An update on the strategies in multicomponent activity monitoring within the phytopharmaceutical field

<p>Abstract</p> <p>Background</p> <p>To-date modern drug research has focused on the discovery and synthesis of single active substances. However, multicomponent preparations are gaining increasing importance in the phytopharmaceutical field by demonstrating beneficial properties with respect to efficacy and toxicity.</p> <p>Discussion</p> <p>In contrast to single drug combinations, a botanical multicomponent therapeutic possesses a complex repertoire of chemicals that belong to a variety of substance classes. This may explain the frequently observed pleiotropic bioactivity spectra of these compounds, which may also suggest that they possess novel therapeutic opportunities. Interestingly, considerable bioactivity properties are exhibited not only by remedies that contain high doses of phytochemicals with prominent pharmaceutical efficacy, but also preparations that lack a sole active principle component. Despite that each individual substance within these multicomponents has a low molar fraction, the therapeutic activity of these substances is established via a potentialization of their effects through combined and simultaneous attacks on multiple molecular targets. Although beneficial properties may emerge from such a broad range of perturbations on cellular machinery, validation and/or prediction of their activity profiles is accompanied with a variety of difficulties in generic risk-benefit assessments. Thus, it is recommended that a comprehensive strategy is implemented to cover the entirety of multicomponent-multitarget effects, so as to address the limitations of conventional approaches.</p> <p>Summary</p> <p>An integration of standard toxicological methods with selected pathway-focused bioassays and unbiased data acquisition strategies (such as gene expression analysis) would be advantageous in building an interaction network model to consider all of the effects, whether they were intended or adverse reactions.</p

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

Michael A Ueberall,1 Gerhard H H Mueller-Schwefe2 1Institute of Neurological Sciences, Nuernberg, Germany; 2Interdisciplinary Center for Pain and Palliative Care Medicine, Goeppingen, Germany Objective: To evaluate the benefit&ndash;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 (&ge;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: &ge;30%/&ge;50%/&ge;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/&lt;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. Keywords: oxycodone/naloxone, tapentadol, chronic low back pain, neuropathic component, noninterventional study, German Pain Registry, random data selection, blinded end point analysis, benefit&ndash;risk profil

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

Michael A Ueberall,1 Gerhard HH Mueller-Schwefe2 1Institute for Neurological Sciences, Nuremberg, Germany; 2Interdisciplinary Center for Pain and Palliative Care Medicine, G&ouml;ppingen, Germany 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&lt;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&ndash;3.44; P&lt;0.001) or MOR (29.7% [89/300]) (OR: 2.84, 95% CI: 2.03&ndash;3.97; P&lt;0.001). Absolute BFI changes of &ge;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&ndash;9.89; P&lt;0.001) and 42.0% for MOR (OR: 6.31, 95% CI: 4.08&ndash;9.76; P&lt;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. Keywords: chronic pain, bowel function, quality of lif

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 [Corrigendum]

Ueberall and Mueller-Schwefe. J Pain Res. 2015 Aug 10;8:459&ndash;475.The PROBE German pain study was incorrectly listed in the abstract and on page 462 as European Union Drug Regulating Authorities Clinical Trials [EudraCT]: 2012-001317-16. The correct registry is European Medicines Agency E-Register of Studies: ENCEPP/SDPP/11035.&nbsp;View original article by Ueberall and Mueller-Schwefe.&nbsp

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

Michael A Ueberall,1 Alice Eberhardt,2 Gerhard HH Mueller-Schwefe3 1Institute for Neurological Sciences, Nuernberg, Germany; 2Mundipharma GmbH, Limburg, Germany; 3Interdisciplinary Center for Pain and Palliative Care Medicine, Goeppingen, Germany 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&lt;0.001) with significantly greater improvements under oxycodone/naloxone (65.2% vs 49.6% for oxycodone and 48.2% for morphine, P&lt;0.001). The proportion of patients without EQ-5D complaints was also significantly higher under oxycodone/naloxone (P&lt;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&lt;0.001): 90.7% of all oxycodone/naloxone patients achieved &ge;30% improvements in quality of life, 72.8% had &ge;50%, and 33.2% &ge;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. Keywords: chronic low back pain, quality of life, oxycodone/naloxone, oxycodone, morphine, routine clinical practice, EQ-5D, SF-12, QLIP&nbsp

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

Michael A Ueberall,1 Ute Essner,2 Gerhard HH Mueller-Schwefe31Institute of Neurological Sciences, 90411 Nuernberg, Germany; 2O.Meany Consultancy, 22339 Hamburg, Germany; 3Interdisciplinary Centre for Pain and Palliative Care Medicine, 73033 Goeppingen, GermanyObjective: To evaluate effectiveness, tolerability and safety of an oromucosal spray containing &Delta;9-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 &plusmn; SD age: 46.3&plusmn;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&plusmn;26.5% (95%-CI: 36.9&ndash;41.1, median: 42, range &minus;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 &ge;50% improvement in at least 5 of 9 ASR factors. With a 54.9&plusmn;17.2% (median: 56%, range: &minus;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&plusmn;12.0, median: 19, range: &minus;12 to 42%) or nociceptive pain (n=54, 6.8%; ASR-9: &minus;11.9&plusmn;10.5, median: &minus;11, range: &minus;41% to 12%; p&lt;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&lt;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 &ndash; especially of neuropathic origin.Keywords: THC:CBD spray, add-on treatment, severe chronic pain, neuropathic pain, retrospective analysis, German pain e-Registr

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

Michael A Ueberall,1 Gerhard HH Mueller-Schwefe,2 Rainer Wigand,3 Ute Essner4 1Institute of Neurological Sciences, Nuremberg, 2Interdisciplinary Center for Pain and Palliative Care Medicine, G&ouml;ppingen, 3Interdisciplinary Center for Rheumatology and Immunology, Frankfurt, 4O.Meany Consultancy, Hamburg, Germany 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 postbaseline 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 &ndash; the primary efficacy end point &ndash; decreased comparably with both treatments and improved with both &shy;treatments significantly vs baseline (OEC 12.6&plusmn;2.4 to 9.1&plusmn;3.9, DIC 12.7&plusmn;2.4 to 9.1&plusmn;4.2, effect size 0.9/0.88; P&lt;0.001 for each). In parallel, movement-related 11-point numeric rating-scale pain intensity improved significantly (P&lt;0.001) and comparably with both treatments from baseline (6.4&plusmn;1.9/6.6&plusmn;1.8) to study end (3.8&plusmn;2.7/3.9&plusmn;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&lt;0.001), and 28.2% vs 72.6% showed an increase in AST, ALT, or GGT (P&lt;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. Keywords: oral enzyme combination, diclofenac, osteoarthritis, randomized controlled trial, meta-analysi

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

Michael A Ueberall,1 Stefan Lorenzl,2 Eberhard A Lux,3,4 Raymond Voltz,5 Michael Perelman6 1Institute of Neurological Sciences, Nuremberg, Germany; 2Institute of Nursing Science and Practice, Paracelsus Private Medical University of Salzburg, Salzburg, Austria; 3Faculty of Medicine, Witten/Herdecke University, Witten, Germany; 4Clinic for Pain and Palliative Care Medicine, St.- Marien-Hospital, Luenen, Germany; 5Department of Palliative Medicine, University Hospital Cologne, Cologne, Germany; 6Archimedes Development Ltd., Nottingham, United Kingdom 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&nbsp;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 &ldquo;time to first effect&rdquo;, &ldquo;time to maximum effect&rdquo;, BTcP relief, as well as changes in BTcP-related impairment of daily life activities, &shy;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 &plusmn; standard deviation = 2.8&plusmn;2.3) compared with either that reported at baseline (8.5&plusmn;1.5), experienced immediately before FPNS application (7.4&plusmn;1.7), or that achieved with previous BTcP medication (6.0&plusmn;2.0; P&lt;0.001 for each comparison). In 12.3% of BTcP episodes, onset of pain relief occurred &le;2 minutes and in 48.4% &le;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&plusmn;16.9 vs 53.1&plusmn;11.9), physical (35.9&plusmn;8.4 vs 26.8&plusmn;6.5), and mental quality of life (38.7&plusmn;8.5 vs 29.9&plusmn;7.9) (P&lt;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. Keywords: breakthrough pain, cancer, fentanyl pectin nasal spray, intranasal administration, efficacy, safety, quality of lif