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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
June 24, 2017

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The Placebo Effect in RLS: A Real Phenomenon?
Does Chronic Fatigue Syndrome Persist During Adolescence?
Are Special Diets Useful for Autism?
For Isolated Urticaria, Skip the Steroids
Managing Low Bone Density and Osteoporosis
Chronic Pain Might Hasten Cognitive Decline in Older Adults
Risk for Breast and Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers:
   Refining Our Estimates
Are Proton-Pump Inhibitors Associated with Chronic Kidney Disease?
Lower Education Level Is Associated with Higher Risk for Cardiovascular Disease

Neurology 2017 Jun 06; 88:2216
The Placebo Effect in RLS: A Real Phenomenon?
Both positive and adverse effects can occur with placebo in restless legs syndrome.
Restless legs syndrome (RLS) is associated with an urge to move the legs at night that is worse at rest and better with movement. To assess the placebo and nocebo responses in RLS, researchers reviewed data on 5046 participants (average age, 54 years; 62% female) from 85 randomized, double-blind, placebo-controlled trials. Most studies included patients with idiopathic RLS. Ropinirole, pramipexole, rotigotine, and gabapentin-enacarbil were the most common active treatments assessed in the included studies.
The primary outcome was change from baseline RLS severity or disability; secondary outcomes included self-reported measures of clinical improvement, daytime sleepiness, and quality of life and objective measures such as the periodic limb movement index. The primary nocebo outcome was adverse effects with placebo; secondary nocebo outcomes included withdrawals due to adverse events.
RLS severity improved with placebo from severe to moderate ranges, and 46% of clinicians and 40% of patients reported clinical improvement with placebo. Overall quality of life, sleep quality, and daytime sleepiness also improved significantly with placebo, but periodic limb movements of sleep did not. Adverse effects were seen in 45% of the participants; withdrawals due to adverse events were seen in <2% of the participants. Both placebo and nocebo responses were stronger in studies lasting 12 or more weeks, pharmacologic studies, idiopathic RLS, unpublished trials, and industry-funded trials.
COMMENT: Both positive and negative subjective responses to placebo can occur in RLS. Whether these responses are as robust in people with RLS due to other causes such as end-stage renal disease still needs to be determined. In interpreting clinical trials in RLS, other factors to consider include effects of medications and caffeine.
CITATION(S):Silva MA et al. Placebo and nocebo responses in restless legs syndrome: A systematic review and meta-analysis. Neurology 2017 Jun 06; 88:2216; [e-pub].
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Arch Dis Child 2017 Jun; 102:522
Does Chronic Fatigue Syndrome Persist During Adolescence?
Approximately 25% of adolescents with CFS identified at age 13 or 16 years still had persistent chronic fatigue 2 to 3 years later.
Chronic fatigue syndrome (CFS), defined as disabling fatigue for 6 months that is often accompanied by additional symptoms, is a poorly understood condition with an uncertain prognosis.
To assess the prevalence and persistence of CFS during adolescence, researchers analyzed data from a longitudinal birth cohort study comprising approximately 14,000 children in England. Data were analyzed at three time points: ages 13, 16, and 18 years. CFS was defined using CDC criteria for symptom duration of >6 months. Results were as follows:

COMMENT: Although these data represent a localized British population, it is reasonable to assume that these data are translatable to other adolescent populations. Unfortunately, the study does not provide insights into factors that might predict resolution. Parents can be somewhat reassured by these findings indicating that CFS improves in many adolescents within a 2- to 3-year window.
CITATION(S): Norris T et al. Natural course of chronic fatigue syndrome/myalgic encephalomyelitis in adolescents. Arch Dis Child 2017 Jun; 102:522.

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Pediatrics 2017 Jun 1; 139:e20170346
Are Special Diets Useful for Autism?
A systematic review found little support but did not examine evidence for supplementation with folinic acid or vitamin D or some positive data on omega-3 fatty acids.
Parents of children with autism spectrum disorder (ASD), especially when children have moderate-to-severe language and social impairments, frequently seek nutritional and dietary approaches. This review, commissioned by the Agency for Healthcare Research and Quality, covered the literature from January 2010 to September 2016.
A systematic literature search yielded close to 6600 publications; 19 randomized, controlled studies, each with ≥10 participants, met inclusion criteria (N=732). Dietary approaches included supplementation with digestive enzymes, vitamin B12, and omega-3 fatty acids, as well as diets free of dairy, gluten, and gluten/casein. Analyses examined outcome, bias, and strength of evidence in the studies. Overall, all publications and the few positive studies showed bias and low strength of evidence.
COMMENT: The sheer number of identified publications attests to researchers' and parents' interest in interventions for an as-yet incurable disorder. However, the authors did not examine studies that provided evidence for other sorts of supplementation. Folinic acid has improved language in children with ASD and is important because it bypasses genetic defects that prevent normal metabolism of dietary folate (NEJM JW Psychiatry Jan 2017 and Mol Psychiatry 2016 Oct 18). Other studies have found low levels of vitamin D in people with ASD (J Pediatr Neurosci 2014; 9:227 and J Autism Develop Dis 2014; 44:2996), leading some authors to suggest ensuring adequate vitamin D in infants as a preventive measure. Finally, omega-3s have improved reading, spelling, motor skills, and attention-deficit/hyperactivity symptom scores in schoolchildren with developmental coordination disorder, suggesting that omega-3s might improve some behaviors and cognitive abilities in patients with ASD (NEJM JW Psychiatry Aug 2005 and Pediatrics 2005; 115:1360).
CITATION(S): Sathe N et al. Nutritional and dietary interventions for autism spectrum disorder: A systematic review. Pediatrics 2017 Jun 1; 139:e20170346.

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Ann Emerg Med 2017 May 3
For Isolated Urticaria, Skip the Steroids
Adding prednisone to levocetirizine provided no additional benefit in a double-blind, randomized, controlled trial.
Antihistamines are the main treatment for isolated urticaria without angioedema, but some physicians also prescribe steroids.
To determine whether combining prednisone with the nonsedating H1 blocker levocetirizine adds benefit in this setting, French investigators at two academic emergency departments conducted a double-blind, randomized, controlled trial involving 100 patients with acute urticaria of ≤24 hours duration. Patients received levocetirizine (5 mg orally per day for 5 days) plus either prednisone or placebo (40 mg orally per day for 4 days).
Similar percentages of prednisone and placebo recipients achieved an itch score of zero at 2 days (62% and 76%, respectively), suffered relapses (30% and 24%), and experienced mild adverse events (12% and 14%); no serious adverse events were reported.
COMMENT: When treating isolated urticaria without angioedema, use a nonsedating antihistamine or diphenhydramine (a sedating antihistamine), if tolerated, and skip the steroids.
CITATION(S): Barniol C et al. Levocetirizine and prednisone are not superior to levocetirizine alone for the treatment of acute urticaria: A randomized double-blind clinical trial. Ann Emerg Med 2017 May 3; [e-pub].
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Ann Intern Med 2017 Jun 6; 166:818
Managing Low Bone Density and Osteoporosis
The updated guideline recommends a 5-year course of bisphosphonate or denosumab as initial therapy.
Sponsoring Organization: American College of Physicians (ACP)
Target Audience: All clinicians
Background and Objective
For fracture prevention, decisions on whom to treat — and for how long — are not always straightforward. This guideline updates previous ACP recommendations for managing low bone density or osteoporosis to prevent fractures. Osteoporosis is defined as having sustained a fragility fracture or having a bone-mineral density (BMD) T-score ≤−2.5.
Key Recommendations
The authors make only two “strong” recommendations (based on high- or moderate-quality evidence):

Four other recommendations are graded as “weak” (based on low-quality evidence):

COMMENT: These guideline authors looked for evidence that an intervention lowers incidence of fractures (and does not simply bring about favorable change on the surrogate endpoint of BMD). Strong evidence results in strong treatment recommendations, whereas weak or inconclusive evidence generally leads the authors to err on the side of nonintervention. In my view, the guideline is reasonably balanced — but one must read beyond the brief bulleted list of six recommendations to appreciate it.
An editorialist who is a clinician–researcher with expertise in this area largely supports these recommendations, noting that “they provide a solid basis for informed clinical decisions about individual patients.” However, he notes that treatment beyond 5 years sometimes is warranted, that BMD monitoring during therapy sometimes is useful (although he considers the recommendation against monitoring to be “generally appropriate”), and that the parathyroid hormone fragment teriparatide (Forteo) could have received more attention.
CITATION(S): Qaseem A et al. Treatment of low bone density or osteoporosis to prevent fractures in men and women: A clinical practice guideline update from the American College of Physicians. Ann Intern Med 2017 Jun 6; 166:818.
Orwoll ES.Clinical practice guidelines for osteoporosis: Translating data to patients? Ann Intern Med 2017 Jun 6; 166:852.
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JAMA Intern Med 2017 Jun 5
Chronic Pain Might Hasten Cognitive Decline in Older Adults
Persistent moderate-to-severe pain was associated with about a 2% increase in absolute risk for developing dementia.
One quarter to one third of older adults have chronic pain, and cross-sectional studies have shown associations between chronic pain and cognitive decline. In this study, researchers used data from a national health and retirement study to explore the longitudinal relation between chronic pain and subsequent cognitive decline in about 10,000 older adults (median age, 73; mostly white women). Participants were assessed every 2 years for pain and cognitive function, and those who reported moderate-to-severe pain at baseline and at 2 years — about 11% of participants — were considered to have persistent pain; those with less or no pain served as the control group. Baseline prevalence of arthritis and depression was higher in the persistent-pain group than in controls (91% vs. 60%).
At median follow-up of about 10 years, cognitive decline was greater in the persistent-pain group than in controls. In analyses adjusted for a wide range of demographic and clinical factors (but not for medications such as opioids or psychotropic drugs), risk for developing dementia was significantly higher in persistent-pain patients than in controls (about 22% vs. 20%). Risk for having difficulty managing medications or finances was also about 2 percentage points higher in persistent-pain patients.
COMMENT: This association between persistent pain and cognitive decline might represent yet another good reason for developing more effective ways to control chronic pain in older adults. The authors note plausible explanations for their observations, including attentional impairment and subsequent memory dysfunction. However, an important limitation of this study is the absence of adjustment for patients' use of medications with central nervous system side effects. Those effects (and not the pain itself) might have contributed to the study's findings.
CITATION(S): Whitlock EL et al. Association between persistent pain and memory decline and dementia in a longitudinal cohort of elders. JAMA Intern Med 2017 Jun 5; [e-pub].
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JAMA 2017 Jun 20; 317:2402
Risk for Breast and Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers:
Refining Our Estimates

Prospective multinational cohort study provides long-term estimates of cancer incidence in this high-risk population.
Accurate estimation of age-specific risk for breast and ovarian cancer can facilitate counseling of BRCA mutation carriers. Investigators followed women enrolled in familial cancer registries primarily in the U.K., Holland, and France. Women were recruited into this cohort from 1997 to 2011 and had not undergone risk-reducing breast or gynecologic surgery; follow-up continued until 2013 (median, 5 years). A total of 6036 BRCA1 and 3820 BRCA2 mutation carriers were followed (median age at study entry, 38).
Cumulative risk for breast cancer by age 80 was 72% in BRCA1 carriers and 69% in BRCA2 carriers; for ovarian cancer, cumulative risk was 44% and 17%, respectively. Peak breast cancer incidence occurred at age 41–50 for BRCA1 carriers (28 per 1000 person-years) and age 51–60 (31 per 1000) for BRCA2 carriers. Incidence of ovarian cancer was 3.6 times higher among BRCA1 than BRCA2 carriers, with peak incidence occurring among women aged 61–70 regardless of mutation type. Cumulative risk of contralateral breast cancer 20 years after the first breast cancer diagnosis was 40% for BRCA1 carriers and 26% for BRCA2 carriers. For both BRCA1 and BRCA2 carriers, breast cancer risk rose with the number of first- and second-degree relatives with breast cancer. In contrast, ovarian cancer risk did not vary by family history.
COMMENT: As most participants in this cohort study were “previvors” (i.e., had no history of cancer) who were identified with screening performed because of family history, these risk estimates should be generally useful for BRCA carriers identified in the course of such testing. In particular, these findings can inform decisions about surveillance and risk-reduction strategies (including chemoprevention and surgery) for these high-risk women.
CITATION(S): Kuchenbaecker KB et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 2017 Jun 20; 317:2402.
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Gastroenterology 2017 Jun 2
Are Proton-Pump Inhibitors Associated with Chronic Kidney Disease?
Associated? Yes. Proven causal? No.
Many recent observational studies suggest associations between proton-pump inhibitor (PPI) use and a host of different disorders (NEJM JW Gastroenterol Jun 13 2017; [e-pub]
 and Gastroenterology 2017 May 18; [e-pub]).
To evaluate whether PPI use is associated with chronic kidney disease (CKD), researchers retrospectively analyzed serum creatinine measurements in approximately 100,000 new PPI users and 10,000 new users of histamine-2–receptor antagonists (H2RAs) in a cohort of Swedish patients. Median follow-up was 2.7 years after initial drug exposure.
PPI users were more likely to have a doubling of serum creatinine (hazard ratio, 1.3) or a 30% decrease in estimated glomerular filtration rate (EGFR; HR, 1.3) compared with nonusers. The association was consistent in subgroup analyses and a propensity-score matched cohort. Associations between PPIs and end-stage renal disease and acute kidney injury were not statistically significant. Higher cumulative PPI dose was associated with both creatinine doubling and decreased EGFR. The authors conclude that PPI use and PPI cumulative dose are related to an increased risk for CKD compared with H2RAs.
COMMENT: As in other studies of PPI-associated disorders, and as the authors of this paper acknowledge, this paper does not prove that PPIs cause CKD. The association is weak and the potential for residual confounding is great. Those taking PPIs were older, took more medications (including nonsteroidal anti-inflammatory drugs) and had more comorbidities. EGFR is only an estimate of kidney function that is dependent on age. There were tenfold more patients taking PPIs than H2RAs. There is no known physiologic mechanism for PPIs to cause CKD. This study does demonstrate a dose-effect relationship. The authors acknowledge that further studies are needed and that patients who have a clear clinical indication for PPI therapy should continue to be treated with the lowest appropriate PPI dose.
Note to readers: At the time NEJM Journal Watch reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.
CITATION(S): Klatte DCF et al. Association between proton pump inhibitor use and risk of progression of chronic kidney disease. Gastroenterology 2017 Jun 2; [e-pub].
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JAMA Intern Med 2017 Jun 12
Lower Education Level Is Associated with Higher Risk for Cardiovascular Disease
More than half of adults who didn't complete high school had adverse CV events during their lifetimes.
Educational attainment is associated with risk for cardiovascular disease (CVD), presumably as a marker or mediator of other traditional risk factors. To clarify the magnitude of this risk, researchers examined population-based data from about 14,000 U.S. adults (age range, 45–64; 27% black) who were free of CVD at baseline. Educational attainment was categorized in six levels ranging from grade school to graduate or professional school. Participants were followed for a median 19 years; about 4500 incident CVD events occurred.
Lifetime risk for CVD was correlated inversely with educational attainment level; for example, overall lifetime risks among those with only grade school educations, those who graduated from high school, and those with graduate or professional school educations were 55%, 42%, and 36%, respectively. Analyses by sex and race showed similar inverse correlations. In graded fashion, traditional CV risk factors were less common at higher education levels, but the analysis did not adjust for these baseline differences.
COMMENT: In this analysis, lower education level was associated with greater risk for CVD. Adults in this study with lower education levels also had less access to medical care, lower levels of physical activity, higher levels of smoking, poorer diets, greater prevalence of hypertension and diabetes, and fewer economic resources. Thus, the association between education level and CVD likely was mediated by many other clinical and nonclinical factors. Nevertheless, knowing a patient's level of educational attainment might improve overall clinical risk assessment by drawing more attention to modifiable risk factors.
CITATION(S): Kubota Y et al. Association of educational attainment with lifetime risk of cardiovascular disease: The Atherosclerosis Risk in Communities study. JAMA Intern Med 2017 Jun 12; [e-pub].
Adler NE and Glymour M.Why we need to know patients' education. JAMA Intern Med 2017 Jun 12; [e-pub].

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