Danielle Petersel

Central amplification and fibromyalgia: disorder of pain processing.

Fibromyalgia (FM), a complex chronic pain disorder affecting a heterogeneous patient population, is an area of active basic and clinical research. Although diagnostic criteria for FM have been available for 2 decades, there remains no definitive diagnostic and no consensus regarding its etiology. Accumulating evidence suggests the underlying cause of FM pain results from abnormal pain processing particularly in the central nervous system rather than from dysfunction in peripheral tissues where pain is perceived. In this review, we examine recent studies investigating abnormalities in central pain processing as a component of FM in both preclinical models of generalized muscle hypersensitivity and clinical research in patients with FM. We focus our discussion on two areas where strong evidence exists for abnormalities in sensory signaling: the reduction of descending control, including suppression of descending inhibitory pathways and/or enhancement of descending facilitatory pathways, and changes in key neurotransmitters associated with central sensitization. Finally, we discuss currently available pharmacological treatments indicated for the management of pain in FM patients, based on their proposed mechanism of action and efficacy.

Survey of physician experiences and perceptions about the diagnosis and treatment of fibromyalgia

BackgroundFibromyalgia (FM) is a condition characterized by widespread pain and is estimated to affect 0.5-5% of the general population. Historically, it has been classified as a rheumatologic disorder, but patients consult physicians from a variety of specialties in seeking diagnosis and ultimately treatment. Patients report considerable delay in receiving a diagnosis after initial presentation, suggesting diagnosis and management of FM might be a challenge to physicians.MethodsA questionnaire survey of 1622 physicians in six European countries, Mexico and South Korea was conducted. Specialties surveyed included primary care physicians (PCPs; n=809) and equal numbers of rheumatologists, neurologists, psychiatrists and pain specialists.ResultsThe sample included experienced doctors, with an expected clinical caseload for their specialty. Most (>80%) had seen a patient with FM in the last 2 years. Overall, 53% of physicians reported difficulty with diagnosing FM, 54% reported their training in FM was inadequate, and 32% considered themselves not knowledgeable about FM. Awareness of American College of Rheumatology classification criteria ranged from 32% for psychiatrists to 83% for rheumatologists. Sixty-four percent agreed patients found it difficult to communicate FM symptoms, and 79% said they needed to spend more time to identify FM. Thirty-eight percent were not confident in recognizing the symptoms of FM, and 48% were not confident in differentiating FM from conditions with similar symptoms. Thirty-seven percent were not confident developing an FM treatment plan, and 37% were not confident managing FM patients long-term. In general, rheumatologists reported least difficulties/greatest confidence, and PCPs and psychiatrists reported greatest difficulties/least confidence.ConclusionsDiagnosis and managing FM is challenging for physicians, especially PCPs and psychiatrists, but other specialties, including rheumatologists, also express difficulties. Improved training in FM and initiatives to improve patient-doctor communication are needed and may help the management of this condition.

Safety Profile and Tolerability of Up to 1 Year of Pregabalin Treatment in 3 Open-Label Extension Studies in Patients With Fibromyalgia

BACKGROUND Pain relief and an acceptable safety profile have been reported in randomized controlled trials (RCTs) of pregabalin in the treatment of fibromyalgia (FM) for up to 14 weeks. OBJECTIVE To evaluate the safety profile and tolerability of pregabalin (75-300 mg BID) treatment for up to 1 year in patients with FM. METHODS Twelve-week data were pooled from 3 open-label extension studies of pivotal RCTs. Study 1 was a 1-year extension of a 13-week RCT, and studies 2 and 3 were 12-week extensions of 14-week RCTs. The 1-year data were separately evaluated. The open-label data are summarized using descriptive statistics. RESULTS Overall, 1206 patients (92.4% female) with a mean (SD) age of 48.8 (10.7) years received open-label extended pregabalin treatment. A total of 119 of 1206 patients (9.9%) permanently discontinued study participation due to treatment-emergent adverse events (all causality) at 12 weeks (pooled data) and 53 of 429 (12.4%) within 1 year. Consistent with previous RCTs, the most commonly reported treatment-emergent adverse events with open-label pregabalin treatment were dizziness, somnolence, headache, peripheral edema, and increased weight. The highest incidence rates in the pooled 12-week data were for dizziness (214 of 1206; 17.7%) and somnolence (96 of 1206; 8.0%). In ratings of severity (mild, moderate, severe), most were reported as mild to moderate. The mean (SD) change in patient-reported visual analog scale pain scores (0-100) from the open-label baseline to the end of treatment was -21 (30.5) in study 1 (1 year), -26.7 (28.8) in study 2 (12 weeks), and -20.1 (26.8) in study 3 (12 weeks). CONCLUSIONS The data from these extension studies suggest that the adverse event safety profile and tolerability of patients with FM treated with open-label pregabalin (75-300 mg BID) for up to 1 year were stable and were consistent with those of previous studies. ClinicalTrials.gov identifiers: NCT00151528 (A0081057 [study 1]), NCT00282997 (A0081078 [study 2]), and NCT00346034 (A0081101 [study 3]).

Long-term Maintenance of Response Across Multiple Fibromyalgia Symptom Domains in a Randomized Withdrawal Study of Pregabalin

Objective: To determine the incidence and duration of response of clinically meaningful improvements with pregabalin across several key symptoms of fibromyalgia (FM). Methods: This was a post hoc analysis of data from a multicenter, double-blind, placebo-controlled, randomized, withdrawal study, originally designed to evaluate the efficacy of pregabalin monotherapy for durability of effect on FM pain based on pain and Patient Global Impression of Change (PGIC) criteria. Responder criteria for Fibromyalgia Impact Questionnaire total score (≥16-point change), Medical Outcomes Study Sleep Scale Sleep Disturbance subscale (≥15.8-point change), and the 36-item Short-Form Health Survey Vitality scale (≥10-point change) were used to evaluate the incidence and duration of improvements in function, sleep, and fatigue for pregabalin versus placebo among pain and PGIC responders. A composite responder index consisting of pain, PGIC, function, and sleep endpoints was used to explore multidimensional response. Results: Approximately 80% of patients meeting pain and PGIC improvement criteria at randomization had clinically meaningful improvement in fatigue, sleep, or function. Higher proportions of patients in the pregabalin group maintained a clinically meaningful response, and pregabalin-treated patients had a significantly longer time to loss of therapeutic response compared with the placebo group. Composite responder Kaplan-Meier analysis, performed with patients demonstrating clinically meaningful improvements in pain, PGIC, function, and sleep at randomization showed a significantly longer median time to loss of therapeutic response for pregabalin-treated patients. Discussion: The results from this post hoc analysis indicate that pregabalin provides long-term effects across multiple domains of FM (ClinicalTrials.gov registry ID: NCT00151489).

The Language of Biosimilars: Clarification, Definitions, and Regulatory Aspects

Biologic therapies have revolutionized treatment of a number of diseases. Patents and exclusivity for a number of biologics are expiring. This has created the opportunity for the development and approval of biosimilars. Biosimilars are biologic products developed using a step-wise approach to result in a biologic that demonstrates no clinically meaningful differences in terms of quality attributes, efficacy, safety, and immunogenicity compared with an existing licensed, originator biologic. As more biosimilars receive regulatory approval and reach the market, it is increasingly important for healthcare providers to understand the terminology about biosimilars. To help support healthcare providers, the aim of this manuscript is to (i) support understanding of the language of biosimilars, (ii) review the regulatory and manufacturing processes employed in developing a biosimilar, and (iii) provide information for clinical decisions about the use of biosimilars. Because biologics are large, structurally complex proteins, biosimilars cannot be considered generic equivalents to the originator. Biosimilars are developed and evaluated using rigorous processes involving detailed analytical and functional studies, nonclinical assessments, and clinical trials. Clinical studies evaluating the potential biosimilar are designed differently than those for approval of a novel biologic since the aim is merely to confirm similar efficacy and safety and not to demonstrate clinical benefit per se. Extrapolation of data may be used to grant approval of biosimilars in indications not directly evaluated in clinical studies using the biosimilar.

Medical conditions in fibromyalgia patients and their relationship to pregabalin efficacy: pooled analysis of Phase III clinical trials

Objective: Patients with fibromyalgia demonstrate high rates of comorbid somatic and psychiatric disorders. The current post hoc study analyzed the prevalence of comorbid conditions and their relationship to pregabalin efficacy in patients with fibromyalgia pooled from four Phase III clinical trials. Methods: Patients diagnosed with fibromyalgia according to the American College of Rheumatology criteria, randomized to placebo or 300, 450, or 600 mg/day pregabalin, and with ≥ 1 postbaseline pain score were included. The frequency of comorbid conditions was obtained from patient-reported, voluntary medical histories. Patients were categorized based on the presence of a medical condition (e.g., irritable bowel syndrome) or a group of medical conditions (e.g., neurological disorders). Two efficacy variables were examined within each comorbid category: endpoint changes from baseline in weekly mean pain diary scores (11-point numeric rating scale) and Patient Global Impression of Change. Results: A large proportion of patients exhibited concomitant headache, immunological (allergy), gastroesophageal, and/or psychiatric disorders. The efficacy analyses performed on these subgroups of patients, amongst others, showed – with few exceptions – consistent pain reductions of similar magnitude with pregabalin. Conclusion: Comorbid conditions are common among patients with fibromyalgia and their presence is not associated with altered pregabalin efficacy.

Pregabalin in Treatment-Refractory Fibromyalgia

Context: Fibromyalgia is a chronic musculoskeletal pain disorder. The pain can be intractable and may not respond to commonly-used treatments, such as tricyclic antidepressants and opioids. Objectives: To evaluate pregabalin response in the subset of patients with fibromyalgia whose pain had been judged refractory to other treatments. Methods: Patients had previously participated in a controlled trial of pregabalin and had moderate to severe pain despite treatment with gabapentin, a tricyclic antidepressant, and a third medication (e.g., other anticonvulsants, opioid, selective serotonin reuptake inhibitors, tramadol). Flexible-dose pregabalin 150-600 mg/day was added for 3-month treatment cycles, each followed by 3- to 28-day pregabalin “drug holiday” that lasted until a relapse occurred. Pain intensity was measured using the visual analogue scale of the Short-Form McGill Pain Questionnaire completed at baseline, the end of each 3-month treatment period and at the relapse visit. Analysis was at 15 months (after 5 cycles). Results: In total, 25 patients were included and 19 completed the 15-month analysis period. At baseline, 88% were receiving ≥1 pain medication. Pregabalin 150-600 mg/day was associated with statistically significant, clinically meaningful pain reduction during each treatment cycle. Pain quickly returned to baseline levels during the “drug holidays” in a median time of 2-4 days. Somnolence (n=5) and dizziness (n=4) were the most common adverse events. Conclusions: These results suggest that pregabalin may be beneficial in patients with fibromyalgia who have had an unsatisfactory response to treatment with other medications.

Efficacy and Safety Outcomes for Originator TNF Inhibitors and Biosimilars in Rheumatoid Arthritis and Psoriasis Trials: A Systematic Literature Review

ObjectiveRegulatory approval of biosimilar versions of originator biotherapeutics requires that new biological products be highly similar to originator products, with no clinically meaningful differences in safety, purity, and potency. In some trials of biosimilars of tumor necrosis factor inhibitors for the treatment of rheumatoid arthritis (RA) and plaque psoriasis (PsO), pre-specified margins for efficacy and safety have been met, but differences in treatment responses between pivotal originator trials and biosimilar trials have been noted. The objective of this systematic review was to examine these differences.MethodsSearches were conducted to identify comparative randomized clinical trials of approved or proposed biosimilars of adalimumab, etanercept, and infliximab.ResultsOf 83 publications identified, 16 publications were included for analysis (RA: originators, n = 5; biosimilars, n = 6; PsO: originators, n = 2; biosimilars, n = 3). American College of Rheumatology 20% response rates were higher among patients with RA receiving originator biologics and biosimilars in biosimilar trials than among patients receiving the originator biologics in pivotal trials. In etanercept studies in PsO, a difference was observed in Psoriasis Area and Severity Index 75% response rates between biosimilar and pivotal trials. Insufficient efficacy data were available from adalimumab and infliximab biosimilar studies in PsO to determine any differences in treatment responses between pivotal and biosimilar studies.ConclusionsObserved differences in treatment response rates between pivotal originator trials and trials of originator biologics and their respective biosimilars may be attributable to fundamental differences in study design and/or baseline patient characteristics, which require further analysis.