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Long-term safety and efficacy of mirogabalin in Asian patients with diabetic peripheral neuropathic pain.
Baba, M, Matsui, N, Kuroha, M, Wasaki, Y, Ohwada, S
Journal of diabetes investigation. 2020;(3):693-698
Abstract
AIMS/INTRODUCTION Diabetic peripheral neuropathic pain (DPNP) affects the functionality, mood and sleep patterns of patients with diabetes. Mirogabalin, an α2 δ ligand with a slower dissociation for α2 δ-1 versus α2 δ-2 subunits, showed efficacy and safety in a randomized, double-blind, placebo-controlled, 14-week study in Asian patients with DPNP. This open-label extension study evaluated the long-term safety and efficacy of mirogabalin in Asian patients with DPNP. MATERIAL AND METHODS This 52-week open-label extension study was carried out in Japan, Korea and Taiwan in patients with DPNP. Patients received mirogabalin, initiated at 5 mg twice daily and increased to a flexible maintenance dosage of 10 or 15 mg twice daily. Adverse events were monitored throughout the study. Patients provided a self-assessment of pain using the Short-Form McGill Pain Questionnaire. RESULTS Of the 214 patients who entered the study, 172 (80.4%) completed the extension study. Of 172 patients who completed the study, 149 received the highest dosage of mirogabalin (15 mg twice daily). The most common treatment-emergent adverse events were nasopharyngitis, diabetic retinopathy, peripheral edema, somnolence, diarrhea, increased weight and dizziness. Most treatment-emergent adverse events were mild or moderate in severity. The incidence of treatment-emergent adverse events leading to treatment discontinuation was 13.1%. The visual analog scale and all other Short-Form McGill Pain Questionnaire subscales (sensory score, affective score, total score and present pain intensity) generally decreased over time from baseline until week 52. CONCLUSIONS This extension study showed the safety and efficacy of a long-term flexible dosing regimen of mirogabalin 10 or 15 mg twice daily in patients with DPNP.
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Lack of Detection of the Analgesic Properties of PF-05089771, a Selective Nav 1.7 Inhibitor, Using a Battery of Pain Models in Healthy Subjects.
Siebenga, P, van Amerongen, G, Hay, JL, McDonnell, A, Gorman, D, Butt, R, Groeneveld, GJ
Clinical and translational science. 2020;(2):318-324
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Abstract
Sodium channel blockers are used for the treatment of pain, but this is limited by the lack of selectivity for different sodium channel subtypes, which can result in central nervous system and cardiovascular side effects. As such, there is special interest in the Nav 1.7 subtype, which is expressed predominantly in nociceptive and sympathetic neurons. The aim was to demonstrate analgesic properties of a potent selective Nav 1.7 sodium channel blocker, PF-05089771, alone and concomitantly with pregabalin in healthy subjects using a battery of human evoked pain models. This was a double-blind, double-dummy, randomized, placebo-controlled, five-period cross-over study with PF-05089771 alone and PF-05089771 concomitantly with pregabalin as treatment arms with pregabalin, ibuprofen, and placebo as control arms (NCT02349607). A battery of human evoked pain models was used to investigate analgesic properties of PF-05089771. Twenty-five subjects were enrolled in the study of which 23 subjects completed all five periods. PF-05089771 alone did not differ from placebo on the primary pain end points. The same holds when comparing PF-05089771 concomitantly with pregabalin and pregabalin alone. Pregabalin showed significant effects relative to placebo on thermal pain on the normal skin and UVB skin (least squares means with 90% confidence interval: 0.63 (0.32-0.93) and 0.53 (0.11-0.96)), pressure stimulation (1.10 (1.04-1.18)), and cold pressor (1.22 (1.14-1.32)). Ibuprofen demonstrated significant effects on thermal pain UVB skin (1.26 (0.82-1.70)) and pressure stimulation assessment (1.08 (1.01-1.15)), consistent with historical results. This study did not demonstrate analgesic properties of PF-05089771 alone or concomitantly with pregabalin in a battery of pain models.
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Effectiveness of a Dietary Supplement Containing Hydrolyzed Collagen, Chondroitin Sulfate, and Glucosamine in Pain Reduction and Functional Capacity in Osteoarthritis Patients.
Puigdellivol, J, Comellas Berenger, C, Pérez Fernández, MÁ, Cowalinsky Millán, JM, Carreras Vidal, C, Gil Gil, I, Martínez Pagán, J, Ruiz Nieto, B, Jiménez Gómez, F, Comas Figuerola, FX, et al
Journal of dietary supplements. 2019;(4):379-389
Abstract
This observational, open, multicenter clinical trial with a single treatment group aimed to evaluate the effectiveness of a dietary supplement whose main ingredients are hydrolyzed gelatin, chondroitin sulfate, glucosamine sulfate, and devil's claw and bamboo extracts for pain reduction and improvement of functional capacities in patients with osteoarthritis (OA) of the knee and/or hip (REDART study). In all, 130 patients with OA recruited from Spanish hospitals received the dietary supplement for 6 months. The primary outcome was the patients' global assessment of pain in the affected joint as measured with a visual analogue scale (VAS). Other outcome measurements included the Lequesne Functional Index (subindexes for pain/discomfort, distance walked, and daily living) and the Western Ontario and McMaster Universities Arthritis Index (WOMAC; subindexes for pain, stiffness, and physical function). Scores were taken at months 3 and 6 of the treatment. Patients (N = 78) showed a reduction of pain of 3.77 ± 1.77 points after 6 months (p < .0001) in the VAS. The total reduction in the Lequesne Functional Index was 6.30 ± 4.08 points after 6 months (p < .0001), with significant reductions in all subindexes of the scale. A similar pattern was found for the WOMAC index, with an overall reduction of 22.49 ± 14.03 points after 6 months (p < .0001) and significant reductions in all subindexes. No major adverse events were noted during the treatment. This exploratory study shows that treatment with the dietary supplement significantly reduces pain and improves locomotor function in patients with OA of the knee and/or hip.
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An open-label, randomized, four-treatment crossover study evaluating the effects of salt form, acetaminophen, and food on the pharmacokinetics of phenylephrine.
Gelotte, CK
Regulatory toxicology and pharmacology : RTP. 2018;:333-338
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Abstract
Phenylephrine hydrochloride (HCl) is a decongestant available in over-the-counter (OTC) medicines. Previously marketed prescription products contained phenylephrine tannate, an extended-release salt, which allowed dosing every 8-12 h. Given the regulatory history that cold medicines marketed before 1962 had limited supporting clinical data, and with widespread replacement of pseudoephedrine by phenylephrine in OTC products over the last ten years, the need for contemporary studies grew. This exploratory crossover study evaluated effects of salt form, acetaminophen, and food on phenylephrine pharmacokinetics and metabolites in healthy adults. Test treatments were 25 mg phenylephrine tannate (equivalent to 10 mg phenylephrine HCl) combined with 200 mg guaifenesin, fasted; 10 mg phenylephrine HCl combined with 650 mg acetaminophen, fasted; and 10 mg phenylephrine HCl, fed. The reference treatment was 10 mg phenylephrine HCl, fasted. Plasma phenylephrine pharmacokinetics and urine metabolites were determined. Although the tannate salt slowed phenylephrine absorption compared with the HCl salt, terminal concentrations were similar, suggesting that products containing the tannate salt should not be dosed less frequently than those containing the HCl salt. The premise that acetaminophen increases phenylephrine bioavailability by competition for presystemic sulfation was corroborated by increased phenylephrine sulfate in urine. Food delayed phenylephrine absorption, but not the total amount absorbed.
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Tolerability, pharmacokinetics, and pharmacodynamics of mirogabalin in healthy subjects: Results from phase 1 studies.
Brown, K, Mendell, J, Ohwada, S, Hsu, C, He, L, Warren, V, Dishy, V, Zahir, H
Pharmacology research & perspectives. 2018;(5):e00418
Abstract
Three phase 1 pharmacokinetic (PK)/pharmacodynamics (PD) studies were conducted in healthy men and women to further characterize the safety, tolerability, and PK/PD of mirogabalin administration with or without food and to guide the dose selection and regimen for phase 2 and 3 clinical development. The 3 studies included 2 randomized, double-blind, placebo-controlled, single- and multiple-ascending-dose studies, and 1 open-label, crossover study to evaluate the PK of mirogabalin administered under fasting and fed (high-fat meal) conditions. Forty-eight and 47 healthy volunteers completed the single- and multiple-dose studies, respectively. Thirty subjects were enrolled and completed the food effect study. Mirogabalin was well tolerated in the fed and fasted states. The most frequent treatment-emergent adverse events (TEAEs)-dizziness and somnolence-were expected based on mirogabalin's mechanism of action. Subjects receiving the highest mirogabalin doses (50 and 75 mg single dose) showed greater dizziness and sedation and higher rates of TEAEs than subjects receiving 3-30 mg. After oral administration, mirogabalin was rapidly absorbed (time to maximum concentration, ∼1 hour) and eliminated through urine unchanged (61%-72% urinary excretion). Exposure increased in a dose-proportional manner after single or multiple mirogabalin doses. No significant accumulation occurred with multiple doses over 14 days. After single doses of mirogabalin (15 mg), the bioavailability was considered equivalent in the fed and fasted states, indicating that mirogabalin can be taken without food restrictions. Based on these data, mirogabalin 15 mg twice daily was selected as the highest target dose for further clinical development.
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A Rosa canina - Urtica dioica - Harpagophytum procumbens/zeyheri Combination Significantly Reduces Gonarthritis Symptoms in a Randomized, Placebo-Controlled Double-Blind Study.
Moré, M, Gruenwald, J, Pohl, U, Uebelhack, R
Planta medica. 2017;(18):1384-1391
Abstract
The special formulation MA212 (Rosaxan) is composed of rosehip (Rosa canina L.) puree/juice concentrate, nettle (Urtica dioica L.) leaf extract, and devil's claw (Harpagophytum procumbens DC. ex Meisn. or Harpagophytum zeyheri Decne.) root extract and also supplies vitamin D. It is a food for special medical purposes ([EU] No 609/2013) for the dietary management of pain in patients with gonarthritis.This 12-week randomized, placebo-controlled double-blind parallel-design study aimed to investigate the efficacy and safety of MA212 versus placebo in patients with gonarthritis.A 3D-HPLC-fingerprint (3-dimensional high pressure liquid chromatography fingerprint) of MA212 demonstrated the presence of its herbal ingredients. Ninety-two randomized patients consumed 40 mL of MA212 (n = 46) or placebo (n = 44) daily. The Western Ontario and McMaster Universities Arthritis Index (WOMAC), quality-of-life scores at 0, 6, and 12 weeks, and analgesic consumption were documented. Statistically, the initial WOMAC subscores/scores did not differ between groups. During the study, their means significantly improved in both groups. The mean pre-post change of the WOMAC pain score (primary endpoint) was 29.87 in the MA212 group and 10.23 in the placebo group. The group difference demonstrated a significant superiority in favor of MA212 (pU < 0.001; pt < 0.001). Group comparisons of all WOMAC subscores/scores at 6 and 12 weeks reached same significances. Compared to placebo, both physical and mental quality of life significantly improved with MA212. There was a trend towards reduced analgesics consumption with MA212, compared to placebo. In the final efficacy evaluation, physicians (pChi < 0.001) and patients (pChi < 0.001) rated MA212 superior to placebo. MA212 was well tolerated.This study demonstrates excellent efficacy for MA212 in gonarthritis patients.
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Analgesic Efficacy of a New Immediate-Release/Extended-Release Formulation of Ibuprofen: Results From Single- and Multiple-Dose Postsurgical Dental Pain Studies.
Christensen, S, Paluch, E, Jayawardena, S, Daniels, S, Meeves, S
Clinical pharmacology in drug development. 2017;(3):302-312
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Analgesic effects of ibuprofen immediate-release/extended-release (IR/ER) 600-mg tablets were evaluated in 2 randomized, double-blind, placebo-controlled dental pain studies. Patients 16-40 years old with moderate-severe pain following third-molar extraction received single-dose ibuprofen 600 mg IR/ER (formulation A or B), naproxen sodium 220 mg, or placebo (2:2:2:1; study 1) or 4 doses of ibuprofen 600 mg IR/ER (formulation A) or placebo (1:1; study 2). In study 1 (n = 196), mean (standard deviation [SD]) time-weighted sum of pain intensity difference scores for placebo, ibuprofen IR/ER A, ibuprofen IR/ER B, and naproxen, respectively, were 0.05 (9.2), 16.87 (9.4), 17.34 (10.5), and 12.66 (10.0) over 0-12 hours and -0.03 (4.1), 6.57 (4.4), 7.14 (5.2), and 5.14 (5.0) over 8-12 hours (all P < .001 vs placebo). In study 2 (n = 106), mean (SD) time-weighted sum of pain relief and pain intensity difference scores were 18.2 (20.0) versus 41.5 (21.0) at 0-12 hours and 10.3 (12.0) versus 18.4 (12.1) at 8-12 hours for placebo versus ibuprofen IR/ER, respectively (P < .001 for both); efficacy was sustained over each of the four 12-hour dosing intervals with ibuprofen. Gastrointestinal adverse events predominated with placebo both after study medication administration and after rescue medication use, if applicable. Ibuprofen 600 mg IR/ER provided safe and effective analgesia after single and multiple doses.
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Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial.
Hoppe, C, Jacob, E, Styles, L, Kuypers, F, Larkin, S, Vichinsky, E
British journal of haematology. 2017;(4):620-629
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Sickle cell anaemia (SCA) is a progressive vascular disease characterized by episodic vaso-occlusive pain. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCA, no directed anti-inflammatory therapies currently exist. Statins are cholesterol-lowering agents shown to confer protection from vascular injury by suppressing inflammation. We previously documented a reduction in soluble biomarkers of inflammation in patients with sickle cell disease treated with simvastatin. To determine the potential clinical efficacy of simvastatin, we treated 19 SCA patients with single daily dose simvastatin for 3 months and assessed changes from baseline in the frequency and intensity of diary-reported pain and levels of circulating nitric oxide metabolites (NOx), high sensitivity C-reactive protein (hs-CRP), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), ICAM-3, E-selectin, and vascular endothelial growth factor (VEGF). Treatment with simvastatin resulted in a significant reduction in the frequency of pain (P = 0·0003), oral analgesic use (P = 0·003) and circulating hs-CRP (P = 0·003), soluble (s)E-selectin (P = 0·01), sICAM-1 (P = 0·02), sICAM-3 (P = 0·02) and sVEGF (P = 0·01). Simvastatin had no effect on pain intensity or levels of NOx, sP-selectin and sVCAM-1. The observed reductions in pain rate and markers of inflammation were greatest in subjects receiving hydroxycarbamide (HC), suggesting a synergistic effect of simvastatin. These results provide preliminary clinical data to support a larger trial of simvastatin in SCA.
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Randomised clinical trial: the analgesic properties of dietary supplementation with palmitoylethanolamide and polydatin in irritable bowel syndrome.
Cremon, C, Stanghellini, V, Barbaro, MR, Cogliandro, RF, Bellacosa, L, Santos, J, Vicario, M, Pigrau, M, Alonso Cotoner, C, Lobo, B, et al
Alimentary pharmacology & therapeutics. 2017;(7):909-922
Abstract
BACKGROUND Intestinal immune activation is involved in irritable bowel syndrome (IBS) pathophysiology. While most dietary approaches in IBS involve food avoidance, there are fewer indications on food supplementation. Palmithoylethanolamide, structurally related to the endocannabinoid anandamide, and polydatin are dietary compounds which act synergistically to reduce mast cell activation. AIM: To assess the effect on mast cell count and the efficacy of palmithoylethanolamide/polydatin in patients with IBS. METHODS We conducted a pilot, 12-week, randomised, double-blind, placebo-controlled, multicentre study assessing the effect of palmithoylethanolamide/polydatin 200 mg/20 mg or placebo b.d. on low-grade immune activation, endocannabinoid system and symptoms in IBS patients. Biopsy samples, obtained at screening visit and at the end of the study, were analysed by immunohistochemistry, enzyme-linked immunoassay, liquid chromatography and Western blot. RESULTS A total of 54 patients with IBS and 12 healthy controls were enrolled from five European centres. Compared with controls, IBS patients showed higher mucosal mast cell counts (3.2 ± 1.3 vs. 5.3 ± 2.7%, P = 0.013), reduced fatty acid amide oleoylethanolamide (12.7 ± 9.8 vs. 45.8 ± 55.6 pmol/mg, P = 0.002) and increased expression of cannabinoid receptor 2 (0.7 ± 0.1 vs. 1.0 ± 0.8, P = 0.012). The treatment did not significantly modify IBS biological profile, including mast cell count. Compared with placebo, palmithoylethanolamide/polydatin markedly improved abdominal pain severity (P < 0.05). CONCLUSIONS The marked effect of the dietary supplement palmithoylethanolamide/polydatin on abdominal pain in patients with IBS suggests that this is a promising natural approach for pain management in this condition. Further studies are now required to elucidate the mechanism of action of palmithoylethanolamide/polydatin in IBS. ClinicalTrials.gov number, NCT01370720.
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Acceptable effect of multimodal analgesic treatment after a Bascom cleft lift operation.
Mohamed, SJ, Kristensen, BB, Lindgaard, L, Bisgaard, T
Danish medical journal. 2015;(1):A4985
Abstract
INTRODUCTION Information on multimodal analgesic efficacy in patients undergoing a Bascom cleft lift operation is limited. The aim of this prospective consecutive study was to evaluate early post-operative pain in patients receiving a standardised multimodal analgesic regimen. METHODS A total of 48 patients undergoing a Bascom cleft lift operation were included over an 8-month period in a day-case set-up. The operation was performed under saddle block. In addition, patients received a standardised multi-modal analgesic regimen consisting of gabapentin, ketorolac, dexamethasone, acetaminophen (paracetamol) and ibuprofen. The intensity of pain was registered preoperatively and at 2, 24, 48 h, and 30 days post-operatively. Nausea, vomiting, dizziness, ability to void, morphine consumption and post-anaesthesia care unit (PACU) time were registered. RESULTS Thirty patients were available for analysis. Post-operative visual analogue scale pain scores were low (at 2, 24, and 48 h (median values: 0 (range: 0-40), 25 (0-70), and 30 (0-60), respectively), but changed significantly over time (p < 0.001). The median overall morphine consumption was 0 (range: 0-30). None of the patients experienced vomiting or dizziness. Only two patients reported mild nausea during the stay in the PACU. CONCLUSION This study suggests that the Bascom cleft lift operation is feasible with minimal post-operative pain when using a multimodal analgesic regimen together with saddle block. FUNDING not relevant. TRIAL REGISTRATION ClinicalTrials.gov: NCT02196727. Regional Ethics Committee Reg. no.: H-3-2013-073. Danish Data Protection Agency Reg. no.: HVH-2013-031, with I-Suite no.: 02408.