Combination of Enzymes and Rutin to Manage Osteoarthritis Symptoms: Lessons from a Narrative Review of the Literature.

Osteoarthritis is the most common joint disorder affecting over 300 million people worldwide. It typically affects the knees and the hips, and is characterized by a loss in normal joint movement, stiffness, swelling, and pain in patients. The current gold standard therapy for osteoarthritis targets pain management using nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are associated with several potentially serious side effects, the most common being gastrointestinal perforation and bleeding. Owing to the side effects, NSAID treatment doses need to be as low as possible and should be continued for the shortest duration possible, which is problematic in a chronic condition like osteoarthritis, which requires long-term management. Numerous clinical trials have examined oral enzyme combinations as a potential new approach in managing pain in patients with osteoarthritis. Oral enzyme combinations containing bromelain in combination with trypsin, both proteolytic enzymes, as well as the plant flavonoid rutin, may be an effective alternative to typical NSAIDs. The aim of this narrative review is to summarize and discuss the evidence on the efficacy of oral enzyme combinations compared to the gold standard (NSAID) in the management of osteoarthritis symptoms. Nine randomized controlled trials identified in this review assessed the efficacy and safety of the oral enzyme combination containing bromelain, trypsin, and rutin in patients with osteoarthritis. Most of the studies assessed the impact of the oral enzyme combination on the improvement of the Lequesne Algofunctional index score, treatment-related pain intensity alterations and adverse events compared to patients receiving NSAIDs. Although largely small scale, the study outcomes suggest that this combination is as effective as NSAIDs in the management of osteoarthritis, without the adverse events associated with NSAID use. INFOGRAPHIC.

Comparison of the Effectiveness and Tolerability of Nabiximols (THC:CBD) Oromucosal Spray versus Oral Dronabinol (THC) as Add-on Treatment for Severe Neuropathic Pain in Real-World Clinical Practice: Retrospective Analysis of the German Pain e-Registry.

PURPOSE: To compare the effectiveness and tolerability of add-on treatment with nabiximols (NBX: delta-9-tetrahydrocannabinol: cannabidiol) oromucosal spray or oral dronabinol (DRO: synthetic tetrahydrocannabinol) in patients with severe neuropathic pain poorly responsive to established treatments. METHODS: An analysis was conducted of anonymized, propensity score-matched real-world data from the German Pain e-Registry, using a sequential non-inferiority superiority approach, for adult outpatients with neuropathic pain who had initiated treatment with NBX or DRO between 10 March 2017 and 31 December 2019. The primary effectiveness variable was percent change from baseline in a 9-factor aggregated symptom relief (ASR-9) score, a composite index of nine distinct pain- and health-related parameters assessed using validated patient-reported instruments. Safety was assessed by the incidence of physician-confirmed treatment-related adverse events (TRAEs), and TRAEs leading to discontinuation. RESULTS: Propensity score-matched data were analyzed for 337 patients treated with NBX and 337 patients treated with DRO. Mean (standard deviation) THC dose over the 24-week evaluation period was 16.6 (6.5) mg for NBX and 17.2 (7.6) mg for DRO (p<0.001). Median (standard error) improvement relative to baseline in the ASR-9 composite score was 55.4% (0.5) for NBX and 40.5% (0.5) for DRO (least squares mean difference, 14.0 (0.7), 95% confidence interval 12.6-15.4; p<0.001), and incidences of TRAEs (21.1 vs 35%) and TRAE-related discontinuations (5.9 vs 14.8%) were significantly lower with NBX than DRO (p<0.001 for both), collectively indicating pre-specified non-inferiority and superiority of NBX. More NBX- than DRO-treated patients discontinued non-cannabinoid background pain medications and rescue analgesics, especially opioid analgesics (p<0.001 for both). CONCLUSION: Add-on treatment with cannabinoids is effective for treatment of severe neuropathic pain with inadequate response to established treatments. In daily practice, NBX had superior effectiveness and tolerability compared to DRO. The results emphasize the importance of combining CBD with THC in this patient population.

Effectiveness and Tolerability of Dronabinol Use in Patients with Chronic Pain: A Retrospective Analysis of 12-Week Open-Label Real-World Data Provided by the German Pain e-Registry.

OBJECTIVE: To evaluate the effectiveness of Δ9-tetrahydrocannabinol (dronabinol [DRO]) as an add-on treatment in patients with refractory chronic pain (CP). METHODS: An exploratory retrospective analysis of 12-week data provided by the German Pain e-Registry on adult patients with treatment refractory CP who received DRO. RESULTS: Between March 10, 2017, and June 30, 2019, the German Pain e-Registry collected information on 89,095 patients with pain, of whom 1,145 patients (1.3%) received DRO (53.8% female, mean ± standard deviation age: 56.9 ± 10.6 years), and 70.0% documented use for the entire 12-week evaluation period. The average DRO daily dose was 15.8 ± 7.5 mg, typically in three divided doses (average DRO dose of 5.3 ± 2.1 mg). Average 24-hour pain intensity decreased from 46.3 ± 16.1 to 26.8 ± 18.7 mm on a visual analog scale (absolute visual analog scale difference: -19.5 ± 17.3; P < 0.001). Among patients who completed follow-up, an improvement from baseline of at least 50% was documented for pain (46.5%), activities of daily living (39%), quality of life (31.4%), and sleep (35.3%). A total of 536 patients (46.8%) reported at least one of 1,617 drug-related adverse events, none of which were serious, and 248 patients (21.7%) stopped treatment. Over the 12-week period, 59.0% of patients reported a reduction of other pain treatments, and 7.8% reported a complete cessation of any other pharmacological pain treatments. CONCLUSION: Add-on treatment with DRO in patients with refractory CP was well tolerated and associated with a significant improvement.

Effectiveness, Safety, and Tolerability of Nabiximols Oromucosal Spray vs Typical Oral Long-Acting Opioid Analgesics in Patients with Severe Neuropathic Back Pain: Analysis of 6-Month Real-World Data from the German Pain e-Registry.

OBJECTIVE: To compare the effectiveness, safety, and tolerability of add-on nabiximols (NBX) oromucosal spray vs typical oral long-acting opioid (LAO) analgesics in patients with severe (± chronic) peripheral neuropathic back pain poorly responsive to other treatments. METHODS: Retrospective analysis of anonymized, propensity score-matched data from the German Pain e-Registry of adult outpatients who initiated NBX or LAO between March 2017 and March 2020. RESULTS: Data were analyzed from propensity score-matched patients treated with NBX (n = 655) or LAO (n = 655): mean age ≈51 years; 57% female; mean pain duration ≈2.6 years; chronic pain 61%; severe dysfunctional pain 93%. At 6 months, NBX was noninferior to LAO for overall symptom relief, based on the least-squares mean difference between cohorts in change from baseline in patient-reported, pain-related aggregated nine-item scale scores (-27.84%; 95% confidence interval [CI] -29.71 to -25.96; P < 0.001) and individual pain-related scale scores. Subsequent prespecified superiority analysis of the primary endpoint showed that NBX was superior to LAO: all secondary endpoints measuring symptoms of pain and physical function improved significantly with NBX and LAO, with between-group differences favoring NBX (all P < 0.001). Fewer patients treated with NBX than LAO experienced treatment-related adverse events (25.5% vs 76.0%; P < 0.001) or discontinued treatment because of treatment-related adverse events (7.9% vs 29.3%; P < 0.001). CONCLUSION: Within study limitations (e.g., observational design, all potential biases), add-on NBX was superior to and better tolerated than add-on treatment with typical oral LAO analgesics in patients with neuropathic back pain inadequately controlled by recommended/established systemic therapies.

Prevalence of drug-induced constipation and severity of associated biopsychosocial effects in patients with nonmalignant pain: a cross-sectional review of depersonalized data from the German Pain e-Registry.

BACKGROUND: Drug-induced constipation (DIC) is a well-known comorbidity of cancer pain, however, data on its prevalence in nonmalignant pain (NMP) and its biopsychosocial effects are few. OBJECTIVE: To assess the prevalence and impact of DIC in patients with NMP. METHODS: Exploratory noninterventional, retrospective, cross-sectional analysis of depersonalized routine data of the German Pain e-Registry on 150,488 NMP patients (EUPAS identifier: 42286). RESULTS: DIC affects 33.5% of NMP patients. The most prevalent risk factors were the use of strong opioid analgesics and analgesic polymedication. Patients with DIC presented with significantly worse biopsychosocial scores as well as significantly higher percentages of individuals with severe deterioration of pain, daily life activities, physical and mental quality of life, mood, and overall wellbeing. Among patients with DIC, those who reported constipation as a clinical symptom and who documented bowel-function index (BFI) scores above the reference range were significantly more affected compared to those who either reported only constipation as an adverse event or elevated BFI scores. 55.9% of patients with DIC reported the use of laxatives, mostly over-the-counter preparations (43.6%), whereas prescription laxatives were taken by only 29.3%. CONCLUSIONS: DIC is a frequent comorbidity of pain management and affects around one-third of patients with NMP. It interferes significantly with pain-related biopsychosocial effects and has to be addressed specifically to improve the overall burden in affected patients. However, the use of laxatives was significantly less frequent than recommended indicating significant room for improvement.

COMET - effectiveness and tolerability of methocarbamol versus oral opioid-analgesics as add-on measure in patients with non-specific low back pain refractory to recommended 1st line treatments. A retrospective analysis of depersonalized propensity score matched open-label real-world 4-week data from the German Pain e-Registry.

BACKGROUND: To compare the 4-week effectiveness and tolerability of an add-on treatment with oral high dose methocarbamol (MET) vs long-acting oral opioid analgesics (LAO) in patients with non-specific low back pain (nsLBP) poorly responsive to recommended 1st line treatments. METHODS: Analysis of anonymized, propensity score-matched real-world data from the German Pain e-Registry, using a sequential non-inferiority superiority approach, for adult outpatients with nsLBP who had initiated treatment with MET or LAO between 1st January 2018 and 31st December 2019 (EUPAS identifier: 38484). The primary effectiveness variable was the absolute change of the average 24-h. pain intensity index (PIX). Safety was assessed by incidence of physician-confirmed drug-related adverse events (DRAEs), and DRAEs leading to discontinuation. RESULTS: Propensity score-matched data were analyzed for 374 patients treated with MET and 374 patients treated with LAO. Mean ± SD (median) MET dose over the 4-week evaluation period was 2390.4 ± 1980 (3000) mg and 69.6 ± 25.9 (60) mg morphine equivalent for LAO. With 25.8 ± 11.4 (median 26, 95%CI: 24.5-27.1) vs. 11.4 ± 6.8 (median 11; 95%CI: 10.6-12.2) mm VAS, absolute 4-week improvement vs. baseline was superior for MET vs. LAO [p < .001; effect size 1.6; least square mean difference 14.4 (95%CI: 13.4-15.3)]. Percentages of patients with a PIX improvement ≥ MCID was 81.8 vs. 24.6% [p < .001; OR: 13.8 (9.7-19.6), RR: 4.0 (3.2-5.0), NNT: 1.7]. A significantly lower number of patients treated with MET vs. LAO reported DRAEs in response to study medication: 36 (9.6%) vs. 139 (37.2%; p < .001; NNT 4), and 9 patients treated with MET (2.4%) vs. 86 (23.0%) treated with LAO discontinued treatment in response to these DRAEs (p < .001; NNT: 5). CONCLUSION: 4-week add-on treatment with MET in patients with nsLBP who showed an inadequate response to recommended 1st line treatments is superior effective to LAO and significantly better tolerated.KEY MESSAGESLow back pain is the most common musculoskeletal problem worldwide.In the majority of patients, LBP does not have a specific cause and the most prevalently coded form is mechanical, non-specific (ns) LBP associated with muscular tension, restrictions in mobility, and static malposition.Current treatment recommendations for nsLBP are largely "non-specific" as well, limited to symptomatic pain-relieving measures.In our propensity score-matched two cohort analyses of depersonalized real-world data from the German Pain e-Registry, a 4-week treatment with the muscle relaxant methocarbamol proved superior effective and significantly better tolerated than treatment with oral long-acting opioid analgesics in patients who poorly responded to recommended 1st line treatments.

Effectiveness and tolerability of THC:CBD oromucosal spray as add-on measure in patients with severe chronic pain: analysis of 12-week open-label real-world data provided by the German Pain e-Registry.

Objective: To evaluate effectiveness, tolerability and safety of an oromucosal spray containing Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), as add-on treatment in patients with severe chronic pain (SCP). Methods: Exploratory analysis of anonymized 12-week routine/open-label data provided by the German Pain e-Registry (GPR) on adult SCP patients treated with THC:CBD oromucosal spray in 2017. Results: Among those 30.228 cases documented in the GPR in 2017, 800 (2.6%; 57% female, mean ± SD age: 46.3±9.7 years) received a treatment with THC:CBD. All patients fulfilled the legislative preconditions for a treatment with cannabis as medicine as defined by the German Act Amending Narcotics and Other Regulations. THC:CBD-treatment was followed by an aggregated nine-factor symptom relief (ASR-9) improvement at end of week 12 vs baseline of 39.0±26.5% (95%-CI: 36.9-41.1, median: 42, range -41 to 85). A full ASR-9 response (ie, a 50%-improvement in all 9 factors) was found for 123 patients (15.4%), while 488 patients (56.0%) presented with an ≥50% improvement in at least 5 of 9 ASR factors. With a 54.9±17.2% (median: 56%, range: -6 to 85) improvement was significantly superior in the neuropathic pain subgroup (n=497, 62.1%) vs those with mixed (n=249, 31.1%; ASR-9: 18.2±12.0, median: 19, range: -12 to 42%) or nociceptive pain (n=54, 6.8%; ASR-9: -11.9±10.5, median: -11, range: -41% to 12%; p<0.001 for each). 159 patients (19.9%) reported at least one of 206 TEAEs, most of them of mild intensity (n=81.6%). Most frequently reported TEAEs were increased appetite (n=50, 6.3%) and dysgeusia (n=23, 2.9%). TEAE-related discontinuations were reported for 32 patients (4.0%). 113 (14.1%) patients discontinued due to inadequate pain relief, most of them with nociceptive pain (n=40, 74.1%), least with neuropathic pain (n=1, 0.2%; p<0.001). Conclusion: THC:CBD oromucosal spray proved to be an effective and well-tolerated add-on treatment for patients with elsewhere refractory chronic pain - especially of neuropathic origin.

Efficacy, tolerability, and safety of an oral enzyme combination vs diclofenac in osteoarthritis of the knee: results of an individual patient-level pooled reanalysis of data from six randomized controlled trials.

OBJECTIVE: To compare efficacy, safety, and tolerability of an oral enzyme combination (OEC) containing proteolytic enzymes and bioflavonoid vs diclofenac (DIC), a nonselective nonsteroidal anti-inflammatory drug in the treatment of osteoarthritis of the knee. MATERIALS AND METHODS: This was an individual patient-level pooled reanalysis of patient-reported data from prospective, randomized, double-blind, parallel-group studies in adult patients with moderate-to-severe osteoarthritis of the knee treated for at least 3 weeks with OEC or DIC. Appropriate trials were identified with a systemic literature and database search. Data were extracted from the original case-report forms and reanalyzed by a blinded evaluation committee. The primary end point was the improvement of the Lequesne algofunctional index (LAFI) score at study end vs baseline. Secondary end points addressed LAFI response rates, treatment-related pain-intensity changes, adverse events, and laboratory parameters. RESULTS: Six trials were identified that enrolled in total 774 patients, of whom 759 had post-baseline data for safety analysis, 697 (n=348/349 with OEC/DIC) for intent to treat, 524 for per protocol efficacy analysis, and 500 for laboratory evaluation. LAFI scores - the primary efficacy end point - decreased comparably with both treatments and improved with both treatments significantly vs baseline (OEC 12.6±2.4 to 9.1±3.9, DIC 12.7±2.4 to 9.1±4.2, effect size 0.9/0.88; P<0.001 for each). In parallel, movement-related 11-point numeric rating-scale pain intensity improved significantly (P<0.001) and comparably with both treatments from baseline (6.4±1.9/6.6±1.8) to study end (3.8±2.7/3.9±2.5). Overall, 55/81 OEC/DIC patients of the safety-analysis population (14.7%/21.1%, P=0.022) reported 90/133 treatment-emergent adverse events, followed by premature treatment discontinuations in 22/39 patients (5.9%/10.2%, P=0.030). Changes in laboratory parameters were significantly less with OEC vs DIC: on average 18.8% vs 86.3% of patients presented a decrease with respect to hemoglobin, hematocrit, or erythrocyte count (P<0.001), and 28.2% vs 72.6% showed an increase in AST, ALT, or GGT (P<0.001). CONCLUSION: When compared with DIC, OEC showed comparable efficacy and a superior tolerability/safety profile associated with a significantly lower risk of treatment-emergent adverse events, related study discontinuations, and changes in laboratory parameters.

Efficacy and tolerability balance of oxycodone/naloxone and tapentadol in chronic low back pain with a neuropathic component: a blinded end point analysis of randomly selected routine data from 12-week prospective open-label observations.

OBJECTIVE: To evaluate the benefit-risk profile (BRP) of oxycodone/naloxone (OXN) and tapentadol (TAP) in patients with chronic low back pain (cLBP) with a neuropathic component (NC) in routine clinical practice. METHODS: This was a blinded end point analysis of randomly selected 12-week routine/open-label data of the German Pain Registry on adult patients with cLBP-NC who initiated an index treatment in compliance with the current German prescribing information between 1st January and 31st October 2015 (OXN/TAP, n=128/133). Primary end point was defined as a composite of three efficacy components (≥30% improvement of pain, pain-related disability, and quality of life each at the end of observation vs baseline) and three tolerability components (normal bowel function, absence of either central nervous system side effects, and treatment-emergent adverse event [TEAE]-related treatment discontinuation during the observation period) adopted to reflect BRP assessments under real-life conditions. RESULTS: Demographic as well as baseline and pretreatment characteristics were comparable for the randomly selected data sets of both index groups without any indicators for critical selection biases. Treatment with OXN resulted formally in a BRP noninferior to that of TAP and showed a significantly higher primary end point response vs TAP (39.8% vs 25.6%, odds ratio: 1.93; P=0.014), due to superior analgesic effects. Between-group differences increased with stricter response definitions for all three efficacy components in favor of OXN: ≥30%/≥50%/≥70% response rates for OXN vs TAP were seen for pain intensity in 85.2%/67.2%/39.1% vs 83.5%/54.1%/15.8% (P= ns/0.031/<0.001), for pain-related disability in 78.1%/64.8%/43.8% vs 66.9%/50.4%/24.8% (P=0.043/0.018/0.001), and for quality of life in 76.6%/68.0%/50.0% vs 63.9%/54.1%/34.6% (P=0.026/0.022/0.017). Overall, OXN vs TAP treatments were well tolerated, and proportions of patients who either maintained a normal bowel function (68.0% vs 72.2%), reported no central nervous system side effects (91.4% vs 89.5%), or completed the 12-week evaluation period without any TEAE-related treatment discontinuations (93.0% vs 92.5%) were similar for both index medications (P= ns for each comparison). CONCLUSION: In daily practice, the BRP of OXN proved to be noninferior to that of TAP in patients with cLBP-NC, but showed a superior efficacy if stricter analgesic response definitions were evaluated.

Efficacy, safety, and tolerability of fentanyl pectin nasal spray in patients with breakthrough cancer pain.

OBJECTIVE: Assessment of analgesic effectiveness, safety, and tolerability of fentanyl pectin nasal spray (FPNS) in the treatment of breakthrough cancer pain (BTcP) in routine clinical practice. METHODS: A prospective, open-label, noninterventional study (4-week observation period, 3 month follow-up) of opioid-tolerant adults with BTcP in 41 pain and palliative care centers in Germany. Standardized BTcP questionnaires and patient diaries were used. Evaluation was made of patient-reported outcomes with respect to "time to first effect", "time to maximum effect", BTcP relief, as well as changes in BTcP-related impairment of daily life activities, quality-of-life restrictions, and health care resource utilization. RESULTS: A total of 235 patients were recruited of whom 220 completed all questionnaires and reported on 1,569 BTcP episodes. Patients reported a significant reduction of maximum BTcP intensity (11-stage numerical rating scale [0= no pain, 10= worst pain conceivable]) with FPNS (mean ± standard deviation = 2.8±2.3) compared with either that reported at baseline (8.5±1.5), experienced immediately before FPNS application (7.4±1.7), or that achieved with previous BTcP medication (6.0±2.0; P<0.001 for each comparison). In 12.3% of BTcP episodes, onset of pain relief occurred ≤2 minutes and in 48.4% ≤5 minutes; maximum effects were reported within 10 minutes for 37.9% and within 15 minutes for 79.4%. By the end of the study, there had been significant improvements versus baseline in BTcP-related daily life activities (28.3±16.9 vs 53.1±11.9), physical (35.9±8.4 vs 26.8±6.5), and mental quality of life (38.7±8.5 vs 29.9±7.9) (P<0.001 for each comparison vs baseline); in addition, health care resource utilization requirements directly related to BTcP were reduced by 67.5%. FPNS was well tolerated; seven patients (3.2%) experienced eight treatment-emergent adverse events of which none was serious. There were no indicators of misuse or abuse. CONCLUSION: FPNS provided rapid and highly effective BTcP relief in opioid-tolerant cancer patients with substantial improvements in daily functioning and quality of life. FPNS was well tolerated and associated with significant reductions in health care resource utilization and nursing assistance.

Quality of life under oxycodone/naloxone, oxycodone, or morphine treatment for chronic low back pain in routine clinical practice.

OBJECTIVE: To compare the quality of life of patients with moderate-to-severe chronic low back pain under treatment with the WHO-step III opioids oxycodone/naloxone, oxycodone, or morphine in routine clinical practice. STUDY DESIGN: Prospective, 12-week, randomized, open-label, blinded end-point study in 88 medical centers in Germany. PATIENTS AND METHODS: A total of 901 patients requiring around-the-clock pain treatment with a WHO-step III opioid were randomized to either morphine, oxycodone, or oxycodone/naloxone (1:1:1). Changes from baseline to week 12 in quality of life were assessed using different validated tools (EuroQoL-5 Dimensions [EQ-5D], Short Form 12 [SF-12], quality of life impairment by pain inventory [QLIP]). RESULTS: EQ-5D weighted index scores significantly improved over the 12-week treatment period under all three opioids (P<0.001) with significantly greater improvements under oxycodone/naloxone (65.2% vs 49.6% for oxycodone and 48.2% for morphine, P<0.001). The proportion of patients without EQ-5D complaints was also significantly higher under oxycodone/naloxone (P<0.001). Although quality of life ratings with the QLIP inventory showed significant improvements in all the three treatment arms, improvements were significantly higher under oxycodone/naloxone than under oxycodone and morphine (P<0.001): 90.7% of all oxycodone/naloxone patients achieved ≥30% improvements in quality of life, 72.8% had ≥50%, and 33.2% ≥70% improvements. Similarly, both physical and mental SF-12 component scores showed significantly greater improvements under oxycodone/naloxone with both scores close to the German population norm after 12 weeks. CONCLUSION: Treatment with morphine, oxycodone, or oxycodone/naloxone under routine daily practice conditions significantly improved state of health and quality of life of patients with moderate-to-severe low back pain over a 12-week treatment period. Comparison between the treatment groups showed significantly greater improvements for oxycodone/naloxone than for the other two opioids.

Physicians Experience with and Expectations of the Safety and Tolerability of WHO-Step III Opioids for Chronic (Low) Back Pain: Post Hoc Analysis of Data from a German Cross-Sectional Physician Survey.

Objective. To describe physicians' daily life experience with WHO-step III opioids in the treatment of chronic (low) back pain (CLBP). Methods. Post hoc analysis of data from a cross-sectional online survey with 4.283 Germany physicians. Results. With a reported median use in 17% of affected patients, WHO-step III opioids play a minor role in treatment of CLBP in daily practice associated with a broad spectrum of positive and negative effects. If prescribed, potent opioids were reported to show clinically relevant effects (such as ≥50% pain relief) in approximately 3 of 4 patients (median 72%). Analgesic effects reported are frequently related with adverse events (AEs). Only 20% of patients were reported to remain free of any AE. Most frequently reported AE was constipation (50%), also graded highest for AE-related daily life restrictions (median 46%). Specific AE countermeasures were reported to be necessary in approximately half of patients (median 45%); nevertheless AE-related premature discontinuation rates reported were high (median 22%). Fentanyl/morphine were the most/least prevalently prescribed potent opioids mentioned (median 20 versus 8%). Conclusion. Overall, use of WHO-step III opioids for CLBP is low. AEs, especially constipation, are commonly reported and interfere significantly with analgesic effects in daily practice. Nevertheless, beneficial effects outweigh related AEs in most patients with CLBP.

Development of opioid-induced constipation: post hoc analysis of data from a 12-week prospective, open-label, blinded-endpoint streamlined study in low-back pain patients treated with prolonged-release WHO step III opioids.

BACKGROUND: Opioid-induced constipation is the most prevalent patient complaint associated with longer-term opioid use and interferes with analgesic efficacy, functionality, quality of life, and patient compliance. OBJECTIVES: We aimed to compare the effects of prolonged-release (PR) oxycodone plus PR naloxone (OXN) vs PR oxycodone (OXY) vs PR morphine (MOR) on bowel function under real-life conditions in chronic low-back pain patients refractory to World Health Organization (WHO) step I and/or II analgesics. RESEARCH DESIGN AND METHODS: This was a post hoc analysis of the complete data set from a prospective, randomized, open-label, blinded endpoint (PROBE) streamlined study (German pain study registry: 2012-0012-05; European Union Drug Regulating Authorities Clinical Trials [EudraCT]: 2012-001317-16), carried out in 88 centers in Germany, where a total of 901 patients requiring WHO step III opioids to treat low-back pain were enrolled and prospectively observed for 3 months. Opioid allocation was based on either optional randomization (n=453) or physician decision (n=448). In both groups, treatment doses could be adjusted as per the German prescribing information, and physicians were free to address all side effects and tolerability issues as usual. The primary endpoint was the proportion of patients maintaining normal bowel function throughout the complete treatment period, assessed with the Bowel Function Index (BFI). Secondary analyses addressed absolute and relative BFI changes, complete spontaneous bowel movements, use of laxatives, treatment emergent adverse events, analgesic effects, and differences between randomized vs nonrandomized patient groups. RESULTS: BFI changed significantly with all three WHO step III treatments, however significantly less with OXN vs OXY and MOR despite a significantly higher use of laxatives with the latter ones (P<0.001). The percentage of patients who maintained normal BFI scores despite opioid treatment was 54.5% (164/301) with OXN and was significantly superior to those seen with OXY (32.8% [98/300]) (odds ratio [OR]: 2.47, 95% confidence interval [CI]: 1.77-3.44; P<0.001) or MOR (29.7% [89/300]) (OR: 2.84, 95% CI: 2.03-3.97; P<0.001). Absolute BFI changes of ≥12mm 100 mm horizontal visual analog scale (VAS100) vs. baseline were seen for OXN in 41.4%, for OXY in 68.7%, and for MOR in 72.3%. Complete spontaneous bowel movements decreased at least by one per week in 10.3% with OXN vs 42.3% for OXY (OR: 6.39, 95% CI 4.13-9.89; P<0.001) and 42.0% for MOR (OR: 6.31, 95% CI: 4.08-9.76; P<0.001). Overall, 359 treatment emergent adverse events (78 [OXN], 134 [OXY], and 147 [MOR]) in 204 patients (41 [OXN], 80 [OXY], and 83 [MOR]) occurred, most affecting the gastrointestinal (49.3%) and the nervous system (39.3%). Treatment contrasts between randomized vs nonrandomized patients were insignificant. CONCLUSION: In this post hoc analysis of data from a real-life 12-week study, OXN treatment was associated with a significantly lower risk of opioid-induced constipation, superior tolerability, and significantly better analgesic efficacy compared with OXY and MOR.

Safety and efficacy of oxycodone/naloxone vs. oxycodone vs. morphine for the treatment of chronic low back pain: results of a 12 week prospective, randomized, open-label blinded endpoint streamlined study with prolonged-release preparations.

BACKGROUND: Opioid-induced constipation (OIC) is the most prevalent patient complaint associated with opioid use and interferes with analgesic efficacy. OBJECTIVES: This PROBE trial compares the overall safety and tolerability of oxycodone/naloxone (OXN) with those of traditional opioid therapy with oxycodone (OXY) or morphine (MOR) in the setting of the German healthcare system. RESEARCH DESIGN AND METHODS: This was a prospective, randomized, open-label, blinded endpoint (PROBE) streamlined study (German pain study registry: 2012-0012-05; EudraCT: 2012-001317-16), carried out in 88 centers in Germany, where a total of 453 patients, requiring WHO step III opioids to treat low back pain, were randomized to OXN, OXY or MOR (1:1:1) for 3 months. The primary outcome was the percentage of patients without adverse event-related study discontinuations who presented with a combination of a ≥50% improvement of pain intensity, disability and quality-of-life and a ≤50% worsening of bowel function at study end. RESULTS: Significantly more OXN patients met the primary endpoint (22.2%) vs. OXY (9.3%; OR: 2.80; p < 0.001) vs. MOR (6.3%; OR: 4.23; p < 0.001), with insignificant differences between OXY vs. MOR (p = 0.155). A ≥50% improvement of pain intensity, functional disability and quality-of-life has been found for OXN in 75.0/61.1/66.0% of patients and thus for all parameters significantly more than with OXY (58.9/49.0/48.3; p < 0.001 for each) or MOR (52.5/46.2/37.3; p < 0.001 for each). A total of 86.8% of OXN patients kept normal BFI scores during treatment, vs. 63.6% for OXY (p < 0.001) vs. 53.8% for MOR (p < 0.001). Overall 189 TEAEs (OXN: 45, OXY: 69, MOR: 75) in 92 patients (OXN: 21, OXY: 44, MOR: 37) occurred, most gastrointestinal (50.8%). One limitation is the open-label design, which presents the possibility of interpretive bias. CONCLUSION: Under the conditions of this PROBE design, OXN was associated with a significantly better tolerability, a lower risk of OIC and a significantly better analgesic efficacy than OXY or MOR.

The LAM-SAFE Study: lamotrigine versus carbamazepine or valproic acid in newly diagnosed focal and generalised epilepsies in adolescents and adults.

OBJECTIVE: To investigate efficacy and safety of lamotrigine (LTG) versus carbamazepine (CBZ) or valproic acid (VPA) in newly diagnosed focal (FE) and idiopathic generalised (GE) epilepsies in adolescents and adults. METHODS: Open-label randomised comparative multicentre 24-week monotherapy trial in newly diagnosed epilepsy patients of >or=12 years of age. Patients with FE were treated with LTG or CBZ, those with GE received LTG or VPA. The primary efficacy variable was the number of seizure-free patients during study weeks 17 and 24. RESULTS: Two hundred and thirty-nine patients were included. One hundred and seventy-six patients suffered from FE and 63 from GE. In the FE group, 88 patients each were treated with CBZ or LTG. Ninety-four percent of the CBZ patients and 89% of the LTG patients became seizure-free according to an intent-to-treat analysis (not statistically different). The rate of patients discontinuing treatment due to adverse events or a lack of efficacy was 19% with CBZ compared to 9% with LTG (not statistically different). In the GE group, 30 patients received VPA and 33 LTG. During study weeks 17 and 24, 61% of the LTG patients and 84% of the VPA patients had become seizure-free (not statistically significant). The drop-out rate due to lack of efficacy or adverse events was 12% with LTG and 3% with VPA (not statistically different). CONCLUSIONS: This study indicates that the effectiveness of LTG in focal and generalised epilepsy syndromes as initial monotherapy in patients >or=12 years is in the range of standard first-line antiepileptic drugs.

Long-term safety and efficacy of cabergoline for the treatment of idiopathic restless legs syndrome: results from an open-label 6-month clinical trial.

STUDY OBJECTIVES: To assess the safety and efficacy of cabergoline in the treatment of idiopathic restless legs syndrome (RLS) patients. DESIGN: Open-label intervention study for 26 weeks; no control group. SETTING: 302 patients (73% women, aged 61 +/- 11 years) from 37 German neurologic outpatient departments and private practices. INTERVENTION: Cabergoline was upwardly titrated over 4 weeks to individually optimized dosages. Median treatment duration was 181 days. The median daily dose of cabergoline was 1.5 mg. MEASUREMENTS: Drug safety was assessed by adverse events; efficacy was evaluated with the RLS-6 and the International RLS Rating Scales. RESULTS: In 48% of the study participants, investigators reported adverse events suspected to be drug related. Most adverse events were mild and transient and related to the gastrointestinal system (nausea: 16.6%) or the central nervous system (dizziness: 7.0%, headache: 4.6%). Premature dropout from the study occurred in 54 patients (17.9%), in 17 patients (3.0%) due to a drug-related adverse event. The severity of RLS symptoms at night, at bedtime, and during the day, as well as the International RLS Rating Scale total score improved during therapy. Satisfaction with sleep was increased (all P values < .001). In 5% of all patients, RLS symptoms worsened, and in a further 6.3%, response to therapy was poor. In 9 patients (3.0%) between 1 and 3 criteria for augmentation were noted. CONCLUSIONS: Long-term therapy with cabergoline is a safe and well-tolerated treatment option for the great majority of patients with idiopathic RLS. The treatment was efficacious both for nighttime and daytime symptoms in this indication and may carry a low risk of augmentation.