pain syndrome.

OBJECTIVE: This systematic review aims to examine the available literature and to synthesize published data concerning the treatment of Complex Regional Pain Syndrome (CRPS) with ketamine. METHODS: The search was conducted utilizing the databases Medline, Embase and the Cochrane Central Registry of Controlled Trials. All relevant articles were systematically reviewed. RESULTS: The search yielded 262 articles, 45 of which met the inclusion/exclusion criteria. Of those included, 6 were reviews, 5 were randomized placebo-controlled trials, 13 were observational studies, and 21 were case reports. CONCLUSION: There is no high quality evidence available evaluating the efficacy of ketamine for CRPS and all manuscripts examined in this review were of moderate to low quality. Therefore, we conclude there is currently only weak evidence supporting the efficacy of ketamine for CRPS, yet there is clearly a rationale for definitive study.

Signs and Symptoms of Myofascial Pain: An International Survey of Pain Management Providers and Proposed Preliminary Set of Diagnostic Criteria.

OBJECTIVE: Myofascial Pain Syndrome (MPS) is highly prevalent in pain medicine, yet there is no "gold standard" or set of validated diagnostic criteria for clinical or research use. A survey collected clinician perspectives on MPS to foster the development of a formal case definition for empirical validation. DESIGN: International survey. METHODS: Clinician members of the International Association for the Study of Pain and the American Academy of Pain Medicine received a survey of the symptoms and signs of MPS and expected response to treatment. Write-in fields were available for each category and to suggest relevant diagnostic studies. RESULTS: Two hundred fourteen responses were received from 4,143 surveys mailed. The most essential components of MPS were tender spots that recreate symptoms when palpated. MPS was also associated with muscle stiffness, decreased range of motion of the affected joints, worsening symptoms with stress, palpable taut band or tender nodule, and referred pain with palpation of the tender spot. Diagnostic studies are reported to be useful for ruling out other pathology, but not to confirm the presence of the condition. CONCLUSIONS: These results were used to propose a set of preliminary diagnostic criteria; expert consensus for case definition and subsequent empirical validation are required for standardization in research and clinical management of MPS.

Use of a medication quantification scale for comparison of pain medication usage in patients with complex regional pain syndrome (CRPS).

OBJECTIVE: To correlate the amount and types of pain medications prescribed to CRPS patients, using the Medication Quantification Scale, and patients' subjective pain levels. DESIGN: An international, multisite, retrospective review. SETTING: University medical centers in the United States, Israel, Germany, and the Netherlands. SUBJECTS/METHODS: A total of 89 subjects were enrolled from four different countries: 27 from the United States, 20 Germany, 18 Netherlands, and 24 Israel. The main outcome measures used were the Medication Quantification Scale III and numerical analog pain scale. RESULTS: There was no statistically significant correlation noted between the medication quantification scale and the visual analog scale for any site except for a moderate positive correlation at German sites. The medication quantification scale mean differences between the United States and Germany, the Netherlands, and Israel were 9.793 (P < 0.002), 10.389 (P < 0.001), and 4.984 (P = 0.303), respectively. CONCLUSIONS: There appears to be only a weak correlation between amount of pain medication prescribed and patients' reported subjective pain intensity within this limited patient population. The Medication Quantification Scale is a viable tool for the analysis of pharmaceutical treatment of CRPS patients and would be useful in further prospective studies of pain medication prescription practices in the CRPS population worldwide.

Short-Term Functional, Emotional, and Pain Outcomes of Patients with Complex Regional Pain Syndrome Treated in a Comprehensive Interdisciplinary Pain Management Program.

BACKGROUND: Complex regional pain syndrome (CRPS) is difficult to effectively treat with unimodal approaches. OBJECTIVE: To investigate whether CRPS can be effectively treated in a comprehensive interdisciplinary pain management program. DESIGN: Observational cohort study of 49 patients aged 18-89 who fulfilled 'Budapest Criteria' for CRPS and completed an interdisciplinary pain management program. Preprogram to postprogram changes in physical functioning, perceived disability, emotional functioning, acceptance, coping, and pain were assessed. The measures used included: Pain Disability Index, Six minute walk test, 2-minute sit-to-stand, Numerical Rating Scale, Center for Epidemiologic Studies Depression Scale, Pain Anxiety Symptoms Scale, Chronic Pain Acceptance Questionnaire, Coping Strategies Questionnaire-Revised, RIC- Multidimensional Patient Global Impression of Change (RIC-MPGIC), and Medication Quantification Scale. For worker's compensation patients, the rate of successful release to work at the end of the program was calculated. RESULTS: Results indicated significant improvements in physical functioning and perceived disability (P's<0.001). Patients reported increased usage of an adaptive coping strategy, distraction (P = 0.010), and decreased usage of maladaptive and passive strategies (P's < 0.001). Patients showed greater chronic pain acceptance (P's ≤ 0.010) and reductions in emotional distress (P's < 0.001). Medication usage at 1-month follow-up was significantly reduced compared to program start (P < 0.001) and discharge (P = 0.004). Patients reported "much improvement" in overall functioning, physical functioning, mood, and their ability to cope with pain and flare-ups (RIC-MPGIC). Patient report of pain was not significantly reduced at discharge (P =0.078). Fourteen (88%) of 16 total worker's compensation patients were successfully released to work at the end of the program. CONCLUSIONS: This study demonstrates short-term improvements in physical and emotional functioning, pain coping, and medication usage. These findings are consistent with the rehabilitation philosophy of improving functioning and sense of well-being as of equal value and relevance to pain reduction.

Phantom limb pain: a systematic neuroanatomical-based review of pharmacologic treatment.

OBJECTIVE: Review the current evidence-based pharmacotherapy for phantom limb pain (PLP) in the context of the current understanding of the pathophysiology of this condition. DESIGN: We conducted a systematic review of original research papers specifically investigating the pharmacologic treatment of PLP. Literature was sourced from PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL). Studies with animals, "neuropathic" but not "phantom limb" pain, or without pain scores and/or functional measures as primary outcomes were excluded. A level of evidence 1-4 was ascribed to individual treatments. These levels included meta-analysis or systematic reviews (level 1), one or more well-powered randomized, controlled trials (level 2), retrospective studies, open-label trials, pilot studies (level 3), and anecdotes, case reports, or clinical experience (level 4). RESULTS: We found level 2 evidence for gabapentin, both oral (PO) and intravenous (IV) morphine, tramadol, intramuscular (IM) botulinum toxin, IV and epidural Ketamine, level 3 evidence for amitriptyline, dextromethorphan, topiramate, IV calcitonin, PO memantine, continuous perineural catheter analgesia with ropivacaine, and level 4 evidence for methadone, intrathecal (IT) buprenorphine, IT and epidural fentanyl, duloxetine, fluoxetine, mirtazapine, clonazepam, milnacipran, capsaicin, and pregabalin. CONCLUSIONS: Currently, the best evidence (level 2) exists for the use of IV ketamine and IV morphine for the short-term perioperative treatment of PLP and PO morphine for an intermediate to long-term treatment effect (8 weeks to 1 year). Level 2 evidence is mixed for the efficacy of perioperative epidural anesthesia with morphine and bupivacaine for short to long-term pain relief (perioperatively up to 1 year) as well as for the use of gabapentin for pain relief of intermediate duration (6 weeks).

A phase 2a, randomized, crossover trial of gabapentin enacarbil for the treatment of postherpetic neuralgia in gabapentin inadequate responders.

OBJECTIVE: To compare the efficacy of high-dose (3,600 mg/day) vs low-dose (1,200 mg/day) oral gabapentin enacarbil (GEn) on pain intensity in adults with postherpetic neuralgia (PHN) and a history of inadequate response to ≥1,800 mg/day gabapentin. DESIGN: Multicenter, randomized, double-blind, crossover study (NCT00617461). SETTING: Thirty-five outpatient centers in Germany and the United States. SUBJECTS: Subjects aged ≥18 years with a diagnosis of PHN. METHODS: During a 2-week baseline period, subjects received open-label treatment with 1,800 mg/day gabapentin. Subjects who had a mean 24-hour average pain intensity score ≥4 during the last 7 days of the baseline period were randomized to receive GEn (1,200 or 3,600 mg/day) for treatment period 1 (28 days), followed by GEn 2,400 mg/day (4 days), and the alternate GEn dose for treatment period 2 (28 days). RESULTS: There was a modest but significant improvement in pain intensity scores with GEn 3,600 mg vs 1,200 mg (adjusted mean [90% confidence interval] treatment difference, -0.29 [-0.48 to -0.10]; P = 0.013). The difference in efficacy between doses was observed primarily in subjects who received the higher dose during treatment period 2; certain aspects of the study design may have contributed to this outcome. Plasma steady-state gabapentin exposure during GEn treatment was as expected and consistent between treatment periods. No new safety signals or adverse event trends relating to GEn exposure were identified. CONCLUSIONS: While the overall results demonstrated efficacy in a PHN population, the differences between treatment periods confound the interpretation. These findings could provide insight into future trial designs.

Complex regional pain syndrome: practical diagnostic and treatment guidelines, 4th edition.

OBJECTIVE: This is the fourth edition of diagnostic and treatment guidelines for complex regional pain syndrome (CRPS; aka reflex sympathetic dystrophy). METHODS: Expert practitioners in each discipline traditionally utilized in the treatment of CRPS systematically reviewed the available and relevant literature; due to the paucity of levels 1 and 2 studies, less rigorous, preliminary research reports were included. The literature review was supplemented with knowledge gained from extensive empirical clinical experience, particularly in areas where high-quality evidence to guide therapy is lacking. RESULTS: The research quality, clinical relevance, and "state of the art" of diagnostic criteria or treatment modalities are discussed, sometimes in considerable detail with an eye to the expert practitioner in each therapeutic area. Levels of evidence are mentioned when available, so that the practitioner can better assess and analyze the modality under discussion, and if desired, to personally consider the citations. Tables provide details on characteristics of studies in different subject domains described in the literature. CONCLUSIONS: In the humanitarian spirit of making the most of all current thinking in the area, balanced by a careful case-by-case analysis of the risk/cost vs benefit analysis, the authors offer these "practical" guidelines.

Treatment outcomes for workers compensation patients in a U.S.-based interdisciplinary pain management program.

OBJECTIVES: Assess the efficacy of an outpatient-based interdisciplinary pain rehabilitation program for patients with active workers compensation claims. PATIENTS: Data were available for 101 patients, primarily with chronic low back pain (75%), who participated in the program. METHODS: Treatment included a 4-week (Monday to Friday), 8-hours/day graded progressive program that included individual and group therapies (pain psychology, physical therapy, occupational therapy, relaxation training/biofeedback, aerobic conditioning, pool therapy, vocational counseling, patient education and medical management). Outcome measures included program completion status, release-to-work status, return-to-work status, total scores on the Beck depression inventory, state-trait anxiety inventory, pain catastrophizing scale, and the McGill pain questionnaire visual analogue scale (MPQ VAS). The majority of the patients (65%) graduated from the program. Pre-postoutcome data were available for those who graduated from the program. For noncompleters, last obtained MPQ VAS was compared with their initial MPQ VAS scores. RESULTS: Of those completing the program, most patients (91%)were released to return to work; with 80% released to full-time status and 11% released to gradual return. Approximately half (49%) of the program completers returned to work. Paired-samples t-tests showed that program completers had significant reductions in depression (P = 0.000), pain-related catastrophizing (P = 0.033), and pain intensity (P = 0.000), but not in anxiety (P = 0.098). Interestingly, the last obtained (at early discharge/withdrawal) pain intensity scores (M = 70.33) were higher than at baseline (M = 61.20) in the noncompleters. This difference was not statistically significant (P = 0.127) but may be clinically meaningful. DISCUSSION: Our results support the efficacy of an outpatient-based 4-week interdisciplinary pain rehabilitation program in decreasing emotional distress, reducing pain intensity, and improving return-to-work status in the majority of completers in this challenging population. Patients reporting increased pain at discharge or those discharged early may have been due to operant factors.

Delphi study to define core clinical outcomes for inclusion in a complex regional pain syndrome international research registry and data bank.

ABSTRACT: Complex regional pain syndrome (CRPS) clinical trials have historically captured a diverse range of outcomes. A minimum set of CRPS patient-reported outcomes has been agreed for inclusion in a future CRPS international clinical research registry and data bank. This study aimed to identify a complementary set of core clinical outcomes. Clinicians and researchers from the international CRPS community informed the content of a 2-round electronic Delphi study. Participation was invited from members of the International Association for the Study of Pain CRPS Special Interest Group and the International Research Consortium for CRPS. In round 1, participants rated the relevance of 59 clinical outcomes in relation to the question "What is the clinical presentation and course of CRPS, and what factors influence it?" (1 = not relevant and 9 = highly relevant). In round 2, participants rerated each outcome in the light of the round 1 median scores. The criterion for consensus was median score ≥7, agreed by 75% of respondents. The core study team considered the feasibility of data collection of each identified outcome in agreeing final selections. Sixty respondents completed both survey rounds, with responses broadly consistent across professions. Nine outcomes met the consensus criterion. Final outcomes recommended for inclusion in the core clinical set were record of medications, presence of posttraumatic stress disorder, extent of allodynia, and skin temperature difference between limbs. Study findings provide robust recommendations for core clinical outcome data fields in the future CPRS international clinical research registry. Alongside patient-reported outcomes, these data will enable a better understanding of CRPS.

Home-based aerobic conditioning for management of symptoms of fibromyalgia: a pilot study.

OBJECTIVE: This pilot study was designed to evaluate the impact of a home-based aerobic conditioning program on symptoms of fibromyalgia and determine if changes in symptoms were related to quantitative changes in aerobic conditioning (VO(2) max). METHODS: Twenty-six sedentary individuals diagnosed with fibromyalgia syndrome participated in an individualized 12-week home-based aerobic exercise program with the goal of daily aerobic exercise of 30 minutes at 80% of estimated maximum heart rate. The aerobic conditioning took place in the participants' homes, outdoors, or at local fitness clubs at the discretion of the individual under the supervision of a physical therapist. Patients were evaluated at baseline and completion for physiological level of aerobic conditioning (VO(2) max), pain ratings, pain disability, depression, and stress. RESULTS: In this pilot study subjects who successfully completed the 12-week exercise program demonstrated an increase in aerobic conditioning, a trend toward decrease in pain measured by the McGill Pain Questionnaire-Short Form and a weak trend toward improvements in visual analog scale, depression, and perceived stress. Patients who were unable or unwilling to complete this aerobic conditioning program reported significantly greater pain and perceived disability (and a trend toward more depression) at baseline than those who completed the program. CONCLUSIONS: Patients suffering from fibromyalgia who can participate in an aerobic conditioning program may experience physiological and psychological benefits, perhaps with improvement in symptoms of fibromyalgia, specifically pain ratings. More definitive trials are needed, and this pilot demonstrates the feasibility of the quantitative VO2 max method. Subjects who experience significant perceived disability and negative affective symptoms are not likely to maintain a home-based conditioning program, and may need a more comprehensive interdisciplinary program offering greater psychological and social support.

Preoperative Predictors of Complex Regional Pain Syndrome Outcomes in the 6 Months Following Total Knee Arthroplasty.

This prospective observational study evaluated preoperative predictors of complex regional pain syndrome (CRPS) outcomes in the 6 months following total knee arthroplasty (TKA). Participants were n = 110 osteoarthritis patients (64.5% female) undergoing unilateral TKA with no prior CRPS history. Domains of negative affect (depression, anxiety, catastrophizing), pain (intensity, widespread pain, temporal summation of pain [TSP]), pain interference, sleep disturbance, and pro-inflammatory status (tumor necrosis factor-alpha [TNF-a]) were assessed preoperatively. CRPS outcomes at 6-week and 6-month follow-up included the continuous CRPS Severity Score (CSS) and dichotomous CRPS diagnoses (2012 IASP criteria). At 6 months, 12.7% of participants met CRPS criteria, exhibiting a "warm CRPS" phenotype. Six-week CSS scores were predicted by greater preoperative depression, anxiety, catastrophizing, TSP, pain intensity, sleep disturbance, and TNF-a (P's < .05). Provisional CRPS diagnosis at 6 weeks was predicted by higher preoperative TSP, sleep disturbance, and TNF-a (P's < .05). CSS scores at 6 months were predicted by more widespread and intense preoperative pain, and higher preoperative TSP, pain interference, and TNF-a (P's < .01). CRPS diagnosis at 6 months was predicted only by more widespread and intense pain preoperatively (P's < .05). Risk for CRPS following TKA appears to involve preoperative central sensitization and inflammatory mechanisms. Preoperative negative affect is unlikely to directly influence long-term CRPS risk. PERSPECTIVE: This article identifies preoperative predictors of CRPS features at 6 months following total knee arthroplasty, including more widespread pain and higher pain intensity, temporal summation of pain, pain interference, and tumor necrosis factor-alpha levels. Findings suggest the importance of central sensitization and inflammatory mechanisms in CRPS risk following tissue trauma.

Objectification of the diagnostic criteria for CRPS.

The current diagnostic criteria for complex regional pain syndrome (CRPS), codified by the International Association for the Study of Pain's taxonomy committee, and newer statistically derived criteria (the "Budapest" criteria), are both deliberately based on bedside testing. Designing criteria that are accessible to any clinician, not requiring any special equipment or training, is very important for clinical diagnosis. However, that approach, albeit pragmatic, forces a very heavy reliance on the subjective (not only the subjective response of the patient, but the subjective impression of the clinician). This is very problematic scientifically and statistically. Fortunately, with some new technologies and new approaches to old technologies, significant improvements can be made not only in terms of quantification, but also in allowing significant objectification of the diagnostic data. We will initiate a discussion of some of these potentially useful approaches.

Negligible analgesic tolerance seen with extended release oxymorphone: a post hoc analysis of open-label longitudinal data.

OBJECTIVE: To examine the development of analgesic tolerance in patients on oxymorphone extended-release (OxymER). DESIGN: Post hoc analysis of data from a previously conducted prospective 1 year multi-center open-label extension study in which patients were able to titrate as needed. PATIENTS: Sample of 153 hip and knee osteoarthritis (OA) subjects on OxymER. Primary analyses were limited to study completers (n = 62) due to the large amount of missing data for the noncompleters (n = 91). OUTCOME MEASURES: Main outcome measures included OxymER doses (pill counts) and pain intensity ratings using a visual analog scale at monthly visits. RESULTS: There were significant dose increases from weeks 1 to 2 and 2 to 6 (P < 0.05). Doses stabilized around week 6, suggesting the completion of what we defined as "titration." Both doses and pain ratings were stable when this titration phase was excluded from the analysis (P = 0.751; P = 0.056, respectively). Only 28% of the patients had any dose changes following this titration. While there was a significantly greater dose at week 52 compared with week 10 (P = 0.010), the increase in dose became insignificant after excluding four subjects who required two dose increases (P = 0.103). CONCLUSIONS: The results showed that most of the titration/dose stabilization changes occurred within the first 10 weeks. A minority (28%) of subjects required dosage increases after this (defined) titration period. Pain reports stabilized statistically after 2 weeks. The findings of this post hoc analysis suggest a lack of opioid tolerance in the majority (72%) of these OA patients who completed this study following a defined titration period on OxymER. SUMMARY: This post hoc analysis of oxymorphone ER consumption in osteoarthritis pain vs pain report showed that most dose changes occurred during an initial "titration period" as defined. Following this titration few subjects increased dose and analgesia remained stable. These findings suggest a lack of longitudinal opioid tolerance in the majority of those OA subjects who completed the trial.