Outcome measures in placebo-controlled trials of osteoarthritis: responsiveness to treatment effects in the REPORT database.

INTRODUCTION: Treatment response in randomized clinical trials (RCT) of osteoarthritis (OA) has been assessed by multiple primary and secondary outcomes, including pain, function, patient and clinician global measures of status and response to treatment, and various composite and responder measures. Identifying outcome measures with greater responsiveness to treatment is important to increase the assay sensitivity of RCTs. OBJECTIVE: To assess and compare the responsiveness of different outcome measures used in placebo-controlled RCTs of OA. SEARCH STRATEGY: The Resource for Evaluating Procedures and Outcomes of Randomized Trials database includes placebo-controlled clinical trials of pharmacologic treatments (oral, topical, or transdermal) for OA identified from a systematic literature search of RCTs published or publicly available before August 5, 2009, which was conducted using PubMed, the Cochrane collaboration, publicly-available websites, and reference lists of retrieved publications. DATA COLLECTION AND ANALYSIS: Data collected included: (1) pain assessed with single-item ratings and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale; (2) patient and clinician global measures of status, improvement, and treatment response; (3) function assessed by the WOMAC function subscale; (4) stiffness assessed by the WOMAC stiffness subscale; and (5) the WOMAC and Lequesne Algofunctional Index composite outcomes. Measures were grouped according to the total number of response categories (i.e., <10 categories or ≥10 categories). The treatment effect (difference in mean change from baseline between the placebo and active therapy arms) and standardized effect size (SES) were estimated for each measure in a meta-analysis using a random effects model. RESULTS: There were 125 RCTs with data to compute the treatment effect for at least one measure; the majority evaluated non-steroidal anti-inflammatory drugs (NSAIDs), followed by opioids, glucosamine and/or chondroitin, and acetaminophen. In general, the patient-reported pain outcome measures had comparable responsiveness to treatment as shown by the estimates of treatment effects and SES. Treatment effects and SESs were generally higher for patient-reported global measures compared with clinician-rated global measures but generally similar for the WOMAC and Lequesne composite measures. CONCLUSIONS: Comparing different outcome measures using meta-analysis and selecting those that have the greatest ability to identify efficacious treatments may increase the efficiency of clinical trials of treatments for OA. Improvements in the quality of the reporting of clinical trial results are needed to facilitate meta-analyses to evaluate the responsiveness of outcome measures and to also address other issues related to assay sensitivity.

Association of self-reported painful symptoms with clinical and neurophysiologic signs in HIV-associated sensory neuropathy.

Sensory neuropathy (HIV-SN) is a common cause of pain in HIV-infected people. Establishing a diagnosis of HIV-SN is important, especially when contemplating opioid use in high-risk populations. However physical findings of HIV-SN may be subtle, and sensitive diagnostic tools require specialized expertise. We investigated the association between self-report of distal neuropathic pain and/or paresthesias (DNPP) and objective signs of HIV-SN. Data were obtained from the Central Nervous System HIV Antiretroviral Therapy Effects Research (CHARTER) study. Out of 237 participants, 101 (43%) reported DNPP. Signs of HIV-SN were measured by a modified Total Neuropathy Score (TNS), composed of six objective sensory subscores (pin sensibility, vibration sensibility, deep tendon reflexes, quantitative sensory testing for cooling and vibration, and sural sensory amplitude). Self-report of DNPP was associated with all six TNS items in univariate analysis and with four TNS items in multivariate analysis. The sensitivity and specificity of self-report of DNPP in detecting the presence of a sensory abnormality were 52% and 92%, respectively with a PPV of 96% and a NPV of 34%. Increasing intensity of pain measured on a visual analog scale was associated with increasing severity of sensory abnormality. In summary, our results suggest that HIV-infected patients reporting symptoms consistent with HIV-SN, such as tingling, pins and needles, or aching or stabbing pain in the distal lower extremities, usually have objective evidence of HIV-SN on neurologic examination or with neurophysiologic testing. This finding holds true regardless of demographic factors, depression or substance use history.

Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of pregabalin in the treatment of postherpetic neuralgia (PHN). METHODS: The authors conducted a multicenter, parallel-group, double-blind, placebo-controlled, 8-week, randomized clinical trial in PHN, defined as pain for 3 or more months following herpes zoster rash healing. Patients (n = 173) were randomized to treatment with pregabalin or placebo. Patients randomized to pregabalin received either 600 mg/day (creatinine clearance > 60 mL/min) or 300 mg/day (creatinine clearance 30 to 60 mL/min). The primary efficacy measure was the mean of the last seven daily pain ratings. Secondary endpoints included additional pain ratings, sleep interference, quality of life, mood, and patient and clinician ratings of global improvement. RESULTS: Pregabalin-treated patients had greater decreases in pain than patients treated with placebo (endpoint mean scores 3.60 vs 5.29, p = 0.0001). Pain was significantly reduced in the pregabalin-treated patients after the first full day of treatment and throughout the study, and significant improvement on the McGill Pain Questionnaire total, sensory, and affective pain scores was also found. The proportions of patients with >or=30% and >or=50% decreases in mean pain scores were greater in the pregabalin than in the placebo group (63% vs 25% and 50% vs 20%, p = 0.001). Sleep also improved in patients treated with pregabalin compared to placebo (p = 0.0001). Both patients and clinicians were more likely to report global improvement with pregabalin than placebo (p = 0.001). Given the maximal dosage studied, pregabalin had acceptable tolerability compared to placebo despite a greater incidence of side effects, which were generally mild to moderate in intensity. CONCLUSIONS: Treatment of PHN with pregabalin is safe, efficacious in relieving pain and sleep interference, and associated with greater global improvement than treatment with placebo.

A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain.

BACKGROUND: Nerve injury results in increases in spinal glutamate, which opens the NMDA ionophore channel, causing an influx of calcium. A glycine-binding site must be occupied for the channel to open. GV196771 is a selective antagonist of the glycine-binding site of the NMDA ionophore. OBJECTIVE: To determine the efficacy of GV196771 in subjects with chronic neuropathic pain in a proof-of-concept study. METHODS: With informed consent, 63 subjects (31 placebo, 32 GV196771) with neuropathic pain (diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, or peripheral nerve injury), a visual analogue score averaging > or =30 mm during the screening period, and a well-defined primary area of mechanical allodynia were recruited for the study. A multicenter, randomized, double-blind, placebo-controlled, parallel-group study design was utilized. Subjects came to the research center for a total of five visits over a 21-day period, which consisted of a 14-day treatment period followed by a 7-day washout period. Spontaneous and evoked pain scores, mechanical sensory testing, quantitative sensory testing, Short Form McGill Pain Questionnaire, patient global satisfaction, and safety assessments were made during the study. RESULTS: There was no significant effect of GV196771 on spontaneous or evoked pain, quantitative sensory testing, or patient global satisfaction. There was a significant effect of GV196771 on the area of dynamic and static allodynia on days 7 and 14. The overall incidence of adverse events during treatment was similar for GV196771 (56%) and placebo (71%). The incidence of drug-related adverse events during treatment was higher for placebo (42%) than GV196771 (28%). CONCLUSIONS: Although the glycine antagonists show anti-hyperalgesic action in animal models of neuropathic pain, GV196771 does not appear to be an effective treatment in subjects with chronic neuropathic pain. This may be due to insufficient penetration of GV196771 to central sites of action, differences between the human and animal glycine receptors, or differences between neuropathic pain in animal models and humans.

Treatment of postherpetic neuralgia: an update.

Postherpetic neuralgia (PHN) is a chronic pain syndrome that is often refractory to treatment and can last for years, causing physical and social disability, psychological distress, and increased use of the healthcare system. In this paper we provide an update on recent developments in the treatment of PHN. We emphasise the results of recent studies that provide an evidence-based approach for treating PHN that was not available until very recently. In randomised, controlled clinical trials, the topical lidocaine patch, gabapentin, and controlled release oxycodone have been shown to provide superior pain relief in patients with PHN when compared with placebo. It has also recently been demonstrated that the tricyclic antidepressant nortriptyline provides equivalent analgesic benefit when compared with amitriptyline, but is better tolerated. Based on these results, nortriptyline can now be considered the preferred antidepressant for the treatment of PHN, although desipramine may be used if the patient experiences unacceptable sedation from nortriptyline. The topical lidocaine patch, gabapentin and controlled release oxycodone all appear to be as effective as tricyclic antidepressants in the treatment of patients with PHN, and the results of these recent studies suggest that each of these treatments should be considered early in the course of treatment. Additional controlled trials are needed to compare the efficacy and tolerability of these 4 treatments- tricyclic antidepressants, gabapentin, the topical lidocaine patch and controlled release opioid analgesics--used singly and in various combinations in the treatment of patients with PHN.

Prospects for the prevention of postherpetic neuralgia in herpes zoster patients.

OBJECTIVE: Herpes zoster is a common and painful disease that is caused by reactivation of the varicella-zoster virus. Herpes zoster pain that persists after healing of the acute infection is termed postherpetic neuralgia (PHN), a chronic pain syndrome that is often refractory to all treatment. The prevalence of PHN is expected to increase substantially in the coming decades, because the incidence of herpes zoster and the risk of PHN will both increase as the population ages. Although the results of recent studies provide a basis for improved treatment of patients with PHN, as many as half of all PHN patients do not obtain relief of their pain. Research on the development of improved treatments is continuing, but it has not been generally recognized that an equally important goal should be the design of interventions to prevent PHN. The prevention of PHN would lead to major reductions in disability, suffering, and the use of health care resources. DESIGN: The results of recent studies that have identified risk factors for the development of PHN and have implicated several peripheral and central mechanisms in its pathophysiology are reviewed. OUTCOME MEASURES: These risk factors and mechanisms of PHN provide a basis for hypothesizing that combining antiviral therapy with analgesic treatment beginning as soon as possible after the onset of herpes zoster would reduce the risk of PHN beyond that achieved by antiviral therapy alone. CONCLUSIONS: This treatment approach would be expected to reduce the risk of PHN in herpes zoster patients by attenuating acute pain and thereby preventing the initiation of central mechanisms of chronic pain.

Toward a model of the pathogenesis of chronic pain.

There is widespread agreement that chronic pain develops from, and is maintained by, a combination of neurobiological, psychological, and social factors. Nevertheless, few comprehensive models have been proposed that present specific testable predictions about how these factors interact. We propose a vulnerability-diathesis-stress model of the pathogenesis of chronic pain. This model is based on diathesis-stress models of psychopathology and on the results of recent research on psychosocial aspects of chronic pain. The goals of research on chronic pain are to understand its pathogenesis, improve its treatment, and prevent its development. To achieve these goals, prospective studies of the development and maintenance of chronic pain are needed. The vulnerability-diathesis-stress model can serve as a basis for designing and analyzing studies of the interaction among biological, psychological, and social risk factors for chronic pain.

Postherpetic neuralgia: impact of famciclovir, age, rash severity, and acute pain in herpes zoster patients.

New and previously reported analyses of the data from a placebo-controlled trial of famciclovir are reviewed in light of recently proposed recommendations for the analysis of pain in herpes zoster trials. The analyses examined the effect of famciclovir treatment on the duration of postherpetic neuralgia (PHN), which was defined as pain persisting after rash healing, pain persisting > 30 days after study enrollment, or pain persisting > 3 months after study enrollment; the baseline characteristics of patients in the famciclovir and placebo groups who developed PHN; the impact of famciclovir treatment on the duration of PHN, while controlling for significant covariates; and the prevalence of PHN at monthly intervals from 30 to 180 days after enrollment. The results of these analyses indicated that greater age, rash severity, and acute pain severity are risk factors for prolonged PHN. In addition, they demonstrated that treatment of acute herpes zoster patients with famciclovir significantly reduces both the duration and prevalence of PHN.

Assessment of pain in herpes zoster: lessons learned from antiviral trials.

Pain typically accompanies acute herpes zoster and, in a proportion of patients, it persists well beyond rash healing. Pain must therefore be analyzed in trials of antiviral agents in herpes zoster, but different methods have been used to analyze pain in recent published trials. These reports are reviewed and their methodological strengths and weaknesses examined. Based on this review, recommendations for the design and analysis of future trials of antiviral agents in herpes zoster are proposed. The principal recommendation is that antiviral efficacy should be evaluated both by distinguishing post-herpetic neuralgia from acute pain and by considering pain as a continuum. The primary endpoint should address both the prevalence and duration of post-herpetic neuralgia and should be examined in those patients who have post-herpetic neuralgia. Adopting the proposed recommendations in design and analysis of future trials should facilitate comparison across trials of the efficacy of antiviral agents in the treatment of herpes zoster.

Pain and its persistence in herpes zoster.

The nature and duration of pain associated with herpes zoster is highly variable. This review of research on pain in acute herpes zoster and postherpetic neuralgia (PHN) explores those observations relevant to the definition and pathogenesis of PHN and the design of treatment trials. A model for the pathogenesis of PHN is presented, which gains support from studies of risk factors. Several directions for future research are identified.

Does affective blunting in schizophrenia reflect affective deficit or neuromotor dysfunction?

Schizophrenia inpatients withdrawn from all neuroleptic medication were administered measures of affective blunting, diminished affective experience, and neuromotor dysfunction. The correlations among the measures provided support for the hypothesis that measures of affective blunting reflect both neuromotor and affective deficits. Because the interpretation of such measures is therefore ambiguous, measures of diminished affective experience may have greater validity in research on affective deficits in schizophrenia than measures of blunted affective expression.

Chronic pain and disease conviction.

OBJECTIVE: The results of cross-sectional and prospective studies suggest that the disease conviction scale of the Illness Behavior Questionnaire (IBQ) provides important information about chronic pain. To examine further the characteristics and correlates of this scale, the relationships between disease conviction and average pain intensity and interference of pain with daily activities were examined in a sample of chronic pain patients. DESIGN: The disease conviction scale and measures of hypochondriasis, psychological distress, pain intensity, and pain interference were administered to a sample of 127 chronic pain patients. RESULTS: The results suggested that pain intensity and interference were more strongly associated with disease conviction than with measures of psychological distress and hypochondriasis. In an analysis in which the relationships between the individual items of the disease conviction scale and pain intensity and interference were examined, disease conviction scale items that reflect consequences of pain and illness were significantly associated with both pain intensity and pain interference, whereas items that reflect disease conviction were in general not associated with either pain intensity or interference. CONCLUSION: These results suggest that items included in the disease conviction scale that reflect consequences of pain and illness, rather than disease conviction, may have contributed to the relationships that have been reported between disease conviction and other aspects of the chronic pain experience.

The dimensions of schizophrenia phenomenology. Not one or two, at least three, perhaps four.

BACKGROUND: This confirmatory investigation examined the underlying structure of schizophrenia phenomenology through examination of the fit of several prominent dimensional models to observed symptom data. METHOD: Confirmatory factor analysis was conducted on a correlation matrix of schizophrenia signs and symptoms derived from case history ratings of 192 individuals with schizophrenia who were the subjects in the major twin studies of schizophrenia. RESULTS: Schizophrenia phenomenology appears best described by four underlying factors, namely negative symptoms, premorbid social adjustment deficits, reality distortion, and disorganisation. Of interest, the premorbid deficit dimension was directly associated with negative symptoms and disorganisation, but was inversely associated with reality distortion. CONCLUSIONS: These data clearly support the multidimensionality of schizophrenia phenomenology and provide objective support for a four-factor model over other models. This four-factor model may be useful in organising existing and future data concerning the genetic, neurobiological, neurological, and psychosocial features of schizophrenia.

Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials.

Meta-analysis of four double-blind, randomized, placebo-controlled trials of oral acyclovir (800 mg five times daily) for the treatment of herpes zoster was conducted to provide definitive assessments of the effect of acyclovir on the resolution of zoster-associated pain. The studies involved a total of 691 patients, and the analysis was performed on an intent-to-treat basis. A range of milestones of pain cessation were evaluated by means of Cox regression models with adjustment for relevant prognostic factors. The proportion of patients with postherpetic neuralgia at 3 and 6 months was also determined. Advancing age and more severe pain at presentation were associated with more prolonged pain. Acyclovir was clearly shown to accelerate pain resolution by all of the measures employed. Benefit was especially evident in patients 50 years of age or older. Fewer acyclovir recipients had postherpetic neuralgia at 3 or 6 months. Overall, the reductions of pain duration and prevalence were approximately twofold.