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Supplemental Digital Content is Available in the Text., Opioids relieve acute pain, but there is little evidence to support the stability of the benefit over long-term treatment of chronic noncancer pain. Previous systematic reviews consider only group level published data which did not provide adequate detail. Our goal was to use patient-level data to explore the stability of pain, opioid dose, and either physical function or pain interference in patients treated for 12 months with abuse deterrent formulations of oxycodone and hydrocodone. All available studies in the Food and Drug Administration Document Archiving, Reporting, and Regulatory Tracking System were included. Patient-level demographics, baseline data, exposure, and outcomes were harmonized. Individual patient slopes were calculated from a linear model of pain, physical function, and pain interference to determine response over time. Opioid dose was summarized by change between baseline and the final month of observation. Patients with stable or less pain, stable or lower opioid dose, and stable or better physical function (where available) met our prespecified criteria for maintaining long-term benefit from chronic opioids. Of the complete data set of 3192 patients, 1422 (44.5%) maintained their pain level and opioid dose. In a secondary analysis of 985 patients with a measured physical function, 338 (34.3%) maintained their physical function in addition to pain and opioid dose. Of 2040 patients with pain interference measured, 788 (38.6%) met criteria in addition. In a carefully controlled environment, about one-third of patients successfully titrated on opioids to treat chronic noncancer pain demonstrated continued benefit for up to 12 months.

Experimental pain sensitivity was assessed in individuals with urologic chronic pelvic pain syndrome (UCPPS) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. A series of computer-controlled pressure stimuli were delivered to the thumbnail bed, an asymptomatic site distant from the area of UCPPS pain that is considered to be indicative of overall body pain threshold. Stimuli were rated according to a standardized magnitude estimation protocol. Pain sensitivity in participants with UCPPS was compared with healthy controls and a mixed pain group composed of individuals with other chronic overlapping pain conditions, including fibromyalgia, chronic fatigue, and irritable bowel syndromes. Data from 6 participating MAPP testing sites were pooled for analysis. Participants with UCPPS (n = 153) exhibited an intermediate pain sensitivity phenotype: they were less sensitive relative to the mixed pain group (n = 35) but significantly more sensitive than healthy controls (n = 100). Increased pain sensitivity in patients with UCPPS was associated with both higher levels of clinical pain severity and more painful body areas outside the pelvic region. Exploratory analyses in participants with UCPPS revealed that pain sensitivity increased during periods of urologic symptom flare and that less pressure pain sensitivity at baseline was associated with a greater likelihood of subsequent genitourinary pain improvement 1 year later. The finding that individuals with UCPPS demonstrate nonpelvic pain hypersensitivity that is related to clinical symptoms suggests that central nervous system mechanisms of pain amplification contribute to UCPPS.

Ian Kudel,1 Markay Hopps,2 Joseph C Cappelleri,3 Alesia Sadosky,2 Kristen King-Concialdi,1 Ryan Liebert,1 Bruce Parsons,2 Patrick Hlavacek,2 Andrea H Alexander,2 Marco D DiBonaventura,4 John D Markman,5 John T Farrar,6 Brett R Stacey7 1Health Outcomes Practice, Kantar Health, New York, NY, USA; 2Pfizer Inc, New York, NY, USA; 3Pfizer Inc, Groton, CT, USA; 4Pfizer Inc, New York, NY, USA; 5University of Rochester Medical Center School of Medicine and Dentistry, Rochester, NY, USA; 6Department of Biostatistics and Epidemiology University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 7UW Center for Pain Relief, University of Washington, Seattle, WA, USA Background: The aim of this study was to identify the clinical characteristics, treatment usage, and health outcomes of US adults diagnosed with neuropathic pain (NeP) by experienced physicians. Methods: Adults with scores exceeding the threshold for probable NeP (painDETECT ≥19) and diagnosed with NeP by a qualified physician completed a questionnaire that included comorbid conditions, pain symptoms and experiences, medication use, health status (3-level EuroQol 5 Dimensions (EQ-5D-3L]: health utilities index and visual analog scale), pain severity and interference with functioning (Brief Pain Inventory), and work and activity impairment (Work Productivity and Activity Impairment questionnaire). Descriptive analyses were performed for each NeP subtype. Results: Participants (n=295) were predominantly female (64.4%), middle-aged (53.9%), and white (51.5%). Chronic low back pain was the most frequently diagnosed major NeP syndrome (n=166), followed by diabetic peripheral neuropathy (n=58), post-trauma neuropathy (n=47), post-surgical neuropathy (n=28), and central NeP (n=23). An additional 45 participants were diagnosed, but did not meet the criteria for the aforementioned subtypes. Participants could be diagnosed with multiple subtypes. Across each NeP subtype, patients reported high rates of comorbid disease, including arthritis (range: 39.1%–64.3%) and high blood pressure (range: 26.1%–69.0%), as well as symptomology that included numbness (range: 68.1%–91.4%) and changes in muscular strength (range: 24.1%–65.2%). The majority of patients reported back pain (range: 77.8%–95.7%) and arthritis/joint pain (range: 68.1%–78.6%). The most commonly reported types of NeP pain medication were non-steroidal anti-inflammatory drugs (range: 43.1%–70.2%), weak opioids (range: 22.2%–39.3%), and strong opioids (range: 8.7%–28.6%). All six NeP groups generally reported similar levels of dysfunction on all self-report measures. The most notable finding was that the EuroQol-5D-3L health utilities index scores for each of the six groups were lower than the US norms by a clinically important amount. Conclusion: These exploratory findings indicate that patients with NeP across different etiologies are medically complex and experience impaired function across multiple domains. Keywords: activity impairment, functional status, health-related quality of life, neuropathic pain, pain medication use, physician diagnosis, work impairment

A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to focus on research gaps and opportunities on drug development for pancreatitis. This conference was held on July 25, 2018, and structured into 3 working groups (WG): acute pancreatitis (AP) WG, recurrent AP WG, and chronic pancreatitis WG. This article reports the outcome of the work accomplished by the AP WG to provide the natural history, epidemiology, and current management of AP; inform about the role of preclinical models in therapy selection; and discuss clinical trial designs with clinical and patient-reported outcomes to test new therapies.

The lack of effective therapeutic agents specifically tailored for chronic pancreatitis has hampered clinical care and negatively impacted patients’ lives. New mechanistic insights now point to novel therapies, which involve both recently developed and/or repurposed agents. This working group focused on two main outcomes for chronic pancreatitis: pain and progression of disease. The goal is to frame the essential aspects of trial design including patient-centered outcomes, proposed methods to measure the outcomes of pain and progression, and study design considerations for future trials to facilitate rapid drug development for patients with chronic pancreatitis.

PURPOSE: Breast cancer treatments may lead to chronic pain. For some breast cancer survivors (BCS), this experience can develop into the perception of living with chronic pain. The majority of BCS are postmenopausal and have hormone receptor-positive (HR+) breast cancer requiring aromatase inhibitors (Als). Neither the prevalence nor risk factors associated with the perception of living with chronic pain among this population are well defined. METHODS: We conducted a cross-sectional survey among postmenopausal, HR+ BCS who previously took or were currently taking Als. The primary outcome was patients’ perception of living with chronic pain over the past 6 months. We measured pain and demographic and clinical variables. Multivariable logistic regression analysis was performed to evaluate risk factors associated with the perception of chronic pain. RESULTS: Among 1280 participants, 167 (13%) reported having the perception of living with chronic pain before their breast cancer diagnosis; 426 (34%) reported this perception after completion of non-hormonal cancer treatment. Seventy-eight percent of BCSs reported experiencing at least one type of treatment-related pain within the past 7 days, with 23% experiencing at least three types. The most common types of pain were Al-induced musculoskeletal pain (49%) and pain at the surgery or radiation site (31%). Younger age (< 56), BMI > 25, and the perception of living with chronic pain before diagnosis were risk factors associated with the perception of living with chronic pain. CONCLUSIONS: One in three postmenopausal, HR+ BCS considered themselves to be living with chronic pain. Effective interventions to reduce chronic pain are needed.

Summary Background The Physical Function Trial (PFT) was one of seven Testosterone Trials (TTrials), the aim of which was to assess the effect of testosterone on mobility, self-reported physical function, falls, and patient global impression-of-change (PGIC) in older men with low testosterone concentrations, self-reported mobility limitation, and walking speed of less than 1·2 m/s. Using data from the PFT and the overall TTrials study population, we also aimed to identify whether the effect of testosterone on mobility differed according to baseline walking speed, mobility limitation, or other participant-level factors. Methods The TTrials included 790 men aged 65 years or older and with an average of two total testosterone concentrations below 275 ng/dL (9·5 nmol/L), of whom 390 had mobility limitation and a walking speed below 1·2 m/s and were enrolled in the PFT. Participants were assigned (by minimisation method) to 1% testosterone gel or placebo gel daily for 12 months, with participants and study staff masked to intervention allocation. The primary outcome of the PFT was an increase in 6 min walk test (6MWT) distance of 50 m or more. Here we report data for absolute change in 6MWT distance and physical component of Short Form-36 (PF10), and for PGIC and falls. Data are reported for men enrolled in the PFT and those who were not, and for all men in TTrials; data are also reported according to baseline walking speed and mobility limitation. Analyses were done in a modified intention-to-treat population in all patients who were allocated to treatment, had a baseline assessment, and at least one post-intervention assessment. The TTrials are registered with ClinicalTrials.gov , number NCT00799617 . Findings The TTrials took place between April 28, 2011 and June 16, 2014. Of 790 TTrials participants, 395 were allocated to testosterone and 395 to placebo; of the 390 participants enrolled in the PFT, 193 were allocated to testosterone and 197 to placebo. As reported previously, 6MWT distance improved significantly more in the testosterone than in the placebo group among all men in the TTrials, but not in those who were enrolled in the PFT; among TTrials participants not enrolled in the PFT, 6MWT distance improved with a treatment effect of 8·9 m (95% CI 2·2–15·6; p=0·010). As reported previously, PF10 improved more in the testosterone group than in the placebo group in all men in TTrials and in men enrolled in the PFT; among those not enrolled in the PFT, PF10 improved with an effect size of 4·0 (1·5–6·5; p=0·0019). Testosterone-treated men with baseline walking speed of 1·2 m/s or higher had significantly greater improvements in 6MWT distance (treatment effect 14·2 m, 6·5–21·9; p=0·0004) and PF10 (4·9, 2·2–7·7; p=0·0005) than placebo-treated men. Testosterone-treated men reporting mobility limitation showed significantly more improvement in 6MWT distance (7·6 m, 1·0–14·1; p=0·0237) and PF10 (3·6, 1·3–5·9; p=0·0018) than placebo-treated men. Men in the testosterone group were more likely to perceive improvement in their walking ability (PGIC) than men in the placebo group, both for men enrolled in the PFT (effect size 2·21, 1·35–3·63; p=0·0018) and those not enrolled in the PFT (3·01, 1·61–5·63; p=0·0006). Changes in 6MWT distance were significantly associated with changes in testosterone, free testosterone, dihydrotestosterone, and haemoglobin concentrations. Fall frequency during the intervention period was identical in the two treatment groups of the TTrials (103 [27%] of 380 analysed in both groups had at least one fall). Interpretation Testosterone therapy consistently improved self-reported walking ability, modestly improved 6MWT distance (across all TTtrials participants), but did not affect falls. The effect of testosterone on mobility measures were related to baseline gait speed and self-reported mobility limitation, and changes in testosterone and haemoglobin concentrations. Funding US National Institute on Aging and AbbVie.

Purpose Hot flashes are a common and debilitating symptom negatively affecting the quality of life of breast cancer survivors. We sought to compare the short and long term effects of electro-acupuncture (EA) vs. gabapentin for hot flashes among breast cancer survivors. Patients and Methods We conducted a randomized controlled trial of EA vs. gabapentin vs. placebos (sham acupuncture [SA] or placebo medication) in women with breast cancer who had completed primary cancer treatments and experienced bothersome hot flashes twice daily or greater. Acupuncturists performed ten EA/SA treatments over eight weeks using a manualized protocol with 2 Hz electro-stimulation delivered by a TENS unit. Acupuncturists administered SA using Streitberger (non-penetrating) needles at non-traditional acupuncture points without electro-stimulation. Gabapentin (900 mg daily) or placebo medication were continued for eight weeks and then weaned off. The primary endpoint was the hot flash composite score measured by the daily diary at the end of the intervention (Week 8). A secondary endpoint, durability of response, was evaluated at Week 24 from randomization. Longitudinal mixed effects models were used to evaluate change in outcomes over time and group differences. Results Of 120 randomly assigned patients, the mean age was 52.3, 75% were White, 12.5% were peri-menopausal, and 20%/25%/37.5% had natural/surgically/chemically induced menopause, respectively. By Week 8, significant group differences were observed. Mean reduction in hot flash composite scores was greatest in the EA group, followed by SA and gabapentin, with placebo medication having the lowest reduction in hot flashes (-7.4 vs. –5.9 vs. –5.2 vs. –3.4, p=0.0003). By Week 24 and off treatment, reduction in hot flashes in the EA group persisted whereas the hot flashes in the gabapentin group retuned to baseline. The reduction in hot flashes was greatest in the EA group, followed by SA, placebo medication, and gabapentin (-8.5 vs. –6.1 vs. –4.6 vs. –2.8, p=0.0024). No serious adverse events were reported in any groups. The gabapentin group had the highest percentage of participants reporting treatment- related adverse events followed by placebo medication, EA, and SA (48.4% vs. 29.0% vs. 19.3% vs. 3.2%, p=0.004). Conclusion: Electro-acupuncture was more effective than gabapentin, sham acupuncture, or placebo medication in reducing hot flashes for breast cancer survivors both short term and long term with few side effects. Gabapentin produced significant short term reduction in hot flashes that did not persist off medication and was associated with more side effects. Clinical Trial Registration: NCT01005108. Citation Format: Jun J Mao, Sharon X Xie, Marjorie A Bowman, Deborah Bruner, Susan Q Li, Angela DeMichele, John T Farrar. A randomized placebo-controlled trial of acupuncture and gabapentin for hot flashes among breast cancer survivors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD4-7.

Identifying methods to improve assay sensitivity in randomized clinical trials (RCTs) may facilitate the discovery of efficacious pain treatments. RCTs evaluating pain treatments typically use average pain intensity (API) or worst pain intensity (WPI) as the primary efficacy outcome. However, little evidence is available comparing the assay sensitivity of these 2 measures. In this systematic review and meta-analysis, we comprehensively reviewed all low back pain, osteoarthritis pain, fibromyalgia, diabetic peripheral neuropathy pain, and postherpetic neuralgia RCTs that used a parallel group design. Eligibility required: 1) primary RCT report published between 1980 and 2016, 2) comparing 1 or more active, efficacious pharmacologic pain treatment(s) with placebo, and 3) providing data on the standardized effect size (SES) for API as well as WPI for all treatment arms. Twenty-seven active versus placebo comparisons were identified in 23 eligible articles. Using a random-effects meta-analysis, API SES and WPI SES did not differ significantly (difference = −.021, 95% confidence interval = −.047 to .004, P = .12). The findings indicate that, depending on the objectives of the study, either API or WPI could be used as a primary outcome measure in clinical trials for the chronic pain conditions included in this analysis. Perspective Understanding the comparative assay sensitivity of API and WPI may advance pain treatment research. A meta-analysis of trials of efficacious pharmacologic treatments in 5 pain conditions did not show a statistically significant difference between the assay sensitivity of API and WPI.

Objective.The antineutrophil cytoplasmic antibody–associated vasculitides (AAV) are multiorgan diseases. Patients with AAV report impairment in their health-related quality of life (HRQOL) and have different priorities regarding disease assessment compared with physicians. The Outcome Measures in Rheumatology (OMERACT) Vasculitis Working Group previously received endorsement for a core set of domains in AAV. Two approaches to measure patient-reported outcomes (PRO) were presented at OMERACT 2016.Methods.A novel 5-step tool was used to facilitate assessment of the instruments by delegates: the OMERACT Filter 2.0 Instrument Selection Algorithm, with a red-amber-green checklist of questions, including (1) good match with domain (face and content validity), (2) feasibility, (3) do numeric scores make sense (construct validity)?, (4) overall ratings of discrimination, and (5) can individual thresholds of meaning be defined? Delegates gave an overall endorsement. Three generic Patient-Reported Outcomes Measurement Information System (PROMIS) instruments (fatigue, physical functioning, and pain interference) and a disease-specific PRO, the AAV-PRO (6 domains related to symptoms and HRQOL), were presented.Results.OMERACT delegates endorsed the use of the PROMIS instruments for fatigue, physical functioning, and pain interference (87.6% overall endorsement) and the disease-specific AAV-PRO instrument (89.4% overall endorsement).Conclusion.The OMERACT Vasculitis Working Group gained endorsement by OMERACT for use of the PROMIS and the AAV-PRO in clinical trials of vasculitis. These instruments are complementary to each other. The PROMIS and the AAV-PRO need further work to assess their utility in longitudinal settings, including their ability to discriminate between treatments of varying efficacy in the setting of a randomized controlled trial.

Although fatigue, sleep disturbance, depression, and anxiety are associated with pain in breast cancer patients, it is unknown whether acupuncture can decrease these comorbid symptoms in cancer patients with pain. The objective of this study was to evaluate the effect of electroacupuncture (EA) on fatigue, sleep, and psychological distress in breast cancer survivors who experience joint pain related to aromatase inhibitors (AIs).The authors performed a randomized controlled trial of an 8-week course of EA compared with a waitlist control (WLC) group and a sham acupuncture (SA) group in postmenopausal women with breast cancer who self-reported joint pain attributable to AIs. Fatigue, sleep disturbance, anxiety, and depression were measured using the Brief Fatigue Inventory (BFI), the Pittsburgh Sleep Quality Index (PSQI), and the Hospital Anxiety and Depression Scale (HADS). The effects of EA and SA versus WLC on these outcomes were evaluated using mixed-effects models.Of the 67 randomly assigned patients, baseline pain interference was associated with fatigue (Pearson correlation coefficient [r]=0.75; P.001), sleep disturbance (r=0.38; P=.0026), and depression (r=0.58; P.001). Compared with the WLC condition, EA produced significant improvements in fatigue (P=.0095), anxiety (P=.044), and depression (P=.015) and a nonsignificant improvement in sleep disturbance (P=.058) during the 12-week intervention and follow-up period. In contrast, SA did not produce significant reductions in fatigue or anxiety symptoms but did produce a significant improvement in depression compared with the WLC condition (P=.0088).Compared with usual care, EA produced significant improvements in fatigue, anxiety, and depression; whereas SA improved only depression in women experiencing AI-related arthralgia.

Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results. Purpose To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and to determine definitively whether testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions. Methods We present the scientific and clinical rationale for the decisions made in the design of this set of trials. Results We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, common approaches to treatment and monitoring, and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data and safety monitoring board, the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in participant selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary outcomes for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation. Potential limitations Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one participant. Conclusion Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.

Arthralgia is a common and debilitating side-effect experienced by breast cancer patients receiving aromatase inhibitors (AIs) and often results in premature drug discontinuation.We conducted a randomised controlled trial of electro-acupuncture (EA) as compared to waitlist control (WLC) and sham acupuncture (SA) in postmenopausal women with breast cancer who self-reported arthralgia attributable to AIs. Acupuncturists performed 10 EA/SA treatments over 8 weeks using a manualised protocol with 2 Hz electro-stimulation delivered by a TENS unit. Acupuncturists administered SA using Streitberger (non-penetrating) needles at non-traditional acupuncture points without electro-stimulation. The primary end-point was pain severity by Brief Pain Inventory (BPI) between EA and WLC at Week 8; durability of response at Week 12 and comparison of EA to SA were secondary aims.Of the 67 randomly assigned patients, mean reduction in pain severity was greater in the EA group than in the WLC group at Week 8 (-2.2 versus -0.2, p=0.0004) and at Week 12 (-2.4 versus -0.2, p0.0001). Pain-related interference measured by BPI also improved in the EA group compared to the WLC group at both Week 8 (-2.0 versus 0.2, p=0.0006) and Week 12 (-2.1 versus -0.1, p=0.0034). SA produced a magnitude of change in pain severity and pain-related interference at Week 8 (-2.3, -1.5 respectively) and Week 12 (-1.7, -1.3 respectively) similar to that of EA. Participants in both EA and SA groups reported few minor adverse events.Compared to usual care, EA produced clinically important and durable improvement in arthralgia related to AIs in breast cancer patients, and SA had a similar effect. Both EA and SA were safe.

Context: The Testosterone Trials are a coordinated set of seven trials to determine the efficacy of T in symptomatic men ≥65 years old with unequivocally low T levels. Initial results of the Sexual Function Trial showed that T improved sexual activity, sexual desire, and erectile function. Objective: To assess the responsiveness of specific sexual activities to T treatment; to relate hormone changes to changes in sexual function; and to determine predictive baseline characteristics and T threshold for sexual outcomes. Design: A placebo-controlled trial. Setting: Twelve academic medical centers in the United States. Participants: A total of 470 men ≥65 years of age with low libido, average T Methods: Men were assigned to take T gel or placebo for 1 year. Sexual function was assessed by three questionnaires every 3 months: the Psychosexual Daily Questionnaire, the Derogatis Interview for Sexual Function, and the International Index of Erectile Function. Results: Compared with placebo, T administration significantly improved 10 of 12 measures of sexual activity. Incremental increases in total and free T and estradiol levels were associated with improvements in sexual activity and desire, but not erectile function. No threshold T level was observed for any outcome, and none of the 27 baseline characteristics predicted responsiveness to T. Conclusions: In older men with low libido and low T levels, improvements in sexual desire and activity in response to T treatment were related to the magnitude of increases in T and estradiol levels, but there was no clear evidence of a threshold effect.

We examined symptom variability in men and women with urological chronic pelvic pain syndrome. We describe symptom fluctuations as related to early symptom regression and its effect on estimated 1-year symptom change. We also describe a method to quantify patient specific symptom variability.Symptoms were assessed biweekly in 424 subjects with urological chronic pelvic pain syndrome during 1 year. To evaluate the impact of early symptom regression subjects were classified as improved, no change or worse according to the rate of change using 1) all data, 2) excluding week 0 and 3) excluding weeks 0 and 2. Patient specific, time varying variability was calculated at each interval using a sliding window approach. Patients were classified as high, medium or low variability at each time and ultimately as high or low variability overall based on the variability for the majority of contacts.Prior to excluding early weeks to adjust for early symptom regression 25% to 38% and 5% to 6% of patients were classified as improved and worse, respectively. After adjustment the percent of patients who were improved or worse ranged from 15% to 25% and 6% to 9%, respectively. High and low variability phenotypes were each identified in 25% to 30% of participants.Patients with urological chronic pelvic pain syndrome show symptom variability. At study enrollment patients had worse symptoms on average, resulting in a regression effect that influenced the estimated proportion of those who were improved or worse. Prospective studies should include a run-in period to account for regression to the mean and other causes of early symptom regression. Further, symptom variability may be quantified and used to characterize longitudinal symptom profiles of urological chronic pelvic pain syndrome.

Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established.We assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials--the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants.Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups.In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.).

This study examined the experience and coping strategies for taste alteration in female breast cancer patients treated with docetaxel or paclitaxel. A purposive sample of 25 patients currently receiving docetaxel or paclitaxel or within 6 months of having completed treatment was recruited. Semi-structured interviews and patient-level data were utilized for this exploratory descriptive study. Interview data were analyzed with the constant comparative method; patient-level data were abstracted from the electronic medical record. Of all side effects reported from taxanes, the most common was taste alteration (8 of 10 docetaxel patients, 3 of 15 paclitaxel patients). Women that experience taste alteration chose not to eat as much, ate on an irregular schedule, and/or lost interest in preparing meals for themselves and/or their family. Women adopted a variety of new behaviors to deal with the taste alteration and its effects, including trying new recipes, eating strongly flavored foods, honoring specific food cravings, eating candy before meals, cutting food with lemon, drinking sweetened drinks, using plastic eating utensils, drinking from a straw, brushing their teeth and tongue before meals, and using baking soda and salt wash or antibacterial mouthwash. Taste alteration affects breast cancer patients’ lives, and they develop management strategies to deal with the effect. While some self-management strategies can be seen as positively adaptive, the potential for increased caloric consumption and poor eating behaviors associated with some coping strategies may be a cause for concern given the observation of weight gain during breast cancer treatment and association of obesity with poor treatment outcomes in breast cancer patients. Further studies are warranted to determine the overall burden of this symptom and measurement of cancer and non-cancer-related consequences of these behavioral adaptations.

This study explored the self-management strategies utilized by female breast cancer patients to cope with the impact of chemotherapy-induced peripheral neuropathy (CIPN) symptoms. We also examined the variety of taxane-related side effects in women with and without CIPN in order to discriminate the CIPN symptom experience.A purposive sample of 25 patients treated with docetaxel or paclitaxel were recruited, half with and half without CIPN. Semistructured interviews and patient level data were utilized for this exploratory, descriptive study. Interview data were analyzed with the constant comparative method; patient level data were abstracted from the electronic medical record.Participants were aged 24-60 years, were currently receiving chemotherapy or within 6 months of having completed treatment, and 14 had CIPN. CIPN impacted routine activities, functions, and behaviors in the areas of domestic, work, and social/leisure life. Multiple self-management and coping strategies to minimize the impact of CIPN symptoms were reported; the focus was on movement to reduce symptoms, attitude awareness, logistics to simplify demands, and environmental change. Women with and without CIPN were similar in the quantity and type of other reported side effects.CIPN affects breast cancer patients' routine activities, functions, and behaviors, but they develop management strategies to reduce the impact. The management strategies reported in this study suggest breast cancer patients may adopt interventions that focus on exercise, mindfulness, occupational therapy, and environmental planning toward the goal of reducing the impact of CIPN symptoms on their lives.

The prevalence of prehypertension and Stage 1 hypertension continues to increase despite being amenable to non-pharmacologic interventions. Iyengar yoga (IY) has been purported to reduce blood pressure (BP) though evidence from randomized trials is lacking. We conducted a randomized controlled trial to assess the effects of 12 weeks of IY versus enhanced usual care (EUC) (based on individual dietary adjustment) on 24-h ambulatory BP in yoga-naïve adults with untreated prehypertension or Stage 1 hypertension. In total, 26 and 31 subjects in the IY and EUC arms, respectively, completed the study. There were no differences in BP between the groups at 6 and 12 weeks. In the EUC group, 24-h systolic BP (SBP), diastolic BP (DBP) and mean arterial pressure (MAP) significantly decreased by 5, 3 and 3 mmHg, respectively, from baseline at 6 weeks (P< .05), but were no longer significant at 12 weeks. In the IY group, 24 h SBP was reduced by 6 mmHg at 12 weeks compared to baseline (P= .05). 24 h DBP (P< .01) and MAP (P< .05) decreased significantly each by 5 mmHg. No differences were observed in catecholamine or cortisol metabolism to explain the decrease in BP in the IY group at 12 weeks. Twelve weeks of IY produces clinically meaningful improvements in 24 h SBP and DBP. Larger studies are needed to establish the long term efficacy, acceptability, utility and potential mechanisms of IY to control BP.

Background. Arthralgia affects postmenopausal women receiving aromatase inhibitors (AIs) for breast cancer. Given the existing evidence for electroacupuncture (EA) for treatment of osteoarthritis in the general population, this study aims to establish the feasibility of studying EA for treating AI-related arthralgia. Patients and Methods. Postmenopausal women with stage I-III breast cancer who reported AI-related arthral gia were enrolled in a single-arm feasibility trial. EA was provided twice a week for 2 weeks followed by 6 weekly treatments. The protocol was based on Chinese medicine diagnosis of “Bi” syndrome with electrostimulation of needles around the painful joint(s). Pain severity of the modified Brief Pain Inventory was used as the primary outcome. Joint stiffness, joint interference, and Patient Global Impression of Change (PGIC) were secondary outcomes. Paired t tests were used for analysis. Results. Twelve women were enrolled and all provided data for analysis. From baseline to the end of intervention, patients reported reduction in pain severity (from 5.3 to 1.9), stiffness (from 6.9 to 2.4), and joint symptom interference (from 4.7 to 0.8), all P < .001; 11/12 considered joint symptoms “very much better” based on the PGIC. Subjects also reported significant decrease in fatigue (from 4.4 to 1.9, P = .005) and anxiety (from 7.1 to 4.8, P = .01). No infection or development or worsening of lymphedema was observed. Conclusion. Preliminary data establish the feasibility of recruitment and acceptance as well as promising preliminary safety and effectiveness. A randomized controlled trial is warranted to establish the efficacy of EA for AI-related arthralgia in breast cancer survivors.

To determine the efficacy of the food supplement OPC Factor to increase energy levels in healthy adults aged 45 to 65.Randomized, placebo-controlled, triple-blind crossover study.Twenty-five (25) healthy adults recruited from the University of Pennsylvania Health System.OPC Factor,trade mark (AlivenLabs, Lebanon, TN) a food supplement that contains oligomeric proanthocyanidins from grape seeds and pine bark along with other nutrient supplements including vitamins and minerals, was in the form of an effervescent powder. The placebo was similar in appearance and taste.Five outcome measurements were performed: (1) Energy subscale scores of the Activation-Deactivation Adjective Check List (AD ACL); (2) One (1) global question of percent energy change (Global Energy Percent Change); (3) One (1) global question of energy change measured on a Likert scale (Global Energy Scale Change); 4. One (1) global question of percent overall status change (Global Overall Status Percent Change); and (5) One (1) global question of overall status change measured on a Likert scale (Global Overall Status Scale Change).There were no carryover/period effects in the groups randomized to Placebo/Active Product sequence versus Active Product/Placebo sequence. Examination of the AD ACL Energy subscale scores for the Active Product versus Placebo comparison revealed no significant difference in the intention-to-treat (IT) analysis and the treatment received (TR) analysis. However, Global Energy Percent Change (p = 0.06) and Global Energy Scale Change (p = 0.09) both closely approached conventional levels of statistical significance for the active product in the IT analysis. Global Energy Percent Change (p = 0.05) and Global Energy Scale Change (p = 0.04) reached statistical significance in the TR analysis. A cumulative percent responders analysis graph indicated greater response rates for the active product.OPC Factor may increase energy levels in healthy adults aged 45-65 years. A larger study is recommended. Clinical Trials.gov identifier: NCT03318019.

Extensive use of complementary and alternative medicine (CAM) among cancer survivors has been described in literature, but the rate has not previously been compared to other groups in a true population sample.We performed a cross-sectional study using data from the 2002 National Health Interview Survey to determine the prevalence of CAM and prayer for health (PFH) use among cancer survivors and compared the rates of such use among cancer survivors with the US general and other chronic diseased populations while controlling for key socio-demographic factors.Among 31,044 adult survey respondents, 1904 had a prior cancer diagnosis, of whom 40% reported CAM and 62% reported PFH use during the year before the survey. The top three CAM modalities were herbs (20%), deep breathing (14%) and meditation (9%). Controlling for other factors, cancer survivors used more CAM than the general population (adjusted odds ratio [OR] 1.36, 95% confidence interval [CI] 1.20-1.53), but similar to those with chronic symptomatic illness (p=0.5). Cancer survivors used PFH more than the general population (OR 1.87, 95% CI 1.66-2.10) and all other groups (p0.001). The greater CAM and PFH use by cancer survivors was seen in both recent and distant diagnoses (10 years).A previous cancer diagnosis is associated with a modest increase in CAM use compared with the general population but similar to other chronic symptomatic illnesses; however, cancer survivors are more likely to pray for health than all other populations. Exploring CAM and prayer use in clinical settings may help clinicians better understand the needs of their patients.

Objective.Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of linked multisystem life- and organ-threatening diseases. The Outcome Measures in Rheumatology (OMERACT) vasculitis working group has been at the forefront of outcome development in the field and has achieved OMERACT endorsement of a core set of outcomes for AAV. Patients with AAV report as important some manifestations of disease not routinely collected through physician-completed outcome tools; and they rate common manifestations differently from investigators. The core set includes the domain of patient-reported outcomes (PRO). However, PRO currently used in clinical trials of AAV do not fully characterize patients’ perspectives on their burden of disease. The OMERACT vasculitis working group is addressing the unmet needs for PRO in AAV.Methods.Current activities of the working group include (1) evaluating the feasibility and construct validity of instruments within the PROMIS (Patient-Reported Outcome Measurement Information System) to record components of the disease experience among patients with AAV; (2) creating a disease-specific PRO measure for AAV; and (3) applying The International Classification of Functioning, Disability and Health to examine the scope of outcome measures used in AAV.Results.The working group has developed a comprehensive research strategy, organized an investigative team, included patient research partners, obtained peer-reviewed funding, and is using a considerable research infrastructure to complete these interrelated projects to develop evidence-based validated outcome instruments that meet the OMERACT filter of truth, discrimination, and feasibility.Conclusion.The OMERACT vasculitis working group is on schedule to achieve its goals of developing validated PRO for use in clinical trials of AAV.

Purpose Hot flashes are a common and debilitating symptom among survivors of breast cancer. This study aimed at evaluating the effects of electroacupuncture (EA) versus gabapentin (GP) for hot flashes among survivors of breast cancer, with a specific focus on the placebo and nocebo effects. Patients and Methods We conducted a randomized controlled trial involving 120 survivors of breast cancer experiencing bothersome hot flashes twice per day or greater. Participants were randomly assigned to receive 8 weeks of EA or GP once per day with validated placebo controls (sham acupuncture [SA] or placebo pills [PPs]). The primary end point was change in the hot flash composite score (HFCS) between SA and PP at week 8, with secondary end points including group comparisons and additional evaluation at week 24 for durability of treatment effects. Results By week 8, SA produced significantly greater reduction in HFCS than did PP (−2.39; 95% CI, −4.60 to −0.17). Among all treatment groups, the mean reduction in HFCS was greatest in the EA group, followed by SA, GP, and PP (−7.4 v −5.9 v −5.2 v −3.4; P = < .001). The pill groups had more treatment-related adverse events than did the acupuncture groups: GP (39.3%), PP (20.0%), EA (16.7%), and SA (3.1%), with P = .005. By week 24, HFCS reduction was greatest in the EA group, followed by SA, PP, and GP (−8.5 v −6.1 v −4.6 v −2.8; P = .002). Conclusion Acupuncture produced larger placebo and smaller nocebo effects than did pills for the treatment of hot flashes. EA may be more effective than GP, with fewer adverse effects for managing hot flashes among breast cancer survivors; however, these preliminary findings need to be confirmed in larger randomized controlled trials with long-term follow-up.

Use of prescription nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) increases the risk of serious upper gastrointestinal toxicity. Less is known about over-the-counter (OTC) NANSAIDs, which are typically used at lower doses and for shorter durations. This study assessed the risk of toxicity with OTC NANSAIDs.A total of 359 case subjects hospitalized for upper gastrointestinal bleeding, perforation, or benign gastric outlet obstruction were recruited from 28 hospitals. A total of 1889 control subjects were recruited by random digit dialing from the same region. Data on medication use were collected via structured telephone interview.Use of OTC NANSAIDs onor = 4 days during the most recent week had an adjusted odds ratio (OR) of 1.83 (95% confidence interval [CI], 1.14-2.95). Use of high-dose OTC NANSAIDs during the index week had an adjusted OR of 5.21 (95% CI, 2.32-11.69). In contrast, use of OTC NANSAIDs4 times during the index week (adjusted OR, 0.67; 95% CI, 0.43-1.06) and use of very low doses of prescription or OTC NANSAIDs during the index week (adjusted OR, 0.74; 95% CI, 0.49-1.12) were not significantly associated with an increased risk of serious gastrointestinal toxicity. We did not observe a significant difference between the risk of toxicity with OTC naproxen versus OTC ibuprofen (adjusted OR, 0.84; 95% CI, 0.26-2.70).Use of OTC NANSAIDs at recommended doses has a relatively good safety profile compared with prescription NANSAIDs. However, use of high-dose OTC NANSAIDs (comparable to a prescription dose) is associated with serious gastrointestinal toxicity.

Objectives: To examine adherence to validated quality indicators assessing the quality of allopurinol use in the treatment of gout and asymptomatic hyperuricaemia. Methods. We determined physician adherence in the UK General Practice Research Database (GPRD) to three validated quality indicators developed to assess the quality of allopurinol prescribing practices. These indicators were developed to assess: (i) dosing in renal impairment; (ii) concomitant use with azathioprine or 6-mercaptopurine; and (iii) use in the treatment of asymptomatic hyperuricaemia. We also examined the association of patient-level factors (sociodemographics, comorbidity, follow-up duration and concomitant medicine use) with the treatment of asymptomatic hyperuricaemia using multivariable logistic regression. Results. Of the 63 105 gout patients, 185 (0.3%) were eligible for Quality Indicator 1 and 52 (0.1%) were eligible for Quality Indicator 2. There were an additional 471 patients with asymptomatic hyperuricaemia eligible for Quality Indicator 3. Rates of practice deviation for the three individual quality indicators ranged from 25 to 57%. Male sex, older age, a history of chronic renal failure, and a greater number of concomitant medications were significantly associated with increased odds of inappropriate treatment for asymptomatic hyperuricaemia. Hypertension and diuretic use were associated with lower odds of this practice. Conclusions. One-quarter to one-half of all patients eligible for at least one of the validated quality of care indicators were subject to possible allopurinol prescribing error, suggesting that inappropriate prescribing practices are widespread with this agent. Future interventions aimed at reducing inappropriate allopurinol use are needed and should be targeted towards high-risk groups, including older men and those receiving multiple concomitant medications.

Objective: To examine the epidemiology of gout and gout treatment in the United Kingdom using a large national practice based population. Methods: Data from the UK General Practice Research Database from 1990 to 1999 were examined. Physician diagnoses and drug codes were used, and trends in gout incidence and treatment examined. Additionally, disease prevalence for the year 1999 was assessed. To examine the association of gout with comorbid disease, the prevalence of select health conditions and drug use was compared with the corresponding prevalences seen in osteoarthritis, adjusting for both age and sex. Results: From 1 January 1990 to 31 December 1999 overall gout incidence remained relatively stable, ranging from a low of 11.9 cases (95% confidence interval (CI) 11.5 to 12.3) in 1991 to a high of 18.0 cases (95% CI 17.6 to 18.4) per 10 000 patient-years in 1994. Gout prevalence in 1999 was 1.4% with rates approaching 7% in men over the age of 65. Drugs used for the treatment of gout remained constant in prevalent cases with the exception of a significant decline in non-steroidal anti-inflammatory drug use over the 10 year follow up. Compared with patients with osteoarthritis, patients with gout were significantly more likely to have cardiovascular disease, hypertension, diabetes, and chronic renal failure, and were more likely to have used diuretics or ciclosporin, or both. Conclusion: Although gout is common in the UK, particularly among older men, the incidence of the disease seems to have remained stable during the 1990s.

Objective Little is known about risk factors that increase the risk of development of opioid side effects. Our objective was to evaluate the effect of the type of opioid, age, gender, and race on the incidence of side effects from short-term opioid use. Methods A secondary analysis of a retrospective cohort study in 35 community-based and tertiary hospitals was done. There were 8855 black or white subjects aged 16 years and older. Patients received meperidine (INN, pethidine), morphine, or fentanyl as part of their treatment. Measurements were made to assess the presence of nausea and vomiting and respiratory depression. Results Of the patients, 26% had nausea and vomiting and 1.5% had respiratory depression after opioid administration. After adjustment for opioid dose, route of administration, age, gender, and race, meperidine produced less nausea and vomiting (odds ratio [OR] = 0.7; 95% confidence interval [CI], 0.5-0.8) and less respiratory depression (OR = 0.6; 95% CI, 0.2-0.9) than morphine. The risk of respiratory depression increased with age. Compared with patients aged between 16 and 45 years, those aged between 61 and 70 years had 2.8 times the risk of development of respiratory depression (95% CI, 1.2-6.6); those aged between 71 and 80 years had 5.4 times the risk (95% CI, 2.4-11.8); and those aged older than 80 years had 8.7 times the risk (95% CI, 3.8-20.0). Men had less nausea and vomiting than women (OR = 0.5; 95% CI, 0.4-0.6). White subjects had more nausea and vomiting than black subjects (OR = 1.4; 95% CI, 1.1-1.7). Conclusions Meperidine produced fewer side effects than morphine during short-term use. The risk of respiratory depression increases substantially after 60 years of age. Women have nausea and vomiting more often than men. The effect of race deserves further investigation. Clinical Pharmacology & Therapeutics (2003) 74, 102–112; doi: 10.1016/S0009-9236(03)00152-8

Importance In one-third of older men with anemia, no recognized cause can be found. Objective To determine if testosterone treatment of men 65 years or older with unequivocally low testosterone levels and unexplained anemia would increase their hemoglobin concentration. Design, Setting, and Participants A double-blinded, placebo-controlled trial with treatment allocation by minimization using 788 men 65 years or older who have average testosterone levels of less than 275 ng/dL. Of 788 participants, 126 were anemic (hemoglobin ≤12.7 g/dL), 62 of whom had no known cause. The trial was conducted in 12 academic medical centers in the United States from June 2010 to June 2014. Interventions Testosterone gel, the dose adjusted to maintain the testosterone levels normal for young men, or placebo gel for 12 months. Main Outcomes and Measures The percent of men with unexplained anemia whose hemoglobin levels increased by 1.0 g/dL or more in response to testosterone compared with placebo. The statistical analysis was intent-to-treat by a logistic mixed effects model adjusted for balancing factors. Results The men had a mean age of 74.8 years and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 30.7; 84.9% were white. Testosterone treatment resulted in a greater percentage of men with unexplained anemia whose month 12 hemoglobin levels had increased by 1.0 g/dL or more over baseline (54%) than did placebo (15%) (adjusted OR, 31.5; 95% CI, 3.7-277.8; P = .002) and a greater percentage of men who at month 12 were no longer anemic (58.3%) compared with placebo (22.2%) (adjusted OR, 17.0; 95% CI, 2.8-104.0; P = .002). Testosterone treatment also resulted in a greater percentage of men with anemia of known cause whose month 12 hemoglobin levels had increased by 1.0 g/dL or more (52%) than did placebo (19%) (adjusted OR, 8.2; 95% CI, 2.1-31.9; P = .003). Testosterone treatment resulted in a hemoglobin concentration of more than 17.5 g/dL in 6 men who had not been anemic at baseline. Conclusions and Relevance Among older men with low testosterone levels, testosterone treatment significantly increased the hemoglobin levels of those with unexplained anemia as well as those with anemia from known causes. These increases may be of clinical value, as suggested by the magnitude of the changes and the correction of anemia in most men, but the overall health benefits remain to be established. Measurement of testosterone levels might be considered in men 65 years or older who have unexplained anemia and symptoms of low testosterone levels. Trial Registration clinicaltrials.gov Identifier:NCT00799617

Importance Most cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions. Objective To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI). Design, Setting, and Participants The Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014. Interventions Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year. Main Outcomes and Measures The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to −26), executive function (Trail-Making Test B minus A; range, −290 to 290), and spatial ability (Card Rotation Test; score range, −80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months. Results Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, −0.07 [95% CI, −0.92 to 0.79];P = .88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (−0.28 [95% CI, −0.76 to 0.19];P = .24), executive function (−5.51 [95% CI, −12.91 to 1.88];P = .14), or spatial ability (−0.12 [95% CI, −1.89 to 1.65];P = .89). Conclusions and Relevance Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions. Trial Registration clinicaltrials.gov Identifier:NCT00799617

The prevalence of sexual dysfunction, low vitality, and poor physical function increases with aging, as does the prevalence of low total and free testosterone (TT and FT) levels. However, the relationship between sex hormones and age-related alterations in older men is not clear.To test the hypotheses that baseline serum TT, FT, estradiol (E2), and sex hormone-binding globulin (SHBG) levels are independently associated with sexual function, vitality, and physical function in older symptomatic men with low testosterone levels participating in the Testosterone Trials (TTrials).Cross-sectional study of baseline measures in the TTrials.The study was conducted at 12 sites in the United States.The 788 TTrials participants were ≥ 65 years and had evidence of sexual dysfunction, diminished vitality, and/or mobility disability, and an average of two TT275 ng/dL.None.Question 4 of Psychosocial Daily Questionnaire (PDQ-Q4), the FACIT-Fatigue Scale, and the 6-minute walk test.Baseline serum TT and FT, but not E2 or SHBG levels had small, but statistically significant associations with validated measures of sexual desire, erectile function, and sexual activity. None of these hormones was significantly associated within or across trials with FACIT-Fatigue, PHQ-9 Depression or Physical Function-10 scores, or gait speed.FT and TT levels were consistently, independently, and positively associated, albeit to a small degree, with measures of sexual desire, erectile function, and sexual activity, but not with measures of vitality or physical function in symptomatic older men with low T who qualified for the TTrials.

© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.Background. We describe the recruitment of men for The Testosterone (T) Trials, which were designed to determine the efficacy of T treatment. Methods. Men were eligible if they were ≥65 years, had an average of two morning total T values 300 ng/mL, and had symptoms and objective evidence of mobility limitation, sexual dysfunction, and/or low vitality. Men had to be eligible for and enroll in at least one of these three main trials (physical function, sexual function, vitality). Results. Men were recruited primarily through mass mailings in 12 U.S. communities: 82% of men who contacted the sites did so in response to mailings. Men who responded were screened by telephone to ascertain eligibility. Of 51,085 telephone screens, 53.5% were eligible for further screening. Of 23,889 initial screening visits (SV1), 2,781 (11.6%) men were eligible for the second screening visit (SV2), which 2,261 (81.3%) completed. At SV2, 931 (41.2%) men met the criteria for one or more trials, the T level criterion and had no other exclusions. Of these, 790 (84.6%) were randomized; 99 (12.5%) in all three trials and 348 (44%) in two trials. Their mean age was 72 years and mean body mass index (BMI) was 31.0 kg/m2. Mean (standard deviation) total T (ng/dL) was 212.0 (40.0). Conclusion: Despite the telephone screening to enrollment ratio of 65 to 1, we met the recruitment goals for each trial. Recruitment of symptomatic older men with low testosterone levels is difficult but feasible.

The millennium provides an opportunity to contemplate and review the recent past and to plan for the future. The last half century, in particular, has been the golden age of gastroenterology, wherein rigorous, scientifically based medicine has revolutionized gastrointestinal diagnosis and therapy. The technologic fantasy and science fiction of 50 years ago has become the real and commonplace. The peptic ulcer that was treated by the Sippy meal, gastric freezing, or gastric radiation 50 years ago is now treated by scientifically based pharmacotherapy, including potent proton-pump inhibitors and antimicrobial therapy. The cecal adenoma that required inpatient laparotomy and colotomy for polypectomy 30 years ago is now simply removed by ambulatory colonoscopic polypectomy. The surgical gastrostomy for long-term enteral feeding of 20 years ago is replaced by percutaneous endoscopic gastrostomy. The awkward, painful, and sometimes dangerous semiflexible endoscope of 42 years ago has been replaced by the simple, convenient, and safe flexible endoscope. The word abdomen is derived from the Latin abdere , meaning hidden or concealed. 62 The flexible endoscope, the computed tomography (CT) scan, and the abdominal ultrasound study have opened this previously inaccessible organ to observation and inspection by the gastroenterologist, radiologist, and surgeon without surgery. The surgeon's knife has become the endoscopist's papillotome, and the laparotomy has become a laparoscopy. The diagnostic laparotomy has become nearly obsolete. The excitement at novel discoveries yields to complacency with time as the inconceivable becomes ubiquitous. Yet what human endeavor has contributed more to the betterment of humanity than medicine? For example, one simple gastroenterologic therapy—oral rehydration with glucose and electrolyte solution—has saved millions of lives per year worldwide from cholera. This revolution was accomplished not by the sword but by the pencil, not by rhetoric but by statistics, and not by climbing the ramparts but by toiling in the laboratory and clinic. This revolution is largely undocumented, unrecognized, and unpraised. The furious pace of magnificent discovery and invention and the preoccupation of the discoverers and inventors with discovery and invention have left little time for writing a history. A gastroenterologic history provides manifold salutary effects. First, individuals who toiled, created, and invented receive overdue and well-deserved recognition. Second, a history provides role models to the initiate or student in gastroenterology. Third, a historical perspective provides the discipline an identity, purpose, and mission. Fourth, a history collates, categorizes, and clarifies the important issues in gastroenterology. An historical perspective helps outline important ongoing areas of controversy and research interest and suggests strategies, approaches, and techniques for further research. Fifth, a history that celebrates great past gastroenterologic achievements may cause legislators to reconsider draconian cutbacks in funding future worthy projects. A contemporaneous history is most meaningful because a contemporary can evaluate the impact of changes, with knowledge of past and present. Immediacy provides impact. This article is included in this issue of the Gastroenterology Clinics in honor of the millennium. To provide a proper perspective, Cappell asked several senior luminaries to vote as a committee on the 50 great landmarks during the past 50 years. The vote revealed surprising concordance, with the largest discrepancy being a difference in six of the selected landmarks. The importance and history of each landmark discovery is discussed to provide an appropriate vehicle for a brief modern history of gastroenterology. The first part of this historical essay, which discussed endoscopic, radiologic, and surgical techniques and upper gastrointestinal disorders, was presented in the March 2000 issue of the Gastroenterology Clinics . This second part completes the historical essay.

During the last half century, many outstanding discoverers have revolutionized the clinical practice and science of gastroenterology. Whereas the scientific results are widely disseminated, the discoverers have received inadequate recognition, and the history of their discoveries is poorly known. At the millennium, a committee selected the 50 landmark discoveries in gastroenterology during the past 50 years. A brief history of each landmark discovery is presented. Part I presents the landmark discoveries in gastrointestinal (GI) procedures and in upper GI disorders. Part II of this presentation, which covers landmark discoveries in other areas of gastroenterology, will publish in Part II of the volume on High Risk Gastrointestinal Bleeding.

To determine the incidence of dose-limiting (DL) chemotherapy-induced peripheral neuropathy (CIPN) events in clinical practice.This retrospective cohort study included 488 women who received docetaxel or paclitaxel. The primary outcome was a DL event (dose delay, dose reduction, or treatment discontinuation) attributed to CIPN (DL CIPN). The paired t test was used to test the difference in received cumulative dose and planned cumulative dose by dose reduction and treatment discontinuation status.A total of 150 unique DL events occurred in 120 women (24.6%). More than one third (37.3%; n=56) of the events were attributed to CIPN. The 56 DL CIPN events occurred in 50 women (10.2%). DL CIPN incidence differed significantly by agent (docetaxel, 2.4%; n=five of 209; paclitaxel, 16.1%; n=45 of 279; P.001). DL CIPN occurred in 24.5% and 14.4% of women who received paclitaxel 80 mg/m2 weekly for 12 cycles and 175 mg/m2 biweekly for four cycles, respectively (adjusted odds ratio, 2.11; 95% CI, 0.97 to 4.60; P=.06). The cumulative dose actually received was significantly lower than the planned cumulative dose among women who had a dose reduction or treatment termination attributed to CIPN (9.4% less; P.001 and 28.4% less; P.001, respectively).Oncologists limited the dosing of chemotherapy because of CIPN in a significant proportion of paclitaxel recipients, most frequently in those who received a weekly regimen. Patients who had their dose reduced or discontinued received significantly less cumulative chemotherapy than planned. The implications of these DL CIPN events on treatment outcomes must be investigated.

Objective: Our objective was to identify patient, study, and site factors associated with assay sensitivity in placebo-controlled neuropathic pain trials. Methods: We examined the associations between study characteristics and standardized effect size (SES) in a database of 200 publicly available randomized clinical trials of pharmacologic treatments for neuropathic pain. Results: There was considerable heterogeneity in the SESs among the examined trials. Univariate meta-regression analyses indicated that larger SESs were significantly associated with trials that had 1) greater minimum baseline pain inclusion criteria, 2) greater mean subject age, 3) a larger percentage of Caucasian subjects, and 4) a smaller total number of subjects. In a multiple meta-regression analysis, the associations between SES and minimum baseline pain inclusion criterion and age remained significant. Conclusions: Our analyses have examined potentially modifiable correlates of study SES and shown that a minimum pain inclusion criterion of 40 or above on a 0 to 100 scale is associated with a larger SES. These data provide a foundation for investigating strategies to improve assay sensitivity and thereby decrease the likelihood of falsely negative outcomes in clinical trials of efficacious treatments for neuropathic pain.

Objective: The purpose of this study was to determine if the opioid risk tool (ORT) was clinically useful in guiding physician decision making during chronic opioid therapy and to determine whether there were differences between the patientcompleted and physician-completed ORT. Design: Retrospective review of prospectively collected data. Setting: A single-center tertiary care outpatient pain management center. Patients, participants: One-hundred twenty-five patients who received chronic opioids as part of their pain therapy. Interventions: Patients receiving care were asked to complete the ORT as part of their initial evaluation. In addition, as part of this study, a pain physician reviewed the information available at the time of the initial evaluation and completed the ORT. Medical records were reviewed for evidence of moderate-to-severe aberrant drug-related behavior (ADRB), according to specified criteria. Main outcome measures: Patient-completed and physician-completed ORT and presence or absence of moderate to severe ADRB. Results: Of the 125 patients included in this study, physician-completed ORT was available for 125 patients, and a patient-completed ORT was available on 87 of these patients. There was good correlation between the patient-completed and physician-completed ORT (correlation coefficient = 0.61). There were 112 observations of ADRB in 53 of 125 patients (42.4 percent) during the observation period of an average of 7.8 months (range 2-17 months). Of these 53 patients, 32 (60.4 percent) were identified by urine drug screen (UDS) alone, 7 (13.2 percent) were identified by physician observation alone, and 14 (26.4 percent) were identified by both UDS and physician observation. Based on the physician-completed ORT, 41 of 106 (38.7 percent) low risk patients had ADRB, compared to 8 of 14 (57.1 percent) moderate risk, and 4 of 5 (80 percent) high risk patients. Conclusions: Neither the patient-completed nor the physician-completed ORT was strongly predictive of moderate-to-severe ADRB in patients receiving chronic opioid therapy for the treatment of noncancer pain in our pain center. Keywords: aberrant drug-related behavior, opioid risk tool, risk assessment tools DOI:10.5055/jom.2013.0159

Currently, no consensus has been reached regarding the management of hyperlipidemia in patients who develop statin-associated myalgia (SAM). Many statin-intolerant patients use alternative lipid-lowering therapies, including red yeast rice. The present trial evaluated the tolerability of red yeast rice versus pravastatin in patients unable to tolerate other statins because of myalgia. The study was conducted in a community-based setting in Philadelphia, Pennsylvania. A total of 43 adults with dyslipidemia and a history of statin discontinuation because of myalgia were randomly assigned to red yeast rice 2,400 mg twice daily or pravastatin 20 mg twice daily for 12 weeks. All subjects were concomitantly enrolled in a 12-week therapeutic lifestyle change program. The primary outcomes included the incidence of treatment discontinuation because of myalgia and a daily pain severity score. The secondary outcomes were muscle strength and plasma lipids. The incidence of withdrawal from medication owing to myalgia was 5% (1 of 21) in the red yeast rice group and 9% (2 of 22) in the pravastatin group (p = 0.99). The mean pain severity did not differ significantly between the 2 groups. No difference was found in muscle strength between the 2 groups at week 4 (p = 0.61), week 8 (p = 0.81), or week 12 (p = 0.82). The low-density lipoprotein cholesterol level decreased 30% in the red yeast rice group and 27% in the pravastatin group. In conclusion, red yeast rice was tolerated as well as pravastatin and achieved a comparable reduction of low-density lipoprotein cholesterol in a population previously intolerant to statins.

BACKGROUND: Arthralgia is common in postmenopausal breast cancer survivors (BCS) who are receiving aromatase inhibitors (AIs). The objective of this study was to evaluate the perceived onset, characteristics, and risk factors for AI-related arthralgia (AIA). METHODS: In a cross-sectional survey of postmenopausal BCS who were receiving adjuvant AI therapy at a university-based oncology clinic, patient-reported attribution of AIs as a cause of joint pain was used as the primary outcome. Multivariate logistic regression analyses were performed to evaluate risk factors. RESULTS: Among 300 survey respondents, 139 (47%) attributed AI as a cause of their current arthralgia. Of those patients, 74% recognized the onset of AIA within 3 months of starting medication, and 67% rated joint pain as moderate or severe in the previous 7 days. In multivariate logistic regression analyses, the time since last menstrual period (LMP) was the only significant predictor of AIA. Controlling for covariates, the women who had their LMP within 5 years had the highest probability of reporting AIA (73%), whereas those who had their LMP ≥10 years previously had the lowest probability of reporting AIA (35%; adjusted odds radio, 3.39; 95% confidence interval, 1.21-9.44; P = .02). Wrists/hands, ankles/feet, elbows, and knees appeared to be associated more strongly with AI-related symptoms than non-AI–related joint symptoms (all P < .01). CONCLUSIONS: AIA was common, began within the first 3 months of therapy in most patients, and appeared to be related inversely to the length of time since cessation of menstrual function. These findings suggest that estrogen withdrawal may play a role in the mechanism of this disorder. Cancer 2009. © 2009 American Cancer Society.

Objective Serotonin release from platelets is important for regulating hemostasis. Some prior studies suggest an association between use of selective serotonin reuptake inhibitors and gastrointestinal bleeding and a possible synergistic effect of these medications with non-steroidal anti-inflammatory drugs (NSAIDs). This study examined the effect of medications that inhibit serotonin uptake on upper gastrointestinal toxicity. Methods 359 case subjects hospitalized for upper gastrointestinal bleeding, perforation, or benign gastric outlet obstruction were recruited from 28 hospitals. 1889 control subjects were recruited by random digit dialing from the same region. Data were collected during structured telephone interviews. Antidepressant medications were characterized according to their affinity for serotonin receptors. Exposure to medications required use on at least 1 day during the week prior to the index date. Results Any moderate or high affinity serotonin reuptake inhibitor (MHA-SRI) use was reported by 61 cases (17.1%) and 197 controls (10.4%). After adjusting for potential confounders, MHA-SRI use was associated with a significantly increased odds of hospitalization for upper gastrointestinal toxicity (adjusted OR = 2.0, 95%CI 1.4–3.0). A dose–response relationship in terms of affinity for serotonin uptake receptors was not observed (p = 0.17). No statistical interaction was observed for use of high dose NSAIDs or aspirin concomitantly with MHA-SRIs (p = 0.5). When MHA-SRIs were used concomitantly with high dose NSAIDs, the adjusted odds ratio for the association with upper gastrointestinal toxicity was 3.5 (95%CI 1.9–6.6). Conclusions Use of MHA-SRIs is associated with an increased risk of hospitalization for upper gastrointestinal toxicity. Copyright © 2008 John Wiley & Sons, Ltd.

Background: Previous research among specific cancer populations has shown high but variable symptom burden; however, very little is known about its extent and pattern among the entire population of US cancer survivors, which is more clinically relevant to primary care physicians. Methods: To determine the prevalence of ongoing symptom burden among cancer survivors and compare it with the general population without cancer, we analyzed data from the 2002 National Health Interview Survey, which included 1,904 cancer survivors and 29,092 controls. Main outcome measures included self-reported ongoing pain, psychological distress, and insomnia. Multivariate logistic regression models were used to adjust for confounders and test for interactions. Results: The rates of ongoing pain, psychological distress, and insomnia among cancer survivors were 34%, 26%, and 30%, respectively, and were significantly higher (all P < .001) than controls without a history of cancer (18%, 16%, and 17%). Compared with controls in the same age groups, younger survivors (younger than 50) were much more likely to report ongoing symptoms than older survivors (older than 64); adjusted odds ratios were 2.96 and 1.36 for pain in the respective age groups (P < .001). Comorbidities also interact with cancer status and contribute to a marked increase in reports of ongoing symptom burden among cancer survivors, with a greater number of comorbidities leading to greater degree of symptom burden in a dose-dependent manner (P < .001). Conclusions: The symptom burden among cancer survivors on a population level is substantial and can be impacted by other comorbidities. Thus, engaging primary care physicians in the design, testing, and implementation of effective interventions is important to reduce the symptom burden among cancer survivors. (J Am Board Fam Med 2007;20:434‐443.)

Objective: To study the safety and efficacy of a cholinesterase inhibitor, donepezil hydrochloride, for the treatment of dementia in Parkinson's disease (PD). Methods: This was a randomised double blind, placebo controlled, crossover study in 22 subjects with PD and dementia. Participants were randomised to receive either donepezil followed by identical placebo, or placebo followed by donepezil. Donepezil was administered at 5–10 mg/day. Treatment periods were 10 weeks with a washout period of 6 weeks between the two periods. The primary outcome measure was the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAScog). Results: Donepezil was well tolerated and most adverse events were mild. There was no worsening of PD symptoms as measured by the total or motor sections of the Unified Parkinson's Disease Rating Scale. There was a 1.9 point trend toward better scores on the ADAScog on treatment compared with placebo that was not statistically significant. The secondary cognitive measures showed a statistically significant 2 point benefit on the Mini Mental Status Examination and no change on the Mattis Dementia Rating Scale (MDRS). The Clinical Global Impression of Change (CGI) showed a significant 0.37 point improvement on donepezil. No improvement was observed on the MDRS or the Brief Psychiatric Rating Scale. Carryover between treatment periods was observed but was not statistically significant. Conclusions: Donepezil was well tolerated and did not worsen PD. There may be a modest benefit on aspects of cognitive function. The possible clinical benefit measured by CGI was reflected in only one of the cognitive scales used in this study.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause peptic ulcer disease and upper GI bleeding. Acid suppression medications effectively treat NSAID-induced ulcers. However, it is unknown what effect the availability of proton pump inhibitors and over-the-counter preparations of NSAIDs and histamine type 2 receptor antagonists have had on population rates of hospitalization and mortality from GI toxicity. This study examines trends in hospitalization and mortality rates from GI toxicity during the 1990s.We performed an analysis of secular trends of hospitalization and mortality rates from peptic ulcer disease, upper GI bleeding, and any GI bleeding using data from the National Hospital Discharge Survey, comparing them with sales of NSAIDs, aspirin, and acid suppression medications from 1992 to 1999.From 1992 to 1999, annual rates of hospitalization and mortality per 100,000 population for peptic ulcer disease declined from 205 to 165 and 7.7 to 6.0, respectively; calendar year was negatively correlated with both peptic ulcer disease hospitalization rates (p = -0.88, p = 0.007) and mortality rates (p = -0.71, p = 0.058). In contrast, these correlations did not reach statistical significance for upper or any GI bleeding (p0.1 for all comparisons). Sales of acid suppression medications were negatively correlated with peptic ulcer disease hospitalization rates (p = -0.76, p = 0.037) and mortality rates (p = -0.83, p = 0.015). Sales of NSAIDs were not positively correlated with hospitalization or mortality rates from peptic ulcer disease or GI bleeding (p0.2 for all comparisons).Despite changing patterns of use of NSAIDs and acid suppression medications during the 1990s, mortality rates from GI bleeding and peptic ulcer disease have been relatively stable, with an apparent decline in hospitalization rates and mortality from peptic ulcer disease. Changing rates of peptic ulcer disease morbidity and mortality were temporally related to increasing sales of antiulcerants but not to change in sales of NSAIDs.

Acute renal failure has been associated with parenteral ketorolac tromethamine, but the risk that is associated with this therapy has not been quantified.To compare the risk for acute renal failure associated with ketorolac with that associated with opioids.Retrospective cohort study.35 hospitals in or near Philadelphia.Patients receiving 10,219 courses of parenteral ketorolac and patients receiving 10,145 courses of parenteral opioids.Acute renal failure was defined by 1) an increase in the serum creatinine concentration of 50% or more and 2) either an absolute increase of 44.2 mumol/L or more for concentrations that were less than 132.6 mumol/L at baseline or an absolute increase of 88.4 mumol/L or more for concentrations that were 132.6 mumol/L or more at baseline. In addition, a secondary definition required a diagnosis by a physician.The overall incidence of acute renal failure was 1.1% after therapy with either ketorolac or opioids. Multivariate-adjusted rate ratios comparing ketorolac with opioids for acute renal failure were 1.09 (95% CI, 0.83 to 1.42) overall, 1.00 (CI, 0.76 to 1.33) for less than 5 days of therapy, and 2.08 (CI, 1.08 to 4.00; P = 0.03) for more than 5 days of therapy. Similar results were obtained when the secondary definition of acute renal failure was used.Overall, acute renal failure was uncommon in this hospitalized population. Compared with opioids, ketorolac administered for 5 days or less did not increase the rate of renal failure. However, among patients who were treated with analgesics for more than 5 days, ketorolac may be associated with an elevated rate of acute renal failure.

6560 Background: Chemotherapy induced peripheral neuropathy (CIPN) is a potentially dose-limiting toxicity. Recent data from early stage breast cancer clinical trials has suggested that black women are at increased risk for CIPN. We examined whether black race was a risk factor for dose-limiting CIPN events in a general academic practice. Methods: This retrospective cohort study included 260 women, (27.3% black) that received neoadjuvant or adjuvant paclitaxel for non-metastatic breast cancer. The primary outcome was a dose-limiting (DL) event (dose delay, dose reduction, or treatment discontinuation) attributed to CIPN (DL-CIPN). Cox proportional hazards models were used to analyze patient level and treatment level factors related to DL-CIPN. Survival time was represented by cumulative dose in milligrams of paclitaxel received. The final model included independent risk factors (p2 weekly for 12 cycles vs. 175mg/m2 bi-weekly for 4 cycles) the risk of DL-CIPN for blacks compared to whites was HR=3.35 (95%CI=1.54-7.28). Conclusions: Our findings contribute to the growing body of evidence that black race is associated with CIPN symptom onset and severity. Efforts to elucidate mechanisms, increase clinicians’ awareness of the greater susceptibility of black women to CIPN, and the development of symptom management strategies, effective in ensuring adequate adherence to chemotherapy, are crucial.