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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 http://blogs.bmj.com/ebm/2016/06/29/primary-care-corner-with-geoffrey-modest-md-tai-chi-for-knee-oa-mindfulness-for-chronic-pain/​ 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).

Details:

— 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.

Results:

— 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)

Commentary:

— 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).

Details:

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

Results:

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

Commentary:

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

For related articles, see:

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

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

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

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

1 Mar, 17 | by EBM

By Dr. Geoffrey Modest

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

Details:

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

Results:

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

Commentary:

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

 

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

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%

Results:

  • 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

Commentary:

  • 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: http://blogs.bmj.com/ebm/2015/02/03/primary-care-corner-with-geoffrey-modest-md-concussion-a-less-aggressive-approach/ for another study suggesting more rapid introduction of physical activity; or http://blogs.bmj.com/ebm/2014/09/09/primary-care-corner-with-geoffrey-modest-md-need-for-safe-sustainable-sports/​ for a study looking at the time-course of postconcussive symptoms in kids seen in the Boston children’s hospital ED

Primary Care Corner with Geoffrey Modest MD: New Gout Management Guidelines

1 Dec, 16 | by EBM

By Dr. Geoffrey Modest

The American College of Physicians just released guidelines on the management of gout (see doi:10.7326/M16-0570 ), sponsored by the Agency for Healthcare Research and Quality (AHRQ).

Details:

  • Risk factors for gout include overweight/obesity, hypertension, alcohol, diuretics, a diet rich in meat/seafood/high fructose foods and drinks, and renal failure
  • Recommended acute gout therapies
    • Lifestyle changes: although there is evidence that vitamin C supplementation reduces serum urate level, there are no data on symptomatic outcomes. Low-quality evidence from one study found that reducing the intake of red meat, shellfish, and yeast-rich foods as well as increasing the intake of low-fat dairy, vegetables, and cherries is no more effective than general dietary counseling (weight loss, decreasing alcohol) for reducing urate levels.
    • Colchicine: high-quality evidence shows that colchicine reduces pain from an acute gout attack. Moderate quality evidence suggests that lower doses of colchicine (initial dose of 1.2 mg followed by 0.6 mg after one hour) is as effective as high-dose (1.2 mg followed by 0.6 mg/hr for 6 hours), with fewer G.I. side effects (77% in the high-dose group vs. 23% in the low dose group)
    • NSAIDs: high-quality evidence and observational data show that NSAIDs reduce pain in patients with acute gout. They are also useful in preventing gout flares during urate-lowering therapy. The main harms are GI side effects, though longer-term use can lead to chronic renal insufficiency. There’s moderate quality evidence that it doesn’t matter which NSAID one uses. The cyclooxygenase-2 inhibitors work as well, with fewer total adverse events as compared to standard NSAIDs (38% vs. 60%)
    • Corticosteroids: no placebo-controlled trials. But high-quality indirect evidence suggests that systemic steroids reduce pain in patients with acute gout. Adverse effects are dose- and duration-dependent and affect the whole body, including significant psych effects (dysphoria, etc). Parenteral corticotropin also reduces pain, similar to NSAIDs and oral steroids, so probably do not have much of a role given their expense.
  • Recommended therapies for hyperuricemia
    • High-quality data suggests that allopurinol and febuxostat lower serum urate levels. But there are no long-term RCTs that compared the incidence of recurrent gout flares between patients treated vs. not treated with urate lowering therapy. Observational data suggests that patients on >1 year of such therapy have fewer gout flares, and that there are fewer flares when the urate level is <7 mg/dL. Although there are rare serious adverse effects associated with allopurinol, including the fatal hypersensitivity reactions, this is particularly common in those with HLA-B*5801, which is prevalent especially in Asian patients [and I think should be tested for]. There is less known about the harms of febuxostat given its limited clinical experience. Febuxostat at 80 mg per day seem to be more effective in lowering serum urate levels than 300 mg of allopurinol. Patient should be on prophylactic colchicine or NSAIDs for more than 8 weeks after starting these medications to reduce gout flares [empirical data suggests 3 months, see below]
    • No studies have documented a specific target uric acid level (i.e., “treat to target”). There is no rock-solid evidence that treating to one level vs. another is beneficial, and targeting a lower level could lead to increased medical visits as well as increased medication and increased adverse effects. There was a post hoc observational analysis from 2 large trials which showed that those patients who had a urate level < 6 mg/dL had fewer gout flares at 12 months than those who did not (5% in those <6 vs. 10-15% in those >6)

Commentary:

  • 9% of US adults have had gout, which increased about 1% in the 10 years before 2007, likely related to changes in the noted risk factors. About $1 billion is spent annually in the ambulatory care for gout
  • My assessment of the above recommended therapies are:
    • I do strongly support decreasing fructose intake, especially ingesting foods or drinks with high fructose corn syrup. My own anecdotal data for several patients is that eliminating daily sodas has led to about a 0.5-1 mg/dL decrease in uric acid levels. Decreasing overweight/obesity, alcohol consumption, and the metabolic syndrome overall, is alsohelpful for serum urate levels, as well as for general health, though these are not included in the above recommendations given lack of specific gout-related rigorous studies. (though, for the patients’ overall morbidity and mortality, these may well be the most important interventions. and using their diagnosis of gout might help spur them on to change)
    • Also, as a side issue, losartan lowers serum uric acid levels (but not other ARBs) and was even included in the list of hyperuricemia treatments in the 2012 American College of Rheumatology guidelines (see DOI 10.1002/acr.21772 ). A large UK database found decreases in clinical gout with losartan (19%) but also with amlodipine (21%), nifedipine (13%) and diltiazem (14%) — see doi:10.1136/bmj.d8190.
    • Colchicine is a great drug. It tends to work most often with an acute attack, especially within the 1st 48 hours or so. It also might have cardioprotective effects (see blog references below)
    • NSAIDs do work quite well, but as per many blogs, I am very concerned about reinforcing their use, given not just the G.I. and renal effects as noted in this paper, but also its effects on heart failure, atrial fibrillation and hypertension (see many prior blogs: go to the blog link at the end, and type NSAID in the search window). Another concern I have is that a lot of people preferentially use indomethacin, given its early history as the NSAID of choice, though it has pretty marked G.I. intolerance and is no better than other NSAIDs.
    • Corticosteroids: I do use oral corticosteroids in patients who have multiple joints involved. A short course seems to work quite well. However, in the vast majority of cases of gout that I’ve seen, only 1-2 joints are involved, and local steroid injection therapy works approximately 100% of the time, and I’m sure I have injected gouty joints at least 2 dozen times. This includes injections into the great toe (1st MTP joint), where I am certain that at least 50% of the time I am not actually getting within the joint itself. there are only some small open-label trials on the efficacy of joint injections in gout… not enough to be endorsed by these guys
  • One issue that these guidelines highlight is what should we do when there are insufficient rigorous studies to recommend a specific therapy. Should one continue doing what seems to be working, pending high-quality studies if they ever happen? Or should one stop because of lack of rigorous data? It seems to me that this clearly varies depending on the history of accrued knowledge and experience in the area, including both the apparent benefits and known risks. And this is informed also by one’s sense of the pathophysiology, which of course may be incorrect. So, in terms of the above, I do think it makes sense to push for the nonpharmacologic changes, since lowering uric acid levels is likely to decrease crystallization and clinical gout, and is better for the patient anyway. I also strongly support steroid injections, given their negligible adverse effects and, at least in my experience, dramatic and almost immediate effectiveness. Also, even though we are lacking studies which target a specific uric acid level in those on prophylactic therapy, it certainly makes sense from our understanding basic chemistry around crystallization, that the lower the urate level, the less likely there is to be a gout exacerbation (and we know that in untreated patients, higher urate levels are associated with more likelihood of crystallization and clinical gout; and lowering the uric acid level to <6 is better than higher levels in preventing recurrent attacks in observational studies).
  • However, I should comment that our understanding of the pathophysiology of gout seems to me to be pretty incomplete. For example, gout flares usually subside on their own without therapy after a couple weeks. Why? Also, it doesn’t seem that lowering uric acid levels has any effect on gout attacks in the 1st 6 months. Why? In fact I had a patient recently who had a uric acid of 10.8, had a gout attack, was put on hyperuricemia therapy (in his case febuxostat), had a uric acid level documented at 4.4 mg/dL for 2 months, and still had another documented recurrent gout flair. One would think that after 2 months of a very low uric acid level that there would not be further crystallization.  A prior blog commented on his case, and referenced an article suggesting that patient should be on at least 3 months of prophylactic therapy, e.g. with NSAIDs or colchicine (see blog reference below). There also are not great data on the dose of colchicine to use. In general they recommend using 0.6 mg twice a day. However I have always used 0.6 mg once a day with good effect and minimal adverse effects.

See http://blogs.bmj.com/ebm/2016/03/31/primary-care-corner-with-geoffrey-modest-md-gout-management-ahrq-report/ for prior review of the full AHRQ report, and reference to the utility of 3 months of prophylaxis after starting a hypouricemic agent

See http://blogs.bmj.com/ebm/2016/03/04/primary-care-corner-with-geoffrey-modest-md-oral-steroids-for-acute-gout/ for a study showing equivalence of oral prednisolone vs indomethacin for acute gout, with more adverse effects with indomethacin

See http://blogs.bmj.com/ebm/2016/04/04/hyperuricemia-allopurinol-decreases-cardiac-events/ which argues that allopurinol may decrease cardiovascular events; http://blogs.bmj.com/ebm/2016/10/14/primary-care-corner-with-geoffrey-modest-md-colchicine-may-lower-cardiac-risk-in-patients-with-gout/ for a study finding cardioprotection from colchicine; and http://blogs.bmj.com/ebm/2015/11/03/primary-care-corner-with-geoffrey-modest-md-uric-acid-lowering-cardiovasc-benefit-and-an-evolutionary-perspective/ which puts the cardioprotection in an evolutionary perspective

Primary Care Corner with Geoffrey Modest MD: Benefits of placebo for low back pain, and some random thoughts

14 Nov, 16 | by EBM

By Dr. Geoffrey Modest

Another really interesting study was published on the benefit of placebo, this time in decreasing chronic low back pain (see doi: 10.1097/j.pain.0000000000000700 ). This study was remarkable in that both the clinicians and the patients were aware that the intervention was placebo vs their current care.

Details:

  • 83 patients (of a total of 243 screened) with chronic low back pain (LBP) for at least 3 months duration were randomized to open-label placebo (OLP) vs treatment as usual (TAU) for 3 weeks. The latter group was told that they would be offered the opportunity to take the placebo pills after the 3 week intervention.
  • Exclusion criteria included taking opioids
  • Mean age 44, 71% women, 74% employed, 87% used pain meds in past week (76% NSAIDs/analgesics, 22% antidepressants, 15% benzos, 40% adjuvants of cyclobenzaprine/gabapentin/thiocolchicoside, 14% complementary medicine).
  • Pain severity assessed in three 0-10 scales: maximum pain, minimum pain, and usual pain. Baseline mean pain overall 1.8 out of 10, mean disability 5 out of 10. All patients were seen by a board-certified pain specialist
  • All patients were given a 15-minute script stating the following: the placebo effect can be powerful; the body can respond to the placebo effect, like Pavlov’s dog; a positive attitude can be helpful but is not necessary; and it is crucial to take all of the pills. Those randomized to the placebo pills were given a bottle of orange gelatin capsules filled with cellulose, labeled “Placebo pills. Take 2 pills twice a day”. Those in the control group were reminded of the importance of being in a control group, and that they too could get placebo after 3 weeks.
  • Those in the placebo group were also asked what they thought of taking placebo, if they expected placebo to work, and what they thought was in the placebo pills. Those in the control group were asked if they were disappointed in not being in the placebo group, and what they thought about the study
  • Outcomes were measured at baseline, 11 days and 21 days

Results:

  • OLP elicited greater reduction in pain in all 3 scales (p<0.001 for the composite), with moderate to large effects.  A reduction of pain by 30% reflects a clinically significant change, which was found in both the usual and maximal pain scales in the placebo group, vs a 9% and 16% reduction in the TAU group. The minimum pain decreased by 16% in OLP, but increased 25% in TAU
  • OLP also reduced disability (a secondary outcome) vs TAU (p<0.001) with a large effect size (a 29% reduction vs 0.02% in the TAU group)
  • Adverse effects were essentially nonexistent
  • Of the 33 respondents in the OLP group, 30 reported that the placebo “was not an active substance”, 3 stated it was a “pain killer” since it worked so well.  21 said that they were skeptical that the placebo would work, 9 thought it would. Most respondents in the TAU group were not disappointed that they were not on placebo, since they “knew” they would have it later.
  • And, 17 patients in the TAU group requested the placebo at the end of the study

Commentary:

  • Chronic LBP is remarkably common and causes more disability than any other medical condition worldwide: in the US it is ranked third in all diseases by disability-adjusted life-years. As a reference point on the degree of pain reduction in the above study, NSAIDs do reduce chronic LBP vs placebo, though the net benefit is less than one point on the 0-10 point scale.
  • There have been a few similar open-label placebo studies, all small, but showing some efficacy for placebo in depression, ADHD, and irritable bowel syndrome

This article was quite remarkable, and brought up several interesting issues:

  • There seemed to be pretty equivalent encouragement and interaction by the investigators for both the OLP and TAU groups, making it unlikely that the positive placebo effect was simply increased contact and empathy from the clinicians
  • There have been many neuroimaging studies which have found that placebo leads to changes similar to those found by medical analgesics, in the same specific areas of the brain and with changes in relevant neurotransmitters.
  • BUT, although these patients had chronic LBP, overall their pain scores were relatively low, the disability score was mid-range, and they were not on opioids. i.e., these patients had pretty mild chronic pain symptomatology and OLP efficacy may not be generalizable to patients with much more severe pain and/or on opioids. And this was a really short (3-week) exploratory study, again limiting interpretation of its potential sustainability in actual chronic pain patients. Also, the individuals who volunteered for a study advertised as a “novel mind-body clinical study” may not reflect well the general population of patients with chronic LBP (though only 14% were actually using complementary treatments, and most of the patients were highly skeptical of the benefit of placebo).
  • We know that in many large randomized-controlled studies, along with the frequent 20-30% treatment efficacy in the placebo wing, there are also pretty frequent adverse events with placebo (sometimes rivaling the number of adverse events in the active treatment wing).  And, as the contrary issue, too much discussion of potential adverse effects of medications can increase the likelihood that the patient will have an adverse event (i.e., the “nocebo effect”, see http://blogs.bmj.com/ebm/2013/11/25/primary-care-corner-with-dr-geoffrey-modest-nocebo/ ). This supports using open-label, transparent prescribing of placebos (I would like to emphasize this pretty striking finding: in those on blinded placebo in controlled studies, they typically have lots of adverse effects attributed to the placebo; but none in the open-label placebo study despite the significant benefit….)
  • A prior blog was on a candesartan study (the CHARM trial) finding that candesartan was indeed superior to placebo in patients with heart failure and reduced ejection fraction. But if one looked only at patients who were adherent in taking their meds (either candesartan or placebo) there was in fact no difference in outcomes (i.e., efficacy was from med taking and not whether it was an active med or placebo). see http://blogs.bmj.com/ebm/2016/04/14/primary-care-corner-with-geoffrey-modest-md-another-blog-on-the-power-of-placebos/
  • An interesting side-line to the placebo effect is that there seem to be some significant genetic influences/determinants to the placebo effect (see http://blogs.bmj.com/ebm/2015/05/07/primary-care-corner-with-geoffrey-modest-md-placebo-genetics-and-the-placebome/  )
  • So, perhaps one advantage to the open-label approach is that it seems that patients knowingly taking open-label placebo, most of whom were initially skeptical of the potential benefit from the placebo, had therapeutic benefit with essentially no adverse effects.

This study also brought up several bigger issues about prescribing placebos:

  • It effectively circumvented ethical concerns about “deceiving patients” (their terminology) by giving them open-label placebo: patients were aware that they were taking placebo, and the majority confirmed that they knew that the placebos were likely not effective. I should comment that the issue of “deceit”, to me, is a bit overstated and has too strong a negative connotation. Given that our goal is to help patients, is it really deceitful if I really don’t give all of the information to a patient? I would argue that all clinicians give partial and subjective information almost all of the time:
  • Our understanding of the best approach to our individual patient is fundamentally subjective, since reading the medical literature is quite complex and the literature is quite incomplete: different studies often have conflicting results from the same treatment, in part because of differing methodologies, in part from different inclusion/exclusion criteria, and in part simply because people are very complex biological systems, and attempts to reduce the person in front of us mathematically to the average study participant (e.g., mean 51 years old, 45% female, 83% white, 14% with diabetes, 18% on a statin, and without renal insufficiency…) may be meaningless in terms of treating my 73 yo Ethiopean woman with renal insufficiency etc etc. (i.e., i am extradorinarily likely to be prescribing an “untested medication” for this particular woman)
  • In addition to the often complex medical conditions, different therapies, etc of our specific patient is the much added complexity of the multitude of psychosocial factors which affect the disease prevalence, severity, response to treatment, etc.  It is really difficult to factor these into interpreting the studies, and by-and-large they are never even included in the studies. And we know from the limited data, for example, that depressed people do less well. Or patients without adequate housing/food/highly stressful lives may not do so well (e.g., see http://blogs.bmj.com/ebm/2016/08/24/primary-care-corner-with-geoffrey-modest-md-neighborhood-deprivation-and-diabetes-risk/ , which shows that these psychosocial/environmental factors influence the development of diabetes). These psychosocial factors are important, but rarely part of the RCTs, again challenging our application of most of the current studies to our individual patient.
  • These last 2 points clearly affect our ability as clinicians to interpret the medical literature and apply it “objectively” to patients. But added to this is that we humans are really a subjective lot. As clinicians, we are influenced disproportionately by our empirical/anecdotal experience (and the more recent experiences weighing more heavily). Also the most recent medical article on a problem seems to hold disproportionate sway over the prior medical studies. We are also influenced by our medical model of the disease process leading us to accept some studies’ conclusions over others, and this is determined by our own accepted medical culture (and many of my previous blogs display many of the inaccuracies of our held medical models). And we are trying to discuss the complexity of these medical issues across the complexity of who the patient is (their education, cultural background, health beliefs, psychological state, etc etc), all of which affect their ability to understand/interpret what we say.
  • And, besides, we have gone through years of medical training, and years of experience (in many cases). And the thought that we can break down complex medical concepts and pathophysiology to explain what we think is going on and what we suggest doing in the context of a 20 minute session with the patient (and often deal with many other issues in the same clinical encounter) reflects mystical thinking
  • So, I think that we as clinicians are always trying to figure out what we think is best for the patient. And, in most cases, that is what the patient wants and expects. We process lots of data, and provide the best advice we can, in the context of and modified by who the patient is sitting in front of us. Is it deceitful that we are doing this??? If we give this patient a not-so-likely-to-work therapy that might help them?? We often give medications that we think are pretty harmless, have little data to support them, but are worth trying (e.g., simethacone for gas). And, they often work… is that deceitful? More deceitful than giving a truly innocuous placebo???
  • I should add to the above points, that I am not a therapeutic nihilist. I do try to figure out what is best for my patients, and do prescribe lots of drugs (though I am increasingly skeptical of new drugs overall, especially if there are old tried-and-true ones which work quite well; I have learned over and over that apparently promising new drugs often fall flat on their faces over time)
  • My untested clinical sense is that my level of enthusiasm about a treatment does affect the results (??enhancing the placebo effect). I learned this a while ago when giving antidepressant meds for the first time (tricyclics, prior to the advent of SSRIs). The results were somewhat muted initially, but as soon as someone responded dramatically, I was much more convinced of the utility of the meds and therefore persuasive in prescribing them, and subsequent patients seemed to respond much more frequently to these same medications.
  • Another correlate of the above is that perhaps we should be interpreting studies a little differently. For complex biopsychosocial medical problems (e.g. chronic LBP), there really are very few nonpharmacologic interventions which have been rigorously tested. Exercise is one of the best evaluated and seems to be quite helpful. But the small studies finding that acupuncture is no better than sham acupuncture in a structured RCT may not mean that acupuncture doesn’t work. It may mean that it really does work, but in a way different from what we thought we understood of how it would work (maybe there does not need to be specific “acupuncture points”, or maybe there are more “points” than we know, and in either case the “sham acupuncture” is actually “real acupuncture”). Maybe we are just involving the patient in a treatment that they feel will really help, and this empowerment of the patient is what is working. Maybe it is just the placebo effect (though perhaps some types of placebos work better in some people than other types, e.g. meds vs physical interventions). But many people do get relief. Again, we should not dismiss a therapy just because it does not stand up to our “scientific rigor”. Maybe we are not asking the right question. Maybe getting benefit from any intervention (including placebo) is really the goal.
  • I do realize this is a long blog with lots of general random thoughts on the interpretation/application of the medical literature, but I think this study does bring many of these issues and assumptions to the fore.
  • So, this study reinforced that there is a clinically important placebo effect (in fact, the Institute of Medicine in 2011 noted that “placebo [could] conceivably be a form of treatment of pain, especially in light of the shortcoming of other modalities or benefits they bring in their right”. As part of patient care, I think that we should figure out creative ways to integrate this powerful placebo effect into routine patient care. Perhaps best as open-label placebo, perhaps as just another prescription. Or, perhaps it might be different from one patient to another. So, to rephrase what pretty much all editorialists say almost all of the time about studies: we need more studies, longer-term and with more types of patients. In this case of LBP, looking at the long-term efficacy/adverse effects of OLPs, and even comparative studies assessing OLPs vs disguised placebos prescribed as active medication …..

Primary Care Corner with Geoffrey Modest MD: Colchicine May Lower Cardiac Risk in Patients with Gout

14 Oct, 16 | by EBM

By Dr. Geoffrey Modest

There have been several articles suggesting that allopurinol is associated with decreased cardiovascular events (for example, see http://blogs.bmj.com/ebm/2016/04/04/hyperuricemia-allopurinol-decreases-cardiac-events/ ). This might be attributed to the cardiotoxic effects of hyperuricemia itself, or perhaps through its association with the metabolic syndrome (see the above allopurinol blog for more details, as well as http://blogs.bmj.com/ebm/2015/11/03/primary-care-corner-with-geoffrey-modest-md-uric-acid-lowering-cardiovasc-benefit-and-an-evolutionary-perspective/ for an evolutionary perspective).  However a recent study found that colchicine in patients with gout also seems to be associated with fewer cardiovascular events (see Solomon DH. Ann Rheum Dis 2015; doi: 10.1136/annrheumdis-2015-207984).

Details:

  • All patients were identified with a diagnosis of gout in their electronic record in a large academic hospital (99% accurate diagnosis, on a sample of 100 records) and linked them with cardiovascular outcome data and medication claims from Medicare.
  • 501 colchicine users (defined as those with colchicine prescribed, but no previous colchicine prescriptions in the past 90 days) and 501 nonusers. Mean follow-up 16.5 months
  • Mean age 73, 36% female, 72% white/18% black/4% Hispanic, 13% known CV disease, 10% prior heart failure, 38% diabetes, 40% on aspirin, 38% never smokers, BMI 30, 42% chronic kidney disease.
  • Primary outcome: MI, stroke, or TIA.
  • However, there were some significant differences between colchicine users and nonusers, including: hypertension in 77% of colchicine users and 28% of nonusers, statin use 50% vs. 16%, uric acid levels 8.4 mg/DL vs. 7.1 (but of note, only 278 of the 1002 patients actually had uric acid levels documented), 42% vs. 16% were on allopurinol, 42% vs. 9% were on NSAIDs, and 42% vs. 12% were on oral steroids.

Results:

  • 28 primary CV events were observed among colchicine users and 82 among nonusers, incidence rates per 1000 person-years were: 35.6 for users and 81.8 for nonusers.
  • With full adjustment (age, gender, race, history of CV disease and risk factors, as well as medications including NSAIDs, allopurinol, chronic kidney disease), colchicine was associated with:
    • 49% lower risk of all primary CV outcomes, HR 0.51 (0.30 – 0.88)
    • 73% reduction in all-cause mortality, HR 0.27 (0.17 – 0.43)
  • The curves for all of these outcomes were tending to splay apart over time. Of note, however, those who were on colchicine for the longest did have more cardiovascular events, with the group doing best being those who used colchicine less than three months.
  • Though only a quarter of the patients had uric acid levels checked, there was a similar trend by uric acid levels as with the primary analysis.

Commentary:

  • The putative mechanism by which colchicine might decrease cardiovascular events is through its down regulation of inflammatory cytokines and neutrophil chemotaxis, decreasing inflammation. And it does have clinical benefit in several inflammatory conditions including recurrent pericarditis, familial Mediterranean fever, …
  • As with all observational studies, there may be inherent biases. They did try to control for underlying diseases, but there still could be some bias to not using colchicine in those who were sicker. There might also have been a bias that those on colchicine may have been more willing to take medications, which could elicit a higher placebo effect. It would be really helpful to have a controlled trial of chronic allopurinol vs. chronic colchicine use in patients with recurrent gout attacks, both to compare the efficacy in preventing gout as well as differences in cardiovascular outcomes.
  • So, how did this study affect our clinical practice? Probably not a lot, without a study showing clearly that colchicine is as effective as allopurinol/hypouricemic agents in decreasing cardiovascular events. Since there are still more data supporting the cardioprotection of hypouricemic agents, I will still continue with them primarily. However, in the remote past, I had many patients on chronic colchicine for recurrent gout with excellent effectiveness in gout attack prevention. At a dose of 0.6 mg per day (though some clinicians used 0.6 mg bid), colchicine was very well-tolerated and seemed to have fewer adverse effects than allopurinol. So, as a result of this current study, I am more inclined to use chronic colchicine again, especially if someone is intolerant of the hypouricemia (In this latter case, I had moved more to treating the recurrent gout attacks with intra-articular steroids.)

Primary Care Corner with Geoffrey Modest MD: Symptomatic Knee Effusions from OA Resolve With Spironolactone?!

5 Oct, 16 | by EBM

By Dr. Geoffrey Modest

And so the wonder drug spironolactone seems to have another possible indication: knee effusions from osteoarthritis (see Elsaman AM. J Rheumatol 2016; 43: 1114).

Details:

  • 200 patients with unilateral knee effusion related to osteoarthritis (OA) based on clinical exam, ultrasound and synovial fluid analysis
  • Mean age 51, 40% male, weight 84 kg, mean duration of effusion 16.5 days, mean thickness of fluid by ultrasound was 7.6 mm thick
  • Randomized to 2 weeks of: spironolactone 25 mg daily; ibuprofen 400 mg three times/d; cold compresses twice a day, for 10 minutes each time; or placebo
  • Assessment: effusion considered if >4mm fluid; complete improvement if <4mm, partial improvement if a decrease but still >4mm

Results:

  • At 2 weeks after treatment
    • Spironolactone group: 66% had complete improvement/20% partial/14% no improvement; mean fluid thickness 3.7 mm
    • Ibuprofen group: 24% had complete improvement/12% partial/64% no improvement; mean fluid thickness 6.3 mm
    • Cold compress group: 28% had complete improvement/14% partial/58% no improvement; mean fluid thickness 5.9 mm
    • Placebo group: 6% had complete improvement/10% partial/84% no improvement; mean fluid thickness 7.3 mm
  • At 4 weeks after treatment
    • Spironolactone group:mean fluid thickness 2.4 mm; 79% no recurrence of effusion/21% recurrence
    • Ibuprofen group: mean fluid thickness 5.1 mm; 44% no recurrence of effusion/56% recurrence
    • Cold compress group: mean fluid thickness 5.0 mm; 38% no recurrence of effusion/62% recurrence
    • Placebo group: mean fluid thickness 6.9 mm; 13% no recurrence of effusion/88% recurrence
  • VAS (visual analog scale of pain, from 0-10):
    • Spironolactone group:at 2 weeks, decreased from 5.42 to 2.66, then at 4 weeks to 1.06
    • Ibuprofen group: at 2 weeks, decreased from 4.64 to 3.70, then at 4 weeks to 2.44
    • Cold compress group: at 2 weeks, decreased from 5.16 to 4.00, then at 4 weeks to 2.53
    • Placebo group: at 2 weeks, decreased from 5.14 to 4.50, then at 4 weeks to 4.00
  • Adverse effects of spironolactone: 8% had lowering of blood pressure, but not below normal; 6% had “disturbances in their sodium and potassium levels”, not otherwise elucidated.

Commentary:

  • About 45% of patients with painful knee OA have an effusion, increasing to 79% during activity in a European study; another study found effusion in 55%
  • In this study, NSAIDs were no better than placebo, though cold compresses were better than placebo
  • Spironolactone was chosen because of its effect on other effusions (e.g. ascites, pleural effusion). Also, it does seem to have anti-inflammatory properties (aldosterone being pro-inflammatory). Other studies have found that spironolactone can improve muscle function in functionally-impaired elderly.
  • Pretty striking response to spironolactone after only 2 weeks of therapy, with lack of recurrence at 4 weeks and impressive continued decrease in effusion size. The VAS pain scale tracked with the effusion resolution, and continued to improve after therapy ended in all groups.
  • One pretty significant problem with the study was that those on spironolactone were hospitalized for the first 3 days, to check the blood pressure every six hours. Not only is this questionably necessary, but it might well distort/increase the “placebo effect” of the intervention.
  • Another very recent article, a proof-of-concept study, found the opposite conclusion in elderly Scottish patients (see McMurdo MET. Arthritis Care & Research 2016; 68:716). Briefly:
    • 86 community-dwelling elderly patients (all >70 yo, with mean age of 77, 62% women) with symptomatic knee OA pain and radiologic OA, were randomized to spironolactone 25 mg vs placebo for 12 weeks
    • Result: no difference in pain, stiffness or physical function scores on WOMAC (Western Ontario and McMaster Universities Osteroarthritis Index)
  • I’m not exactly sure why these outcomes are so different. But though both dealt with patients with symptomatic OA, they are very different studies. The latter was older patients, no comment on whether effusion was present or not, 50% were on opiates, 66% on nonopioid preparations, and 18% were on neuropathic drugs (amitriptyline, pregabalin, gabapentin). The study above, however, was pretty much the opposite (younger patients with short-term knee effusions and not on other meds, though they did not comment explicitly on how often patients took any other meds during the 2-week study or in the month after the study)
  • So, given the increasing indications and use of spironolactone over the past decade or more (resistant hypertension, hyperaldosteronism, heart failure, hirsutism, ….) and that we in primary care in general are pretty comfortable using it and monitoring for safety, its short-term use in patients with symptomatic OA is appealing. I think it is overall less toxic than many of the other meds we use (esp NSAIDs), so it might be reasonable to consider. Larger and confirmatory studies would be helpful prior to a stronger recommendation. My go-to therapy in most patients with symptomatic and functionally-impairing painful knee OA is still steroid knee injections for OA (really rapid response and ability to get back to their activities; a local therapy, which works almost all of the time, with minimal systemic effects).

Primary Care Corner with Geoffrey Modest MD: Long Term Alendronate Effectiveness and Safety

14 Jul, 16 | by EBM

By Dr. Geoffrey Modest

There have been concerns that long-term alendronate use could lead to more complications, such as subtrochanteric femur fractures, but a recent Danish registry study was reassuring (See doi: 10.1136/bmj.i3365).

Details:

  • 61990 men and women 50-94 yo on alendronate, in the Danish prescription registry from 1996-2007, which holds almost 20 years of drug exposure data, were linked to all fracture outcomes treated in-hospital.
  • Mean age 72, 83% women, baseline major osteoporotic fracture 31%, diabetes 5%, CKD 1%, chronic pulmonary disease 19%, prednisolone in past year 25%
  • 2 nested case-control studies: one looked at those with hip fractures and compared them to 3 controls matched for age, sex, year of starting treatment, and follow-up time; the other similarly-controlled looked at subtrochanteric/femur shaft (ST/FS) fracture but matched to 5 controls.
  • All alendronate dosing was at 70 mg/week. Mean follow-up 6.9 years (range 0-17.9)
  • Results: [though of those who took their meds regularly, only 30% (18,242) completed 5 years of treatment, 4% (2465) completed 10 years, and only about 1000 completed >=14 years]
    • Incident ST/FSfracture in 1428 people, at rate of 3.4/1000 person-years (CI 3.2-3.6)
    • Incident hip fracture in 6784 people, at rate of 16.2/1000 person-years (CI 15.8-16.6)
    • Higher medication adherence and longer term use of alendronate led to 27% decreased risk of hip fracture [HR 0.73 (0.68-0.78), p<0.001]
    • Longer term alendronate usage was associated with decreased risk of hip fracture:
      • 5-10 dose years: HR 0.75 (0.67-0.83), p<0.001
      • >10 dose years: HR 0.74 (0.56-0.97), p=0.03
    • There was no association of ST/FS fracture with cumulative use of alendronate in those taking alendronate >10 years (in fact, there was a 57% reduced risk of subtrochanteric femur fractures and no change in shaft fractures), or in those currently taking it vs past users, though the likelihood of ST/FS was higher in those with comorbidities including diabetes, chronic lung disease, and those on proton pump inhibitors (PPIs).
    • The NNT (number-needed-to-treat for an additional 5 year to prevent one additional fracture) was 38, and the NNH (number-needed-to-harm by causing a ST/FS fracture in one person with an additional 5 years of therapy) was 1449.

Commentary:

  • There has been concern that using prolonged bisphosphonates could lead to more problems with atypical femur fractures, and, perhaps related to that, the usage of these meds has decreased by 50% in the US and similarly in the European Union
  • The above Danish study is observational, and therefore subject to biases. So, hard to make a firm recommendation. Potential biases and limitations include:
    • The registry was almost exclusively of North Europeans. There is some concern that some groups (e.g. South Asians) may be at higher risk of atypical femur fractures
    • They did not look at osteonecrosis of the jaw, another uncommon event related to bisphosphonates
    • The consequences/morbidity of an atypical hip fracture can be high, though typically less than that of a regular hip fracture
    • The above data were more impressive in those patients who adhered more to treatment with alendronate, and this group might be different from the general population (perhaps educational differences, or this group was convinced they were at higher risk of fracture and took the meds more often, etc.)
    • They did not have data on calcium/vitamin D intake.
  • In the Danish study, assuming a worst-case scenario (i.e., 100% of the ST/FS fractures are atypical/related to alendronate, there was 0 background rate of these fractures, and comparing the upper 95% confidence limit in the harm:benefit models rather than the observed 50% rate), there was still a clear benefit of alendronate for up to 13 years (and part of the issue beyond that is that there were so few patients on the med for >11 years that the confidence intervals were quite wide)
  • There are some data from a randomized trial (see Bone, HG. N Engl J Med. 2004; 350: 1189) where a subset of postmenopausal women were randomized to stopping alendronate after 5 years or continuing another 5 years, finding some decrease in BMD and increase in markers of bone turnover in the former group but no significant difference in fractures (except for slightly higher risk of fractures detected by x-ray and some nonsignificant decrease in height loss). But it is important to note that women at higher risk of fracture were excluded(either T-scores below -3.5, or T-score after 5 years which was worse than their baseline). No one in either group developed jaw osteonecrosis, and bone biopsies showed no qualitative abnormalities.
  • So, the above data are impressive, suggesting that continued alendronate, even up to 14+ years, is associated with continued decrease in hip fracture risk and no real change in ST/FS. My approach, which is reinforced by this Danish study, is to put all patients with an osteoporotic fracture or a BMD less than -3.5 on long-term therapy (which in several cases has been in the 15 year range so far). For the others, I check a BMD after 5 years, and if their BMD is worse than their initial one, I continue with the alendronate. And, the ones that I stop the alendronate in, I recheck their BMD in 2-3 years to make sure it is not deteriorating (my bias is that this is a pretty benign therapy overall, the functional/quality-of-life consequence of a hip fracture or a painful vertebral fracture can be quite significant, and, especially in a younger person with a long life expectancy, the further deterioration in BMD and increase in bone turnover markers on stopping the alendronate, as in the N Engl J Med trial, is concerning in the long-term even if no significant increase in these fractures happened in the next 5 years that they studied). The above Danish study was reassuring that long-term alendronate was associated with a continued 30% decrease risk of hip fracture and there was no increase in subtrochanteric and femoral shaft fractures
  • And, I will add my longstanding tirade that it is really important to down-titrate PPIs whenever possible, given the multitude of well-defined adverse effects including decrease in BMD/ 30% increase in fractures (in a large meta-analysis). I have found that most of my patients are able to downgrade to H2 blockers or calcium tablets, if not able to get off the meds completely

See http://blogs.bmj.com/ebm/2016/01/28/primary-care-corner-with-geoffrey-modest-md-guidelines-on-length-of-bisphosphonate-therapy/ for the American Society for Bone and Mineral Research guidelines on the length of bisphosponate therapy, which goes into further depth on the randomized controlled trials, and is not so different from my assessment above, just that the Danish trial does give further reassurances for using longer-term bisphosphonates.

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