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Primary Care with Geoffrey Modest MD: Diabetic peripheral neuropathy, and more drug company shenanigans

4 Apr, 17 | by gmodest

By Dr Geoffrey Modest

There was a recent systematic review in the journal Neurology on pharmacotherapy for diabetic peripheral neuropathy pain and its effect on quality of life (see doi. org/ 10. 1212/ WNL. 0000000000003882). This appeared right after the recent guidelines from the American Diabetes Association (see link below), but had several eye-opening differences.


— the researchers updated a 2014 systematic review of 57 studies (see  Griebeler ML. Ann Intern Med 2014; 161:639, and prior blog on this  here) with 24 additional published studies and 25 unpublished studies. All trials were published between 1990 and 2015. The number of participants range from 20 to 804. They referenced the website clinical on March 9, 2016 to get data on unpublished studies.


Results, from placebo-controlled RCTs (those with moderate or large effect are highlighted):

— for anticonvulsants:

   — pregabalin, 16 RCTs, small effect, with low strength of evidence (SOE)

   — gabapentin, 5 RCTs, not effective, low SOE

— serotonin-norepinephrine reuptake inhibitors/antidepressants:

   — duloxetine, 7 RCTs, large effect, moderate SOE

   — venlafaxine, 2 RCTs, large effect, moderate SOE

   — tricyclic antidepressants, 4 RCTs, moderate effect, low SOE

— opioids

   — typical opioids (eg, oxycodone), 4 RCTs, not effective, low SOE

   — atypical opioids (tramadol, tapentadol), 5 RCTs, moderate effect, low SOE

— topical agents

   — capsaicin cream 0.075%, 5 RCTs, not effective, low SOE

— other agents

   — dextromethorphan, 3 RCTs, not effective, low SOE

   — mexiletine, 5 RCTs, not effective, low SOE

   — botulinum toxin, 2 RCTs, moderate to large effect, low SOE

–there were not enough data to evaluate the effect of these medications on quality-of-life.

–adverse effects: varied by agent. Dropout rates in the studies varied from 2.5% to 70% for oral agents, very low for topicals



— Unfortunately, few of the studies extended beyond 3 months (mean follow-up was 8.8 weeks with a maximum of 22 weeks), limiting their clinical utility some.

— The presumptive difference between the typical and atypical opioids as above is that the atypical ones have activity as norepinephrine reuptake inhibitors as well as mu agonists, with moderate effectiveness (vs oxycodone, a mu agonist, which was no more effective than placebo)

— I was a little surprised that capsaicin cream had no benefit, given the initial studies. And I have had patients do pretty well, with essentially no adverse effects. But, even if this is mostly a placebo effect, it is a pretty harmless med and if it works…

— The American Diabetes Association review  gave primary billing to pregabalin and duloxetine (see here  )

— The ADA review also did find a small benefit for oxcarbazepine, with low SOE, but not for other anticonvulsants such as topiramate, valproic acid, or lamotrigine.

— So, why are the above conclusions so different from those of the American Diabetes Association?  Of the 25 additional studies in which were unpublished, 18 were actually completed. The researchers were able to include 7 of these 18 completed studies. Of note, though pregabalin seemed to be effective, with a moderate reported effect size, when the 6 additional unpublished studies were included (all with negative results), the effect size decreased to “small”. In fact an analysis which included these negative studies found that the number of patients who would need to be treated with pregabalin for one patient to achieve a 50% pain relief was 7.7, so pretty few patients seem to benefit from pregabalin (Finnerup NB. Lancet Neurol 2015; 14:162)

–I suspect that the reason that gabapentin was considered ineffective but pregabalin not is mostly related to the serendipity of the studies done. Their anticipated physiologic effect is essentially the same, though gabapentin may be more slowly and erratically absorbed. In both cases there have been published studies suggesting positive efficacy of the medications, but on digging a tad under the surface, there are several large unpublished studies for each finding no benefit.  My guess is that they really do have similar and probably low levels of effectiveness. As with most drugs, some patients may benefit more than others. Is this from genetic differences in receptors or other drug mechanism?  Or maybe placebos work better in some people when they have mild to moderate adverse effects, and these meds both certainly do…(I have never seen anything written on this, but I suspect that meds with more systemic adverse effects may have more placebo effect as well, since some patients may internalize that meds with adverse effects must be stronger meds???…).The recent negative study of pregabalin in sciatica does also raise the question of its overall utility (see here  ). So, I’m not convinced that we should use pregabalin (only available as an expensive brand-name drug) over gabapentin (widely available generic), if we decide to use one of these types of drugs.

— One important finding in the current Neurology review was that venlafaxine, available as an inexpensive generic, was found to have a large effect size, with moderate SOE. This was also found for tricyclic antidepressants, though with moderate effect size. I am a bit hesitant to endorse venlafaxine as the single best agent (largest effect size of meds, somewhat larger than duloxetine which has no generic), since there were only 2 studies published on it. But I will add it to my short list of initial meds to try, along with tricyclics.

–so, bottom line here: the American Diabetes Association’s top 2 drugs, pregabalin and duloxetine, have both been knocked down by this more extensive Neurology review….. and, I think all systematic reviews should include looking at to find potentially pivotal negative studies which have not been published.


But, I think there are a few pervasive generic issues that this systematic review brings up:

–one of the biggest issues raised by this systematic review is: what should we trust in the medical literature? Clearly meta-analyses and systematic reviews can come to different conclusions based on their study inclusion criteria (see here for some of my thoughts on this). But additionally, we have moved to a place where the majority of large-scale medical studies are industry-funded. And they have a very clear bias to publishing the most positive results and putting the most positive spin on their results. And negative results are often not reported (this was the reason the feds required new studies to be logged into when they are initially approved, a law enacted in 1997). And the finding above about pregabalin is a case in point (a similar issue prevailed in the initial gabapentin studies, where there were also large, unpublished negative studies).  So, though pregabalin was highlighted in the recent Am Diabetic Assn recommendations 2 weeks ago, when the unreported negative studies are included, it really does not look so good…

–And,  as per here  companies often do not conform to government regulation/requirements, including rarely providing post-marketing data as required by the feds (their compliance rate was on  the order of 15%!!!!!). And, and, and, this whole situation is very likely to get whole lots worse with Trump, as the FDA moves to earlier licensing of drugs and medical devices, with less rigorous attention paid to their actual clinical benefit. So, the really difficult challenge is “what should I believe in the medical literature??”  I’m not sure how to answer that. But we need to be diligent, skeptical, and even less ready to jump on the bandwagon for new meds and medical devices. (One of my real purposes in writing these blogs is to critique studies or guidelines, and to assess their real generalizability and utility in the context of primary care clinical practice. And I hope they provide some context to help assess applicability of the studies/guidelines…..)


Primary Care with Geoffrey Modest MD: pregabalin did not help sciatica

3 Apr, 17 | by gmodest

​By Dr. Geoffrey Modest


A recent Australian RCT found no significant benefit for pregabalin in patients with acute or chronic sciatica (see Mathieson S. N Engl J Med 2017: 376: 1111).


— 207 patients were randomized to pregabalin initially at a dose of 150 mg per day, adjusted to a maximum of 600 mg per day versus placebo for 8 weeks

— sciatica was defined as radiating pain to one leg below the knee, accompanied by nerve root or spinal nerve involvement as indicated by at least one of dermatomal leg pain, muscular weakness, sensory deficits, or diminished reflex. The sciatica had to be present for a minimum of one week and a maximum of one year, and considered at least moderate in intensity or had resulted in at least moderate interference with daily activities

— mean:  55% female, 53 yo, dermatomal pain in 85%, motor deficits in 30%, neurologic deficits in 35%, sensory deficits in the 4%, pain in both legs in 8%, pain on straight leg raising in 63%, clinical level of spine causing problems S1 in 50% /L5 in 33%/L4 in 22%/S2 in 10%/more than one level in20%, PainDETECT <12 in 45% (which suggests that a neurologic component was unlikely)/13-18 in 25% (neurologic component unclear)/greater than 18 in 25% (neurologic component likely). Mean duration of leg pain was 63 days.

— the primary outcome was  leg pain intensity, measured on a 10 point scale, 0 being no pain and 10 worst pain; secondary outcome was the extent of disability, back pain intensity, and quality of life measures. Measurements were made at 8 weeks and at one year.


— 74% of patients in each group were considered to have adhered to the dosing schedule, defined as taking at least 80% of their prescribed trial regimen.

— at week 8, the mean unadjusted leg pain intensity score was 3.7 in the pregabalin group and 3.1 in placebo group, nonsignificant

— at week 52 the mean unadjusted leg pain intensity score was 3.4 in the pregabalin group and 3.0 in placebo group, nonsignificant

— no significant differences were observed with respect to any of the secondary outcomes at either week 8 or 52, including either physical or mental components of quality of life scores, global perceived effect, or extent of disability. Also there was no difference in the number of hours that the patients were absent from work over the year, the percentage of patients who used additional medications pain, or the percentage of patients who used health services.

— Post hoc analysis showed that the duration of leg pain did not modify the effect of pregabalin [though most of the patients had sciatica for less than 3 months, so were not in the chronic category.]

— 227 adverse events reported in the pregabalin group and 124 in the placebo group, with dizziness being the most common in the pregabalin group (70 events versus 19)


— I am not sure how to reconcile the baseline PainDETECT scores, which suggests that a neurologic component to the pain was most likely present in only 25% or so, with the reported 63% having pain on straight leg raising, 44% having a sensory deficit, 30% with a motor deficit and 35% with a neurologic deficit. This PainDETECT tool is a validated questionnaire which basically includes all of the regular subjective questions for radicular pain (as documented appropriately in the study above) and their intensity, and does not include the physical exam, which, as in the above study, found many patients with significant deficits and positive straight leg raising sign. But all of the patients sounded clinically like they had neuropathic pain and were likely to be treated as such (as above, all of them had: “radiating pain to one leg below the knee, accompanied by nerve root or spinal nerve involvement as indicated by at least one of dermatomal leg pain, muscular weakness, sensory deficits, or diminished reflex”). And, when the researchers did control for the PainDETECT score, they did not find that it modified the results.

— One limitation of the study was that most patients had relatively short-term symptoms of sciatica, and three quarters of patients spontaneously have resolution of symptoms within 3 months (see Ropper AH. N Engl J Med 2015; 372: 1240)

— So, my sense is that, based on this study, it seems that pregabalin had no benefit for patients who might present to us in primary care with clinical acute-to-chronic sciatica.  Which raises a very real and common clinical dilemma: what is the best way to treat such a patient???? Though this study undercuts a potential role for the medication pregabalin, are there other meds targeted for neuropathy which might work, such as tricyclics or duloxetine/venlafaxine?? Unfortunately, the data are quite meager regarding the use of nonpharmacologic interventions in those with radicular pain (see the Ropper article referenced above), including physical therapy, spinal manipulation, exercises, yoga/back strengthening exercises, etc, though there are better data supporting some of these for regular old low back pain. Since patients with sciatica do better with activity than rest, it does seem reasonable to provide analgesia to allow the patient to do more activity (though unproven). And, though not mentioned in this Ropper review, are some of the more recently described nonpharmacologic interventions used in non-neuropathic pain: see  blog here which also includes links to several other blogs supporting the utility of tai chi, mindfulness stress reduction, cognitive behavioral therapy. Bottom line: we just do not have great meds for chronic pain, these nonmedical interventions do seem to help for chronic pain, and they may be worth trying (and studying) for neuropathic pain.

— And, this dearth of information for treatment of sciatica from well-conducted studies does point to a fundamental problem in our medical research approach: we (ie drug companies, with some governmental/public support) spend huge amounts of resources to develop (really expensive) meds for rare diseases, yet some common and really disabling conditions (eg sciatica) are not investigated rigorously, especially for nonpharmacologic interventions, but also for existing meds (there is not much incentive to test an already-approved drug like pregabalin, since it is probably already being prescribed widely, so the downside of a negative study for the drug company is much greater than the upside of a positive study).



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 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 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)


  • 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 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: vitamin B12 and diabetic autonomic neuropathy

23 Feb, 17 | by EBM

By Dr. Geoffrey Modest

A recent Danish study found that vitamin B12 deficiency was associated with diabetic cardiovascular autonomic neuropathy, CAN (see Hansen CS. J Diabetes Complic. 2017; 31(1); 202)


  • 469 type II diabetic patients were screened for CAN by several measures, as well as for peripheral neuropathy.
  • Mean age 59, 60% male, diabetes duration 10 years, 5% excessive alcohol consumption, 12% smokers, BMI 32, blood pressure 132/82, 6% on vitamin B12 supplementation (though 16% in those in the highest B12 quartile), 80% on lipid-lowering drugs, 75% on metformin, 4% on PPIs alone and 10% on the combination with metformin, 40% on insulin
  • CAN was measured after a 5-minute supine resting period:
    • Heart rate variability (HRV)
    • 3 tests assessing cardiovascular autonomic reflexes:
      • Lying-to-standing test
      • Deep breathing test (E/I ratio), a measure of heart rate variation during deep breathing [which is affected by an abnormality in the parasympathetic nervous system]
      • Valsalva
    • Peripheral neuropathy was measured electronically by vibration sensation


  • B12 level varied from the lowest quartile mean of 190 to the highest quartile of 486 pmol/l
  • Serum levels of B12 were significantly lower in those on metformin or proton pump inhibitors, p <0.001.
  • Higher level of B12 were significantly associated with a lower odds ratio of CAN, p=0.04
  • A 25 pmol/l higher level of vitamin B12, adjusted for age, sex, diabetes duration, and alcohol consumption, was associated with:
    • 6% lower level of CAN diagnosis, odds ratio 0.94 (0.88-1.00, p= 0.034)
    • An increase of E/I ratio of 0.21% (p= 0.038)
    • A decrease in resting heart rate of 0.25 bpm (p= 0 .025)
  • No association between B12 levels and decreased vibration/peripheral neuropathy


  • Cardiovascular autonomic neuropathy is very common in patients with type II diabetes, ranging in prevalence from 20 to 65% and increasing with length of diabetes. CAN is also an independent predictor of cardiovascular mortality and morbidity. But CAN may well be overlooked clinically until a patient is symptomatic, typically late in its course.
  • Vitamin B12 deficiency is also quite common in diabetics, with estimates from 2-33%, potentially mediated in part by the use of metformin through a not-so-well understood mechanism. This relationship is both metformin dose-dependent and treatment duration dependent, and may be measurable in as little as 4 months after the onset of use. In addition, the frequent use of proton pump inhibitors may decrease vitamin B 12 levels. Another potential and common mechanism for B12 deficiency in older patients is the age-associated decrease in several digestive enzymes, leading to the inability to liberate B12 from foods thereby decreasing its absorption (studies have found b12 deficiency in 10-25% of elderly, typically asymptomatic).
  • This was an observational study, therefore it is difficult to attribute causation. In addition, there is no compelling evidence that correcting B12 deficiency decreases the likelihood of CAN [one Indian population-based study of healthy elderly showed that B12 supplementation in those deficient led to normalization of decreased heart rate variability (see Sucharita S. Autonoom Neurosci 2012; 168 (1-2); 66)].
  • Also, the effect of B12 deficiency on CAN in the study was not particularly large. Part of this is that there were very few patients (0.6% of their population) who they defined as having vitamin B12 deficiency (that being below 125 pmol/l in this study, though many consider the cutpoint to be <148 pmol/l, which translates to <200 pg/ml), so the lowest quartile had lots of patients who were probably not actually B12 deficient. And the likely reason for the low B12 deficiency rates was that the standard clinical practice in that area was to check B12 levels in patients every other year. They did not test for methylmalonic acid or homocysteine, which might have been relevant in those with borderline B12 deficiency (35% had B12 levels between 125 and 250 pmol/l, though others consider borderline to be between 148 and 221 pmol/l​, or 200-300 pg/ml). Also, the fact that the effect was particularly evident for the E/I ratio with deep breathing suggests that a parasympathetic abnormality may predominate, and parasympathetic denervation is in fact typically the first abnormality in CAN, leading to increased sympathetic tone.
  • Of note, several different studies, but not all, show that those with peripheral neuropathy associated with B12 deficiency do improve with B12 supplementation, though the degree of improvement tracks inversely with both the extent and duration of disease.

So, my take on this is that given the clear importance of vitamin B12 for several aspects of health (neurologic, psychiatric, hematologic), and that some of these manifestations may be pretty subtle/very hard to detect early on, I personally think it makes sense to check vitamin B12 levels in the elderly as well as those on metformin and PPIs. And now, perhaps more so in diabetics overall, perhaps when they reach the ripe old age of 50 or so.

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: Celiac disease and neuropathy

22 May, 15 | by EBM

By: Dr. Geoffrey Modest 

Peripheral neuropathy has been associated with celiac disease in past studies, typically based in referral centers. The current population-based study in Sweden looked more systematically at the association (see doi:10.1001/jamaneurol.2015.0475​). As background, celiac disease is pretty common, with prevalence of about 1%, and peripheral neuropathy is present in 2-7% of the population. Details of the study:

–Data collected on small intestine biopsies performed at Sweden’s 28 pathology departments from 1969-2008

–They compared the risk of neuropathy in 28,232 patients with celiac disease vs 139,473 age- and sex-matched controls (median age at diagnosis of 29: 42% were 0-19 yo, 18% 20-39, 22% 40-59, 18% >60; 62% female; comorbidity of type 1 diabetes in 3.2 vs 0.4% in controls, alcohol use in 2.7 vs 2.6%). Patients had confirmed celiac disease (CD), with villous atrophy, Marsh 3

–CD was associated with a 2.5-fold (2.1-3.0, p<0.001) increased risk of later neuropathy (0.7% vs 0.3% in controls, absolute risk of 64/100K vs 15/100K)

–CD also associated with increased risk of

–chronic inflammatory demyelinating neuropathy: 2.8-fold (1.6-5.1, p<0.001)

–autonomic neuropathy: 4.2-fold (1.4-12.3, p=0.009)

–mononeuritis multiplex: 7.6-fold (1.8-32.4, p=0.006)

–but not with acute inflammatory demyelinating polyneuropathy: 0.8-fold (0.3-2.1, p=0.68)

–No difference in neuropathy by sex, or age. Overall risk decreased minimally from 2.5 fold to 2.3-fold (1.9-2.7) after controlling for educational level, SES, type 1 or 2 diabetes, autoimmune thyroid disease, rheumatologic diseases, pernicious anemia, vitamin deficiencies, and alcoholic disorders.

–Association with neuropathy was pretty consistent in group with <1 yr of followup vs 1-5 yr, vs >5 yr

–There was a positive association between any neuropathy and CD, even when the diagnosis of neuropathy preceded the diagnosis of CD with an odds ratio of  1.8; 1.4-2.2, p<0.001

So, seems like we really should add an evaluation for CD as part of our neuropathy workup. In small studies, it seems that the association of CD with neuropathy is not necessarily associated with CD-related vitamin deficiencies (one study of 18 patients with confirmed CD and neuropathy found that they all had normal vitamin B12 levels). My sense, given the pretty low absolute association as noted above in Sweden, is that screening questions about GI symptoms seem appropriate. It might also be reasonable to perform serologic studies for CD, since there are some data suggesting that a gluten-free diet may either prevent or ameliorate the neuropathy (this is not very robust data), and on the other hand there are data suggesting that there are many people with “asymptomatic” CD who actually do feel better on a gluten-free diet, they might have significant malabsorption issues that should be detected/addressed, and (data not so robust) asymptomatic patients may still be at higher risk of lymphoma or autoimmune diseases which decreases with a gluten-free diet.


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