Cytokine Receptor-like Factor 1 (CRLF1) and Its Role in Osteochondral Repair.

BACKGROUND: Since cytokine receptor-like factor 1 (CRLF1) has been implicated in tissue regeneration, we hypothesized that CRLF1 released by mesenchymal stem cells can promote the repair of osteochondral defects. METHODS: The degree of a femoral osteochondral defect repair in rabbits after intra-articular injections of bone marrow-derived mesenchymal stem cells (BMSCs) that were transduced with empty adeno-associated virus (AAV) or AAV containing CRLF1 was determined by morphological, histological, and micro computer tomography (CT) analyses. The effects of CRLF1 on chondrogenic differentiation of BMSCs or catabolic events of interleukin-1beta-treated chondrocyte cell line TC28a2 were determined by alcian blue staining, gene expression levels of cartilage and catabolic marker genes using real-time PCR analysis, and immunoblot analysis of Smad2/3 and STAT3 signaling. RESULTS: Intra-articular injections of BMSCs overexpressing CRLF1 markedly improved repair of a rabbit femoral osteochondral defect. Overexpression of CRLF1 in BMSCs resulted in the release of a homodimeric CRLF1 complex that stimulated chondrogenic differentiation of BMSCs via enhancing Smad2/3 signaling, whereas the suppression of CRLF1 expression inhibited chondrogenic differentiation. In addition, CRLF1 inhibited catabolic events in TC28a2 cells cultured in an inflammatory environment, while a heterodimeric complex of CRLF1 and cardiotrophin-like Cytokine (CLC) stimulated catabolic events via STAT3 activation. CONCLUSION: A homodimeric CRLF1 complex released by BMSCs enhanced the repair of osteochondral defects via the inhibition of catabolic events in chondrocytes and the stimulation of chondrogenic differentiation of precursor cells.

Laceration of the Sciatic Nerve After Closed Reduction of a Dislocated Total Hip Arthroplasty.

Sciatic nerve injury after closed reduction of a dislocated total hip arthroplasty (THA) is an exceedingly rare but tremendously devastating complication. Closed reduction is the standard of care and is typically associated with a low complication rate. There have only been seven sciatic nerve injuries after closed reduction of a dislocated THA reported in the literature, and none were secondary to nerve laceration. We report a case of sciatic nerve laceration after attempted closed reduction of a dislocated THA. This resulted in complete loss of sensory and motor sciatic nerve function. This case highlights the importance of a detailed neurologic examination before and after closed reduction of a dislocated total hip, the importance of using careful reduction maneuvers, and transitioning to open reduction when necessary.

Effect of documented and undocumented psychiatric conditions on length of stay and discharge destination after total knee arthroplasty.

INTRODUCTION: Length of stay (LOS) and readmissions are quality metrics linked to physician payments and substantially impact the cost of care. This study aims to evaluate the effect of documented and undocumented psychiatric conditions on LOS, discharge location, and readmission following total knee arthroplasty (TKA). METHODS: Retrospective review of all primary, unilateral TKA from 2015 to 2020 at a high-volume, academic orthopedic hospital was conducted. Patients were separated into three cohorts: patients with a documented psychiatric diagnosis (+Dx), patients without a documented psychiatric diagnosis but with an actively prescribed psychiatric medication (-Dx), and patients without a psychiatric diagnosis or medication (control). Patient demographics, LOS, discharge location, and 90 days readmissions were assessed. RESULTS: A total of 2935 patients were included; 1051 patients had no recorded psychiatric medications (control); 1884 patients took at least one psychiatric medication, of which 1161 (61.6%) were in the-Dx and 723 (38.4%) were in the +Dx cohort. Operative time (+Dx, 103.4 ± 29.1 and -Dx, 103.1 ± 28.5 vs. 93.6 ± 26.2 min, p < 0.001 for both comparisons) and hospital LOS stay (+ Dx, 3.00 ± 1.70 and -Dx, 3.01 ± 1.83 vs. 2.82 ± 1.40 days, p = 0.021 and p = 0.006, respectively) were greater for patients taking psychiatric medications when compared to the control group. Patients taking psychiatric medication with or without associated diagnosis were significantly more likely to be discharged to a secondary facility-22.8% and 20.9%, respectively-compared to controls, at 12.5% (p < 0.001). Ninety-day readmission rates did not differ between the control and both psychiatric groups (p = 0.693 and p = 0.432, respectively). CONCLUSION: TKA patients taking psychiatric medications with or without a documented psychiatric diagnosis have increased hospital LOS and higher chances of discharge to a secondary facility. Most patients taking psychiatric medication also had no associated diagnosis. Payment models should consider the presence of undocumented psychiatric diagnoses when constructing metrics. Surgeons and institutions should also direct their attention to identifying, recording, and managing these patients to improve outcomes. LEVEL III EVIDENCE: Retrospective Cohort Study.

Impact of Admission Source on Shoulder Arthroplasty.

BACKGROUND: The purpose of this study was to determine the relationship between admission source and postoperative length of stay (LOS), index admission hospital charges, and discharge disposition, in patients undergoing shoulder arthroplasty. METHODS: The New York Statewide Planning and Research Cooperative System (SPARCS) was used to identify all patients that underwent elective shoulder arthroplasty from 1994 through 2015. Patients were grouped into institutionalized (INS) versus non-institutionalized (n-INS) groups based on admission source. The two groups were compared regarding demographics, Charleston comorbidity index (CCI), postoperative blood transfusion requirement, LOS, and total charges. RESULTS: A total of 33,248 patients were identified (32,875 n-INS, 373 INS). Patientsin the INS cohort were significantly older (71.9 versus 68.1 years) and had a higher CCI (1.3 vs. 0.7). The mean LOS in the INS group was nearly 1 week longer(9.5 days vs. 2.8 days) and had a significantly higher postoperative blood transfusion rate (37.5% vs. 9.2%, odds ratio: 5.9). The mean total hospital charges in the INS group were also significantly higher ($63,988 vs. $36,826). DISCUSSION: Institutionalized patients undergoing shoulder arthroplasty have a protracted postoperative hospital course and this ultimately resulted in poorer outcomes and increased resource utilization.

Dual Mobility in Total Hip Arthroplasty.

Dual mobility designs in total arthroplasty allow for increased range of motion prior to impingement and dislocation. While valuable for reducing dislocation, dual mobility has its own unique complication profile that includes intraprosthetic dislocation, corrosion, and femoral notching. Despite these relatively rare complications, dual mobility articulations are valuable options for patients at higher risk of dislocation-both early and contemporary reports on dual mobility in total hip arthroplasty suggest that it can reduce the risk of dislocation without leading to unacceptable rates of complication or early revision. Cost analyses and longer follow-up studies on newer dual mobility designs will help determine the future of dual mobility in total hip arthroplasty.

Changes in the Synovial Fluid Cytokine Profile of the Knee Between an Acute Anterior Cruciate Ligament Injury and Surgical Reconstruction.

BACKGROUND: Changes in the intra-articular inflammatory state during the immediate period after an acute anterior cruciate ligament (ACL) rupture are not well defined. PURPOSE: To evaluate changes in the concentration of select proinflammatory and anti-inflammatory synovial fluid cytokines during the interval between an ACL injury and surgical reconstruction. STUDY DESIGN: Descriptive laboratory study. METHODS: In patients with an acute ACL injury, a synovial fluid sample was obtained from the injured knee during the initial office visit within 2 weeks of the inciting traumatic event. An additional synovial fluid sample was collected at the time of ACL reconstruction just before the surgical incision. Synovial fluid samples from both the acute injury and the surgery time points were processed with a protease inhibitor, and the concentrations of 10 cytokines of interest were measured using a multiplex magnetic bead immunoassay. The primary outcome was the change in cytokine concentrations between time points. RESULTS: A total of 20 patients with a mean age of 30.2 ± 8.3 years were included. The acute injury synovial fluid samples were collected at 6.6 ± 3.8 days after the injury. The surgical synovial fluid samples were collected at 31.6 ± 15.6 days after the acute injury samples. Based on a series of linear mixed-effects models to control for the effect of concomitant meniscal injuries and by-patient variability, there was a statistically significant increase in the concentrations of RANTES and bFGF and a statistically significant decrease in the concentrations of IL-6, MCP-1, MIP-1ß, TIMP-1, IL-1Ra, and VEGF between time points. CONCLUSION: This study demonstrates the ongoing alterations in the intra-articular microenvironment during the initial inflammatory response in the acute postinjury period. We identified 6 synovial fluid cytokines that significantly decreased and 2 that significantly increased between the first clinical presentation shortly after the injury and the time of surgery 1 month later. CLINICAL RELEVANCE: This study describes the molecular profile of the inflammatory changes between the time of an acute ACL injury and the time of surgical reconstruction 1 month later. A greater understanding of the acute inflammatory response within the knee may be helpful in identifying the optimal timing for a surgical intervention that balances the risk of chondral damage with the likelihood of successful, well-healed reconstruction.

Cementless Primary Total Knee Arthroplasty Will this be the Future?

Cementless fixation in total knee arthroplasty (TKA) offers the potential for biologically active osseointegration and the potential for life-long fixation. With early cementless TKA designs, several design issues were identified related to early failure, particularly with the tibial and patellar components. However, in the recent two decades, with improvements upon the early designs, particularly in porous metal technology as well as improved early biomechanical stability, interest was re-established in cementless TKA. The surgical technique for cementless TKA is more exacting than cemented technique, with an important emphasis on indications, accurate resections, and component alignment. Modern cementless TKA designs have demonstrated excellent early- and mid-term survivorship equivalent to cemented TKA. More long-term studies are needed to study this comparison. While implant cost maybe higher with cementless designs, there is emerging evidence that there may be an overall cost saving with the use of cementless components given the shorter operative time and the savings in the cost of supplies associated with the use of cement. As the population undergoing TKA is becoming younger and more active, interest in the use of cementless implants will likely increase.

Aseptic Loosening of Porous Metaphyseal Sleeves and Tantalum Cones in Revision Total Knee Arthroplasty: A Systematic Review.

Bone loss often complicates revision total knee arthroplasty (TKA). Management of metaphyseal defects varies, with no clearly superior technique. Two commonly utilized options for metaphyseal defect management include porous-coated metaphyseal sleeves and tantalum cones. A systematic review was conducted according to the international Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We combined search terms "Total knee arthroplasty" AND/OR "Sleeve," "Cone" as either keywords or medical subject heading (MeSH) terms in multiple databases according to PRISMA recommendations. All retrieved articles were reviewed and assessed using defined inclusion and exclusion criteria. A total of 27 studies (12 sleeves and 15 cones) of revision TKAs were included. In the 12 studies on sleeve implantation in revision TKAs, 1,617 sleeves were implanted in 1,133 revision TKAs in 1,025 patients. The overall rate of reoperation was 110/1,133 (9.7%) and the total rate of aseptic loosening per sleeve was 13/1,617 (0.8%). In the 15 studies on tantalum cone implantation in revision TKAs, 701 cones were implanted into 620 revision TKAs in 612 patients. The overall rate of reoperation was 116/620 (18.7%), and the overall rate of aseptic loosening per cone was 12/701 (1.7%). Rates of aseptic loosening of the two implants were found to be similar, while the rate of reoperation was nearly double in revision TKAs utilizing tantalum cones. Variability in the selected studies and the likely multifactorial nature of failure do not allow for any definitive conclusions to be made. This review elucidates the necessity for additional literature examining revision TKA implants.

Subsidence Following Revision Total Hip Arthroplasty Using Modular and Monolithic Components.

BACKGROUND: The ideal femoral component in revision total hip arthroplasty (rTHA) remains undetermined; however, tapered, fluted, titanium (TFT) stems are now widely used with favorable results in all types of revision scenarios. With both modular and monoblock TFT stem options, neither has been proven to be superior. Femoral stem subsidence has been linked to aseptic loosening, instability, and leg length discrepancy. This study aims to assess stem subsidence of modular and monoblock TFT stems at a single urban orthopedic specialty hospital within a tertiary academic medical center. METHODS: Electronic medical records of rTHAs performed between January 2013 and March 2018 utilizing modular and monoblock TFT stems were examined. Data collected included baseline demographics, surgical indication, femoral Paprosky classification, and stem subsidence at most recent follow up (3 months to 3 years). Two-sample t-tests and chi-squared tests were used for statistical analysis. RESULTS: A total of 186 patients (106 modular, 80 monoblock) were included in the analysis. Modular stems underwent significantly greater subsidence than monoblock stems at latest radiographic follow-up (3.9 ± 2.6 vs 2.3 ± 2.5 mm, P < .001). A significantly greater proportion of modular stems underwent >5 mm of subsidence at latest follow-up (29.2% vs 11.3%, P < .001). CONCLUSION: Monoblock TFT stems have displayed promising clinical results in prior studies, and now have been shown to decrease the incidence of postoperative subsidence. With the potential for stem subsidence to lead to aseptic loosening, limb length discrepancy, and instability, the orthopedic surgeon should weigh the risks and benefits of utilizing modular vs monoblock TFT stems in rTHA.

Understanding the adverse event experience in the S-TRAC adjuvant trial of sunitinib for high-risk renal cell carcinoma.

Until recently, the sole treatment for patients with nonmetastatic renal cell carcinoma (RCC) was nephrectomy followed by observation. As metastatic RCC (mRCC) remains largely incurable (5-year survival rate ∼12%), adjuvant treatment, with potential to prevent/delay disease recurrence, is needed. In November 2017, sunitinib was approved in the USA as the first adjuvant therapy for patients at high risk for recurrent RCC postnephrectomy based on results from the S-TRAC trial. Patients eligible for adjuvant treatment have no evidence of disease and may be less willing to tolerate side effects. Therefore, proactive adverse event management is critical for keeping patients on adjuvant treatment and requires understanding the subtle differences in the adverse event profile of sunitinib in the adjuvant versus metastatic RCC setting.

Safety and effectiveness of classical and alternative sunitinib dosing schedules for metastatic renal cell carcinoma: a meta-analysis.

The optimal dosing schedule to maintain the effectiveness of sunitinib for metastatic renal cell carcinoma - while reducing toxicity - remains an important clinical question. A meta-analysis of randomized trials and observational studies assessed the relative treatment effects of 4/2, 2/1 and transitional-2/1 schedules on outcomes and adverse events using Bayesian network meta-analysis methods. Treatment with 2/1 reduced the risk of disease progression or death by 25% and had lower odds of hand-and-foot syndrome compared with the 4/2. A numerical but not 'statistical' benefit in progression-free survival was observed with the transitional-2/1 compared with 4/2. Alternative schedules with the 2/1 and transitional-2/1 may be more clinically beneficial in metastatic renal cell carcinoma than the 4/2 schedule.

Nonmodular Stems Are a Viable Alternative to Modular Stems in Revision Total Hip Arthroplasty.

BACKGROUND: Nonmodular and modular femoral stems have been associated with complications after revision total hip arthroplasty (rTHA). As such, the ideal femoral component for rTHA remains undecided. This study aims to report outcomes of titanium, tapered-fluted, modular and nonmodular femoral components in rTHA. METHODS: From January 1, 2013 to September 30, 2017, all rTHAs using modular or nonmodular femoral stems were identified. Demographic data including age, gender, and American Society of Anesthesiologists scores were collected. Surgical details including operative time and implant cost were also collected. Clinical outcomes including length of stay, dislocation, infection, fracture, reoperation, and re-revision were collected. Statistical analysis was performed using chi-square test and Student's t-test for all categorical and continuous variables, respectively. RESULTS: One hundred forty-six rTHA cases (103 modular and 43 nonmodular) were identified with an average follow-up of 29 months (range 3-59 months). Nonmodular stems had a significantly lower cost when compared to modular implants (modular stems 120.8% higher cost; P < .001). The surgical time of nonmodular components was significantly greater (193 minutes vs 163 minutes; P = .029). There were no differences observed in any other surgical details or clinical outcomes assessed, including length of stay (P = .323), rate of re-revision of the femoral implant (P = .389), rate of re-operation (P = .383), and postop complications (P = .241), including infection (P = .095), dislocation (P = .778), and fracture (P = .959). CONCLUSIONS: Nonmodular components provide encouraging clinical results with significantly lower costs compared to modular implants in rTHA. The use of titanium, tapered-fluted, nonmodular components may offer a more cost-effective approach to rTHA compared to their modular counterparts.

Alterations in Synovial Fluid Biomarker Levels in Knees With Meniscal Injury as Compared With Asymptomatic Contralateral Knees.

BACKGROUND: Changes in the joint microenvironment after an injury to the articular surface of the knee have been implicated in the pathogenesis of osteoarthritis. While prior studies focused on changes in this microenvironment after anterior cruciate ligament ruptures, few have explored the biomarker changes that occur in the setting of meniscal injuries. PURPOSE: To determine whether meniscal injury results in significant alterations to synovial fluid biomarker concentrations as compared with noninjured contralateral knees. Additionally, to explore the relationship between synovial fluid biomarkers and the degree of cartilage injury seen in these patients. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Patients undergoing surgery for unilateral meniscal injury were prospectively enrolled from October 2011 to December 2016, forming a cohort that had synovial fluid samples collected from both the injured knee and the contralateral uninjured knee at the time of meniscal surgery. Synovial fluid samples were collected just before incision, and the concentrations of 10 biomarkers of interest were determined with a multiplex magnetic bead immunoassay. The concentrations of synovial fluid biomarkers from the operative and contralateral knees were compared. Additionally, the synovial fluid biomarker concentrations of operative knees from patients with associated high-grade cartilage lesions were compared with those with low-grade lesions. RESULTS: The current analysis included synovial fluid samples from 82 knees (41 operative and 41 contralateral) from 41 patients undergoing arthroscopic surgery to treat a symptomatic meniscal injury. The mean ± SD age of patients was 49.86 ± 11.75 years. There were significantly greater concentrations of 4 of the 5 proinflammatory biomarkers (IL-6, MCP-1, MIP-1ß, and MMP-3) in symptomatic knees as compared with asymptomatic knees when controlling for the duration of symptoms, body mass index, age, and the random effects of by-patient variability. In the injured knees, associated high-grade cartilage lesions were predictive of elevated MCP-1, MIP-1ß, and VEGF levels. Low synovial fluid concentration of TIMP-1 or a greater ratio of MMP-3 to TIMP-1 was associated with the presence of synovitis. Increasing age was found to be an independent predictor of increased IL-6, MCP-1, and VEGF concentrations in the setting of symptomatic meniscal injury. CONCLUSION: The authors identified 4 proinflammatory synovial fluid biomarkers whose concentrations were significantly different after meniscal injury as compared with uninjured contralateral knees. Furthermore, they describe the effects of associated cartilage damage, synovitis, and patient age on biomarker concentrations.

Therapy Management Using Modified 2-Weeks-On/1-Week-Off Dosing Schedule in Patients With Metastatic Renal Cell Carcinoma Receiving Sunitinib: A Hypothetical, Illustrative Case Scenario.

This patient case is fictional and does not represent events or a response from an actual patient. The authors developed this fictional case for educational purposes only. Brady, a 54-year-old white male, was diagnosed with metastatic renal cell carcinoma (mRCC). Two and a half years prior, he had undergone a complete left nephrectomy for clear-cell RCC, with clean margins and negative lymph nodes. Post nephrectomy, he was routinely surveyed (every 3-6 months) by radiologic imaging. After 15 months of monitoring, a CT scan revealed small nodules in the left lung. Repeated scans were ordered to be taken in 6 weeks to assess growth kinetics, wherein an increase in the size of a number of nodules was detected. Of particular concern was the location of one of the larger nodules very close to a bronchus. Consequently, a needle biopsy was performed, which recovered malignant cells consistent with mRCC. It was then decided to begin systemic treatment for mRCC. Prior to starting treatment, Brady's Eastern Cooperative Oncology Group performance status (ECOG PS) was 0, and he had a Karnofsky score of 90, as he had only slightly diminished stamina that was considered disease related. Accordingly, he was classified as favorable risk by both Memorial Sloan Kettering Cancer Center and International Metastatic Renal Cell Carcinoma Database Consortium criteria (Table 1). Brady is married and lives with his wife. He drinks alcohol occasionally but does not have a history of smoking. For the past 22 years, he has been employed full time as a factory assembly line worker, performing skilled, light assembly. In this capacity, Brady works with his hands and must remain on his feet approximately 30% of the working day. As Brady is eligible for early retirement in 11 months, he intends to continue working full time during treatment, if possible. Brady's medical history includes nonvalvular atrial fibrillation, which is treated with apixaban; hypertension that is adequately controlled (blood pressure 137/79 mm Hg) with lisinopril at 20 mg/day; coronary artery disease; and hyperlipidemia that is treated with atorvastatin at 20 mg/day. He is also taking daily low-dose aspirin (81 mg).

Guidelines for Instrumentation for Total Knee Replacement Based on Frontal Plane Radiographs.

OBJECTIVE: The objective of this study was to measure the dimensions and the angulations of the femur and tibia for arthritic knees that were scheduled for total knee surgery. The purpose was to provide information for the design of surgical instruments such as cutting guides. Instruments made using three-dimensional printing were a particular consideration because of the variations in sizing that are possible. MATERIALS AND METHODS: Sixty-six frontal plane EOS radiographs were obtained of patients with osteoarthritis who were under consideration for total knee arthroplasty. The images were imported into computer-assisted design software. The anatomic and mechanical axes and the joint lines were constructed for the femur and tibia. The angles between the axes and lines and key dimensions including the femoral canal diameters were measured. RESULTS: The angle between the anatomic and mechanical axes was 5.5° ± 1.4°, the femoral joint line sloped 2.2°, and the tibial joint line 4.3° to the mechanical axes. The values were similar to non-arthritic knees except for a higher tibial slope. The femoral canal diameter at 150 mm from distal was 19 ± 5 mm. CONCLUSIONS: In a total knee replacement procedure, aligning perpendicular to the mechanical axis results on average about 2° more valgus and 2° to 3° tilt of the joint line. Instruments could be calibrated for individual patients, but the maximum variations based on long-term follow-up should be recognized. A multi-diameter system is needed for the femoral intramedullary rod to limit errors to 1° or less.

Effect of Baseline Characteristics on the Pain Response to Pregabalin in Fibromyalgia Patients with Comorbid Depression.

Objective: To evaluate the effect of baseline characteristics on the treatment response to pregabalin in fibromyalgia (FM) patients with depression. Design: Post hoc analysis from a randomized, double-blind, placebo-controlled, two-way crossover study of pregabalin (300 or 450 mg/day, twice daily). Subjects: A total of 193 FM patients taking an antidepressant for comorbid depression. Methods: The effect of patient baseline characteristics on the treatment response to pregabalin vs placebo was assessed for the primary efficacy end point (mean pain score on an 11-point numeric rating scale). Variables were analyzed using a linear mixed effects model with sequence, period, and treatment as fixed factors, and subject within sequence and within subject error as random factors. Results: Pregabalin significantly improved mean pain scores vs placebo irrespective of age, duration of FM, number of prior FM medications, depression diagnosis, shorter-term depression (<10 years), prior or no prior opioid use, pain severity, anxiety severity, and sleep disruption severity (all P < 0.05). Compared with placebo, pregabalin did not significantly affect mean pain scores in patients with comorbid insomnia, irritable bowel syndrome, or gastroesophageal reflux disease; severe FM; a diagnosis of depression before FM, longer-term depression (≥ 10 years), more severe depression, or who were taking a high dose of antidepressant. Conclusions: Pregabalin significantly improved mean pain scores when compared with placebo for the majority of baseline characteristics assessed in FM patients taking an antidepressant for comorbid depression.

Dose-response of pregabalin for diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia.

OBJECTIVES: The pregabalin dose-response for pain, Patient Global Impression of Change (PGIC), and sleep quality measures in painful diabetic peripheral neuropathy (pDPN), postherpetic neuralgia (PHN), and fibromyalgia (FM) is relevant for physicians treating these patients. This analysis aimed to demonstrate the dose-response of pregabalin for each indication and describe the onset (incidence), onset/continuation (prevalence), and resolution of adverse events (AEs) occurring during treatment. METHODS: Data from 14 placebo-controlled, fixed-dose pregabalin trials in pDPN, PHN, and FM were pooled within each indication. Patients had mean baseline pain scores ≥6 on an 11-point numeric rating scale. A hyperbolic Emax dose-response model examined the dose-response of pregabalin for pain, PGIC, and sleep quality. Safety assessments included onset and prevalence of common AEs each week, and resolution in the first 2 months of treatment. RESULTS: In all indications, the likelihood of patients experiencing pain relief and improvements in PGIC and sleep quality increased in a dose-dependent manner with increasing doses. In all indications, new incidences of dizziness and somnolence were highest after 1 week of treatment, with few subsequent new reports at a given dose. Prevalence rates decreased steadily after 1 week of treatment. In FM, new onset weight gain emerged 6-8 weeks following treatment; prevalence rates generally increased then remained steady over time. With the exception of weight gain, many AEs resolved in month 1. CONCLUSION: The dose-response of pregabalin for pain, PGIC, and sleep quality was demonstrated, highlighting the benefit of achieving the maximum recommended dose of 300 mg/day for pDPN, 300-600 mg/day for PHN, and 300-450 mg/day for FM. Common AEs are generally seen within 1 week of starting treatment, with few subsequent new reports at a given dose. New onset weight gain occurs after 6 weeks of treatment, reinforcing the need for regular monitoring of weight.

Does Duration of Neuropathic Pain Impact the Effectiveness of Pregabalin?

BACKGROUND: Patients with chronic pain conditions such as neuropathic pain frequently experience delays in diagnosis and treatment. Ideally, all patients should be treated in a timely manner, but in those patients with more established disease it is important to know that approved treatments remain effective. METHODS: This was a pooled analysis of 19 randomized placebo-controlled trials of pregabalin for peripheral neuropathic pain conditions, including diabetic peripheral neuropathy, postherpetic neuralgia, and post-traumatic/postsurgical pain. Patients were divided into 5 pain duration categories based on time since onset of pain (< 6 months, 6 months to < 1 year, 1 year to < 2 years, 2 years to < 5 years, and ≥ 5 years). Mean change in pain score at endpoint, vs. placebo, was assessed for each category, together with changes in Patient Global Impression of Change (PGIC) responders ("very much" or "much" improved at endpoint). RESULTS: The analysis included 5,783 patients (n = 3,619 pregabalin; n = 2,164 placebo). Mean baseline pain scores were similar across the pain duration categories (range 6.3 to 6.5). Pregabalin significantly improved pain score at endpoint, vs. placebo, in all patients together (treatment difference [95% confidence interval], -0.59 [-0.67, -0.52], P < 0.0001) and similarly in each pain duration category (P < 0.0001 for each). There were significantly more PGIC responders with pregabalin, vs. placebo, for all patients (45.0% vs. 30.9%, P < 0.0001) and each category separately (P < 0.001 for each). There were no consistent, significant differences in treatment response between the different pain duration categories. CONCLUSIONS: Pregabalin significantly improves pain irrespective of the length of time since onset of neuropathic pain.

Improvement in pain severity category in clinical trials of pregabalin.

BACKGROUND: Pregabalin is approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM), diabetic peripheral neuropathy (DPN), postherpetic neuralgia (PHN), and neuropathic pain due to spinal cord injury (SCI). Approval was based on clinical trial data demonstrating statistically significant differences in pain scores versus placebo. However, statistically significant pain relief may not always equate to clinically meaningful pain relief. To further characterize the clinical benefit of pregabalin, this analysis examined shifts in pain severity categories in patients with FM, DPN/PHN (pooled in this analysis), and SCI treated with pregabalin. METHODS: Data were pooled from 23 placebo-controlled trials in patients with FM (1,623 treated with pregabalin, 937 placebo), DPN/PHN (2,867 pregabalin, 1,532 placebo), or SCI (181 pregabalin, 175 placebo). Pain scores were assessed on an 11-point numeric rating scale and categorized as mild (0 to <4), moderate (4 to <7), or severe (7 to 10). Only patients with mean score ≥4 at baseline were randomized to treatment. The percentage of patients shifting pain category from baseline to endpoint for pregabalin and placebo was analyzed using a modified ridit transformation with the Cochran-Mantel-Haenszel procedure. RESULTS: A higher proportion of patients shifted to a less severe pain category at endpoint with pregabalin compared with placebo. With flexible-dose pregabalin, the percentage of patients improving from: severe to mild (pregabalin versus placebo) was 15.8 versus 13.4 in FM patients, 36.0 versus 16.6 in DPN/PHN patients, 14.3 versus 7.7 in SCI patients; severe to moderate was 28.7 versus 28.2 in FM patients, 32.5 versus 28.2 in DPN/PHN patients, 35.7 versus 28.2 in SCI patients; and moderate to mild was 38.3 versus 26.4 in FM patients, 59.5 versus 41.4 in DPN/PHN patients, 38.6 versus 27.2 in SCI patients. CONCLUSION: Compared with placebo, pregabalin is more often associated with clinically meaningful improvements in pain category in patients with FM, DPN, PHN, or SCI.