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Archive for March, 2017

Primary Care Corner with Geoffrey Modest MD: Diabetic Neuropathy Guidelines

14 Mar, 17 | by EBM

By Dr. Geoffrey Modest

The American Diabetes Association just came out with their position paper on diabetic neuropathy (see DOI: 10.2337/dc16-2042). I will limit my points to type 2 diabetes, though type 1 is covered in this paper

Summary of points:

  • Diabetic neuropathy is a diagnosis of exclusion: diabetic patients may well have non-diabetic causes of neuropathy that should be pursued.
  • 50% of diabetic neuropathies are asymptomatic. It is important to assess for them, for example, to decrease the likelihood of significant foot trauma, improve symptoms and quality of life, and decrease sequelae
  • Prevention of neuropathy:
    • Data are largely for distal symmetric polyneuropathy (DSPN) and for cardiovascular autonomic neuropathy (CAN).
    • Best evidence is for those with type I diabetes where it is important to optimize glucose control as early as possible: 78% relative risk reduction with enhanced diabetes control
    • Risk reduction seems to be less in glucose control with type 2 diabetes, perhaps in part reflecting the different pathophysiology and comorbidities: type 2 diabetes tends to be associated more with overweight, polypharmacy, older age; but also many patients with type 2 diabetes have been prediabetic or diabetic for many years prior to diagnosis. In fact 10-15% of newly diagnosed diabetes already have evidence of DSPN.
  • Distal symmetric polyneuropathy (DSPN)
    • Most common (75% of all neuropathies). Defined clinically by symptoms or signs. Electrophysiologic testing or neurology referral are rarely needed.
    • 50% of people have DSPN after 10 years of disease, and is associated with levels of glycemia, height (perhaps as a proxy of nerve length), smoking, blood pressure, weight, and lipids
    • Those with predominantly small-fiber neuropathy present with pain, burning or tingling feeling, sometimes with a shooting sensation. There may also be hyperalgesia. And this may be found in 10 to 30% of patients just with impaired glucose tolerance. Those with large fiber involvement have numbness, tingling without pain, and loss of protective sensation
    • DSPN is associated with foot ulceration/amputation risk (important to assess regularly and refer to podiatry early), Charcot neuro-arthropathy, unsteadiness and falls (should assess gait/balance, though minimal data to support), and quality of life (DSPN can really affect quality of life, and is associated with depression, anxiety, medication nonadherence)
    • Patient should be assessed annually, those with type I diabetes should be assessed starting 5 years after the diagnosis. Consider assessing those with glucose intolerance as well. Assessment should include temperature or pinprick sensation (small fiber function), vibration sense with a 128 Hz tuning fork, proprioception, ankle reflexes, and 10-g monofilament (large fiber function), and the 10 g monofilament also helps assess risk for ulceration and amputation
    • Important to rule out the myriad of other causes of neuropathy, including vitamin B12 (see blog http://blogs.bmj.com/ebm/2017/02/23/primary-care-corner-with-geoffrey-modest-md-vitamin-b12-and-diabetic-autonomic-neuropathy/ which notes the overall increased incidence of B12 deficiency in diabetics) as well as infections (HIV, hepatitis B, Lyme), thyroid disease, paraproteinemia, alcohol or medications, heavy metal poisoning/work-related exposures, etc.
    • Symptom management: consider pregabalin or duloxetine as the initial​ approach. Though gabapentin may also be used (they do comment that pregabalin has a more linear, dose-proportional absorption and more rapid onset of action). They also note that tricylcic antidepressants (TCAs) are effective but beware of adverse effects. There seems to be some efficacy for the selective norepinephrine/serotonin reuptake inhibitor venlafaxine (dose 150-225 mg/d), mechanistically similar to duloxetine. Opioids should be avoided, given the risks of addiction, as either first- or second-line agents. However, tapentadolextended release, which has analgesic effects both through the m-receptor and noraderenaline reuptake inhibition, is FDA-approved, though there are systematic reviews/ meta-analyses which challenge its effectiveness. And some patients do seem to respond to adding low doses of these opioids in combo with the above agents).
  • Autonomic Neuropathies
    • Cardiovascular autonomic neuropathy (CAN)
      • May be present prior to a formal diagnosis of diabetes, ​is found in up to 60% of patients after 15 years, and is an independent risk factor for cardiovascular mortality (2+ fold increased risk, controlling for other risk factors), arrhythmia, silent ischemia, any major cardiovascular event, and myocardial dysfunction.
      • May be asymptomatic early and detected only by decreased heart rate variability with deep breathing, esp with EKG monitoring (see http://blogs.bmj.com/ebm/2017/02/23/primary-care-corner-with-geoffrey-modest-md-vitamin-b12-and-diabetic-autonomic-neuropathy/ which discusses ways to measure CAN), but can include symptoms of light-headedness, weakness, palpitations, fainting/syncope. Exam may show resting tachycardia, or orthostatic hypotension without compensatory increase in pulse.
      • Symptom management:
        • Optimize glucose control (to prevent or delay CAN, though this is most evident in type 1 diabetes, but some benefit in studies with type 2), reinforcing lifestyle interventions both in prediabetics and diabetics prior to developing CAN. For those with orthostatic hypotension, can use both nonpharmacologic treatments (exercise, assuring adequate fluid intake/volume repletion) and meds (fludrocortisone, midodrine)
      • Gastrointestinal neuropathies can be anywhere in GI tract, from esophageal dysmotility to gastroparesis to lower GI symptomsof diarrhea, constipation, incontinence
        • Gastroparesis
          • ​May be present in 1% of type 2 diabetics, from a community-based study (higher in type 1 diabetes). Can affect glucose variability and unexplained hypoglycemia because of changes in food absorption. [my experience suggests that gastroparesis may well be more common than this]
          • ​Consider checking for symptoms in those with other microvascular complications  (“C” recommendation), exclude other causes (g. opiates, GLP-1 agonists (grade “C” recommendation”) [and, I would add, considering decreasing dose of metformin, esp since 500mg once a day or even 250mg seems to add substantial clinical benefit], and can do gastric emptying studies to document (grade “B” recommendation”) [I would also add that gastroparesis is usually evident by history, and that it is probably useful just to try the nonpharmacologic and even pharmacologic therapies empirically]
          • Treatment includes eating multiple small meals/d, decreasing dietary fat (which also causes gastroparesis), decreasing other drugs than those mentioned above which can make it worse (g. anticholinergics, pramlintide and ? DPP-4 inhibitors), and one can prescribe metoclopramide, the only FDA-approved agent, though it is associated with extrapyramidal symptoms, acute dystonic reactions, akathisia, tardive dyskinesia, acute dystonic reactions) and is recommended to use for only 5 days (which is problematic for such a chronic condition, and I have patients on this agent for much longer, with frequent assessments by me for the above adverse reactions)
        • Urogenital neuropathies includes bladder and sexual dysfunction, the latter including erectile dysfunction (3x more common in diabetics, may involve combo of autonomic neuropathy, vascular disease, and I would add psych issues, such as depression, stress, etc.) and/or retrograde ejaculation in men and sexual dysfunction in women (decreased sexual desire, increased pain with intercourse, decreased sexual arousal, inadequate lubrication).
          • Bladder dysfunction should be assessed in those with recurrent urinary tract infections, pyelonephritis, incontinence, palpable bladder
          • Recommendations: consider screening men with other forms of neuropathy for ED (grade C) and women with other forms of neuropathy for lower urinary tract symptoms and sexual dysfunction (grade E)
        • ​Sudomotor dysfunction includes dry skin, anhidrosis, or heat intolerance, and occasionally gustatory sweating (food consumption, and occasionally just the smell of food, leading to sweating of head and neck area)
        • Other neuropathies:
          • Mononeuropathies: especially of median, ulnar, radial and common peroneal nerves. cranial neuropathies are rare but include cranial nerves III, IV, VI, VII and usually resolve spontaneously over months
          • Diabetic radiculoplexus neuropathy (also called diabetic amyotrophy): unilateral thigh pain, weight loss, followed by motor weakness. self-limited (though I have a type 1 diabetic patient with this in one of his shoulders)

Commentary:

  • They do promote pregabalinand duloxetine as their primary go-to’s. I personally do not use them till much later in the pyramid of meds, partly because they are relatively new agents (and the older ones have stood the test of time), partly because there are mechanistically similar drugs available (gabapentin and venlafaxine), partly because these are non-generic and quite expensive, and partly (e., a lot) because they require prior approvals from many insurers.​
  • In the vast majority of cases, I have prescribed tricyclic antidepressants with great success. Although amitriptyline is the one used the most overall, it has the most adverse effects. I prescribe either desipramine or nortriptyline, which work as well and with many fewer adverse effects (desipramine has the fewest, but nortriptyline is helpful to take at night if the patient has trouble sleeping). The usually effective doses are desipramine 25-50mg (occasionally 75), or nortriptyline 10-50mg. Not sure why, but the 2012 ADA guidelines (see Diabetes Care 35:2451–2458, 2012) found that there was no significant difference between amitriptyline, duloxetine and pregabalin, though the current guidelines seems to have booted TCAs off the top tier (they are generic with long history of use and knowledge of long-term adverse effects, both plusses, which does raise the question to me of adverse drug-company induced bias….)
  • Gabapentin is used a lot for neuropathy, though the studies have been mixed (and the drug company has been taken to task for withholding large, unpublished negative studies).  And in my limited experience, is associated with many adverse effects and requires a very slow titration up.

So, a pretty useful compilation of diabetic neuropathies, along with reasonable approaches (though there are no medications which actually treat the neuropathies, only ameliorate the symptoms). My own approach is that anyone with any mono or polyneuropathy should be checked for diabetes (for example, they limit the cranial nerve neuropathies to the facial and extraocular movement nerves, though I have seen a couple of diabetic patients with anosmia.) Also, they do not comment that it is not so uncommon in diabetics to have radiculopathies typically on the trunk which simulating zoster clinically and respond to the above meds.

See http://blogs.bmj.com/ebm/2015/01/29/primary-care-corner-with-geoffrey-modest-md-meds-for-diabetic-neuropathy/ for a meta-analysis of the meds used for DSPN, finding that SNRIs, capsaicin, tricyclics and anticonvulsants work for short-term pain control (seemed that SNRIs and TCAs were best). Opiates were last by a fair margin.

Primary Care Corner with Geoffrey Modest MD: Probiotics in c diff

9 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A recent systematic review with a meta-analysis looked at 19 published studies on the efficacy of probiotics in preventing C. difficile infections (CDI) in inpatients put on antibiotics, finding benefit if given close to the 1st dose of antibiotics (see 10.1053/j.gastro.2017.02.003).

Details:

  • 6261 subjects were involved in these 19 studies
  • The studies were done in the USA, UK, Turkey, Canada, Norway, China, Italy, and Germany. Several different probiotic formulations were used, most with Lactobacillus species. The daily dose of probiotics varied dramatically from 4 to 900 colony forming units, most started the probiotics within the 1st 2 days of beginning the antibiotics, duration of probiotics varied from 14 days to 14 days after completion of the antibiotic course, and the age varied from those greater than 18 up to age 80 (weighted average 68 years). Commonly excluded groups were those who were pregnant, immunocompromised, required intensive care, had pre-existing GI disorders. The hospitals’ baseline incidence of CDI range from 1.5 to 7.4%
  • Overall 4 probiotic species were studied: Lactobacillus, Saccharomyces, Bifidobacterium, and Streptococcus.

Results:

  • The overall incidence of CDI in the probiotic cohort was 1.6% (54/3277); in the control group it was 3.9% (115/2984), with p<0.001.
  • The pooled relative risk of CDI was decreased 58% with probiotics, RR 0.42 (0.30-.57)
  • The number needed to treat was 43 patients to prevent one case of CDI
  • Meta-regression analysis showed that there was a significant decline in probiotic efficacy for each day in delay of starting probiotics after the 1st dose of antibiotic, with an 18% decrease for every day the probiotics were delayed (p=0.04)
    • Probiotics given within the 1st 2 days of starting antibiotics had a 68% risk reduction of CDI, RR 0.32 (0.22-0.48) than starting later, where there was a 30% reduction, RR 0.70 (0.40-1.23)
  • No adverse events attributable to probiotics (in general adverse events tended to be less in the probiotic group)
  • Overall quality of the evidence was high. The magnitude of efficacy was the same when analysis was limited only to the high qualities trials

Commentary:

  • CDI incidence has increased dramatically in the past 10 years, more than doubling and costing $4.8 billion, with attendant morbidity and mortality (more than 29,000 deaths in 2011). The standard treatment has approximately 20% treatment failure and around half of the patients have recurrence, especially those who are older.
  • Certain probiotics seem to colonize the gut well, despite concurrent use of antibiotics: specifically Lactobacillus and Bifidobacterium.
  • To me it is difficult to assess with certainty their conclusions about timing, given the inconsistency of the approach to treatment (huge variability in types and doses of probiotics), as well as the fact that the vast majority of studies treated early, within the first 2 days or so. However, it does make intuitive sense that if we are to protect the gut with probiotics, that should be done early, especially before there is a large overgrowth of C. difficile
  • The best guess of the authors, though not definitive, was at the most efficacious probiotics were: Lactobacillus, and Lactobacillus in combination with either Streptococcus or both Streptococcus and Bifidobacterium
  • A review of the individual studies found that they all found benefit from the probiotics, though for some of the individual studies these did not reach statistical significance.
  • A cost-benefit analysis done in the UK suggested that using a Lactobacillus probiotic in hospitalized patients over 65 on antibiotics would lead to a cost savings of over $500 per patient. Another study in Canada also suggested cost savings.
  • So, though current guidelines, for example from the American College of Gastroenterology, do not recommend the use of probiotics for the primary prevention of CDI, this meta-analysis is pretty convincing that they work with no evident adverse effects. And, I would think, should be strongly considered in outpatients put on broad-spectrum antibiotics (e.g. Ciprofloxacin).

Prior blogs:

http://blogs.bmj.com/ebm/2014/12/03/primary-care-corner-with-geoffrey-modest-md-probiotics-in-irritable-bowel-syndrome/ is a blog on the efficacy of probiotics in irritable bowel syndrome

http://blogs.bmj.com/ebm/category/microbiome/ has a slew of blogs on the microbiome

http://blogs.bmj.com/ebm/category/clostridium-difficile/ has many blogs C. diff

and, http://blogs.bmj.com/ebm/category/antimicrobial-resistance/ has many on antimicrobial resistance

Primary Care Corner with Geoffrey Modest MD: Penicillin Allergy???

8 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A large concern in treating patients with infections is the very high prevalence of “penicillin allergy”, leading to the use of broad-spectrum antibiotics as well as 2nd or 3rd line medications, which are usually more toxic, along with their attendant effects on antimicrobial resistance as well as secondary infections such as C. difficile­­­­. A recent article looked at 2 methodologies to determine the safety of using beta-lactams in these “penicillin allergic” patients (see 10.1016/j.jaci.2017.02.005).

Details:

  • Of 1000 medicine in-patients with a noted penicillin allergy in a single Boston hospital, 625 were admitted with a presumed infection: mean age 66, 60% female, 70% white/16% black, reported penicillin allergy was rash or hives in 60%/angioedema 15%, anaphylaxis 8%
  • Patients were assessed during 3 different time periods: 148 patients in a standard-of-care group (SOC), 278 in a penicillin skin testing group (ST), and 199 in a group using a computerized guideline-based management app (APP) to predict real allergy
  • ST group: excluded patients with penicillin intolerance (such as GI upset), patients taking medications that might interfere with skin testing (such as antihistamines), and also patients with multiple beta-lactam allergies, penicillin anaphylaxis in the last 5 years, or type II-IV hypersensitivity reactions to penicillin
  • APP group: the clinical support basically divided people into low risk (benign delayed maculopapular rash); medium-to high-risk (urticaria, angioedema, anaphylaxis, recent or severe delayed maculopapular rash; and those who should avoid a beta-lactam (history of Stevens-Johnson syndrome, toxic epidermal necrolysis or exfoliative dermatitis; DRESS syndrome or acute interstitial nephritis; or serum sickness-like reaction)
  • Primary outcome was the actual use of penicillin or cephalosporin during the hospitalization

Results:

  • ST group: 179 (64%) were felt to be skin test eligible, but only 43 (24%) actually receive skin testing and none of those were allergic, defined as negative skin test and tolerance of an oral amoxicillin 250 mg test dose. As compared to the SOC group,
    • Nonsignificant 30% increased odds of use of penicillin or cephalosporin overall, adjusted OR 1.3 (0.8-2.0), but a highly-significant 5.7-fold increased use in a per protocol analysis, adjusted OR 5.7 (2.6-12.5), p<0.001 [the per protocol analysis limited the analysis to those few who actually got the skin test]
    • Of the ST per protocol patients, there was increased odds of penicillin or cephalosporin prescriptions for discharge treatment, with OR 2.5 (1.04-6.2)
  • APP group: 292 unique website views (averaging 26 seconds only), 112 users (38%) completed clinical decision support. Patients in the low or moderate-to-high risk groups as above were given test doses of beta-lactam antibiotics with an initial dose of 1/10 of an IV dose or 1/4 of an oral dose. The 2nddose was administered 30 minutes later, comprising the remainder of the therapeutic dose. Nurses assessed patients every 30 minutes for the duration of the challenge. As compared to the SOC group,
    • Significant 80% increased odds of use of penicillin or cephalosporin, adjusted OR 1.8 (1.1-2.9), p=0.03

Commentary:

  • Penicillin allergy is remarkably common, up to 15% of all inpatients are recorded as having a penicillin allergy, and 5-25% of inpatients who are treated for infections. Three quarters of patients with an alleged penicillin allergy would otherwise use a beta-lactam antibiotic in other studies, but in the SOC group only half of them received one.
  • Not using a beta-lactam antibiotic when that would otherwise be indicated leads to more treatment failures, adverse events, and antibiotic resistant organisms such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus.
  • There were few patients who actually had skin testing, mostly because of difficulty in coordinating the testing for those felt to be eligible, which the authors note would have been different if they hired an on-site clinician for that purpose (some patients also refused skin testing).
  • Another concern about skin testing is that fewer than 15% of US hospitals have the appropriate reagent on formulary. The per protocol analysis of the ST arm may be open to bias (vs the intention-to-treat analysis looking at the overall group), however the low numbers of patients getting skin testing clearly biased the results to negative.
  • However, it is quite remarkable how much effect the pretty simple computerized guideline and decision support provided. It should, however, be pointed out that this was not a clean randomized-controlled trial, so there are potential inherent biases (including the possibility that there were different sensibilities and approaches to treating infections, perhaps related to the different time periods above, or proclivities of the ID departments, ward attendings, residents, etc.)
  • These results parallel those in a prior blog regarding skin testing. See http://blogs.bmj.com/ebm/2013/09/12/primary-care-corner-with-geoffrey-modest-md-most-with-pcn-allergy-will-test-negative-for-it-and-can-be-given-pcn-safely/which found that of 146 patients with history suggestive of IgE-mediated penicillin allergy (but excluding those with history of anaphylaxis), only one patient had a positive skin test, and the remaining 145 did fine with oral penicillin. Of note, as opposed to the prior blog, those with Type I (IgE- mediated) hypersensitivity reactions were excluded from the above study.
  • Why is “penicillin allergy” so rampant?? as a singular anecdote, 25 years ago one of my children had otitis media in the middle of the night when he was less than a year old, and as a really tired parent I decided to watch him instead of getting antibiotic treatment (he wasn’t really very sick appearing, and at that point in Europe most otitis media was not being treated with antibiotics), he remained relatively stable for the next day or 2, then developed a maculopapular rash. If he had been given a beta-lactam antibiotic, he would have been labeled as penicillin allergic perhaps for the rest of his life. I do realize that there are negatives to treating family members, however my tiredness won out….
  • So, what does this all mean? The combination of the current and prior blog strongly suggest that true penicillin allergy is really quite unusual (the number quoted is <5% of those with listed penicillin allergy). And the ability to use beta-lactams for common outpatient (and inpatient) infections is really useful, especially as we are trying so hard to protect our microbiome and decrease resistance. [And, by the way, adverse reactions, need for hospitalization, costs…]. It would be really great to have a large study looking at the computer-assisted app to see the real incidence of bad allergic reactions to beta-lactams in each of the low and moderate-to-high risk groups, with an eye to using beta-lactams, perhaps initially in a monitored setting (depending on the actual incidence of severe reactions in these cohorts in subsequent studies).

Primary Care Corner with Geoffrey Modest MD: Fructose and NASH

7 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A recent study found that fructose consumption and serum uric acid were independently associated with non-alcoholic steatohepatitis (NASH) in obese kids with non-alcoholic fatty liver disease (NAFLD), (see doi.org/10.1016/j.jhep.2016.12.025).

Details:

  • 271 obese children (by BMI) with NAFLD were studied
  • NASH was diagnosed by biopsy, with a NAFLD score of at least 5, and by the fatty liver inhibition of progression (FLIP) algorithm (another algorithm for the diagnosis of NASH)
  • Fructose intake was determined by a food frequency questionnaire
  • Hyperuricemia was defined as a serum uric acid level >5.9 mg/dl

Results:

  • NASH occurred in 37.6% of the children
  • Mean age 11.5, 38% female, BMI 27, waist circumference 87cm, AST 48/ALT 62, uric acid 5.8, LDL 100/HDL 45, BP 112/68, TNF-a Of note, there were significant differences between those with NASH and those without, but only for: waist circumference, AST/ALT, total cholesterol (but not LDL, HDL alone), triglycerides, fructose consumption, and TNF- a
  • Hyperuricemia was found in 47% of the kids with NASH, vs 29.7% without NASH (p=0.003)
  • Adjusting for multiple measured confounders:
    • Uric acid level was associated with NASH, OR 2.49 (1.87-2.83), p=0.004
    • Fructose consumption was associated with NASH, OR 1.61 (1.25-2.85), p=0.001
    • These associations with NASH were independent of each other
    • Though, fructose consumption was still independently associated with hyperuricemia, OR 2.02 (1.66-2.78), p=0.01
    • These data on NASH were confirmed by using the FLIP algorithm

Commentary:

  • As noted in prior blogs, there seems to be a pretty consistent relationship between fructose consumption and uric acid levels, as was shown in this study. And there are data suggesting that dietary fructose can be part of the pathogenesis of NAFLD (induction of de novo lipogenesis, inflammation, insulin resistance). Studies in adults have found that hyperuricemia is associated with insulin resistance, type II diabetes and metabolic syndrome.
  • There are many dietary sources of fructose. The major ones for most people are table sugar (sucrose, a disaccharide of glucose and fructose) and high fructose corn syrup (in a surprising number of foods, as a very cheap and potent sweetener). Perhaps the “low-hanging fruit” here is sodas, consumed by very large numbers of people (https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6332a2.htm#Tab2 , finding that on average 26.3% of US adults consume at least one sugar-sweetened beverage daily, up to 41.4% in Mississippi, the highest of states, and that soda by itself was consumed by 24.5% of those 18-34 yo, and 47.4% in Mississippi). And a NHANES study (Welsh JA. JAMA 2010; 303(15): 1490) found that on average, 15.8% of calories came from added sugars, and that >25% of the patients got >25% of their total energy from added sugar. My experience is that it is easier to help people stop sodas and juices, substituting water, than other dietary interventions.
  • I am not sure why we focus so exclusively on BMI, since the data are pretty consistent over the decades that abdominal obesity is really the bad actor, more metabolically active and associated with inflammatory markers, diabetes/insulin resistance/metabolic syndrome and is independently associated with cardiovascular risk (BMI is not: its association is mediated by its association with other risk factors, such as blood pressure, lipids). Waist circumference is a much better, though not perfect, marker of visceral obesity than BMI. That being said, there is a pretty strong relationship (but not always) between BMI and waist circumference, especially in those with BMI >35. The most reasonable recommendations I have seen is to measure the waist circumference regularly, especially if the BMI is between 25-35. Although practically we should reinforce lifestyle changes in all patients with high BMI, independent of waist circumference, I think the patient should understand that for those with a high waist circumference, their cardiometabolic risk is even higher. See http://blogs.bmj.com/ebm/2015/12/02/primary-care-corner-with-geoffrey-modest-md-central-obesity/ for the fuller argument

So, this study does add some important information: it confirms that both uric acid levels and fructose are associated with NASH in kids that they are associated with each other, but that they are also independent predictors (and there are several studies which show that decreasing fructose consumption, as in sodas, is associated with decreased uric acid levels. See blogs below). So, bottom line is that fructose consumption is bad and should be decreased, even if the uric acid level is just fine.

See http://blogs.bmj.com/ebm/2015/12/11/primary-care-corner-with-geoffrey-modest-md-fructose-restriction-and-cardiometabolic-and-weight-improvement/ for prior blog of fructose consumption in kids and cardiometabloic and weight improvements

http://blogs.bmj.com/ebm/2016/09/13/primary-care-corner-with-geoffrey-modest-md-non-alcoholic-fatty-liver-disease-3/ is one of 3 articles on NAFLD, highlighting an important role of fructose

http://blogs.bmj.com/ebm/2016/03/18/primary-care-corner-with-geoffrey-modest-md-microbiome-changes-and-severity-of-nafld/  more on the microbiome and hepatic changes with fructose

Primary Care Corner with Geoffrey Modest MD: Internet-based improvement in knee pain

6 Mar, 17 | by EBM

By Dr. Geoffrey Modest

There have been several articles recently dealing with nonpharmacologic management of chronic pain (see blogs at end). A recent Australian one looked at the effectiveness of an Internet-delivered training intervention, finding remarkable and apparently durable benefit in patients with chronic knee pain (see doi:10.7326/M16-1714).

Details:

  • 148 people over 50 years old with chronic knee pain: mean age 61, 56% female, 57% urban/43% rural, mean BMI 31, symptom duration 2-10 years in 50%/> 10 years in 27%, 57% employed/30% retired, 38% on acetaminophen combinations/23% NSAIDs/21% on topical anti-inflammatories/only one person on opiates, 50% anticipated moderate improvement by the intervention/17% anticipated large improvement, 60% used the Internet for social media daily
  • Those randomized to the intervention received 3 Internet delivered treatments
    • Educational material about exercise and physical activity, pain management, emotions, healthy eating, complementary therapies, and medications. Those in the control group also received this material
    • An interactive automated physiotherapist-prescribed home exercise in pain-coping skills training (PCST) called PainCOACH, and were asked to complete eight 35- to 45-minute modules, one per week, and practice pain-coping skills daily
    • Seven Skype sessions with a physiotherapist over 12 weeks, sessions lasted 30- 45 minutes(videoconferencing). The physiotherapist performed a brief assessment and prescribed a lower limb strengthening home exercise program to be performed 3 times a week. Exercise progression was monitored. Patients were provided with instructions, video demonstrations, and equipment such as resistive bands and ankle weights.
    • Pain was assessed using an 11 point numerical rating scale (NRS) as well as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 3 months. Primary outcomes were pain during walking using the NRS, and physical function using WOMAC.  Secondary outcomes were knee pain, quality of life, global change, arthritis self-efficacy/coping/pain catastrophizing.
    • The minimum clinically important difference (MCID) for the NRS pain score is 1.8 units, and for the WOMAC physical function subscale is 6 units.

Results:

  • The educational material was accessed by 78% of participants in the intervention group and 88% in the control group. Those in the intervention group attended a mean of 6.3 of 7 Skype physiotherapy sessions and completed 6.4 of 8 of the PainCOACH modules. 68% of the prescribed home exercise sessions and 64% of the PCST practice sessions were completed.
  • The intervention group had significantly more improvement in pain (mean difference 1.6 units) and physical function (mean difference 9.3 units) versus the control group at 3 months.
  • These improvements were sustained at 9 months, with a mean difference of 1.1 units for pain and 7.0 units for physical function.
  • In terms of secondary outcomes: there was significant difference between the groups in essentially all of the secondary outcomes
  • Adverse events from the intervention were minor, with increased knee pain being most common in both groups but more so in the active intervention group.

Commentary:

  • Given the problem with chronic pain meds, be they NSAIDs and their multitude of renal/ GI/cardiovascular complications, or the very significant concerns regarding using opiates for chronic pain, it is reassuring that non-pharmacologic and patient-empowering strategies can be effective.
  • And, as we all know, chronic knee pain is remarkably common: the anticipated projection is that 1/2 of US adults will develop knee osteoarthritis by age 85, but 50% of people with symptomatic knee OA are less than 65 yo.
  • It is notable that the functional differences in the intervention group were well more than what is considered minimally clinically important improvement, and this was almost reached for pain. It is also notable that these benefits were apparent at 9 months, 6 months after the intervention was over.
  • The study had the benefit of having both urban and rural patients, which is especially important for the latter group given their decreased access to face-to-face interventions.
  • One limitation of the study is that it seemed that this was a reasonably healthy cohort, given that most anticipated significant improvement by the intervention and most were only on mild analgesics [They did not define what “acetaminophen combinations” were, in either the article or supplement, but I assume these did not include opiate combinations, since they say only one person was on opiates], and participants could not have such severe knee pain that it limited their ability to exercise.
  • But, as an encouraging result, we in primary care do see lots of patients who have only mild-to-moderate pain, that meds work variably well (and have their toxicities), and it does seem that the results of this 3-month non-pharmacologic intervention is durable for at least the next 6 months.
  • And, it turns out that there currently are a slew of apps available: including Pain Coach (free, but not the same as above), some for back pain exercises, chronic pain relief, several for yoga/meditation, etc. I looked at a couple and they have some useful information, and may be a useful tool to help/empower some patients, though I did not find any as complete as in this study. Let me know if you have found any great ones.
  • So, this study reinforces and adds to the growing body of literature that suggest that a cornerstone of chronic pain therapy, this time for the knee, is non-pharmacologic (see other recent blogs below). One hopeful sign in the US is that in 2016, 87% of those older than 50 and 64% older than 65 do use the internet. I.e., if there are education-level appropriate, linguistically-diverse, culturally-sensitive materials available, they might really help people. Even those who are unable to read could benefit from these materials (perhaps with the help of a younger family member….)

For related articles, see:

http://blogs.bmj.com/ebm/2016/06/29/primary-care-corner-with-geoffrey-modest-md-tai-chi-for-knee-oa-mindfulness-for-chronic-pain/ for a review of an article showing the benefits of tai chi,

http://blogs.bmj.com/ebm/2016/04/07/primary-care-corner-with-geoffrey-modest-md-low-back-pain-improves-with-stress-reduction-mindfulness-and-cognitive-behavioral-therapy/ for an article on the benefits of mindfulness stress-reduction and cognitive behavioral therapy

http://blogs.bmj.com/ebm/2016/03/25/primary-care-corner-with-geoffrey-modest-md-new-cdc-guidelines-for-opiate-prescribing/ reports the CDC guidelines, stressing the use of adjuvant meds prior to starting opiates, though giving short shrift to non-pharmacologic therapies and, for a slew of other articles in the folder: http://blogs.bmj.com/ebm/category/pain/​ ​list

Primary Care Corner with Geoffrey Modest MD: texas abortion law changes and its effects

3 Mar, 17 | by EBM

By Dr. Geoffrey Modest

This blog will not shock you: when Texas closed abortion facilities, decreasing access and making women travel further distances to get an abortion, there was a substantial decrease in the number of abortions done with a small increase in out-of-state abortions (see doi:10.1001/jama.2016.17026).

Details:

  • In 2013 Texas enacted a restrictive abortion law which was partially reversed by the Supreme Court in 2016 as being unconstitutional
  • After passage of the law, the number of abortion facilities declined, with the following changes:
    • 2012 (prior to the law): 66,098 abortions done in Texas, 97 done out-of-state. 41 abortion facilities in 17 counties in Texas
    • 2014: 53,882 abortions done in Texas, 254 done out-of-state. 21 abortion facilities in 6 counties in Texas
  • The median distance to a facility increased by 51 miles. There was a clear, consistent trend between the decrease in abortions and the distance to the nearest facility (p<0.001 for trend):
    • 0 distance assoc with 1.3% decline
    • 25-49 miles assoc with 25.3% decline
    • >100 miles assoc with 50.3% decline
  • Even counties with open facilities and minimal distance (within 5 miles)  had a 15.9% decline in abortions [perhaps from less local access, with the number of women seeking abortions being greater than the new capacity]

Commentary:

  • The above does not include abortions done in Mexico, or self-induced abortions
  • Adding together the in-state and out-of-state abortions confirms a 18.2% decline, despite the shift to more being out-of-state
  • None of this is terribly surprising. The concern now is that the new US president and vice-president, their Cabinet appointees, their likely Supreme Court appointees, and the Republican House and Senate are pretty likely to make matters much more difficult for women in the near future. And perhaps decrease funding for/access to birth control, making the situation even more untenable (g. closing Planned Parenthood or not funding abortion/contraceptive services). Especially for poorer women with fewer resources/alternatives.
  • I would just add that in Illinois in the late 1960s/early 1970s, when abortion was illegal, I was told that there were 2 full wards at Cook County Hospital (about 50 people) filled with women having septic abortions (serious uterine infections, in this case after “back-alley” abortions done by coat-hangers, ). And there was a 10% mortality rate….

Primary Care Corner with Geoffrey Modest MD: antibiotic-resistant bacteria of concern

2 Mar, 17 | by EBM

By Dr. Geoffrey Modest

The WHO just published a list of 12 bacterial families that they feel pose the greatest threat to human health (see http://www.who.int/mediacentre/news/releases/2017/bacteria-antibiotics-needed/en/ ). These are considered the “priority pathogens”, which should serve as a focus for research and development of new antibiotics. The most critical group includes multi-drug-resistant bacteria that pose a particular threat in hospitals, nursing homes, and among patients who require devices such as ventilators and blood catheters. These bacteria have become resistant to a large number of antibiotics including carbapenems and third-generation cephalosporins, the best available drugs for treating multidrug resistant bacteria. The 2nd and 3rd tier priorities include increasingly drug-resistant bacteria that can cause more common diseases such as gonorrhea and salmonella. The goal is to spur governments to incentivize basic science and advance research and development, both public and private sector, to invest in new antibiotic discovery. The list does not include tuberculosis, which does have increasing resistance, but is covered by other programs.

Priority 1: critical

  1. Acinetobacter baumanii, carbapenem-resistant
  2. Pseudomonas aeruginosa, carbapenem-resistant
  3. Enterobacteriaceae, carbapenem-resistant, ESBL-producing

Priority 2: high

  1. Enterococcus faecium, vancomycin-resistant
  2. Staphylococcus aureus, methicillin-resistant, vancomycin-intermediate and resistant
  3. Helicobacter pylori, clarithromycin-resistant [see http://blogs.bmj.com/ebm/category/gi-h-pylori/​ for multiple blogs on H Pylori resistance and optimal treatment strategies]
  4. Campylobacter spp., fluoroquinolone-resistant
  5. Salmonellae, fluoroquinolone resistant
  6. Neisseria gonorrheae, cephalosporin-resistant, fluoroquinolone-resistant

Priority 3: medium

  1. Streptococcus pneumoniae, penicillin-non-susceptible
  2. Haemophilus influenzae, ampicillin-resistant
  3. Shigella spp., fluoroquinolone-resistant

Commentary:

  • This WHO publication follows others which have warned of scarily increasing bacterial antibiotic-resistance world-wide (e.g., see http://blogs.bmj.com/ebm/2014/07/11/primary-care-corner-with-geoffrey-modest-md-whos-remarkable-scary-report/ )​
  • The focus of this current publication is to spur on research and development of new antibiotics.  BUT, though not mentioned, the elephant in the room is that we need to decrease the future development and spread of antibiotic-resistant bacteria. Some of this is decreasing the unnecessary use of antibiotics for nonbacterial illnesses (see prior blogs, as below, in the file: http://blogs.bmj.com/ebm/category/id-microbial-resistance/). But the largest part of this has to do with industrial use of antibiotics in livestock, where antibiotics are used to increase the weight of animals and prevent infections largely in the setting of huge industrial farms, where there is great opportunity for sharing of pathogens. Although there are different estimates out there on the quantity of antibiotics used, one study by the Union of Concerned Scientists suggested that 24.6 million pounds of antimicrobials are used annually for nontherapeutic purposes in chickens, cattle, and swine vs 3.0 million pounds used for humans (see Landers TF. A review of antibiotic use in food animals: perspective, policy, and potential. Public Health Rep. 2012 Jan-Feb 127(1): 4.).  i.e. 90% goes to animals….
  • An additional issue is that drug companies have been loath to develop new antibiotics. As for-profit organizations, they see much more income from life-long drugs, such as those for lipids, diabetes, etc. (the gift that keeps on giving), vs those prescribed for just a 10-day course. (The apparent exception is for hepatitis c, where the meds are given for several months, these were new meds for a very serious and very common condition, and they were able to jack up the price independent of their actual costs of R&D). And, many of the drug-resistant bugs, at this point, are in areas of the world where there is not lots of money to be made (see http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf?ua=1​ ) .  From the blog of 7/11/14: “at this point we really need new antibiotics developed. There have been no new class of antibiotics since 1987. Issue is that the $$ is in chronic meds. Even over-charging for antibiotics doesn’t help much if it’s for only a 10 day course. And, will append below a previous blog  which shows that the vast majority of R&D by big pharma is for look-alike drugs and not for important break-throughs (though their arguments supporting the huge costs of drugs hinges on the expense of R&D)”
  • So, bottom line, we do need new antibiotics to deal with the spread of these “superbugs”. But we really do need to intensify internal pressure on clinicians to decrease antibiotic overprescribing and, especially, external pressure on industrial farming to dramatically decrease antibiotic usage.

 

Primary Care Corner with Geoffrey Modest MD: physical activity and depression in childhood

2 Mar, 17 | by EBM

By Dr. Geoffrey Modest

And, perhaps the last blog on exercise, at least for now…

A Norwegian study assessed the relationship between physical activity, sedentary lifestyle, and DSM-IV defined major depressive disorder (MDD) in kids aged 6 to 10 years old (see DOI: 10.1542/peds.2016-1711​).

Details:

  • Community sample of 6-year-old children (n=795) in Trondheim, Norway were followed-up at 8 and 10 years of age.
  • Physical activity was recorded by accelerometry – wearing an accelerometer for 7 consecutive days, 24 hours a day, and only removing when bathing or showering; they assessed the time period of 6 AM till midnight and excluded periods of time where there were greater than 20 minutes of 0 counts (suggesting they were not wearing the unit); sedentary activity was <100 counts per minute; and moderate-to-vigorous physical activity, MVPA, was >2296 counts per minute). Major depression was assessed through semistructured clinical interviews of parents and children using the Preschool Age Psychiatric Assessment (PAPA), with a summed score creating the DSM-IV defined MDD; and the Child and Adolescent Psychiatric Assessment (CAPA) was used as well for children 8 and 10 years old.

Results:

  • DSM-IV defined MDD decreased from age 6 to 8 but then increase from age 8 to 10. (the prevalence of MDD was around 0.5% in all of the age groups)
  • Minutes of MVPA did not change from age 6 to 8 but decreased from age 8 to 10
  • Sedentary activity increased from age 6 to 8 and increased further from age 8 to 10
  • The symptoms of MDD and sedentary activity were modestly stable over this time. MVPA was more stable.
  • Cross-sectional findings
    • The symptoms of MDD were negatively correlated with MVPA at age 8 and 10, but were unrelated to sedentary activity.
    • At both ages of 6 and 8, higher levels of MVPA predicted fewer symptoms of MDD 2 years later, with a reduction of 0.2 symptoms of depression per daily hour spent in MVPA
    • There was no difference between males and females.
    • MVPA predicted reduced numbers of MDD symptoms from age 6 to 8, but depression did not predict later MVPA (i.e. it seems to be unidirectional). And there were no effects of sedentary activity on depression or vice versa

Commentary:

  • Some studies have found that physical activity may reduce the likelihood of the symptoms of major depressive disorder in adolescents and adults (see Craft LL. Prim Care Companion J Clin Psychiatry 2004; 6: 104, which includes meta-analyses showing exercise’s therapeutic benefit, on the order of cognitive therapy).It has been unclear whether this was related to the physical activity or the lack of sedentary behavior (these 2 are not perfectly correlated, and, for example, children may do periods of intense activity but have a lot of sedentary behavior time). This Norwegian study assessed these factors prospectively in younger children, finding that MVPA mattered but sedentary behavior time did not
  • One particular strength of this study is that they did look at symptoms of depression over time, since these often wax and wane. Also the study allows us to looks at the bi-directionality of the relationship between physical activity and depression, finding that the results were unidirectional from MVPA to MDD. Another advantage of the study over others is that they used a formal assessment of depression as well as a formal assessment of exercise.
  • The effect size of MVPA on MDD symptoms was small, but still on the order of magnitude of those of psychosocial intervention programs in children. And medications do not always work (and probably have more adverse effects than exercise…). So, exercise may well be an important therapeutic approach to treating depression in kids (i.e., not just preventative, as suggested in this study, and should probably be formally evaluated).
  • Some postulates as to why physical activity might decrease depressive symptoms include: these activities might distract children from thinking about negative events; physical activity in children also may bolster their self-esteem; and physically active children are more socially integrated into peer groups.
  • The mechanism by which physical activity might have helped include: higher availability of neurotransmitters which are depleted in people with depression and which may have antidepressant effects if augmented (e.g. serotonin, dopamine and norepinephrine); the potentially positive role for exercise-induced endorphins (see above cited article by Craft); also, there is evidence of increased cerebral blood flow and cognitive function with exercise. Other studies have shown that children taking exams in school do better when they are more physically active prior to taking those exams.
  • One quite concerning social evolution is that many schools have cut out physical education/activity in order to cram in more academic subjects. Unfortunately, this could not just lead to decrease school performance, but also reinforce future patterns of inadequate physical activity. It is concerning in this study that exercise decreased and sedentary time increased from ages 8 to 10.

So, MVPA did predict fewer future MDD symptoms in children, and such symptoms were relatively stable from ages 6 to 10. Sedentary activity however did not affect the risk of future symptoms of depression, and depression does not seem to influence the likelihood of MVPA or sedentary behavior. Their conclusion was that increasing MVPA at a population level may prevent depressive symptoms or MDD. And I think it makes sense for us in primary care to strongly encourage physical activity and advocate for more exercise in schools, and that exercise be considered an integral part of the curriculum, emphasized and promoted by the school system. And that there be more neighborhood-friendly and safe exercise venues, etc. Per the prior blogs and the myriad articles on the benefits of exercise, this is not just to prevent depression…

Primary Care Corner with Geoffrey Modest MD: Acute low back pain diazepam not help

1 Mar, 17 | by EBM

By Dr. Geoffrey Modest

An urban emergency room study found lack of utility of diazepam in patients with acute low back pain (see doi.org/10.1016/j.annemergmed.2016.10.002).

Details:

  • 114 patients with acute, nontraumatic, nonradicular low back pain (LBP) of <2 weeks and Roland-Morris Disability Questionnaire (RMDQ) >5 points (a 24-item patient self-administered questionnaire score which measures functional disability, with questions like “I stay at home most of the time because of the pain in my back”, where a 5 point change is considered clinically significant).
  • Mean age 36, 55% male, 73% worked >30hrs/week; median RMDQ score in the ER was 18 [which means substantial functional disability], median duration of LBP before coming to ER 2.5 days, 45% no prior history of LBP/ 48% “few times before”, 5% depressed
  • Randomized to naproxen 500mg bid prn, with either diazepam 5mg or placebo, to take 1-2 tabs every 12 hours prn. All patients got a 10-minute LBP educational session

Results:

  • 112 patients (98%) provided 1-week follow-up
  • At 1 week:
    • Frequency of med use:
      • Naproxen: 70% more than 1x/d, 17% 1x/d
      • Diazepam: 38% more than 1x/d, 32% 1x/d
      • Placebo: 38% more than 1x/d, 29% 1x/d
    • 18 of 57 patients on diazepam (32%) reported moderate or severe LBP
    • 12 of 55 on placebo (22%) had moderate or severe LBP
  • At 3 months:
    • 6 of 50 patients on diazepam (12%) reported moderate or severe LBP
    • 5 of 53 on placebo (9%) had moderate or severe LBP
  • Adverse events: 12 of 57 on diazepam (21%) vs 8 of 55 on placebo (15%)

Commentary:

  • LBP leads to 2.4% of all ER visits (2.7 million annually)
  • Of those presenting with acute LBP, most recover, though 20% have moderate to severe LBP-related functional impairment at 3 months
  • Benzos are sometimes prescribed for sleep and well as for “muscle relaxation”, though the data to support benefit are meager at best. And diazepam is prescribed in about 300,000 ER visits for LBP annually. Hence this study – which showed no benefit but more adverse effects with diazepam
  • The authors comment that most medications do not improve low back pain (see relevant blogs below), also including steroids or acetaminophen; that complimentary therapies (acupuncture, yoga, massage) have little data to support (see blog below on the AHRQ review), and that spinal manipulation is unlikely to benefit ER patients with acute low back pain.
  • This is the same ER group that did a similar study a couple of years ago looking at the efficacy of adding cyclobenzaprine or oxycodone/acetaminophen to naproxen for the same issue (see Friedman BW JAMA 2015; 314(15): 1572), briefly:
    • 323 patients with nontraumatic, nonradicular LBP for < 2 weeks’ duration, given naproxen 500mg bid plus either placebo, cyclobenzaprine 5mg or oxycodone 5mg/acetaminophen 325, to take 1-2 tablets of these q8h as needed, along with a 10 minute LBP educational session
    • They assessed pain by the Roland-Morris Disability Questionnaire (RMDQ), as above
    • Results: at 1-week follow-up, no significant difference between groups, as follows:
      • Naproxen: 72% of patients took naprox >1x/d, 13% took it 1x/d
      • Naproxen, along with:
        • Placebo: RMDQ improved 9.8 points (33% took placebo > 1/d, 31% 1/d)
        • Cyclopbenzaprine: RMDQ improved 10.1 points (31% took it > 1/d, 38% 1/d), more adverse effects than placebo by 13%, NNH (number needed to harm) =7.8
        • Oxycodone/acetaminophen: RMDQ improved 11.1 points (32% took it > 1/d, 21% 1/d), more adverse effects than placebo by 19%, NNH =5.3
      • Overall about 2/3 of patients reported clinically significant improvement 1 week later, though 40% reported moderate or severe pain
      • Also no difference at 3 months, though about ¼ of the patients still reported moderate or severe LBP
    • So, similar to the diazepam study: no evident benefit from either cyclobenzaprine nor oxycodone (though notable perhaps that relatively few patients took the meds much)
    • It should be noted in the oxycodone study that, of multiple exploratory analyses, one did show modest pain relief in the group who took oxycodone more than 1x/d, though the NNT was 6 and the NNH was 5.  So they could not exclude the possibility of modest benefit in those taking more oxycodone
    • See http://blogs.bmj.com/ebm/2015/11/06/primary-care-corner-with-geoffrey-modest-md-opiates-for-acute-low-back-pain/ for a more complete analysis of this study
    • And other studies have not found benefit of the combo of NSAIDs with cyclobenzaprine (either one seems to be equally effective, the combo doesn’t add much)

 

So, these studies do add to the approach to acute low back pain: adding “muscle relaxants” to NSAIDs does not add any clear benefit but does add harms (though another study did find benefit of cyclobenzaprine by itself). And acute treatment by oxycodone, at least in the doses they prescribed, also showed no clear benefit. I would add to this the results from a few other blogs:

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