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Primary Care Corner with Geoffrey Modest MD: Benzos may not increase mortality risk

17 Jul, 17 | by

by Dr Geoffrey Modest

​ The BMJ just had an article assessing mortality from benzodiazepines from a large US commercial healthcare database, showing minimal increased mortality risk (see


— 1,252,988 randomly selected patients, comparing those initiated on a benzodiazepine during a medical visit within the prior 14 days vs 1,252,988 non-initiators, from 2004-2013

— all patients were required to fill at least one prescription for any medication both in the 90 days and 91- 180 days before the index date (ie, they were plugged into medical care and filling prescriptions), and high dimensional propensity scoring was done (see below).

— Mean age 46, 85% men, mean Charlson comorbidities score 0.5 (ie, low), 5% smokers, 4% obesity/overweight, 28% hypertension, 1% heart failure, 5% ischemic heart disease, 25% hyperlipidemia, 10% diabetes, 3% COPD, 5% asthma, 10% neuropathic pain, 20% back pain, 3% kidney disease, 10% cancer, 10% anxiety, 10% sleep disorder, 11% depression, 2% drug or alcohol misuse [reaffirming that this is a pretty healthy and younger population overall]

— Medications included SSRIs in 18%, opioids in 30%, barbiturates in 2%, antipsychotics in 2%, other anxiolytics in 1%

— of note, in comparing benzodiazepine initiators vs non-initiators, prior to propensity scoring, the benzodiazepine group had more smokers, hypertensives, atherosclerotic disease, hyperlipidemia, COPD/asthma, neuropathic pain, cancer, a lot more anxiety and depression, and were much more likely to be on beta blockers, steroids, opioids (35% vs 24%!!), anticonvulsants, SSRIs (22 vs 12%), and other hypnotics. All of these characteristics were well-balanced after propensity score matching

— Short acting benzodiazepines were more frequently prescribed, 75% of the filled prescriptions, and alprazolam was the most commonly prescribed of them (47.2%), and diazepam was the most commonly prescribed long-acting agent (87.8%). On review of their supplementary materials, they did include clonazepam as a short acting benzodiazepine, though it’s half-life is actually quite similar to that of diazepam  (both about 20 hours, sometimes much more: >60 hours)​. Not sure why they did that.

— main outcome: all-cause mortality, as determined by linking to the Social Security Administration Death Master File. The overall mean follow-up was 159 days for the benzodiazepine initiators and 146 days for the non-initiators.

— secondary analysis: comparing mortality in patients initiating benzodiazepines with other active treatments (i.e. SSRI antidepressants), also with high dimensional propensity score matching



— over 6 months of follow-up, there were 12.2 events per 1000 person-years in the benzodiazepine initiators vs 6.9 events per 1000 person-years non-initiators, a 78% increased mortality risk. But, given the different baseline characteristics of these groups, probably  the most relevant finding was that after the high dimensional propensity scoring, there were 5061 deaths in benzodiazepine initiators vs 4,691 in non-initiators, 9.3 vs 9.4 events per 1000 person-years; HR 1.00 (0.96 1.04 ). ie no difference

— a 4% increased mortality risk was observed in those on benzodiazepines when the observation period was extended to 12 and 48 months of follow-up.

— benzodiazepines were associated with a 9% increased risk as compared to those starting SSRIs

— in subgroup analysis, older patients initiating benzodiazepines with a longer half-life had no increased risk of all-cause mortality, however younger patients and patients using the short-acting benzodiazepines did have a 9% increased risk.


— Propensity match scoring was used to mathematically control for potential measured confounders. The high dimensional propensity score algorithm also used above is an automated technique which prioritizes/controls for more than 300 covariates that may serve as proxies for unmeasured confounders in large electronic databases. but it is important to reinforce that even large observational studies as this one do not enable us to draw definitive conclusions about causality: there still could be unmeasured variables which are primarily responsible for any associations. This population overall was pretty healthy, those on benzodiazepines less so, emphasizing that there might well have been other significant differences between these groups (though the lack of association is reassuring, since these sicker patients, controlling for their measured sicknesses but were probably at higher risk for other unidentified sicknesses and more likely to have a less healthy lifestyle, and they did not have higher mortality than the much less sick non-benzo initiators).

— As we know, benzodiazepines are frequently used in the outpatient setting, in 2008 approximately 5.2% of US adults aged 18 to 80 used benzodiazepines, increasing from 4.1% in 1996 to 5.6% in 2013. Similar numbers were found in British Columbia, Canada. Use increases with age, with a higher usage in those older than 50, especially for anxiety and sleep disorders. The concerns about their use in the elderly is related to prior reports of a threefold or more increased risk of all-cause mortality, even for short duration usage. And concerns remain about increased falls and fractures in the elderly. it should also be emphasized that this population above is a younger one, a selection bias related to the fact that this was a commercial healthcare database.

— It seems pretty remarkable that in the overall population, 35% of those who initiated benzodiazepines were on opioids vs 24% who did not start benzodiazepines. Given the apparent higher mortality of benzodiazepines in those on opioids found in a few observational studies (eg, see blog), it would have been useful to know specifically how the opioid subgroup fared. One concern that I have regarding the potentially increased mortality of combination of benzodiazepines and opioids is whether it is really from the combination or from the patient mortality associated with the conditions that the benzodiazepines might be treating (e.g. the significantly increased mortality of panic or other anxiety disorders).


—  the increases in mortality found in the subgroup analyses above were very small, though statistically significant because of the huge number of patients evaluated​. so, clinically they found essentially no difference in those initiating benzos

— from a clinical practice perspective, this study to me is largely reassuring​: I have certainly seen many older patients (again, not well represented above) who are severely functionally affected by anxiety, resistant to non-pharmacologic therapies as well as non-benzodiazepine drugs. I have prescribed benzodiazepines in many if them with excellent results. Preferentially I have used longer acting benzodiazepines, such as clonazepam (though as noted, they consider this a short acting benzodiazepine in the above study, but i think that might be an erratum), even in patients in their 90s. Patients certainly understand the potential increased risks of falls and possible increased mortality, but are desperate for immediate symptomatic relief.

Primary Care Corner with Geoffrey Modest MD: Home-based CBT for low back pain

6 Apr, 17 | by

​by Dr Geoffrey Modest


As mentioned in a recent blog (see here ), the effectiveness of medications for chronic pain is somewhat limited, and more studies have been coming out about nonpharmacologic therapy, either as solo or adjunctive therapy. Cognitive behavioral therapy (CBT) has been shown to benefit patients with chronic low back pain (see blog referenced below), but patient access to such therapy may be limited. In this light, a new trial showed that home-based, telephonic therapy may be as good as in-person CBT (see doi:10.1001/jamainternmed.2017.0223).


— Details:

— a single center VA study enrolled 125 patients with chronic back pain, allocated equally to interactive voice response-based CBT (IVR-CBT) versus standard CBT

— this was a non-inferiority study, with primary outcome being change from baseline to 3 months in patient-reported Numeric Rating Scale (NRS) of pain, a scale from 0 to 10. Secondary outcomes included pain-related interference in daily activities; and emotional functioning, sleep quality, and quality of life at 3, 6, and 9 months. These were assessed by the West Haven-Yale Multidimensional Pain Inventory, and the Morris Disability Questionnaire.

— 97 men and 28 women, 65% white/26% black, mean age 60, 20% full-time employed/14% part-time/15% unemployed/29% retired, 18% disabled, 26% with history of substance abuse, mean duration of back pain was 11 years, 55% with nonspecific cause/43% with radiculopathy or spinal stenosis, 12% with opioid prescriptions at baseline, average NRS pain rating was 5.58,

— All patients received a manual specific to their intervention (CBT versus IVR-CBT), to be followed over 10 weeks. The manual included an introductory module about the rationale for CBT, 8 pain-coping skill modules, and a relapse prevention module. All patients received IVR, consisting of 11 weeks of daily telephone calls to the patient to assess pain, sleep, step count, and pain-coping skill practice; if patients were engaged in a progressive walking program; and if they continue to receive care from their primary care clinician. All patients in both groups received these calls.

— In-person CBT involved weekly 30 to 40 minute treatment sessions, where the therapist reviewed the IVR reports and provided feedback during the sessions

— IVR-CBT involved receiving therapist reviews of the IVR reports in a 2 to 5 minute personalized feedback session


— Results:

— 82% completed at least 3 treatment sessions, though the IVR-CBT group attended 2.3 more sessions than in-person CBT (8.9 versus 6.6)

— NRS score: IVR-CBT decreased 0.77 points, versus a decrease of 0.84 with CBT, signifying noninferiority. Both groups had statistically significant reductions in average pain intensity at 3 and 6 months post-baseline but not after 9 months. These improvements were considered clinically meaningful changes, though of modest effect size.

— Statistically significant improvements in physical functioning, sleep quality, and physical activity of life at 3 months occurred in both treatment groups, with no difference between the groups.

— Post-treatment, 33% of those with standard CBT reported clinically meaningful improvement in pain intensity of at least 30% compared with 19% in those receiving IVR-CBT, not statistically significant.

— Adverse events: 46 participants, mostly related to increased pain from exercise, no difference between groups


— Commentary:

— IVR-CBT seems to offer a more accessible and lower cost treatment option for patients with chronic low back pain, which may well apply to other types of chronic pain (there are data supporting CBT benefit for back pain, osteoarthritis, and fibromyalgia). CBT involves helping patients reconceptualize pain as influenced not only by biological but by psychological, behavioral, and social factors. Patients learn cognitive (e.g. reframing catastrophic thoughts) and behavioral (e.g. relaxation techniques) coping skills through this process, as elaborated in the article.

— It is notable that patients were more engaged with the IVR-CBT-based therapy, attending significantly more sessions, than with standard CBT therapy. This suggests not just the acceptability of this IVR-CBT therapy, but likely also the decrease in burden/increase in accessibility and appeal of this treatment.

— There are several limitations to the study, including the fact that it was carried out in only one VA Hospital and with a small number of patients. Also, there was no nonintervention/placebo arm. However, this last concern may be less significant given that the average duration of pain was 11 years, suggesting that patients actually act as their own control.

— Also, it would be really interesting to know how those with a history of substance use disorder (26% in this article) or those on prescription opioids (12%) would do with IVR-CBT. The numbers of patients in this study was probably too small to get meaningful insight into this.


So, this may well be a viable and accessible alternative or adjunct for chronic pain management, and may really help patients who are functionally impaired by the pain, adding to the increasing numbers of nonpharmacologic therapies for this common and difficult problem. It also adds to the impetus for us to offer these types of therapies instead of just jumping to prescribe medications.

see​ which reviews a few articles: the main one on tai chi for knee arthritis, another on mindfulness-based stress reduction for chronic pain, and another on CBT for back pain




Primary Care Corner with Geoffrey Modest MD: Fluoroquinolone Warning

16 Dec, 16 | by EBM

By Dr. Geoffrey Modest

There was another FDA warning recently, this time regarding systemic fluoroquinolones (ciprofloxacin, levofloxacin, etc.), leading to a boxed warning, the FDA’s strongest warning (see for the summary, and for the full report).


  • Fluoroquinolones are associated with disabling and potentially permanent adverse effects on tendons (tendinitis, tendon rupture), muscles (muscle weakness or pain), joints (joint pain or swelling), peripheral nerves (peripheral neuropathy), and the central nervous system (anxiety, depression, hallucinations, suicidal thoughts, psychosis, confusion). Other adverse effects include worsening of myasthenia gravis, skin rash, sunburn (photosensitivity/phototoxicity), irregular heartbeat (including prolonged QT interval), severe diarrhea (they are the leading cause of Clostridium difficile-associated diarrhea). Multiple problems can occur in the same patient. The peripheral neuropathy may be irreversible.
  • Therefore, fluoroquinolones should only be used in patients where no other treatment options are available for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections. Also for serious bacterial infections where the benefits outweigh the risks.
  • The prior warnings for tendinitis, tendon rupture, and worsening of myasthenia gravis has been extended by the above problems.
  • Side effects may occur within hours to weeks after starting the fluoroquinolone and continue an average of 14 months to as long as nine years after stopping the medicines. (Though, as noted, some may be irreversible)
  • The majority (74%) of reported cases were in patients 30 to 59 year-olds, some with severe resulting disabilities. Most of the adverse reactions involve the musculoskeletal system, peripheral nervous system, and central nervous system. Long-term pain was most commonly reported symptoms, 97% of all cases reporting pain associated with musculoskeletal adverse effects
  • And one should stop treatment at the first sign of an adverse reaction


  • Although many of the musculoskeletal and central nervous system effects have been known for many years, the above update includes many other conditions. And some of the newly included conditions (e.g. peripheral neuropathy) can last forever.
  • My sense locally is that fluoroquinolones are still being used quite frequently for uncomplicated urinary tract infections and other relatively minor infections. Hopefully the above warning will further discourage their potentially unnecessary usages.
  • I’m also very concerned about antibiotic resistance overall, as many of you know. Please see for many blogs highlighting in rather scary detail the increasing antibiotic resistance in general, both in the US and worldwide. And I am also concerned about the effect of broad-spectrum antibiotics in particular and fundamental changes in the gut microbiome which can lead to many known, and probably many more unknown, health complications (see many blogs in )

Primary Care Corner with Geoffrey Modest MD: FDA Warnings Fluoroquinolones, Aripiprazole, Olanzapine

31 May, 16 | by EBM

By Dr. Geoffrey Modest

The FDA has sent out several Drug Safety warnings in the past few weeks.

  1. Fluoroquinolones
  • Given the widespread reports of adverse effects of fluoroquinolones, the FDA issued a report in 2013 requiring a label change (see ). Specifically, they noted an association with disabling peripheral neuropathy (with the onset of peripheral neuropathy often within a few days of starting the fluoroquinolone, and ongoing symptoms for more than a year in some patients, long after stopping the med).
  • There already were labels warning about risks of tendinitis, tendon rupture, CNS effects, exacerbations of myasthenia gravis, QTc prolongation/torsades, phototoxicity, and hypersensitivity (and I did send one patient to the ICU with anaphylaxis from ciprofloxacin around 15 years ago)
  • The actual warning from 5/12/16 states that the FDA “is advising that the serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with sinusitis, bronchitis, and uncomplicated urinary tract infections who have other treatment options”. See .
  1. Aripiprazole
  • The FDA just issued a safety alert for aripiprazole (goes by trade name Abilify). See This medication has FDA approved indications for treating schizophrenia, bipolar disorder, Tourette’s disorder, and irritability associated with autistic disorder. It is also used (and apparently advertised widely on TV) in combination with antidepressants to treat depression. The FDA is warning that it might be associated with compulsive or uncontrollable urges to gamble, binge eat, shop, and have sex. And these urges desist on stopping the drug or with dose reduction. But 4 cases had a return to this behavior with rechallenge. They do note that these impulse-control problems are rare (184 case reports since 2002, though there are apparently 1.6 million patients on the drug), with pathological gambling being the most common. The recommendation is just that we and patients be alert to this possibility. And we should closely monitor patients at higher risk for impulse-control problems, including personal/family history of obsessive-compulsive disorder, impulse-control disorder, bipolar disorder, impulsive personality, alcoholism, drug abuse, or other addictive behaviors. But in most cases there was no prior history of compulsive behaviors overall, and none had a history of pathological gambling, compulsive sexual behavior, binge eating, or compulsive shopping prior to taking aripiprazole.
  • On reading about aripiprazole it is quite remarkable the array/diversity of actions it has: (per com) — “Aripiprazole exhibits high affinity for dopamine D2and D3, serotonin 5-HT1A and 5-HT2A receptors, moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors, and moderate affinity for the serotonin reuptake site. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptor.]” It is certainly true that many CNS-active drugs have multiple effects on multiple neurotransmitters, leading to many of their attendant adverse effects, though aripiprazole outdoes seem to outdo some of the others.
  1. Olanzapine
  • The FDA issued a drug safety communication about olanzapine and DRESS syndrome (see ).
  • DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) often starts as a rash that spreads to all parts of the body, and includes 3 or more of: rash, eosinophilia, fever, lymphadenopathy, and systemic complications (hepatitis, myocarditis, pericarditis, nephritis, pancreatitis, pneumonitis), and often occurs after a long latency of 2-8 weeks after drug exposure. there is a 10% mortality rate
  • 23 cases of DRESS have been reported since 1996. One patient has died.


So, as with all FDA reports, these cases likely significantly underestimate the true incidence of problems, since in a busy clinical session, it is difficult/time-consuming to report the adverse events. But it is important for us as clinicians to know about these potential issues. The most important one for us is the fluoroquinolone advisory. As many blogs and articles have articulated: many too many antibiotics are being used for non-bacterial infections (bronchitis, sinusitis…), and there has been a very unfortunate shift to using more broad-spectrum and resistance-producing antibiotics (more azithromycin for strep, etc., than narrower antibiotics like penicillin). And I think many of us do still use ciprofloxacin for uncomplicated urinary tract infections.

See for studies on antibiotic overprescribing and their consequences

Primary Care Corner with Geoffrey Modest MD: Low Back Pain Improves with Stress Reduction — Mindfulness and Cognitive Behavioral Therapy

7 Apr, 16 | by EBM

Dr. Geoffrey Modest

I recently sent out the review from AHRQ on low back pain (LBP) management, noting that psychological therapies (especially restoration or cognitive-behavioral therapies) have small-to-moderate effect for improving pain or function (for full review of pharmacologic and nonpharmacologic therapies, see . A new study was just published in JAMA on the efficacy of mindfulness-based stress reduction (MBSR) in reducing pain and improving function in those with chronic low back pain (see JAMA. 2016;315(12):1240). This study was sponsored by the National Center for Complementary and Alternative Medicine of the NIH.


  • 342 adults aged 20-70 with chronic low back pain of at least 3 months, recruited from 2012-2014 and randomly assigned to MBSR or cognitive behavioral therapy (CBT) vs usual care
  • Mean age 49.3, 65.7% women, 82.5% white/6.8% Hispanic, mean duration of LBP of 7.3 years
  • Interventions:
    • 8 weekly 2-hour MBSR sessions, including education about mindfulness, increasing awareness of body sensations, techniques to promote mindful practice (yoga, meditation), learning how to understand and change how we react to stress, understand the relationship between stress and pain, etc. People were asked to practice this daily for up to 45 minutes during the intervention and afterwards. Most instructors were trained in the Center for Mindfulness at U Mass Medical School. [MBSR focuses on “increasing awareness and acceptance of moment-to-moment experiences including physical discomfort and difficult emotions”, with the hypothesis that “practicing mindfulness skills improves one’s ability to experience pain without excessive emotional reactivity, leads to cognitive changes, and promotes relaxation”.]
    • 8 weekly 2-hour CBT sessions, focusing on education about maladaptive thoughts (e.g. catastrophizing) and beliefs, education about chronic pain and the relation between thoughts and emotional and physical reactions, challenging negative thoughts, using positive coping strategies…
    • Usual care typically includes using meds, seeing primary care providers, physical therapists, etc.
  • Assessed: clinically meaningful (≥ 30%) improvement in functional limitations by the Roland Disability Questionnaire (RDQ) on a scale from 0-23 (baseline mean was 11.4), and in self-reported LBP bothersomeness on a scale from 0-10 (baseline mean was 6.0)


  • 53.7% of individuals (n=123) attended 6 or more of the 8 sessions
  • In intention-to-treat analyses at 26 weeks
    • 60.5% assigned to MBSR and 57.7% with CBT had clinically meaningful improvements in RDQ, vs 44.1% in usual care (p=0.04)
      • RR for MBSR vs usual care was 1.37 (1.06-1.77); RR for CBT vs usual care are 1.31 (1.01-1.69)
    • 43.6% in the MBSR and 44.9% in the CBT groups had clinically meaningful improvements in pain bothersomeness at 26 weeks vs 26.6% of usual care (p=0.01)
      • RR for MBSR vs usual care was 1.64 (1.15-2.34); RR for CBT vs usual care are 1.69 (1.18-2.41)
    • At 52 weeks
      • Little change in the MBSR group for either RDQ questionnaire or pain bothersomeness symptoms; there was some deterioration of CBT for both of these outcomes, leading to their not being statistically significant
    • These differences in RDQ and bothersomeness of pain were considered to be of moderate degrees.

So, several issues:

  • As we know in primary care, chronic LBP is one of the hardest and most frustrating diagnoses (for both the patients and us), since we do not have great treatments. As noted in the AHRQ review, there are remarkable limitations to both the pharmacologic and nonpharmacologic approaches. (See the blog for more details and comments)
  • It is certainly impressive that both of these psychological interventions seem to work, and better than our “usual treatment”. But perhaps the most interesting point is that they work long-term, that in some ways these therapies, after only an 8-week intervention, seems to enable and empower people to take care of themselves better (in both the MBSR and CBT groups, people were given DVDs and other aids to help them continue the therapy after the intervention)
  • These results were likely dwarfed by the fact that only about 1/2 of the patients actually participated fully in the psych interventions. The article did not give specific statistics about benefit in those who fully participated, but one might presume that they did especially well. And that if we were even more successful in encouraging patients in participating, we might have even better results (in fact, we as primary care clinicians with strong relationships with patients might well do better in encouraging patient participation than people hired in this study did)
  • So, it seems that both MBSR and CBT are effective therapies for chronic LBP, with potentially long-lasting moderate efficacy. And, though there are other studies showing the effectiveness of CBT in patients with chronic LBP, access to CBT is not universal, so MBSR seems to provide a reasonable alternative with perhaps even better long-term benefit.

Primary Care Corner with Geoffrey Modest MD: Phobias and Propranolol

28 Jan, 16 | by EBM

By Dr. Geoffrey Modest

There was a recent op-ed in the NY Times by the psychiatrist Richard Friedman on phobias and medical therapy (see ).

His points:

  • 29% of Americans have some anxiety at some point in their lives
  • He cites a pretty remarkable study on using propranolol to block this anxiety, perhaps from blocking norepinephrine action (see article and review below)
  • He also raises the interesting contrary concern: stimulants (e.g. ritalin) can cause release of norepinephrine and could theoretically enhance fear/anxiety, or even PTSD in those exposed to trauma. He notes that soldiers exposed to stimulants did in fact have more

A small study was done looking at the effects of the b-blocker propranolol in inhibiting memory reconsolidation and decreasing the phobia (see Biological Psychiatry 2015; 78:880). The stimulus for the study was that fear memories are now considered not to be indelible memories, but ones which on reexposure to the object of fear, leads to neural protein synthesis and reconsolidation of that memory. Animal studies suggest that b-blockers can disrupt this process of reconsolidation and decrease anxiety. Based on this model, a small study was done of humans with arachnophobia. Wolf_spider_on_white


  • 15 people with arachnophobia (fear of spiders) received a single dose of propranolol, 40mg, vs 15 who received placebo, after a 2-minute exposure to a tarantula. An additional group received propranolol without the arachnid exposure
  • After the above treatment (propranolol or placebo), the patients stood in front of an open-caged tarantula at a distance of 60cm, then were asked to approach and attempt to touch the spider with their bare fingertips. Patients were tested at 16 days post-exposure, 3 months, and again at 1 year


  • ​The effect of the propranolol was striking and longstanding: patients were able to handle the tarantula after propranolol but not placebo, from the 16-day test to that at 1 year, without any falloff over time. In fact, all of the participants in the propranolol group were able to touch the tarantula 16 days later, 3 months later and 1 year later. In the other groups (both those on placebo and those on propranolol but not previously exposed to the tarantula), patients “barely touched the container” and demonstrated fears on approaching the container throughout the follow-up period. So, it was not just giving propranolol alone: taking propranolol without the tarantula exposure had no protective effect
  • In the group exposed to the tarantula, there was no effect of the propranolol in the patients’ self-declared fear of spiders at the 16 day post-exposure test (though, as noted, they were able to physically handle the spider at that time). But at 3 months there was less reported fear of spiders, and this persisted for the 1-year test

So, a few points:

  • Pretty remarkable that a single dose of propranolol can block the phobia for at least one year (though there were small numbers of patients in this study, propranolol certainly seems worth trying, it being a known and pretty innocuous med). Data from cognitive-behavioral therapy and extinction therapy (progressively increasing exposure to the feared object) show effectiveness, though that lasts only a brief time (personal testimony: I have some significant fear of heights. When I need to work on the roof of my house, it is really anxiety-provoking the first or second time up the ladder. But after a few times, I am fine going up and down, without concern — except that I am very careful. But then several months later, I am back to square one….)
  • And it is pretty interesting that the physiologic effect of propranolol is initially distinct from the cognitive effect, in that patients still stated they were still afraid of spiders at the day-16 test.
  • There are also some preliminary evidence that b-blockers decrease physiological responses to re-experiencing trauma in people with PTSD (it might be really interesting to try propranolol just after a person with PTSD has an experience which brings back memories of their trauma…). But, as a conceptual aside,​ I have seen several articles on the use of prazosin for PTSD (e.g., see AnnPharmacother 2007; 41: 1013)​, especially for decreasing the associated nightmares, and I have treated several patients with great, rather unexpected success. The concept is that sleep disorders are common with PTSD (70%), and that prazosin inhibits norepinephrine and perhaps thereby decreases the arousal in response to a stressor. In my experience, even very low dose prazosin has had dramatic results (e.g. 1-3 mg at night), though a recent article (Ther Adv Psychopharmacol 2014; 4: 43) notes that often higher doses are needed for full responses. These researchers also present 2 cases of patients of patients with psych comorbidities, one with PTSD and underlying major depressive disorder, but with a lot of daytime symptoms as well (hyperarousal, flashbacks, and re-experiencing the trauma) who responded pretty dramatically to prazosin 15mg in the am, 10mg at noon, and 20mg at night, and this high dose was very well-tolerated. The second patient with long-standing treatment-resistant major depressive disorder, PTSD and panic disorder and having failed a litany of meds, had lots of flashbacks, hypervigilance, reliving the experience, avoidance, nightmares, insomnia and concentration difficulties. She was titrated up to a dose of prazosin 15mg in am, 5mg at noon, and 10mg at night, and was also put on clomipramine for the depression, with a phenomenal response (PHQ-9 of 0 and asymptomatic PTSD).
  • So, as more studies unfold, the brain seems to be increasingly plastic/reprogrammable (i.e., it is not set for life at age 2, or 20, or ….)

Primary Care Corner with Geoffrey Modest MD: Spicy Foods and Mortality

13 Aug, 15 | by EBM

By Dr. Geoffrey Modest

A large epidemiologic study from 10 diverse areas in China looked at total and cause specific mortality in those eating spicy foods (see BMJ 2015;351:h3942).


  • Spices (esp capsaicin) have antibacterial activity and modify the intestinal microbiome (no clear data on exactly how the microbiome is altered, or to what effect)
  • Capsaicin has been studied in small populations or experimental conditions, finding it has anti-obesity, antioxidant, anti-inflammatory, anti-cancer, antihypertensive effects, and improves glucose homeostasis.​
  • Ingestion of hot red pepper decreases the appetite of both Asian and white people (?decreasing obesity-related morbidity/mortalitychili-61898_640)
  • A large ecological study has found higher spice consumption is associated with lower cancer incidence (these are rough-and-dirty studies which just show that in areas of high spice consumption there is less cancer, without the specifics showing individuals who eat spice have less cancer)

Details of this study:

  • 199,293 men and 288,082 women aged 30-79, without known cancer, heart disease or stroke at baseline, had an initial food questionnaire including consumption frequency of spicy foods, then followed 7.2 years (3.5M person-years of followup) between 2004-2013.
  • mean age 50, BMI 23, 5% diabetic, 35% hypertensive
  • 11,820 men and 8404 women died during this time period
  • those who consumed more spicy foods were from more rural areas (48% of low consumers, 82% high), more likely to smoke (57% vs 70% for men and 1.8 vs 3.0% for women) and drink alcohol (27% vs 47% men and 1.2 vs 3.8% women), and more frequently consumed red meat, vegetables and fruits (though not huge differences in these numbers).  Most common spice was fresh or dried chili peppers
  • Absolute mortality rates (in deaths/1000 person years):
    • ​6.1 for those eating spicy foods <1x/week
    • 4 for those eating spicy foods 1-2x/week, adjusted hazard ratio compared to those <1x/week=0.90 (0.84-.96)
    • 3 for those eating spicy foods 3-5x/week, adjusted hazard ratio compared to those <1x/week=0.86 (0.80-.92)
    • 8 for those eating spicy foods 6-7x/week, adjusted hazard ratio compared to those <1x/week=0.86 (0.82-.90) — ie, a 14% relative risk reduction
    • The above numbers adjusted for underlying hepatitis, smoking, prevalent diabetes or hypertension, red meat or vege consumption, alcohol, SES, BMI, physical activity, family history
    • Overall, women did better than men, with a 20% risk reduction, vs 10% for men
  • The relationship between eating spicy food was stronger in those not consuming alcohol (p=0.033 for interaction). somewhat stronger benefit if eating fresh vs dried chili peppers
  • Inverse relations also noted for deaths due to cancer, ischemic heart disease, and respiratory diseases

So, a couple of comments:

  • This is a large epidemiologic study, subject to the usual caveats: concerns about adequacy of consumption data (only one initial dietary assessment, and self-reported; also those with high chili consumption likely used other unmeasured spices and ingredients) and adequacy of outcome data (quality of death reports). Also, hard to separate the non-measured differences between those living in more rural than more urban settings (and the difference in spicy food consumption was pretty striking in the different settings). Though it is notable that the high spicy food consumers did have some not-so-great lifestyle parameters (smoking alcohol, red meat). And, perhaps most importantly, epidemiologic studies preclude determining that a relationship is causal
  • In this study, there was a threshold: when people consumed spicy foods 1-2x/week, they achieved almost all of the benefit
  • But my real bottom line is that I should now add fresh chilies to my dark chocolate snacks.

[Here are a couple of the blogs on chocolate: and ]​

Primary Care Corner with Geoffrey Modest MD: Post-op Delirium in Elderly

12 Aug, 15 | by EBM

By: Dr. Geoffrey Modest

A recent study found a significant relationship between inflammatory markers and the development of delirium post-operatively (see doi:10.1093/gerona/glv083). This study assessed 566 patients >70yo undergoing major noncardiac surgery from the Successful Aging after Elective Surgery Study (SAGES), and compared 12 different cytokine levels in those patients who developed delirium vs not. Funded by the National Institute on Aging.


  • Inflammatory markers have been linked to a variety of outcomes in the elderly, including frailty, dementia and cognitive decline, as well as several medical diseases (diabetes, heart disease…)
  • Delirium is associated with systemic inflammatory states (eg, infections), perhaps related to inflammation-related breakdown of blood-brain barrier, microglial activation, and neuroinflammation.

Details of this study:

  • Mean age 77, 56% female, vascular comorbidity approx 45%, General Cognitive Performance mean of 55 (this is a composite measure reflecting vulnerability to delirium, which to my reading is a scale normalized to 50 for the elderly, with a score of 50 roughly correlating to an MMSE of 26, and a score of 55 correlating with 28)
  • Cytokines were measured at 4 times in all patients: pre-op (PREOP), post-anesthesia (PACU), post-op day 2 (POD2), and post-op day 30 (POD1M)
  • This was a case-control study matched for age, sex, surgery type, baseline cognition, vascular comorbidity, apo E genotype
  • Delirium was assessed by the Confusion Assessment Method algorithm
  • There was a 3-stage approach: a discovery cohort (n=272, comparing 39 matched pairs of delirium cases vs no-delirium controls), a replication cohort (36 matched pairs from the remaining SAGES sample), and a combo of these 2 (with 75 matched pairs).
  • Results:
    • The most consistently elevated statistically significant cytokines in the different cohorts:
      • IL-2, especially on POD2
      • IL-6 (the most elevated, and dramatically so), esp POD2
      • IL-12 was decreased, mostly POD1M
      • TNF-a (tumor necrosis factor alpha) and VEGF (vascular endothelial growth factor): both peaking on POD2
      • The association was found in all the cohorts, though less impressively in the replication cohort

This study confirms some previous studies finding an association between cytokines and delirium. In other studies IL-6 has been found to be associated with age-related frailty and dementia. IL-2 regulates growth and differentiation of T cells and affects the development of the immune system and also seems to induce blood-brain barrier dysfunction. A strength of the current study is that it had a real baseline cytokine measurement (some of the studies of patients with hip fractures could have had cytokine increases based on the trauma. This study was in patients getting elective surgery). Also, the cytokines measured in the current study did not include acute phase reactants.

So, delirium is a pretty awful disease for patients and family, with increased mortality, increased hospital stays with their attendant morbidity and cost, high rates of institutional placement, and perhaps even high risk of subsequent dementia. This study provides both a potential means to identify patients at high risk of delirium early, and could ultimately lead to new medications to prevent delirium (all to be determined). I did send out a previous blog on the efficacy of melatonin-like meds in preventing delirium (see )

Primary Care Corner with Geoffrey Modest MD: Early Life Stress (in Mice), Changes in Microbiome, and Later Anxiety

11 Aug, 15 | by EBM

By: Dr. Geoffrey Modest

I heard about this on NPR and realized that I had not blogged for awhile on the microbiome…  This study basically showed that early life stress in mice leads to changes in their intestinal microbiome, which seems to be largely responsible for altered behavior later in life (see doi:10.1038/ncomms8735).  


  • There are a few human studies finding an association between traumatic childhood events and the later development of psychiatric diseases and functional bowel disorders

  • Animal studies find that maternal separation leads to long-lasting behavioral changes, gut dysfunction, hyper-responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis, depression/anxiety, visceral hypersensitivity, and increased intestinal permeability in adulthood

  • Intestinal microbiota can affect host behavior: germ-free animals have altered HPA responses to stress which is reversed by colonization by commensal bacteria, germ-free mice have lower anxiety-like behaviors, and there are an array of altered changes in neural and hormonal function (eg, microbial colonization in early life can affect hippocampal function)

Details of this study:

  • Both germ-free (GF) mice (ie, no intestinal microbiome) and specific pathogen-free (SPF) mice (ie, all having the same intestinal microbiome) developed equally large increases in their serum corticosterone levels when submitted to the stress of maternal separation shortly after weaning.

  • The microbiota of those SPF mice changed a lot when subjected to the stress of maternal separation, having only 55-70% similarity to those not exposed to stress. And this “early-life dysbiosis” in their microbiome did not change as the mice reached adulthood.

  • Later anxiety levels were higher in the mice exposed to the maternal separation, but only in the SPF group. there were 3 assessments of anxiety: a step-down test (going down from an elevated platform), light preference test (amount of time in illuminated compartment) and tail suspension test (how long they were immobile).

  • The altered microbiota was transferred from the SPF mice with maternal separation into healthy GF mice, finding that these GF mice did not maintain this abnormal microbiome and did not have abnormal responses to the 3 anxiety tests. Since those mice with early trauma developed a long-lasting dysbiotic microbiome but just implanting this dysbiotic microbiome was not long-lasting and did not alter them clinically, this suggests that there are a combination of stress-induced microbiome changes in addition to host factors that affect later anxiety.

So, my interest in the microbiome is that it provides an insight mechanistically into at least one physiologic way that animals (including humans, though it is much easier to study mice) are changed by their environment. There are several of my blogs dealing with different diets, food additives (eg artificial sweeteners) and their effect on the microbiome, along with the attendant effects on heart disease, glucose intolerance etc. But I really liked the one on diabetic mice showing that those on metformin improved their glycemic profile (as expected), but there was a significant increase in the bacterium Akkermansia. In a parallel experiment, just increasing this bacterium (in the absence of metformin) also enhanced glucose tolerance and decreased adipose tissue inflammation, suggesting that an additional mechanism of action for metformin may be through its effect on the microbiome (see )  — and this blog even looks at a study in humans, finding that meat-eaters have changes in their intestinal microbiome which lead to the production of an atherogenic chemical (TMAO), which was not found in vegetarians given meat (before their gut flora could be changed).  In the current mouse study, it is impressive that subsequent anxiety is not simply a genetic/epigenetic response to a traumatic early childhood event, but that the putative mechanism for this later anxiety seems to be mediated through a combination of microbiome and host changes. This study, of course, begs for followup ones looking at the outcome of potential microbiome improvements after the initial stress insult, such as through diet, exercise, or even meds. Interesting stuff…

Primary Care Corner with Geoffrey Modest MD: Substance use and mental health in youth and adults 2014

2 Apr, 15 | by EBM

By: Dr. Geoffrey Modest

SAMHSA (Substance Abuse and Mental Health Services Administration) just released a 2014 report on where we are at in the US regarding substance abuse and mental health issues (see here). A pretty brief summary:

Youth substance use/mental health (note: there are different surveys used for these data):

–Past month marijuana use, 2002-2013

–slight decrease in adolescents 12-17 to 7.1% (peak in 2011 at 7.9%)

–9th-12th graders without much change, at 23%. 8th-10th graders at 12.5% (sl increase)

–Past-year nonmedical pain reliever use, 2002-2013

–12th grade males: significant decrease, was up to 11.6% in 2002, decreased to mid-10 range til 2009, now down to 8.4%

–12th grade females: pretty flat at around 8% til 2011, then decreased to 5.6%

–age 12-17 males and females was in the 7.2% range, now decreased to 4.5-4.8%

–Past-month illicit drug use, 2009-2013

–age 12-17 with overall decrease in total, White, Latino to 8.8%, but no change in black, at 10.5%

–comparing the different illicits: marijuana most common at 7.1%; nonmedical use of psychotherapeutics next at 2.2%; then hallucinogens, inhalants, cocaine and heroin, all 0.6% or less.

–Past-month cigarette use, 2009-2013

–age 12-17: decreasing in all ethnicities, but highest in white (7.2%), then latino (3.7%), then black (3.2%)

–Past month binge alcohol use, 2008-2013

​–age 12-17: similar in males and females, decreasing to 6.2%. highest in White (7.3%), then Latino (6.3%), then Native American/Alaskan (5.6%), then Black (3.9%), then Asian (2.8%)

–Past year initiated substance use, in age 12-17, from 2009-2013

–alcohol: dec from 10.8% to 9.7%

–marijuana: dec from 5.5% to 4.8%

–cigarettes: dec from 5.2% to 3.7%

–nonmedical use of psychotherapeutics: dec from 3.5% to 2.4%

–and pretty similar %’s of above for white, black, latino

–Major depressive disorders, in age 12-17,in 2013

–overall: 10.7% (2.6 million…)

​–males: highest in Asian (6.5%), then Latino (5.7%) and White (5.6%), then Black (3.0%)

–females: highest in Latino (17.4%), then White (16.3%), then Black (14.4%), and Asian (13.9%)

–Past year depression treatment for major depressive disorder, among age 12-17, in 2103

–around 60-70% did not receive treatment (males 70%, females 59%), and White 58%, Black 71%, Latino 63%

Adult substance use/mental health

–Suicidal thoughts, age 18 and older, in 2013

–highest in 18-25 (7.4%), then decreasing to 4.0% age 26-44, 3.7% age 45-64, and 1.5% if older than 65

–also higher in those not insured (5.7% vs 3.6%) and in those <100% of federal poverty level (6.6% vs 3.5%)

–Serious mental illness, age 18 and older, in 2103

–more female (4.9% vs 3.5%), more in uninsured (5.9% vs 3.9%), and more in those <100% of poverty level (7.7% vs 3.6%)

–did not receive treatment: more men (36.4% vs 28.4%), and more younger (46% in 18-25 yo vs 24% in 45-64), and (not a shocker) more without insurance (49.4% vs 28.6%)

–Alcohol dependence and abuse, age 12 and older, in 2103

–more male (8.7% vs 4.6%), most in the 18-25 age group (13%) then decreasing stepwise through the >65 yo group (2.1%)

–more in uninsured (9.7% vs 6.0%)

–trend decreasing from 2009-2013 (eg, in those 18-25, decreased from 16.1% to 13.0%)

–Illicit drug use, aged 12 and older, in 2013

–highest in 18-25 yo (7.4%),  then decreasing stepwise through the >65 yo group (0.4%)

–Enrollment in substance abuse treatment (single-day counts 2009-2013)

–increasing from 2010 to 2013, from 1.175 million to 1.250 million, pretty evenly divided between “drug use only” at 39.6% and “both drug and alcohol use” at 43.0%

–Past-year treatment for alcohol use, age 12 and older, in 2013

–Highest in 12-17yo (9.8%), then rest in 5.3%-7.3% range

–Of note, 90.6% did not receive treatment and did not perceive a need for treatment!

–People in opioid treatment programs 2009-2013

–methadone: increase from 2009 from 283K to 330K in 2013

–buprenorphine: increase from 2009 from 24K to 48K in 2013

–in 2013, only 13.4% were in treatment, 5.7% perceived need for treatment but did not receive it, and 80.9% did not perceive need for treatment.  those in treatment tended to be older (26-44 yo group, at 18.2%)

So, a few issues from the mass of numbers above:

–These surveys are subject to many biases in terms of reporting, both by sample selection and the general cultural issues (in the largest sense, including those related to ethnicity, as well as those relating to gender, age, local social environment, peer pressure, etc which affect one’s level of introspection/ability to verbalize it as well as interpreting what is “normal”)…all limiting the generalizability and interpretation of the results

–The trends for most of the above regarding substances are in fact getting better!! as well as the use of methadone/buprenorphine, etc

​–One sore point is the psych data: large numbers of people with serious mental illnesses. with lots who are poor and without insurance (there is certainly an aspect of “social drift”, in that those with serious mental illnesses tend to “drift” into poverty, but there is undoubtedly a component of poverty leading to lack of insurance, leading to lack of treatment, leading to lack of ability to function in society, leading to lack of ability to improve the situation…..


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