Single vs composite measures of pain intensity: relative sensitivity for detecting treatment effects.

Assay sensitivity remains a significant issue in pain clinical trials. One possible method for increasing assay sensitivity for detecting changes in pain intensity is to increase the reliability of pain intensity assessment by increasing the number of intensity ratings obtained, and combining these ratings into composite scores. The current study performed secondary analyses from a published clinical trial to test this possibility. The reliability and assay sensitivity pain intensity scores made up of 1 to 9 24-hour pain intensity recall ratings were compared. Although the reliability of the outcome measures improved as the number of items increased, this increase in reliability was not associated with an increase in assay sensitivity. A single 24-hour recall rating was about as valid (sensitive) for detecting treatment effects as composite scores made up of 2 to 9 different ratings. If this finding replicates in other pain populations, it has significant implications for the design and conduct of pain clinical trials. Specifically, it suggests the possibility that assessment burden (and associated costs and problems related to missing data) might be greatly reduced by specifying a single recall rating as the primary outcome variable. Research is needed to explore this possibility further.

The meaning of global outcome measures in pain clinical trials: more than just change in pain intensity.

OBJECTIVES: To understand the factors that contribute to patient and physician global outcome ratings and the extent to which receiving different doses of opioids or placebo might influence the importance of these factors better. METHODS: A secondary analysis was performed using data from a prospective, multicenter, double-blind placebo-controlled, and active-controlled parallel group dose-ranging study comparing the efficacy of oxymorphone extended release (ER) 20 mg (ER20, N=121); oxymorphone ER 40 mg (ER40, N=121); oxycodone controlled release 20 mg (Oxy20, N=125); and placebo (N=124) in a sample of patients with osteoarthritis. We performed 2 regression analyses to identify the predictors of pretreatment to posttreatment improvement in patient and physician global ratings of arthritis status. RESULTS: Improvement in global ratings of arthritis status was strongly associated with a decrease in pain intensity. Pretreatment to posttreatment improvement in physical and psychological functioning made independent contributions to the prediction of both criterion variables. DISCUSSION: The findings underscore the importance of change in pain intensity as a key correlate of ratings of global improvement. However, pain intensity is not the only important factor. In the current sample, improvement in both physical and psychological functioning made independent contributions to improvements in ratings of osteoarthritis status, supporting global ratings as assessing multicomponent domains. Overall, the findings suggest that when a patient or physician reports that the patient is "doing better," the patient is likely reporting less pain intensity and engaging in more physical activity and feeling better emotionally.

An open-label pharmacokinetic study of oxymorphone extended release in the presence of naltrexone in the older adult.

OBJECTIVE: The aging population generally has greater need for analgesics and is best served by having as many good therapeutic options as possible. Geriatric analgesia requires special consideration of age-associated physiologic changes that can affect drug dosing. The study of extended-release (ER) oxymorphone in older (≥ 65 years of age) versus younger (18-40 years of age) male and female volunteers was described. METHODS: In this multiple-dose, parallel-group, open-label trial, healthy volunteers received a single oral dose of 20 mg oxymorphone ER on day 1, followed by a 48-hour washout period, then two oral doses of 20 mg oxymorphone ER tablets every 12 hours from day 3 to day 8, and a single oral dose of 20 mg oxymorphone ER on day 9. Naltrexone was administered each day to the subjects. RESULTS: The elderly had significantly higher plasma levels of oxymorphone, 6-OH-oxymorphone, and oxymorphone-3-glucuronide than the younger group (1.36-fold higher area under the concentration versus time curve [AUC] and 1.45-fold higher C(max)) when they were treated with a single dose (20 mg) of oxymorphone. Steady-state AUC and C(max) also were higher in the older group. Following adjustment for body weight, AUC values for oxymorphone and its metabolites were about 40 percent higher and the mean C(max) values were 30-35 percent higher in the older group compared to the younger group. CONCLUSION: The results of the current study of an ER formulation revealed no pharmacokinetic features that would preclude dosing in the elderly. As with any drug and any age group (but particularly the elderly), oxymorphone ER should be initiated at lower doses in elderly compared to younger patients and titrated to optimal level.

Reliability and validity of individual and composite recall pain measures in patients with cancer.

OBJECTIVES: To evaluate and compare the validity and reliability of individual and composite recall pain intensity measures. DESIGN: Secondary analyses using data from a published 14-day open-label crossover clinical trial comparing two active treatments. SETTING: Multiple settings. PARTICIPANTS: Fifty-two adults with a history of chronic cancer pain. MEASURES: Recall ratings of least, worst, and average pain during the past 2 days; composite score representing recalled characteristic pain in the past 2 days; and daily diary ratings of pain intensity from which "actual" least, worst, and average pain scores were derived. RESULTS: Recall ratings of least and average pain, and a composite score representing recalled characteristic pain were accurate (differed no more than three points from "actual" scores on a 0-100 scale). Although the recall rating of worst pain significantly (P < 0.05) overestimated actual worst pain, the differences were minor (i.e., seven to eight points on a 0-100 scale). All of the recall measures demonstrated validity via their strong associations with the measures of actual pain intensity. The recall measures also demonstrated excellent test-retest stability, although the diary-derived measures tended to be more stable than the recall measures did. The composite measure of recalled characteristic pain demonstrated a high level of internal consistency (Cronbach's α = 0.90). CONCLUSIONS: Individual recall ratings and a composite score representing recalled characteristic pain intensity are reliable and valid measures of actual pain in patients with cancer. The findings support their use as outcome measures in clinical trials.

Long-term tolerability and effectiveness of oxymorphone extended release in patients with cancer.

OBJECTIVE: To evaluate the long-term safety, tolerability, and effectiveness of oxymorphone extended release (ER) in patients with cancer-related pain. DESIGN: Post hoc analysis of two-1-year open-label extension studies. SETTING: Multiple US cancer treatment facilities. PATIENTS: Patients with cancer pain who had participated in two short-term crossover comparator trials of oxymorphone ER: one open-label and one double-blind randomized. INTERVENTIONS: Patients who had been taking oxymorphone ER continued the dose established in the previous study. Patients who had been taking a comparator opioid were switched to an equianalgesic dose of oxymorphone ER. All patients underwent individualized oxymorphone ER dose titration to optimize effectiveness and tolerability. ASSESSMENTS: Current, average, worst, and least pain scores were normalized to a 100-point scale. Patients rated treatment on a five-point global assessment of study medication (Poor = 1 to Excellent = 5). All adverse events (AEs) were recorded. RESULTS: Of the 80 patients who entered the extension trials, 26 completed 52 weeks, 7 discontinued owing to loss of effectiveness, and 20 discontinued owing to AEs, most of which were unrelated to study drug. No significant increase in mean (standard deviation [SDD average pain intensity was observed from baseline (30.5 [19.6], 100-point scale) to final visit (35.9 [21.1], p = 0.37). The most common AEs were concomitant disease progression (28.8 percent, n=23), nausea (22.5 percent, n=18), dyspnea (16.3 percent, n=13), fatigue (16.3 percent, n=13), and edema of the lower limb (15 percent, n=12). CONCLUSIONS: In these patients with pain related to cancer, oxymorphone ER was generally well tolerated and provided stable long-term pain control.

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.

Factors affecting acceptability of titrated oxymorphone extended release in chronic low back pain - an individual patient analysis.

OBJECTIVE: To evaluate the influence of age, sex, and previous opioid experience on the likelihood of successfully titrating opioid-naive and experienced patients with chronic low back pain (CLBP) to an effective and well-tolerated dose of oxymorphone extended release (ER). METHODS: Post hoc analysis of open-label titration phases of two enriched-enrollment randomized-withdrawal phase III trials in 575 adults with moderate-to-severe CLBP. Opioid-naive patients (n = 325) initiated oxymorphone ER at 10 mg/day (5 mg q12 h). Opioid-experienced patients (n = 250) initiated at a dose equianalgesic to their previous opioid and were allowed doses of 5 mg oxymorphone immediate-release rescue medication every 4-6 h, as needed. Oxymorphone ER was gradually titrated to a dose that reduced pain to or=65 years were less likely than patients aged <65 years to complete titration (45 vs. 63%; p = 0.002; 95% CI, -0.30 to -0.06) and more likely to discontinue owing to adverse events (40 vs. 15%; p < 0.001; 95% CI, 0.14-0.36). Oxycodone-experienced patients were less likely than hydrocodone-experienced patients to complete titration (46 vs. 62%, p = 0.03; 95% CI,-0.30 to -0.02). Among successfully titrated patients, pain decreased regardless of prior opioid therapy, sex, or age. CONCLUSIONS: Most patients with CLBP were titrated to an effective, generally well-tolerated oxymorphone ER dose. Older patients and those converted from oxycodone may require more gradual titration. A study limitation is that patients initiated oxymorphone ER to comply with protocol, whereas treatment failure typically motivates opioid initiation or switching in clinical practice.

The assessment of pain quality: an item response theory analysis.

UNLABELLED: Item Response Theory (IRT) is being increasingly used to develop and evaluate outcome measures. However, many pain measures, including those that assess pain quality, have yet to be evaluated from the IRT perspective. The current study evaluated the scales of a commonly used measure of pain quality (the Pain Quality Assessment Scale, or PQAS) using IRT analyses in 3 samples of patients with chronic pain. The findings indicated variability in the precision of the scales, suggesting that all 3 of the PQAS scales are precise when pain is severe and that the Paroxysmal and Deep scales but not necessarily the Surface scale are precise when pain is of moderate or lower severity. In addition, 2 potential problems with the 11 (ie, 0 to 10) response levels used for the PQAS items were identified: (1) a high degree of overlap between adjacent response levels and (2) a lack of interval scaling. Research is needed to determine the extent to which these problems do, or do not, threaten the validity of the PQAS items and scales as outcome measures in pain clinical trials. PERSPECTIVE: IRT analyses provide important information about the psychometric and practical qualities of pain measures that is not provided by standard (classical test theory) analyses. IRT analyses of the PQAS subscales indicate that some of the scales are more precise than others at different levels of pain severity and provide important directions for further research to better understand the PQAS. IRT analyses would probably similarly provide important information concerning the utility of other measures commonly used in pain research.

The relationship of changes in pain quality to pain interference and sleep quality.

UNLABELLED: Pain is a complex multidimensional experience that includes overall intensity/magnitude, unpleasantness/bothersomeness (affect), location, and quality. However, there is a paucity of research examining the importance of pain quality to patient functioning; most research focuses only on the intensity and affective components of pain. This study sought to address this gap by examining, in a sample of patients with carpal tunnel syndrome (CTS), the associations between pain quality and 2 domains of patient functioning: pain interference and sleep quality. We found that measures of pain quality contributed to the prediction of pain interference and sleep quality over and above the effects of global pain intensity and unpleasantness. In our sample, both throbbing and itchy pain emerged as contributing the most unique variance to the prediction of patient functioning. The findings indicate that the presence of pain described as throbbing or itchy, regardless of the overall magnitude of pain, may make patients with CTS particularly vulnerable to the negative impact of pain on quality of life. The findings support the need for experimental studies to determine if treatments can be identified that address these 2 pain qualities, and if effective treatments for these qualities in particular result in significant improvement in the quality of life of patients with CTS. PERSPECTIVE: A growing body of research supports the importance of assessing multiple domains of pain in clinical and research settings. The current findings suggest the possibility that, in patients with carpal tunnel syndrome, itchy and throbbing pain may play key roles in patient functioning above and beyond global pain intensity and unpleasantness. More research is needed to confirm this finding, and whether treatments can be identified that address these pain qualities specifically.

The pain quality response profile of oxymorphone extended release in the treatment of low back pain.

OBJECTIVE: In controlled trials of analgesics, the primary outcome variable is most often a measure of global pain intensity. However, because pain is associated with a variety of pain sensations, the effects of analgesic treatments on different sensations could go undetected if specific pain qualities are not assessed. This study sought to evaluate the utility of assessing the multiple components of non-neuropathic pain in an analgesic clinical trial. METHODS: A secondary analysis was performed using data from a clinical trial involving 140 individuals with low back pain who were converted from prestudy opioids to an equianalgesic dose of an extended release (ER) formulation of oxymorphone (OPANA ER), which was then titrated to a stable dose [defined as visual analog scale

The dimensions of pain quality: factor analysis of the Pain Quality Assessment Scale.

OBJECTIVE: To provide a better empirical understanding of the dimensionality of neuropathic and non-neuropathic pain quality. METHOD: An exploratory factor analysis (FA) was performed with baseline pain quality data [assessed using the Pain Quality Assessment Scale (PQAS)] from patients with osteoarthritis of the knee (n=368) and low back pain (n=455) who had participated in a series of analgesic clinical trials. The results of the FA were then confirmed in a sample of patients with neuropathic pain secondary to carpal tunnel syndrome (n=138). Comparisons between the diagnostic groups on scale scores derived from the FA results were also made using t tests. RESULTS: Three clear pain quality factors emerged that seemed to represent (1) paroxysmal pain sensations (PQAS descriptors: shooting, sharp, electric, hot, and radiating), (2) superficial pain (itchy, cold, numb, sensitive, and tingling), and (3) deep pain (aching, heavy, dull, cramping, and throbbing). The PQAS tender pain item did not load strongly on any of the 3 factors. DISCUSSION: The findings support the hypothesis that pain qualities cluster into distinct groups. If replicated in additional samples, the pain quality domains identified may provide clinicians and researchers with a useful way to summarize data from pain quality measures, and may also provide meaningful end points that would allow for treatment differentiation between various pharmacologic entities.

Comparison of the effectiveness and tolerability of lidocaine patch 5% versus celecoxib for osteoarthritis-related knee pain: post hoc analysis of a 12 week, prospective, randomized, active-controlled, open-label, parallel-group trial in adults.

BACKGROUND: Cyclooxygenase-2 (COX-2) selective inhibitors and nonselective NSAIDs are commonly used to treat osteoarthritis (OA) of the knee. OBJECTIVE: The aim of this study was to compare the effectiveness of the lidocaine patch 5% with that of celecoxib 200 mg/d in the treatment of OA-related knee pain; however, the study was terminated prematurely by the sponsor because of tolerability concerns regarding the class of COX-2 selective inhibitors. A post hoc analysis of the available data is presented here. METHODS: This multicenter, randomized, open-label, active-controlled, parallel-group study included patients >or=18 years of age with unilateral or bilateral moderate to severe OA of the knee. Patients were randomized to receive treatment with either the lidocaine patch 5% or celecoxib 200 mg/d. The primary efficacy end point was change from baseline to 12 weeks in the Western Ontario and McMaster Universities (WOMAC) OA Index pain subscale. Secondary end points included additional WOMAC subscales and Brief Pain Inventory (BPI) measures. Because this trial was prematurely terminated, a post hoc analysis was performed using a random pattern-mixture model of all observed cases of the intent-to-treat population. RESULTS: A total of 143 patients were randomized to treatment (lidocaine patch 5%, 69 patients; mean [SD] age, 60.2 [11.4] years; 65.2% female; 66.7% white; weight, 94.1 [23.3] kg) or celecoxib 200 mg/d (74 patients; age, 58.2 [12.1] years; 63.5% female; 68.9% white; weight, 94.3 [22.5] kg). Baseline pain WOMAC OA subscale scores (lidocaine patch 5%, 12.087; celecoxib 200 mg/d, 12.514) and mean rates of change over time (baseline to week 2, -1.5916 vs -1.6513 per week; weeks 2-6, -0.0168 vs -0.119 per week; weeks 6-12, -0.1818 vs -0.1579 per week) were not significantly different between the 2 groups. Improvement in additional WOMAC subscales and in several BPI measures were not significantly different between the 2 groups. Treatment-related adverse events were reported in 8 patients in each treatment group (11.6% in the lidocaine patch 5% group and 10.8% in the celecoxib 200-mg/d group) and were considered mild or moderate in severity. CONCLUSION: Statistically significant differences in effectiveness and tolerability were not found between these 2 treatments in these patients with OA knee pain.

A comparison of the lidocaine patch 5% vs naproxen 500 mg twice daily for the relief of pain associated with carpal tunnel syndrome: a 6-week, randomized, parallel-group study.

OBJECTIVES: Carpal tunnel syndrome (CTS) is a common entrapment neuropathy caused by median nerve compression. This pilot clinical trial was designed to compare the safety and effectiveness of the lidocaine patch 5% to that of naproxen 500 mg twice daily for the treatment of neuropathic pain associated with CTS. METHODS: In this 6-week, randomized, parallel-group, open-label, multicenter study, participants from 2 practice sites, aged 18 to 75 years with clinical/electrodiagnostic evidence of CTS, were randomized to receive up to 3 lidocaine 5% patches every 24 hours or naproxen 500 mg twice daily for 6 weeks. Outcome assessments included mean changes between baseline and Week 6 average pain intensity (Brief Pain Inventory [BPI]: Question 5, Average Pain Intensity [API]), an Investigator Clinical Global Impression of Improvement (CGI-I) over the course of the treatment period and a comparison of patient satisfaction (Clinical Global Assessment of Treatment [CGAT]). RESULTS: One hundred patients were randomized in this study, 52 in the lidocaine patch 5% group and 48 in the naproxen 500 mg twice daily group. Significant reductions in API scores were observed between baseline and Week 6 for both lidocaine patch 5% (P < .0001) and naproxen 500 mg twice daily (P = .0004); however, there were no statistically significant differences between treatments (P = .083). There was a significant (P = .016) difference in the CGI-I for lidocaine patch 5% (51.1%) compared with naproxen 500 mg twice daily (24.3%). Whereas 71.8% of the lidocaine patch 5% patients reported being "satisfied" to "very satisfied" with the treatment, only 63.2% of naproxen 500 mg twice daily patients reported likewise, although the difference was not statistically significant. Both treatments were well tolerated. Two patients reported treatment-related adverse events in the lidocaine patch 5% group and 6 in the naproxen 500 mg twice daily group, all of which were considered mild or moderate in severity. CONCLUSIONS: This study demonstrates that the lidocaine patch 5% is effective in significantly relieving the pain associated with CTS and is well tolerated. The patch may offer patients an effective, nonsystemic, noninvasive treatment for the management of their symptoms. Further controlled studies are warranted.

Efficacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetes.

BACKGROUND: Type 2 diabetes is a growing problem in Mexico. The present study was undertaken to evaluate the efficacy and safety of rosiglitazone 2 mg or 4 mg twice daily (bd) in combination with metformin 2.5 g/day in Mexican patients whose type 2 diabetes was inadequately controlled with metformin alone. METHODS: This randomized, double-blind, placebo-controlled study was conducted at four centers in Mexico. A total of 116 patients were randomized to metformin 2.5 g/day plus placebo (n=39), metformin 2.5 g/day plus rosiglitazone 2 mg bd (n=37), or metformin 2.5 g/day plus rosiglitazone 4 mg bd (n=40) for 26 weeks. RESULTS: Mean hemoglobin A(1c) (HbA(1c)) levels decreased significantly from baseline to Week 26 in the rosiglitazone 2 mg bd (-0.7%; p=0.0052) and 4 mg bd (-1.2%; p=0.0008) groups, but increased in the placebo group (+0.3%; p=0.2651). Mean fasting plasma glucose and fructosamine levels also improved significantly with metformin plus rosiglitazone therapy in a dose-ordered manner compared with placebo (p