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Primary Care Corner: Hyperuricemia and cardiometabolic disease

12 Jun, 17 | by gmodest

​A recent study suggested that hyperuricemia itself predicts the development of several cardiac risk factors, including hypertension and hyperlipidemia (see doi: 10.1161/HYPERTENSIONAHA.116.08998.)


— 5899 Japanese subjects were enrolled who at baseline did not have overweight/obesity (BMI>25), hypertension (>140/90 after resting quietly for 5 min), diabetes (meds or A1c>6.4), and dyslipidemia (LDL >140, HDL <40, and/or TG >150), as well as any history of gout or hyperuricemia on medications, or chronic kidney disease with the eGFR <60. [ie, a pretty normal cohort medically]

— 282 men and 133 women had  hyperuricemia defined as serum uric acid (SUA) > 7 mg/dL in men or >6 mg/dL in women

— Mean age 47, 1864 men, there was small but statistically significant differences between those with hyperuricemia versus normal SUA at baseline (e.g. in men, BMI 22.4 vs 21.8, blood pressure 116/73 vs 114/72, eGFR 87 vs 82, albumin 4.5 vs 4.4, with similarly small differences in women) though there was a more convincing difference in drinking habits at 72% vs 62%).

— SUA on average was 7.65 in hyperuricemic men vs 5.59 in those with SUA <7; 6.44 in hyperuricemic women vs​ 4.20 in those with SUA < 6

— patients had an initial exam in 2004, and a follow-up exam in 2009


— hyperuricemia was associated with an increased cumulative incidence of (all OR’s expressed as per SUA increase of 1 mg/dL):

— hypertension, 14.9% vs 6.1% (p<0.001), odds ratio (OR) of 1.5 [ie, the OR is much higher in those with much higher SUA levels]

— dyslipidemia, 23.1% vs 15.5% (p<0.001), OR of 1.3

— chronic kidney disease, 19.0% vs 10.7% (p<0.001), OR of 1.3

— overweight/obesity, 8.9% vs 3.0% (p<0.001),  OR of 1.5

— diabetes, 1.7% vs 0.9% (p<0.001), OR 1.5

–in the above, there were some differences between men and women: there was no increase in diabetes in men (though in women was 2.3% vs 0.5%, with p=0.011); and in women no increase in dyslipidemia (though in men 5.2% vs 19.2%, p=0.020) or overweight/obesity (trend in women with p=0.08, but in men was 11.0% vs 4.9%, p<0.001)

— multivariate analysis:

–model 1 (controlling for age, sex, and smoking/drinking), all looking at OR and p value per SUA increase of 1gm/dL:

–hypertension increased with OR of 1.4, p<0.001

–dyslipidemia increased with OR of 1.3, p<0.001

–CKD increased with OR of 1.3, p<0.001

–model 2 (controlling also for eGFR), all looking at OR and p value per SUA increase of 1gm/dL:

–hypertension increased with OR of 1.5, p<0.001

–diabetes increased with OR of 1.5, p=0.004

–dyslipidemia increased with OR of 1.3, p<0.001

–CKD increased with OR of 0.9, p=0.006 [ie, lower odds ratio]

–overweight/obesity increased with OR of 1.4, p<0.001

–model 3 (also controlling for BMI), all looking at OR and p value per SUA increase of 1gm/dL:

–hypertension increased with OR of 1.4, p<0.001

–diabetes increased with OR of 1.4, p=0.01

–dyslipidemia increased with OR of 1.2, p<0.001

–CKD increased with OR of 0.9,  p=0.004

–overweight/obesity increased with OR of 1.1,  p nonsignificant


— this study is particularly interesting because it isolates any of the cardiometabolic issues ​from hyperuricemia, which have historically been conflated with them, by choosing people who had hyperuricemia initially but none of these issues at baseline and following them 5 years later. It has been quite unclear what the directionality is (or if it exists): does hyperuricemia in fact lead to these medical problems, or do these issues lead to hyperuricemia through its effects on insulin resistance (leading to the various components of the metabolic syndrome), and renal vasoconstriction and reduced GFR (leading to decreased renal uric acid excretion). Or are both hyperuricemia and cardiometabolic risk factors both related to a third entity, perhaps insulin resistance. Animal studies have supported the role of uric acid as causal in these conditions. This study would have been stronger if they had intermediate exams, not just at the beginning and 5 years later, but still would not answer the issue of causality definitively.

— one big issue with multivariate adjustment (as a general issue), which really comes to the fore in this study, is that it really depends on the variables being independent. For example, controlling for eGFR even within the <60 range and finding no significant relationship between SUA and developing CKD does not necessarily mean that there really is no relationship. Perhaps a mild reduction of eGFR within the normal range is leading to reduced excretion of SUA (and higher blood levels) from this mild decrease in GFR itself (so controlling for eGFR may create the perhaps erroneous impression that SUA is unrelated). Or, controlling for BMI within the normal range may similarly not show that SUA elevation is not predictive of subsequent overweight/obesity, since mild increases of BMI may be associated with some increased insulin resistance leading to higher BMI in the future. So, I would not attach much significance to models 2 or 3 above.


so, this study complements and adds to the previously noted association between hyperuricemia and cardiovascular disease (see blogs noted below). However, one can still not definitively show causation, because the hyperuricemia could be an innocent bystander associated with the real cause.

— But, based on these studies, it seems reasonable to me to check SUA levels for 2 reasons (and I have been doing so pretty regularly):

— there are important lifestyle risk factors for increased SUA levels, especially fructose intake. I have been successful in a few cases of working with patients to decrease their consumption of sodas and other products with high fructose corn syrup, often finding pretty dramatic decreases in SUA levels (eg from the 8.5 range to the 7 range). And decreasing alcohol consumption

— In addition, I also think it would be reasonable to be even more aggressive in primary prevention of cardiac disease in those patients who have high SUA levels, both in terms of discussing the importance of healthy lifestyles and also having a lower threshold for starting meds. And the meds chosen might be different: eg, using losartan (but not other ARBs) or amlodipine/nifedipine for hypertension, since these lower SUA levels: see below.

a Danish study suggested that treating hyperuricemia in those with allopurinol led to fewer cardiovascular events

— another study provides an interesting evolutionary perspective on hyperuricemia, as well as a Taiwanese study finding a dramatic decrease in cardiovascular events by treating hyperuricemia

–here is my very brief blog on antihypertensives and uric acid from 2012, predating the bmj website:

— large study of general practices in UK, looking at 25K pts with gout. I had seen some older studies finding that losartan (but NOT other arb’s or ace-I’s) lower uric acid levels.  In this large UK database, they found a 19% dec risk of clinical gout with losartan (compared to other hypertensive pts), 13% with ccbs (21% dec with amlodipine, 13% with nifed, and 14% with dilt), with inc gout risk with diuretics, b-blockers, ace-I’s, other arb’s besides losartan.  They note in their discussion some studies (which I looked at and are pretty small…) find that ccbs (esp nifed and amlod) and losartan are uricosuric and decrease serum uric acid levels.  See doi:10.1136/bmj.d8190 ).  there have been some recent reports that high fructose corn syrup is perhaps the largest (or close to it) dietary component which increases uric acid.

Primary Care Corner with Geoffrey Modest MD: Steroid knee injections: do they help??

23 May, 17 | by gmodest

by Dr Geoffrey Modest

A recent article in JAMA found that regular injections of intra-articular steroids was associated with decreased knee cartilage volume and no real improvement in pain in patients with knee osteoarthritis (see doi:10.1001/jama.2017.5283).


–140 patients with symptomatic knee osteoarthritis as well as synovitis by ultrasound (evidence of effusion synovitis, with suprapatellar pouch depth >2mm) were randomized to receiving intra-articular 1cc triamcinolone 40mg vs 1cc saline every 3 months for 2 years, both without local anesthetic

–mean age 58, 54% women, BMI 31, 65% white, mean hemoglobin A1c=6%, CRP 0.5

–all patients had radiographic evidence of Kellgren-Lawrence knee OA grade 2 or 3 (grade 2= definite osteophytes and possible joint space narrowing on anteroposterior weight-bearing radiograph; grade 3= multiple osteophytes, definite joint space narrowing, sclerosis, possible bony deformity)

–knee MRI was done at baseline and then annually


–there was greater cartilage loss with injected steroids (volume loss of 0.21 mm vs 0.10 mm with normal saline), though the amount of superficial fibrillations (fraying of the articular surface) was more common in the saline group (34% vs 13%)

–no significant difference between the groups in pain scores, or functional activities such as the 20 meter-walk time or the chair-to-stand time (these were all measured after asking patient to not take pain meds for 2 days prior to their evaluations)

–adverse events: overall more significant in saline group (63 vs 52, p=0.02), though no difference in what was considered treatment-related.  Cellulitis in one patient in the saline group, also hemoglobin A1c actually decreased significantly in the steroid group (-0.1% vs increase of 0.2% in the saline group, and this was controlling for BMI, radiographic DJD classification, sex). No difference in hypertension


–As noted in a recent blog on the lack of benefit of arthroscopy in patients with degenerative knee disease (see here​ ), knee DJD is remarkably common and a leading cause of  disability (and medical costs, largely for procedures)

–the physiologic rationale for intra-articular steroid injections is that DJD is typically associated with synovitis, with its associated elaboration of biochemical mediators having the potential for causing further joint destruction (collagenases, aggrecanases, cytokines). And local steroids might decrease the inflammation and this destructive cycle. Animal studies have supported this hypothesis. This study, utilizing MRI to assess the steroid effects on cartilage, seems better designed than prior studies which have used xrays, given how insensitive xrays are to assessing the radiolucent cartilage.

–so, how can one reconcile the conclusions of this study (negative impact on cartilage and no effect on pain) with the other studies finding pain improvement in the 4 weeks after the injection, an older but smaller study of 68 patients with the same basic protocol as in this study finding some benefit for pain, and with the huge anecdotal experience of benefit (steroid injections are done increasingly commonly)???

–these patients had pretty mild DJD, especially in terms of baseline symptoms, with a WOMAC pain score of 8.3. This score is based on 5 items (pain during walking, using stairs, in bed, sitting or lying, and standing upright, each with a score of 0-4, ranging from  None (0), Mild (1), Moderate (2), Severe (3), and Extreme (4); ie total maximum score of 20, with an average score of 8, as in the above study, being between mild and moderate.

–one issue with knee OA is how to define it or its progression objectively. The Framingham Study found a poor correlation between radiographic knee OA and symptoms (see Hannah MT. J Rheumatol 2000; 27: 1513, for example). And there is no accepted minimal clinically important difference for MRI cartilage measurement, as duly noted by the authors of this study. Also, I am concerned about the increase found in cartilage fibrillation found in the non-steroid group, since this early splitting of the tangential cartilage surface might harken more severe and clinically important cartilage changes over the somewhat longer term

–they only assessed pain relief at the 3-monthly evaluation, with no data on how patients fared in the first 1 or 2 months [and, in my pretty extensive experience with knee injections, probably around 1000 over the years, the vast majority of patients getting relief for the first few months, some much longer, and that relief translates into dramatic improvement in function and pain relief; ie they can walk and actually do things they couldn’t do before]

–there are even some literature (a meta-analysis of 38 studies) supporting saline injections as  helping with pain relief [ie, their control injections were not necessarily sham injections; saline itself may have some benefit. Which is an important difference. There seems to be a more profound placebo effect with injections than pills, so perhaps the real control for this injection study should be a needle in the joint with no meds injected???]

–and, in terms of generalizability of these results, it is important to stress that these patients had clinically mild knee OA at baseline, but still received injections every 3 months [not necessarily common clinical practice for those with mild-to-moderate symptoms], so their results might not apply to many patients who are actually getting knee injections for more severe, functionally limiting pain despite exercise/physical therapy/etc

–what about the decrease in cartilage thickness?? This is certainly concerning, though perhaps there are non-measured countervailing processes going on: are patients getting a lot of early pain relief [a good thing], but then using their knees more [walking, etc] which leads to more cartilage destruction through wear-and-tear???  And, though small, does the relative improvement in A1c in the steroid group reflect the patients’ ability to do more exercise?


So, how should this study affect clinical practice??

–my non-rigorously-tested finding, through loads of knee injections, is that 90+% of patients have much less pain and are able to function much better after injections, and I will continue to do injections

–that being said, injections should be accompanied with aggressive patient education around the importance of quadriceps strengthening exercises, which often help a lot [there were older studies suggesting this may not be true in patients with misaligned knees, perhaps from more severe DJD, where the patella does not track correctly and quad strengthening might exacerbate knee symptoms, but my sense is that this is relatively uncommon].  And some patients need a knee injection in order to do more exercise or physical therapy…

–other therapeutic options are sparse. Arthroscopic meniscal repair or joint lavage seems to do nothing . Physical therapy is important, but does not help many patients much (especially those who are frail, have advanced DJD, are unable to do the necessary home-based exercises,…). NSAIDs have a wide array of undesirable adverse effects, especially in the population with symptomatic knee OA, since they are typically older and have lots of comorbidities (and in this study, unlike NSAIDs, steroids were not associated with hypertension, for example)

–I also use the equivalent of 40 mg triamcinolone with 2cc of 1% lidocaine. This might have better efficacy (unknown to me) than just 1 cc of triamcinolone alone, since the added volume of the anesthetic may help the steroid reach more areas of the inflamed knee joint, and perhaps the anesthetic improves the pain relief beyond the steroid itself.

–after I have done a few knee injections, especially if there are diminishing returns (the first injections working for much longer than subsequent ones), I do discuss and recommend consideration of surgical management (usually knee replacement surgery)

–but I am certain that I will continue having patients, especially older ones, who often have serious medical comorbidities, who adamantly refuse surgery and really want repeated knee injections (even every 2-3 months) in order to function.  This study will change my practice in that I will discuss the issue of potential cartilage harm more forcefully than previously.

–one important general issue is my concern about the quick summaries of potentially clinically very important articles:  the one-line synthesis of this study was “Intra-Articular Corticosteroids Show No Benefit in Knee Osteoarthritis” in Physician’s First Watch/NEJM Journal Watch, and there was little more added in the few summary lines. I am very concerned that this type of analysis may undercut an important therapeutic modality for many patients, perhaps leading to fewer injections even though the patient may achieve very important pain relief and improved functioning/quality of life.  This brings up one of the reasons I do these blogs: we in primary care clinical practice are inundated with new articles (mostly drug-company sponsored) and new guidelines (often done by specialty societies whose members directly or indirectly are involved with drug companies, etc) on a daily basis. It is essentially impossible to keep up with the information onslaught. The summary services such as Journal Watch are really helpful in scanning the literature and alerting us to new articles/guidelines that might affect our clinical practice. But they may well have the very negative effect of dumbing down the literature to quick quips (sound bites?) that really make it impossible to figure out if a certain article or guideline really should apply to the patient sitting in front of us. My hope with these blogs is to look at a few of these articles that might well affect practice, give sufficient (and accurate) summaries of the methodology, types of patients involved, procedures done, and their results; then briefly put in my sense of how this article fits in with older literature and our model of disease physiology; and provide some specific concerns, if any, which might affect its clinical utility. This way, the reader can decide what they think about the article (or guideline), be able to review the specifics of the study​, even use my link to see the study itself for more details, and then figure out how or if they will integrate it into their practice

Primary Care Corner with Geoffrey Modest MD: Against arthroscopy for DJD of knees

16 May, 17 | by gmodest

by Dr Geoffrey Modest

The BMJ just published a systematic review comparing knee arthroscopy versus conservative management in patients with degenerative knee disease (see doi:10.1136/bmjopen-2017- 016114), an update of a prior review, adding ten new studies.


— 13 RCTs and 12 observational studies were included

— studies were diverse: the analysis included those with symptomatic degenerative knee disease, defined as persistent knee symptoms that affect quality of life and does not respond to conservative treatment, but with or without osteoarthritis and, in those getting arthroscopic surgery, “including any or all of debridement and/or partial  meniscectomy”.  Those with acute trauma were excluded.


— knee arthroscopy led to a very small reduction in pain in the first three months (mean difference 5.4 on 100 point scale), and very small or no pain reduction up to two years (mean difference of 3.1), high-certainty evidence. The MID (minimally important difference) being 12 points.

— knee arthroscopy led to a very small improvement in function in the short term (4.9 on a 100-point scale) and very small or no improvement at two years (difference of 3.2), moderate-certainty evidence. The MID being 8 points.

— very low probability of serious complications after knee arthroscopy, low-quality evidence. The most common serious adverse effect was venous thromboembolism, at a rate of 5/1000, followed by infection at 2/1000.



–symptomatic degenerative knee disease is remarkably common after age 45, affecting about 25% of people, from osteoarthritis of the knee joint lining and/or menisci.

–arthroscopic knee surgery for DJD (degenerative joint disease) is the most common ambulatory orthopedic procedure in the US (and 9th most common of all ambulatory procedures), associated with transient improvement in pain but requiring activity restriction for 2-12 weeks.

–so, this study found  evidence of minimal benefit from knee arthroscopy at 3 months (not considered clinically significant), which decreased further over the next 2 years, for both pain and function.

–one recent study was cited as an impetus for this systematic review, which included 140 adults (mean age 50; duration of pain 15 months). Though 96% did not have definitive radiographic evidence of OA (osteoarthritis), 91% had MRI-documented meniscal degeneration grade 3a or 3b, which is the worst grade. Patients were randomized to exercise therapy alone vs arthroscopic partial meniscectomy (see For the exercise group:  progressive neuromuscular and strength exercises over 12 weeks, 2-3 sessions/week. For those getting surgery: instruction for home-based exercises 2-4x/day to regain knee ROM  and reduce swelling. For the primary outcomes, no difference in pain at 2 years, using the KOOS (knee injury and osteoarthritis outcome score) subscales on pain, other symptoms, function in sports and recreation, and knee related quality of life (also no difference at 3 months; but the exercise group had had greater improvement in all muscle strength variables at 3 months). On secondary analysis the meniscectomy group had lower pain scores at 12 months that was considered clinically significant (though the exercise group had greater muscle strength at that time). [However, this study does not really rule-out the possibility that meniscectomy with aggressive PT afterwards is superior to both of their interventions, since the therapy post-surgery was just the suggestion to do home-based exercises].


so, the current study comes to the same conclusions as prior analyses, but by adding 10 more studies reinforces those conclusions that arthroscopy is not generally indicated in those with degenerative knee disease. And, I think, it does apply well to primary care, since it did not limit patients to specific MRI or xray findings (and I get MRIs of patients with typical chronic knee pain only quite rarely; and in general the utility of xray itself is questioned, since there is a pretty poor correlation with symptoms per the Framingham Study), or even to specific clinical findings, but seems to apply simply to those with undifferentiated chronic knee pain not responsive to conservative treatment, but affecting quality of life.

Primary Care Corner with Geoffrey Modest MD: Osteoporosis treatment guideline

11 May, 17 | by gmodest

​by Dr Geoffrey Modest

The American College of Physicians just updated their clinical practice guideline on the treatment of low bone density/osteoporosis to prevent fractures in women and men (see doi:10.7326/M15-1361).


–treatment options

–bisphosphonates: high quality evidence that they reduce vertebral, nonvertebral and hip fractures in postmenopausal osteoporotic women (specifically shown with alendronate, risedronate, and zolendronic acid; ibandronate shown to reduce radiologic vertebral fractures; zoledronic acid reduces vertebral fractures in osteoporotic men). [BUT, these differences in bisphosphonates probably reflects the studies that have been done and may not indicate true differences between these meds. eg, we tend to assume that all ACE inhibitors are similar without specific studies showing true equivalence. Though it may not be true…..]. Adverse events: low-quality evidence that they can be associated with atypical subtrochanteric fractures (FDA issued warning), though very uncommon, in 1.78/100K in women taking bisphosphonates for <2 years, and up to >100/100K if >7 years (though these numbers pale in relation to fractures prevented in high risk patients). also, low quality evidence for osteronecrosis of the jaw (also rare). older concerns about atrial fibrillation were not found in newer studies. similarly with MI. but high-quality evidence of association with mild upper GI symptoms; hypocalcemia, flu-like symptoms, uveitis, and episcleritis with zoledronic acid; myalgias/joint symptoms with ibandronate and zoledronic acid. uncertain risk for cancer

​–denosumab (monoclonal antibody which prevents the development of osteoclasts through RANKL inhibition): high quality evidence that it reduces radiographic vertebral, nonvertebral and hip fractures  in post-menopausal women. Adverse events: high-quality evidence for mild upper GI symptoms; moderate quality evidence of increased risk of infection, (eg bacterial cellulitis, though no increase in serious infections); rash/eczema. also rate atypical femoral fracture and osteonecrosis of the jaw through 8 years of therapy

–teriparatide (hormone fragments of PTH):  high quality evidence that ​it reduces radiographic vertebral and nonvertebral fractures in post-menopausal women. Adverse events: high-quality evidence of association with mild upper GI symptoms, headache, hypercalcemia. also renal effects, hypercalciuria.

–SERMs (selective estrogen receptor modulators): high quality evidence that ​raloxifene reduces vertebral fractures in osteoporotic women, but non-statistically-significant decrease in risk of nonvertebral or hip fractures. Adverse events: high-quality evidence of hot flashes, thromboembolic events (incl pulmonary embolism, cerebrovascular death)

–estrogens: moderate quality evidence that ​it does not reduce fractures in postmenopausal women (a change in recommendations, based on newer data on postmenopausal women with established osteoporosis). Adverse events: high-quality evidence of association with cerebrovascular and thromboembolic events; higher incidence of breast cancer

​–calcium and vitamin D: moderate quality evidence​ that calcium or vitamin D alone has uncertain effect on fracture risk. Adverse events: probably no increase in MI with calcium (though shown in one analysis). increased risk of hypercalciuria with vitamin D

–physical activity: insufficient data to show conclusively that there is benefit for preventing fracture risk. no studies looking at comparative benefit of physical activity vs other interventions [though data show that physical activity can regulate bone maintenance and stimulate bone formation, increasing mineral content, and improving muscle strength (which protects the bone)]

–comparative benefits of above meds: insufficient head-to-head studies. and network meta-analysis to assess likely differences between meds did not find any


​–offer pharmacotherapy for women with known osteoporosis with alendronate, risedronate, zoledonic acid, or denosumab, to reduce risk of hip and vertebral fractures. strong recommendation, high-quality evidence

–treat osteoporotic women with pharmacologic therapy for 5 years. weak recommendation, low-quality evidence​​. the studies to support this excluded patients with severe osteoporosis (total hip BMD in the beginning T-score worse than -3.5),  or whose total hip BMD at 5 years was lower than their baseline. and post-hoc analysis found that those with pre-existing fractures or T <-2.5 after 5 years of therapy may benefit from continued treatment

–offer pharmacologic treatment with bisphosphonates to reduce the risk for vertebral fracture in men who have clinically recognized osteoporosis. weak recommendation, low-quality evidence​

–do NOT do bone mineral density (BMD) monitoring during the 5-year drug treatment period for osteoporosis in women. weak recommendation, low-quality evidence​.

–do NOT use estrogens or raloxifene in post-menopausal women in the treatment of osteoporosis. strong recommendation, moderate-quality evidence​

–make decision whether to treat women >65yo with osteopenia who are at high risk for fracture based on discussion, fracture risk profile, and benefits/harms/cost of meds. weak recommendation, low-quality evidence​ (there are some studies on post-hoc analysis suggesting those with T scores near the osteoporosis range finding that treatment with risedronate significantly reduced the risk for fragility fractures by 73%



–osteoporosis is exceedingly common: 200 million people worldwide, and 54 million in the US have osteoporosis or low bone density (50% of Americans >50yo are at risk for osteoporotic fractures). also, huge economic impact on health care system: $25.3 billion/yr by 2025.

–risk factors (per the article): age, female sex, menopause, hypogonadism or premature ovarian failure, low body weight, history of parental hip fracture, ethinicity (white people at higher risk), prior fracture (clinical or not), prior fracture with minimal trauma (“fragility” fracture), rheumatoid arthritis, smoking, alcohol (>2 drinks/d), low BMD, vitamin D deficiency, low calcium intake, hyperkyphosis, falling, immobilization, long term use of some meds (glucocorticoids, anticoagulants, anticonvulsants, aromatase inhibitors, cancer chemotherapies, gonadotropin-releasing hormone agonists). by the way, older studies have suggested that the compilation of risk factors of body weight/BMI, smoking, alcohol, and ethnicity only account for aoubt 15% of the risk variability (ie,  patients with lots of these risk factors  may well have normal BMDs and vice versa)

–BMD definitions: T-score in postmenopausal women and men >50yo is 2.5 SD below the young female adult mean (reported as worse than -2.5). BUT only 1/2 of the people with osteoporotic fractures have this low a BMD (which is probably because the BMD is a quantitative assessment of the amount of calcium in a cross-section of bone and does not reflect the internal qualitative structure of the bone). And, on the other side, osteoporotic patients on bisphosphonates with no improvement in BMD still have large reductions in fractures. There is also the Z-score, which compares people to those of the patient’s age and sex, and those better than -2.0 are “within the expected range for age”. The FRAX score (see and has been used about 5 million times, per the website) combines clinical risk factors, which can include BMD but does not need it, though data on benefit of FRAX are lacking. the threshold to treat varies by health care system and by clinical judgment, but rough guidelines, eg from the North American Menopause Society (see osteoporosis NAMS 2010 in dropbox, or DOI: 10.1097/gme.0b013e3181cdd4a7) is at least 20% for major osteoporotic fracture or at least 3% for hip fracture.

–in terms of physical activity, there are a slew of observational studies showing benefit, reasonable mechanistic support (the more one stresses one’s bones, the stronger they are; and conversely the less stressed, as through immobilization or prolonged bed rest esp in the elderly, the weaker). But it turns out that drug companies, the major sponsors of studies these days, are less interested in this nonpharmacologic modality. and, practically, it is probably unethical to randomize people to exercise vs not and follow them for years, given the multitude of exercise benefits, physically and mentally… and there are no real comparative effectiveness trials of the different meds because, I would guess,  drug companies choose the low bar of placebo control for their studies instead of comparing to another active med in order to maximize the likelihood for benefit and FDA approval.

–also, there really are limited data on treatment of men

— I would also add to the list of risk factors: HIV and some HIV meds (eg tenofovir disoproxil fumarate) and renal failure, as well as other medical conditions (hyperparathyroidism, monoclonal gammopathy and myelomas, etc)

–in terms of stopping therapy, I have been repeating the BMD after 5 years of therapy and continuing with bisphosphonates if the T-score is worse than pre-treatment or if it is more than about -2.5 to -2.7, after discussion with patients.  I am concerned that some clinicians are just stopping the bisphophonates at 5 years without reassessing the patient with another BMD, based on not knowing the exclusions or posthoc analysis of the relevant studies, which may put some patients at significant risk (see blog)


so, seems to me to be pretty reasonable recommendations overall. I do have lots of women on bisphosphonates without adverse effects, including into well-advanced age. The rationale here is that the risk of falls increases with age, as does the risk of hip osteoporosis. And the benefit of bisphosphonates in terms of fracture protection is evident within 11 months, and 8 months in those >70yo (see DOI 10.1007/s40266-016-0344-7).


see prior blog for a more detailed review of the studies on stopping bisphosphonates after 5 years.

Primary Care Corner with Geoffrey Modest MD: Higher allopurinol dosages for gout

9 May, 17 | by gmodest

by Dr Geoffrey Modest

A recent New Zealand study assessed the efficacy and safety of higher allopurinol doses in patients with pretty severe gout and comorbidities (see doi: 10.1136/annrheumdis-2016-210872​).


–183 patients with gout and taking creatinine clearance (CrCL)-based allopurinol therapy were randomized to continuing routine care vs monthly escalating allopurinol dose to achieve a target serum urate level of <6 mg/dL. Non-blinded study, patients followed 12 months

–mean age 60, 87% male, mean duration of gout 17 years, creatinine 1.58, CrCL 60, BMI 35, 44% palpable tophi, 38% on colchicine/13% NSAIDs/13% on prednisone. 34% diabetic/72% hypertensive/57% hyperlipidemic, 43% cardiovascular disease

–52% had CrCL <60ml/min, 13% CrCL <30 ml/min

–mean baseline serum urate level (SU) was 7.15 mg/dL on mean allopurinol dose of 269 mg/d.

–dose escalation group: increase allopurinol monthly, 50mg if CrCL <60ml/min, otherwise 100mg, to achieve target SU level


–mean change in SU was -0.34 mg/dL in the control group (?better med adherence by being in the study) vs -1.5 mg/dL in the dose escalation group (p<0.001). This separation was achieved within about 4 months, though took 7 months in those with CrCL <60.

–at month twelve: 32% of controls and 69% in dose escalation group achieve SU <6 mg/dL; this SU level was achieved in each of the last 3 visits in 14% vs 59% (odds ratio, OR=8.0)

–no difference in gout flares or tophus size during the study

–adverse events: 25 in controls, 35 in 22 dose escalation patients . Only one adverse event considered likely to be related to allopurinol, in a patient in the dose escalation group who had high INR after starting warfarin for elective mitral valve replacement.

–mild elevations of LFTs in both groups, and a few had moderate increases in GGT

–no difference in renal function between the groups (increases from their baselines). Both groups had about 10% of patients getting >20% decrease in CrCL, but similar numbers of patients actually had improvement in CrCL.

–no difference in other lab tests, including CBC (and eosinophilia)


–one presupposition for this study is that it is important to treat SU levels to specific targets. Several groups, including the American College of Rheumatology in 2012 (see DOI 10.1002/acr.21772) and the European League Against Rheumaone blogtism (EULAR) in 2016 (​ ), suggest targets of SU levels <6mg/dL in those with recurrent gout and <5 mg/dL in those with severe gout (tophi, chronic arthropathy, frequent attacks). However, there is a counterargument: one blog  questions the validity of treating-to-target for SU levels, noting that there are no studies looking at the clinical outcome of titrating to different targets in an RCT. Observational studies do confirm that those with SU levels <6 have fewer gout flares, but we do not really have the data to make a truly informed decision. These conclusions questioning treating-to-target were similar to the 2016 the AHRQ analysis of the data on the management of gout (see another blog)

–allopurinol is FDA-approved to a dose of 800mg, though in the pretty remote past I had a patient with tophaceous gout on even higher levels than that in an attempt to dissolve the extensive tophi (and this was done not uncommonly for those with very high SU levels, probably often due to inborn errors of metabolism), and overall many patients were on higher doses of allopurinol to achieve SU levels <6. However, doses >300mg/d seem to be rarely used more recently, as confirmed in a 2006 study. The concern about higher doses has been adverse effects, including the pretty rare allopurinol hypersensitivity syndrome (fever, rash, eosinophilia, hepatic abnormalities, renal failure, found in <0.1%, so this current study was not powered to detect this), which typically occurs in the first 2 months of therapy and is more common in those with higher starting doses or CKD, and perhaps with concomitant thiazide therapy

–EULAR guidelines comment that it is best to start with allopurinol 100mg/d in those with normal renal function, then increase every 2-4 weeks to achieve the SU target. but, with the most usual prescribed allopurinol dose of 300mg/d, only 50-70% reach the 6 mg/dL target; and those on up to 600-800 mg/d had a 75-80% chance to achieving that target. Starting at a low dose with slow increments seems to reduce the likelihood of gout flares from the allopurinol, and decreases the risk of severe cutaneous reactions. In those with renal impairment, allopurinol should be renal-dosed, starting at 50mg, and  the maximal dose of allopurinol should be adjusted by creatinine clearance in order to decrease the likelihood of severe cutaneous reactions.  If the SU level is not adequately controlled on high-dose allopurinol, consider adding a uricosuric, or consider switch to feboxustat, which seems more effective in patients with CKD. The American College of Rheumatology suggested continued gradual allopurinol dose escalation above the CrCL-based doses to achieve target SU level, with no maximum dose, though they specifically comment that in patients with CKD, it’s okay to exceed 300mg/d.

–not sure how to interpret the lack of clinical improvement in the current study (gout flares, tophi) in those on higher dose allopurinol, though the true separation of SU levels began after 4 months of therapy, so only 8 months of pretty much sustained SU differences between the groups, and only 5 months in those with renal compromise. The lack of benefit from high dose allopurinol is consistent with the observed finding that SU lowering drugs have no clinical effect for 6 -12 months. But why is this? why did a patient of mine with 2+ months of SU level of 4.4 mg/dL on meds have a gout flare?? Not so clear. Part of this may be that patients put on allopurinol can have an increase in gout flares in the first 3-6 months (and, EULAR recommends gout prophylaxis for 6 months after starting urate-lowering therapy), which could counterbalance a protective effect in other patients (no data provided in this study, but perhaps concomitant colchicine prophylaxis could help sort this out). Also, this study did not attempt to achieve SU <5mg/dL, which really is the goal recommended as the target for those with tophaceous or severe gout as in this study (ie, their target was perhaps too high)

— this blog  comments on the role of decreasing fructose intake in lowering uric acid levels (and I have seen some pretty impressive results from stopping sodas), as well as the effect of antihypertensives on SU levels and gout (losartan, especially, but also calcium channel blockers, especially amlodipine, decrease SU levels.)

–also, as a perhaps important side issue, there may also be cardiovascular benefits from  lowering SU levels (see this blog)


so, CKD does not seem to be a contraindication for using higher doses of allopurinol, especially when slowly titrating up doses to achieve SU in target range, as shown in this population of patients with pretty severe gout and lots of comorbidities. The next step is to have some studies with real clinical outcomes, ideally targeting different levels of SU for patients with different severities of gout, and with concomitant preventive therapy for the first 6 months.​ to the list

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

6 Apr, 17 | by gmodest

​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 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: 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).


  • 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.


  • 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.


  • 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: for a review of an article showing the benefits of tai chi, for an article on the benefits of mindfulness stress-reduction and cognitive behavioral therapy 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:​ ​list

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


  • 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


  • 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%)


  • 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 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:

Primary Care Corner with Geoffrey Modest MD: Early Activity After Concussion?

26 Jan, 17 | by EBM

By Dr. Geoffrey Modest

A large Canadian study looked at outcomes in kids according to whether there was strict rest versus different levels of physical activity in the week after a concussion (see doi:10.1001/jama.2016.17396​ ).

Details at initial exam:

  • 2413 participants aged 5 to 18 with acute concussion completed the questionnaires in the emergency room, at day 7, and at day 28 post-injury. The researchers assessed persistent postconcussive symptoms (PPCS, defined as at least 3 new or worsening individual symptoms vs preconcussion status) to see how that varied according to the amount of physical activity begun within 7 days of the ED visit.
  • Mean age 11.8 years, 39% female, arrived at ED a median of 8.7 hours after injury, 24% lost consciousness (11% >3 minutes), 2% had seizure, 8% had prior concussions lasting more than a week.
  • 49% appeared dazed and confused, 41% answered questions slowly, 14% repeated the questions, 21% were forgetful.
  • Parental report of headache in 87%, nausea in 59%, balance problem in 44%, dizziness in 70%, drowsiness 73%, increased sleeping 35%, sensitivity to light or noise 37%, irritability 27%, sadness 40%, seemed mentally foggy 40%, increased fatigue 75%, poor concentration 37%, acts more emotional 40%


  • 1677 (69.5%) participated in early physical activity, 736 (30.5%) had no physical activity:
    • Light aerobic exercise (e.g. walking, swimming, or stationary cycling) in 795 (32.9%)
    • Sport-specific exercise (e.g. running drills in soccer or skating drills in ice hockey) in 214 (8.9%)
    • Noncontact drills (e.g. complex passing drills) in 143 (5.9%)
    • Full contact practice (e.g. normal training activities) in 106 (4.4%)
    • Full competition (e.g. normal game play) in 419 (17.4%)
  • PPCS at 28 days occurred in 733 people (30.4%)
  • The incidence of PPCS at 7:
    • Those who engaged in early physical activity: 523 (31.3%) were symptom-free and 803 (48%) had at least three persistent or worsening postconcussive symptoms.
    • Those not engaging in physical activity: 584 (79.5%) had at least three persistent or worsening postconcussive symptoms
  • The incidence of PPCS at 28 days, by propensity score matching:
    • Early physical activity: 28.7% versus 40.1% for no physical activity
    • Among those symptomatic at day 7, the incidence of PPCS:
      • Light aerobic activity: absolute risk benefit of 6.5% over no activity
      • Moderate activity: absolute risk benefit 14.3% over no activity
      • Full contact activity: absolute risk benefit 16.8% over no activity


  • Pediatric concussion guidelines uniformly recommend an initial period of cognitive as well as physical rest after a concussion. These recommendations include modification of school attendance and mental activities as well as avoidance of any physical activity until postconcussive symptoms have returned to baseline, and then a gradual resumption of activities. However, there is no actual evidence to support these recommendations: they reflect a concern for preventing harm.
  • It is, however, very clear from the literature, that re-injury and recurrent concussions are deleterious.
  • This study, though quite large, is an observational study. They did propensity score matching as a means to mathematically control for differences between the different groups of activity level, in an attempt to decrease the inherent bias in an observational study (by mathematically adjusting the groups for likely relevant variables). It was notable that of the 20 items that they asked parents initially (e.g. headache, balance problem, drowsiness, etc., as noted above), there really was not much difference between the groups that performed physical activity and those that did not. However, this study still does not rise to the same evidence quality as a randomized controlled trial (i.e., mathematically modeling is just not the same…). A further caveat is that they did not look at cognitive rest, and it is conceivable that those who did not do any physical activity had much more cognitive activity, and it was the cognitive activity actually caused an increase in PPCS (not so likely, but possible). Also, the cutpoint of beginning exercise within the first 7 days of injury is arbitrary. It would be useful to see data on when exercise was started, perhaps over the first 3 weeks post-concussion and stratified by the initial concussion scores, to see what was the optimal timing or degree of exercise postconcussion
  • It was also impressive that there was an apparent dose-response curve: those that did more activity seemed to benefit the most
  • There really are an array of reasons that might support the conclusions of the study: for some children having to avoid all activity creates significant dysphoria (being the parent of two kids who had concussions, I can attest that not participating in sports created a lot of unhappiness) which can account for some of the psychological symptoms such as fatigue, poor concentration, irritability, etc. As a contrary issue, it is quite clear in the literature that physical activity is important for skeletal health, cardiorespiratory fitness, improvement in symptoms of depression, anxiety, self-esteem, cognitive performance, and academic achievement. In addition, exercise may well lead to improved cerebral blood flow and promote neuro-plasticity,
  • The study is very important in challenging a long-held, though not rigorously demonstrated, view about dealing with injury, in this case concussion. Similarly, for a long time, we were all advised to limit any activity at all for patients with low back pain, for a minimum of two weeks. That also seemed prudent at the time, but turned out to be the antithesis of what we should have been doing. And in these cases, I think this conception that rest is the right prescription really undercuts the power of exercise in preserving and restoring health.

So, based on the study as well as some others, it seems to make sense to have a gradual resumption of physical activity as soon as tolerated after an acute concussion, but avoiding activities that might risk re-injury, given how much better kids did who resumed exercise within a week after a concussion. However, it certainly makes sense to have a real randomized controlled trial to assess the optimal degree of physical activity and its timing after concussion, as well as specific characteristics of the concussion which might dictate different exercise programs. And, also to look at the effect of cognitive rest (which, i think, may be nearly impossible in our technological era, given the intense cognitive stimulation of smartphones, electronic devices, etc.)

For prior blogs: for another study suggesting more rapid introduction of physical activity; or​ for a study looking at the time-course of postconcussive symptoms in kids seen in the Boston children’s hospital ED

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