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Lynn R Webster,1 Martin E Hale,2 Tadaaki Yamada,3 James E Wild4 1PRA Health Sciences, Salt Lake City, UT, USA; 2Gold Coast Research LLC, Plantation, FL, USA; 3Shionogi, Inc., Florham Park, NJ, USA; 4Upstate Clinical Research Associates, Williamsville, NY, USACorrespondence: Lynn R WebsterPRA Health Sciences, Salt Lake City, UT, USATel +1 801 269-8200Email lrwebstermd@gmail.comPurpose: Naldemedine, an oral, peripherally acting μ-opioid receptor antagonist approved for the treatment of opioid-induced constipation (OIC), is renally excreted. This subgroup analysis integrated data from 3 Phase 3 trials (COMPOSE-1, COMPOSE-2, COMPOSE-3) to evaluate the safety and efficacy of naldemedine in patients with renal impairment (RI).Patients and Methods: Patients age 18– 80 years with chronic non-cancer pain (CNCP) and OIC received oral naldemedine 0.2 mg or placebo once daily. RI subgroups consisted of patients with normal function (baseline glomerular filtration rate ≥ 90 mL/min/1.73 m2), mild (≥ 60 to < 90 mL/min/1.73 m2), and moderate (≥ 30 to < 60 mL/min/1.73 m2) RI. Safety assessments based on ≤ 12 weeks of treatment from all 3 studies included incidence of treatment-emergent adverse events (TEAEs). Efficacy was based on the proportion of responders in COMPOSE-1 and COMPOSE-2 only, defined as ≥ 3 spontaneous bowel movements (SBMs)/week and a ≥ 1-SBM/week increase from baseline for ≥ 9 of 12 weeks and ≥ 3 of the last 4 weeks.Results: In total, 2328 patients were included in this analysis. The incidence of TEAEs was similar in the naldemedine and placebo groups (overall, 47.1% vs 45.6%; normal, 44.6% vs 43.6%; mild RI, 49.0% vs 44.7%; moderate RI, 46.6% vs 55.9%). GI-related TEAEs occurred more frequently in the naldemedine group versus placebo (overall, 21.8% vs 13.8%; normal, 21.6% vs 12.5%; mild RI, 22.6% vs 14.7%; moderate RI, 18.0% vs 14.2%). A significantly greater proportion of patients in the naldemedine 0.2 mg group were responders versus the placebo group (overall, 50.1% vs 34.1%, P< 0.0001; normal, 52.0% vs 39.3%; mild RI, 48.3% vs 30.3%; moderate RI, 52.5% vs 31.7%).Conclusion: This integrated analysis confirmed that OIC treatment with naldemedine 0.2 mg was generally well tolerated and effective in patients with CNCP and mild or moderate RI. Safety and efficacy results were consistent with the overall population.Clinicaltrials.gov Registration: COMPOSE-1: NCT01965158; COMPOSE-2: NCT01993940; COMPOSE-3: NCT01965652.Keywords: opioid-related disorders, opioid analgesics, naldemedine, renal insufficiency, constipation; chemically induced

Background: Two studies demonstrated the efficacy and safety of naldemedine in adult patients with chronic non-cancer pain and opioid-induced constipation (OIC). However, no studies have compared the efficacy of peripherally acting µ-opioid receptor antagonists in patients with adequate and inadequate responses to prior OIC therapy with laxatives. This post hoc analysis of integrated data from the two previous studies compared the efficacy of naldemedine in patients who were unsuccessfully treated with laxatives [poor laxative responders (PLRs)] with those who either did not receive laxatives >30 days prior to screening or those who only received rescue laxative at or after screening (non-PLRs)., Methods: Patients with OIC were randomized to once-daily treatment with naldemedine 0.2 mg or placebo. The primary efficacy endpoint was the proportion of responders [⩾3 spontaneous bowel movements (SBMs)/week and an increase from baseline of ⩾1 SBM/week for ⩾9 weeks of the 12-week treatment period and ⩾3 weeks of the final 4 weeks of the 12-week treatment period]. Additional endpoints included change in SBM frequency, change in frequency of SBMs without straining, proportion of complete SBM (CSBM) responders, change in CSBM frequency, and time to first SBM. Treatment-emergent adverse events (TEAEs) were assessed., Results: The analysis included 538 (317 PLRs, 221 non-PLRs) and 537 (311 PLRs, 226 non-PLRs) patients in the naldemedine and placebo arms, respectively. There were significantly more responders in the naldemedine PLR (46.4%; p  < 0.0001) and non-PLR (54.3%; p  = 0.0009) subgroups versus the placebo groups (30.2% and 38.9%, respectively). In both the PLR and non-PLR subgroups, naldemedine treatment was superior to placebo on all additional endpoints. Overall incidence of TEAEs in the PLR subgroups treated with naldemedine or placebo was similar., Conclusion: This integrated analysis further supports the efficacy and tolerability of naldemedine in the treatment of OIC and demonstrates a consistent effect in both PLR and non-PLR subgroups.[ClinicalTrials.gov identifier: NCT01965158 and NCT01993940]., Competing Interests: Conflict of interest statement: MH was a clinical trial investigator, consultant to Shionogi Inc. and received a stipend for review of the clinical study report. JW received a stipend from Shionogi Inc. for review of the clinical study report. T Yamada is an employee of Shionogi Inc. who may or may not own stock options. T Yokota is an employee of Shionogi & Co., Ltd. who may or may not own stock options. JT has provided scientific advice to Allergan, Kyowa Kirin, Shionogi, and Shire, has been a speaker for Allergan and Kyowa Kirin, and has received a research grant from Kyowa Kirin related to opioid-induced constipation. VA has received speaker and/or consultant fees from Allergan, Bayer, Falk, Ferring, Hexal, Kyowa Kirin, 4M-Medical, Sanofi, and Shionogi. AMD has no conflicts to declare., (© The Author(s), 2021.)

Objective: A single-agent, extended-release formulation of hydrocodone (HC) has been developed for treatment of chronic moderate-to-severe pain. This study was designed to examine the safety and efficacy of HC extended release in opioid-experienced adults with moderate-to-severe chronic low back pain (CLBP)., Methods: This multicenter, enriched enrollment, randomized withdrawal study comprised an open-label conversion/titration phase (≤6 weeks) followed by placebo-controlled, double-blind treatment (12 weeks). During the conversion/titration phase, subjects (N = 510) converted from their current opioid and were titrated to a stabilized dose of HC extended release (20-100 mg every 12 hours). During treatment, subjects (N = 151 per group) received HC extended release or placebo; rescue medication was permitted. The primary efficacy end point was mean change in average pain intensity from baseline to day 85. Response rates (30% pain improvement) and satisfaction (Subject Global Assessment of Medication) were assessed., Results: Demographic and baseline characteristics were similar between groups. Mean ± SD change in average pain intensity score from baseline to day 85 was significantly lower in the HC extended-release treatment group vs placebo (0.48 ± 1.56 vs 0.96 ± 1.55; P = 0.008). Significantly more responders were in the treatment group (68% vs 31%; P < 0.001). Mean Subject Global Assessment of Medication scores increased significantly (0.8 ± 1.3 vs 0.0 ± 1.4; P < 0.0001), indicating greater satisfaction with HC extended release. The adverse event profile was consistent with other opioids., Conclusions: Extended-release HC is well tolerated and effective, without acetaminophen-associated risks of liver toxicity, for treatment of CLBP., (Wiley Periodicals, Inc.)

Background: Tapentadol is a novel, centrally acting analgesic with 2 mechanisms of action: µ-opioid receptor agonism and norepinephrine reuptake inhibition. This randomized, open-label phase 3 study (ClinicalTrials.gov Identifier: NCT00361504) assessed the long-term safety and tolerability of tapentadol extended release (ER) in patients with chronic knee or hip osteoarthritis pain or low back pain., Methods: Patients were randomized 4:1 to receive controlled, adjustable, oral, twice-daily doses of tapentadol ER (100 to 250 mg) or oxycodone HCl controlled release (CR; 20 to 50 mg) for up to 1 year. Efficacy evaluations included assessments at each study visit of average pain intensity (11-point numerical rating scale) over the preceding 24 hours. Treatment-emergent adverse events (TEAEs) and discontinuations were monitored throughout the study., Results: A total of 1,117 patients received at least 1 dose of study drug. Mean (standard error) pain intensity scores in the tapentadol ER and oxycodone CR groups, respectively, were 7.6 (0.05) and 7.6 (0.11) at baseline and decreased to 4.4 (0.09) and 4.5 (0.17) at endpoint. The overall incidence of TEAEs was 85.7% in the tapentadol ER group and 90.6% in the oxycodone CR group. In the tapentadol ER and oxycodone CR groups, respectively, TEAEs led to discontinuation in 22.1% and 36.8% of patients; gastrointestinal TEAEs led to discontinuation in 8.6% and 21.5% of patients., Conclusion: Tapentadol ER (100 to 250 mg bid) was associated with better gastrointestinal tolerability than oxycodone HCl CR (20 to 50 mg bid) and provided sustainable relief of moderate to severe chronic knee or hip osteoarthritis or low back pain for up to 1 year., (© 2010 World Institute of Pain.)

Background: Menstrual Toxic Shock Syndrome (mTSS) is thought to be associated with the vaginal colonization with specific strains of Staphylococcus aureus TSST-1 in women who lack sufficient antibody titers to this toxin. There are no published studies that examine the seroconversion in women with various colonization patterns of this organism. Thus, the aim of this study was to evaluate the persistence of Staphylococcus aureus colonization at three body sites (vagina, nares, and anus) and serum antibody to toxic shock syndrome toxin-producing Staphylococcus aureus among a small group of healthy, menstruating women evaluated previously in a larger study., Methods: One year after the completion of that study, 311 subjects were recalled into 5 groups. Four samples were obtained from each participant at several visits over an additional 6-11 month period: 1) an anterior nares swab; 2) an anal swab; 3) a vagina swab; and 4) a blood sample. Gram stain, a catalase test, and a rapid S. aureus-specific latex agglutination test were performed to phenotypically identify S. aureus from sample swabs. A competitive ELISA was used to quantify TSST-1 production. Human TSST-1 IgG antibodies were determined from the blood samples using a sandwich ELISA method., Results: We found only 41% of toxigenic S. aureus and 35.5% of non-toxigenic nasal carriage could be classified as persistent. None of the toxigenic S. aureus vaginal or anal carriage could be classified as persistent. Despite the low persistence of S. aureus colonization, subjects colonized with a toxigenic strain were found to display distributions of antibody titers skewed toward higher titers than other subjects. Seven percent (5/75) of subjects became seropositive during recall, but none experienced toxic shock syndrome-like symptoms., Conclusions: Nasal carriage of S. aureus appears to be persistent and the best predicator of subsequent colonization, whereas vaginal and anal carriage appear to be more transient. From these findings, it appears that antibody titers in women found to be colonized with toxigenic S. aureus remained skewed toward higher titers whether or not the colonies were found to be persistent or transient in nature. This suggests that colonization at some point in time is sufficient to elevate antibody titer levels and those levels appear to be persistent. Results also indicate that women can become seropositive without experiencing signs or symptoms of toxic shock syndrome.

A retrospective analysis was conducted to evaluate whether studies from three geographically diverse locations have similar response profiles to the positive and negative controls in a standard 14-day cumulative irritation study (1). The positive irritant control (0.1% sodium lauryl sulfate, SLS) and the negative control (0.9% sodium chloride, saline) data from seventeen 14-day cumulative irritation studies were reviewed. The studies were compiled from three locations representing dry/hot, humid/hot, and dry/cold environments (Scottsdale, Arizona; St. Petersburg, Florida; and Winnipeg, Manitoba, respectively). Irritation scores were generated by trained skin graders from a total of 442 subjects studied between 1999 and 2005. Cumulative irritation scores were reviewed and compared between study locations. The irritation scores for the positive and negative controls were not significantly different between locations. Temperature and relative humidity (RH) variation did not correlate significantly with overall irritation. However, the dryer climate (i.e., negative or low dew point) had a tendency to induce a higher overall irritation level for both positive and negative controls.

Menstrual toxic shock syndrome (mTSS) is thought to be associated with colonization with toxic shock syndrome toxin 1 (TSST-1)-producing Staphylococcus aureus in women with insufficient antibody titers. mTSS has been associated with menstruation and tampon use, and although it is rare, the effects can be life threatening. It remains of interest because of the widespread use of tampons, reported to be about 70% of women in the United States, Canada, and much of Western Europe. This comprehensive study was designed to determine S. aureus colonization and TSST-1 serum antibody titers in 3,012 menstruating women in North America between the ages of 13 and 40, particularly among age and racial groups that could not be assessed reliably in previous small studies. One out of every four subjects was found to be colonized with S. aureus in at least one of three body sites (nose, vagina, or anus), with approximately 9% colonized vaginally. Eighty-five percent of subjects had antibody titers (> or =1:32) to TSST-1, and the vast majority (81%) of teenaged subjects (13 to 18 years) had already developed antibody titers. Among carriers of toxigenic S. aureus, a significantly lower percentage of black women than of white or Hispanic women were found to have antibody titers (> or =1:32) to TSST-1 (89% versus 98% and 100%). These findings demonstrate that the majority of teenagers have antibody titers (> or =1:32) to TSST-1 and are presumed to be protected from mTSS. These findings also suggest that black women may be more susceptible to mTSS than previously thought.

Published research indicates that regular use of toothpaste containing sodium bicarbonate is effective in reducing volatile sulfur compounds (VSCs) and oral malodor. Gaffar initially reported on the use of sodium bicarbonate as an agent to affect VSCs, indicating that sodium bicarbonate had the potential to alter the VSCs to nonvolatile compounds. Chewing gum would also be suspected of providing benefits in controlling oral malodor through its claimed ability to mechanically aid in the removal of dental plaque. Based on the length of chewing time, the opportunity exists for chewing gum to reach places in the mouth that might be missed during brushing. This activity could contribute to reductions in the amount of viable plaque mass that could produce VSCs.

Nylon bristle end-rounding provides important soft tissue benefits to modern toothbrushes. In these studies, the proportion of acceptably end-rounded bristles have been compared for a new rippled bristle design toothbrush (Crest Complete) and a flat bristle control toothbrush (Oral-B). Toothbrush bristles were examined using a stereomicroscope by a grader blind to brush type and assigned empirical grades of acceptable/unacceptable based upon the Silverstone and Featherstone scale used previously in the literature (1988). Thirty brushes of each type (soft and medium texture brushes obtained from commercial sources) were selected and ten random bristles from five randomly selected tufts were isolated for grading. In both soft and medium texture brushes, bristles in Crest Complete demonstrated 89% acceptable end-rounding. These results were significantly different (p less than 0.0001) from those found for the control toothbrush, where 53 and 51% acceptable end-rounding was observed. These results demonstrate the newly designed rippled bristle brush (Crest Complete) exhibits excellent end-rounding.

Research was conducted among young children to determine whether or not the bitter tasting substance denatonium benzoate added to liquid detergents would effectively reduce the risk that large quantities of such products might be ingested. The research design involved essentially no risk to the young subjects and was approved by an Institutional Review Board prior to initiation. The value of an effective deterrent material is apparent based on the number of reported ingestions of detergent products each year. Denatonium benzoate was chosen as a potential deterrent based on its existing uses in alcohol as a denaturant and in thumb-sucking and nail-biting deterrent products. In the present research, 108 children ranging in age from 18 to 47 months were offered a drink of either a dilute soapy tasting solution or that same solution with denatonium benzoate added. The results showed that for the liquid containing denatonium benzoate, significantly less liquid was ingested, significantly fewer subjects accepted a second taste, and significantly more subjects displayed behavior indicating immediate and intense aversion to the taste of denatonium benzoate. The data indicate that the addition of denatonium benzoate to a liquid detergent would be expected to significantly reduce, but most likely not eliminate, the probability of an accidental ingestion involving multiple swallows by a young child.