You don't need to be signed in to read BMJ Blogs, but you can register here to receive updates about other BMJ products and services via our site.


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: opiate prescribing in the elderly and subsequent dependence

22 Feb, 17 | by EBM

By Dr. Geoffrey Modest

Two important articles were just published in NEJM which I think should stimulate a change in clinical practice regarding prescribed opiates.


One article assessed the relative importance of physician prescribed opiates and the subsequent use of opioids in the elderly (see Barnett ML. N Engl J Med 2017; 376: 663).


  • Retrospective analysis of a random 20% sample of continuously-enrolled Medicare beneficiaries who had an emergency department (ED) visit from 2008-2011, and had not received opioid prescription for the prior six months
  • Mean age 69, 65% female, 76% white, 50% also on Medicaid, 37% disabled, mean of 3.5 chronic conditions (most commonly hypertension in 78%, hyperlipidemia in 70%, acute MI in 50%, depression 40%, diabetes 38%, COPD 28%), with 38% from the South/24% Midwest/20% Northeast/17% West
  • ED physicians at the hospitals were classified as either high-intensity or low-intensity opioid prescribers, according to their quartile of prescribing rates at that same hospital.
  • The rates of continued opioid use were compared, defined as 180 days supplied in the 12 months after that ED visit


  • 215,678 patients received treatment from low-intensity and 161,951 from high-intensity prescribers. The overall clinical characteristics of the patients treated by these different providers were very similar.
  • Within individual hospitals, the opioid prescribing rates varied by the type of providers: 7.3% versus 24.1% (p<0.001), for the low versus high-intensity prescribers. There was minimal correlation between the physicians’ prescribing rate and the median initial dose of the opioid prescribed.
  • There was a 30% increase in long-term use of opioids by patients treated by the high-intensity prescribers, adjusted odds ratio 1.30 (1.23-1.37), p<0.001. The number-needed-to-harm was 49 patients receiving an opioid prescription leading to one excess long-term opioid user.
  • There was a stepwise increase in long-term opioid use, tracking with increased quartiles of physician prescribing rates.
  • Those patients seeing a high-intensity opioid prescriber had higher rates of subsequent hospital encounters (a 3% significant increase) and encounters for fall or fracture (a 7% significant increase), with no difference in non-opioid-related encounters


  • It is notable that the rates of hospitalizations for opioid overdoses in the elderly Medicare population has quadrupled from 1993 to 2012.
  • It is also quite concerning that the elderly are more likely to have adverse consequences from even therapeutic doses of opioids, including more sedation, falls, fractures, and death from any cause.
  • Although this was an observational study, which limited the rigor of its conclusions or its ability to determine causality, these researchers seem to have done an excellent job of including huge numbers of patients, comparing providers in the same institution with each other, and controlling well for likely comorbidities of the patients (though they don’t have a clear assessment of the intensity of the pain of the individual patients, it does seem unlikely that patients would be assigned to high-intensity opioid prescribers just because they had more pain and thereby creating a bias in the study)
  • As noted in several prior blogs, one of my major concerns about opioid prescribing is the dearth of good clinical evidence. This leads to a not so infrequent clinical conundrum: what to do with an elderly patient who has significant chronic pain, perhaps from osteoarthritis, to the point that they have very limited function and extremely poor quality of life. Perhaps a trial of NSAIDs does not help (and NSAIDs have their own attendant morbidities), and neither does acetaminophen nor topical or other adjuvant therapies. Perhaps they have had multiple steroid injections with diminishing or limited effectiveness. And perhaps they are not interested in surgery, or are not healthy enough for it. As a result, to improve their quality of life and after extensive discussion of adverse effects, I have sometimes prescribed tramadol or codeine or even low-dose oxycodone, often in combination with other adjuvant therapies, with excellent clinical and quality-of-life results. And, I think that is in the patients’ best interests and is appropriate care. Even in patients who are 90+ years old.
  • However, this article does reinforce the peril of prescribing opiates to the elderly. Given that the patients given opiates did not seem to differ clinically from those not given opiates, it pretty clearly suggests that we as providers may be playing a significant role in creating long-term opiate users. Our experience in Boston has shown pretty dramatic changes in ED opiate prescribing over the past couple of years. During that time period of this study, it was unusual for one of my patients who had gone to the ED for pain not to come home with an opiate prescription, even if they explicitly stated to the ED doctor that they did not want or need these meds. That is no longer the case. And we should all take seriously studies which show, for example, that even renal colic, considered one of the more severe pains, seems to respond to NSAIDs similarly to opiates (e.g., see Teichman JMH. New Engl J Med. 2004; 350: 684). And many patients do well with NSAIDs post-op (my clinical observation).
  • Although the study targeted older patients, it is consistent with a prior blog in which adolescents with low risk of illicit drug dependence but given legitimate prescription opiates as 12th graders (for surgery, etc.), were up to 3-fold more likely to have opiate use disorder at age 23 (see​ )

Given that clinicians seem to be more consciously decreasing/limiting their opiate prescriptions and more hesitant to start opiates, there not only may be fewer prescription opiates available on the street, but also fewer patients requesting/needing continued opiate prescriptions subsequently. So, the more optimistic take on this issue of opiate dependence is perhaps that the future is bright/there may be fewer people with opioid dependence going forward.


An editorial highlighted the huge public health threat of fentanyl (see Frank RG. N Engl J Med 2017; 376:605), making several important points:

  • Fentanyl-related deaths have been increasing dramatically, especially in the eastern United States: from 2628 in 2012, to 5544 in 2014, with 41% of heroin-related deaths involving fentanyl
  • Fentanyl is mixed with a multitude of street drugs, including heroin, MDMA (methylenedioxymethamphetamine), OxyContin, Xanax, and Narco (acetaminophen-hydrocodone). A recent Canadian analysis found that 89% of seized counterfeit OxyContin tablets contained fentanyl
  • Fentanyl is cheap, going for $3500 per kilogram, as compared to $65,000 per kilogram for heroin (and this is despite heroin’s declining prices, which had made it much more attractive in the streets than prescribed opiates, such as Percocet)
  • This all further supports harm reduction strategies, especially since most who die from fentanyl overdose are unaware they are taking it, including: improved monitoring of street drugs for fentanyl, drug enforcement approaches which emphasize use reduction (e.g., not targeting buyers with syringes, which may actually increase the risk of needle sharing and other higher-risk behaviors, etc.), improved access to treatment programs, improved access to naloxone (which, as per prior blogs, may need a higher dose for fentanyl overdoses).


  • This article highlights the devastating and escalating effects of illicit fentanyl, apparently largely produced in China, emphasizing appropriately the importance of harm reduction as a key strategy
  • Of note, I had been unaware that fentanyl was mixed with so many different street drugs, and not just with heroin. This article highlighted how widespread fentanyl-lacing can be, and this message needs to be transmitted to our drug-using population.​

For relevant recent blogs: highlights the increasing opiate death rates, esp from fentanyl describes a study looking at Tai Chi and mindfulness to treat chronic pain is an interesting study finding that even placebo works pretty well for chronic pain from osteoarthritis and, in general​ for a slew of articles on chronic pain and opiates, with descriptions and critiques of published guidelines


Primary Care Corner with Geoffrey Modest MD: Increasing Deaths From Opioids

10 Feb, 17 | by EBM

By Dr. Geoffrey Modest

The CDC just published their report tracking drug and opioid-involved overdose deaths in the United States from 2010 to 2015 (see​ ).


  • Background: from 1999 to 2014 there was a tripling of drug overdose deaths, with 47,055 total drug deaths in 2014, and 60.9% involved an opioid. During 2013-2014, deaths from natural/semisynthetic prescribed opioids [this class includes natural opioids (morphine and codeine), and semisynthetic opioids (oxycodone, hydrocodone, hydromorphone, and oxymorphone)] increased slightly, but there was a rapid increase in deaths from heroin and “synthetic opioids other than methadone” (including tramadol, fentanyl).
  • In 2015, there were 52,404 drug overdose deaths including 33,091 (63.1%) involving an opioid. This death rate calculates to 16.3/100000 population (it was 12.3/100000 population in 2010, a 33% increase)
  • From 2014 to 2015 the death rate from “synthetic opioids other than methadone”, which includes fentanyl, increased by 72.2%, and heroin death rates increased by 20.6%. Natural/semisynthetic opioid death rates increased by 2.6%, but methadone death rates decreased by 9.1%
  • The rates of death involving heroin and “synthetic opioids other than methadone” increased among all demographic groups, regions, and most states (Florida and South Carolina had both decreasing and then increasing trends during this time: Florida decreased from 2010 to 2013 and then increased til 2015; South Carolina decreased from 2010 to 2012 and then increased til 2015)
  • The largest absolute rate increases in deaths from “synthetic opioids other than methadone” occurred in Massachusetts, New Hampshire, Ohio, Rhode Island, and West Virginia. The largest percent increases in rates occurred in New York (135.7%), Connecticut (125.9%) and Illinois (120%). The largest absolute rate increases in heroin deaths were in Connecticut, Massachusetts, Ohio, and West Virginia, and the largest percentage increases were in South Carolina (57.1%), North Carolina 46.4%, and Tennessee (43.5 percent)


  • The above includes 28 states with high quality reporting on death certificates, including specific drugs involved in overdoses. [Seems like all states should be tracking this. And this is why our national statistics and epidemiologic studies pale in comparison to western European countries, where they have large and inclusive national registries. Would be great to fix this…. much better data to act on]
  • Deaths from illicitly-manufactured fentanyl were probably largely responsible for the increase in deaths attributed to “synthetic opioids other than methadone” and were largely concentrated in eight of the 27 states examined. Actual fentanyl prescribing rates did not change during this time [confirming that this was likely illicitly-manufactured]
  • Factors likely involved in these changes include:
    • My guess is that the decrease in overdoses due to methadone is related to more vigorous efforts by the federal and state governments to limit its use in chronic pain. This shows that targeted strategies seem to work.
    • The smaller increase in natural/semisynthetic opioid deaths may also be related to changes in policies/education, use of the prescription drug monitoring program, and legislative changes in naloxone prescription and distribution.
    • The implementation of harm reduction strategies, including syringe exchange programs, increased access to naloxone, more available medication assisted treatments, strategies to reduce the transmission for hepatitis C and HIV, etc., are likely very important in decreasing the extremely important sequelae of drug use
    • But, ironically, it seems that as there is less availability of prescription opioids in opioid prescribing, many patients are taking some more dangerous but now much cheaper drugs such as heroin, which may well be laced with fentanyl (i.e., these opioid substitutes may be being used more, and these may even be more fatal, such as by the increase in fentanyl-related deaths).
  • So, the bottom line here for me is that single targeted measures (decreasing methadone prescribing) can lead to shifts in drug usage with potentially even worse clinical outcomes. Which really speaks to the need to deal with the underlying problems of poverty, lack of hope/avenues to advancement felt by many young (and old) people, lack of positive social supports, poor quality education for many, increasing income inequalities, etc. etc. etc.
  • As I have mentioned in several blogs, including one which evaluated/critiqued the CDC guideline for prescribing opioids for chronic pain (see past blogs below), the issue of chronic pain control is often one of the most difficult clinical issues we encounter in primary care. There are very clear examples (at least to me) of patients who need chronic opioids to function and lead reasonably normal lives. And several need very high doses (for a multitude of reasons, likely including genetic differences in mu receptors). There also are pretty clear examples of clinicians overprescribing opioids, from surgeons/emergency rooms as well as from primary care, and these can have profound social sequelae, such as drug diversion and opioid-related deaths. And, there are whole group of people in the middle, where it is not entirely clear and is a judgment call by the treating clinicians. The first two groups are easier to deal with; this middle group where there is more uncertainty about the need for opiates is quite challenging clinically and more socially concerning given the reality of the explosion of illicit drug use and deaths.
  • I would also like to mention again a prior blog finding that 12th graders prescribed opioids by clinicians (e.g. for surgery) but were considered beforehand to have a very low likelihood of using illicit drugs in the future per a standardized and validated questionnaire, had a much higher rate of opioid abuse at age 23 than a similar group who were not prescribed these opioids (see below).

Past blogs: for the array of blogs on opiates and chronic pain for a critique of the CDC guidelines for the blog on 12th graders at low risk of addiction by a validated questionnaire, then getting prescribed opiates, finding that by age 23, there was a 33% increased risk of opioid misuse

Primary Care Corner with Geoffrey Modest MD: Tai Chi for Knee OA; Mindfulness for Chronic Pain

29 Jun, 16 | by EBM

By Dr. Geoffrey Modest

  1. A recent studyfound that Tai Chi was at least as good, and sometimes better, than physical therapy (PT) for patients with painful knee osteoarthritis, OA (see doi:10.7326/M15-2143). There have been some earlier studies finding efficacy of Tai Chi for knee osteoarthritis, rheumatoid arthritis, and fibromyalgia, by decreasing pain and improving physical and psychological health. The current study compared Tai Chi with PT.


  • 204 people with symptomatic knee OA
  • Mean age 60, 70% women,  53% white/35% black, BMI 33, duration of knee pain 8 years, mostly moderate radiologic OA (Kellgren-Lawrence grade 2 in 38%, 3 in 37%), 50% hypertensive, 20% diabetic, mean WOMAC pain score (Western Ontario and McMaster Universities Osteoarthritis Index) 253 (range 0-500)
  • Interventions (patients allowed to continue meds, including acetaminophen and NSAIDs):
    • Tai Chi: 60 minute sessions 2x/week for 12 weeks. Explanation of mind-body exercise theory and procedures. Patients instructed to do home Tai Chiat least 20 min/d (videotaped with feedback throughout the study). At end of 12 weeks, patients asked to continue at home for the duration of the study
    • PT: 30 minute sessions 2x/week for 6 weeks. Individual assessment and targeted regimens. Exercise at home. At end of 6 weeks, patient asked to continue with 30-minute sessions 4 x/week for 6 weeks. [i.e., shorter intervention than Tai Chi, but this is a standard PT regimen]
  • Results (with 52 week follow-up)
    • Overall attendance: 74% for Tai Chi and 81% for PT
    • Clinical outcomes (WOMAC pain, physical function and stiffness scores; patient global assessment score; Beck depression inventory;  SF-36,  a health survey; arthritis self-efficacy score; and both the 6-minute and 20-minute walk scores): patients in each group showed improvement over time, including at 52 weeks, well after the active interventions. But, comparing the interventions: Tai Chiwas better than PT for essentially every outcome and at weeks 12, 24 and 52. However, the difference was statistically significant only for the physical component of SF-36 and Beck depression inventory.
    • Use of NSAIDs and analgesics: also generally less with Tai Chi, but not reach statistical significance.


  • This was perhaps a somewhat unexpected finding since the focus of PT is so different from Tai Chi. PT largely involves stretching and strengthening exercises and some local therapies, leading to improved quadriceps dynamics in particular, developing increased support for the knee and decreasing the load on the joint itself (at least that is my understanding. Studies have shown that quadriceps weakness correlates with the degree of knee pain). Tai Chicombines meditation, slow and gentle movements, deep diaphragmatic breathing and relaxation (i.e., physical as well as psychosocial/emotional/behavioral elements).
  • In this study on Tai Chi, it is impressive that the results remained pretty consistent at 12, 24, 52 weeks. My guess is that the Tai Chi group did continue their home-based exercises after the formal study stopped (data not in article), but either way, that suggests that the benefits are durable (and perhaps Tai Chi really can be incorporated into one’s life long-term)


  1. A complementary article appeared near the same time in JAMA, stressing a role for mindfulness meditation in pain management (seedoi:10.1001/jama.2016.4875). Briefly, mindfulness meditation involves an increasing awareness of body sensations (e.g. breathing), techniques to promote mindful practice (yoga, meditation), learning how to understand and change how we react to stress, understanding the relationship between stress and pain, and viewing the reactions to stress without judgment. This JAMA Perspective highlights some pretty impressive studies:
  • A randomized controlled trial showing that mindfulness-based stress reduction (MSBR)was comparable to cognitive behavioral therapy (CBT) in reducing chronic low back pain, finding that there was no difference between MBSR and cognitive behavioral therapy (CBT), both with about a 45% reduction in pain (vs 25% with usual care). For my review of full article, see prior blog:
  • Another RCT involved 282 older adults with chronic low back pain, also finding that those with 8 weeks of mindfulness meditation followed by 6 monthly sessions showing that 45% of the patients experienced >30% reduction in pain vs 25% of the patients in the control group.
  • Using functional magnetic resonance imaging of volunteers exposed to a noxious stimulus, those who practiced mindfulness meditation had a 57% decrease in how unpleasant the stimulus felt and a 40% decreased rating of pain intensity vs control (and those who paid attention just to breathing did not have these benefits). They found that meditation was associated with more activation of the orbitofrontal cortex (OFC), an area of the brain which “controls how people put into context what they sense in the environment”. Subjects commented that they did in fact feel the pain but were able to “let it go” and not dwell on it. The meditation also led to less activation of the thalamus, which serves as the pain gateway from the spinal cord to the brain, and activation of the anterior cingulate cortex (ACC), involved in cognitive control and emotional regulation. And, interestingly enough, though there are plenty of opioid receptors in the OFC and ACC, mindfulness did not affect these receptors (naloxone had no effect).


Overall Commentary:

  • These articles reinforce the intimate connection between pain perception and one’s psychosocial state.
  • There seems to be a shift in thinking about chronic vs acute pain, with argument that the issue with chronic pain involves different/more extensive central involvement (hyperalgesia, changes in functional neuroimaging, more somatic symptoms such as fatigue, memory problems, insomnia, mood disorders), which supports the use of different CNS-directed treatments (SNRIs, anticonvulsants) — for more info see Phillips K. Best Pract Res Clin Rheumatol 2011; 25: 141.
  • Those with chronic pain often have increased response to peripheral stimuli (hyperalgesia/allodynia), rate pain as more severe, and those with chronic widespread pain often have specific focal triggers, such as myofascial trigger points, ligamentous trigger points, or osteoarthritis of the spine or joints. And these focal triggers can lead to/perpetuate the chronic pain (see Staud R. Best Pract Res Clin Rheumatol 2011; 25: 155.) This ties together the complex interaction between peripheral triggers/local changes (e.g. increased lactic acid production, cytokines) and the central interpretation of that pain, including the sensation of chronic widespread pain. (It is really common for a patient with a particularly painful local site to have much more diffuse bodily pain. in my experience, I have sometimes been able to treat the triggering source with injections, leading to a generalized decrease in pain overall).
  • Also, it is pretty clear that stress itself may be a bad actor: stress leads to muscle tightness (perhaps part of the fight/flight response and readiness to act). But chronic stress leads to chronic muscle tightness and pain transmitted largely through the spinothalamic tract pain fibers to the thalamus/ACC/etc. and then to the cerebral primary somatic sensory cortex. As noted above, several of these processing stations alter their pain response by meditation.
  • In terms of the peripheral musculoskeletal effects of chronic stress, it seems to me that there are certain areas of muscle tightness that are more common with chronic stress, such as at the occipital insertion of the trapezius, diffusely in the muscles around the cranium/tension headaches, costochondral areas in the sternum, lower back, and several of the “trigger points” of fibromyalgia.)
  • To me, the above studies suggest a couple of things:
    • Decreasing the functional impact of stressors, whether through mindfulness meditation, Tai Chi or CBT, can decrease the direct effects of stress on the muscles (and there is the argument that many people with chronic pain “catastrophize” it: thinking negative thoughts about how pain will affect their function, which might expectantly exacerbate pain sensation. these psychological techniques directly affect how stress is perceived and handled)
    • And, there are impressive data that there are also meditation effects on how various parts of the brain itself (thalamus, anterior cingulate cortex, etc.) fundamentally respond to painful stimuli
  • The CDC stresses that the preferred therapy for pain management is maximizing nonpharmacologic and nonopioid pharmacologic pain management (see for review)
  • So, whether the beneficial effect of mindful meditation, CBT or Tai Chi is through moderating the perception of stress or the changing the way pain is handled centrally, or both (hard to separate), it seems to me to be increasingly clear that there are some important and perhaps fundamental differences in how patients with chronic pain experience their pain, and that we should be more aggressively pursuing a more global approach, including mindfulness meditation, Tai Chi, or CBT as a really important nonpharmacologic component to helping people with chronic pain. this approach coincides with the CDC focus on maximizing nonpharmacologic adjunctive therapies as a way to avoid opiates or at least minimize their use. In this context, it is intriguing that the above alterations in central pain pathways by mindfulness meditation do not seem to be entirely related to opiate receptors, both suggesting that either endogenous or exogenous opiates may not be necessary for effective chronic pain management and that there may be room for development of other, nonopiate meds as part of chronic pain treatment…

Primary Care Corner with Geoffrey Modest MD: 2 CDC Reports on Spread and Toxicity of Fentanyl

12 May, 16 | by EBM

By Dr. Geoffrey Modest

A couple of brief reports on opiates in the community.

  1. MMWR reported that there was an outbreak of poisonings in people in San Francisco taking a counterfeit Norco (a combo of hydrocodone and acetaminophen, but with a sinister name) See 7 cases were reported, with some differences in the apparent composition of the counterfeit drug: all had fentanyl (a potent synthetic opioid, 100x that of morphine, and a full m-opioid receptor agonist. fentanyl has high lipophilicity, allowing it to enter the CNS rapidly. It is not marketed as an oral pill, so its presence in pill form confirms its being illicit); some had promethazine (used for nausea/vomiting, motion sickness, and it may potentiate the opiate high), some trace amounts of cocaine and several with no detectable hydrocodone.


  • The illicit drugs appeared very similar to the real thing, including the inscription “M367”
  • Patients present to the ER with lethargy, bradypnea, unresponsiveness

So, just an alert. There has been an increase in these illicit/counterfeit products over the past few years, with fentanyl often being part of the problem. And this counterfeiting seems to be more sophisticated, with pills that look pretty much identical to the legal drugs.

  1. Another DEA alert on fentanyl (see ) which also highlights the increased street prevalence of products containing illicit fentanyl or acetyl-fentanyl (at this time, most of the fentanyl-related overdoses are from illicit/manufactured drug, not diverted pharmaceutical fentanyl). Fentanyl is often mixed with heroin to increase the high, but sometimes sold alone as a highly potent drug (sometimes with street name “China White”).

A few points:

  • Drug seizures by the DEA have found dramatic increases in fentanyl: from 618 in 2012 to 945 in 2013 to 4,585 in 2014
  • >80% of the drug seizures were in 10 states, from highest to lowest:
    • Ohio (1245)
    • Massachusetts (630)
    • Pennsylvania (419)
    • Maryland (311)
    • New Jersey, Kentucky, Virginia, Florida, New Hampshire, Indiana (all between 133 to 238)
  • It often takes more than one dose of naloxone to revive a patient with a fentanyl overdose.

So, perhaps the most important issues are the increasing availability of fentanyl on the streets, and its high potency means that we may need to use more than one dose of naloxone to revive a patient. And, when we give naloxone to patients to have at home, we need to advise them/their supports that it may take more than one dose.

Primary Care Corner with Geoffrey Modest MD: Meds for OA, Including Placebo

5 Apr, 16 | by EBM

By Dr. Geoffrey Modest

The lancet just published a network meta-analysis of NSAIDs, acetaminophen, or placebo for hip or knee osteoarthritis (OA) pain (see S0140-6736(16)30002-2​). A network meta-analysis is a mathematical device which allows one to infer the comparative effectiveness of different interventions from different randomized clinical trials, even though there may not have been actual trials with direct comparisons.


  • 74 RCTs were included in the analysis with a total of 58,556 patients with predominantly knee or hip OA. All trials had at least 100 patients per group and had prespecified primary and secondary outcomes of pain and physical function.
  • They developed a network comparison chart with 23 nodes, each with a treatment (several nodes had the same drug but in different doses), and the relationships between them.


  • When looking at what was considered a clinically significant medication pain response vs placebo, the following were significant  (anything <-0.35 is considered clinically significant):
    • ​Of the 7 the most clinically effective, rofecoxib and etoricoxib at varying doses represented 6 of them (neither available in the US)
    • Of the ones available, diclofenac 150mg was the best, with effect size of -0.57 (the highest was rofecoxib with effect size of -0.62). None of the lower doses of diclofenac were effective
    • Naproxen 1000 mg/d and ibuprofen 2400 mg/d trended to being clinically significant, but did not make the cut
    • Lower doses of naproxen and ibuprofen weren’t even close
    • Acetaminophen was much worse, with the dosage of 3900-4000mg having a clinically-nonsignificant effect size of -0.17, and lower doses being no different from placebo
    • Celecoxib at 100mg was not effective, but at higher doses came close to having a clinical effect
  • When looking at physical function, the results were much worse:
    • Only rofecoxib and diclofenac unequivocally reached clinical significance.
    • Naproxen 1000 mg/d and ibuprofen 1200 or 2400 mg/d trended to a benefit
    • Acetaminophen wasn’t even close
  • ​Of importance: several of these are COX-2 inhibitors — rofecoxib (vioxx) was pulled from the US market because of increased heart attacks and strokes; etoricoxib has not been approved and has associated severe skin reactions; and lumiracoxib, which is structurally different from the other COX-2 inhibitors (and more similar to diclofenac) causes liver failure and was never approved​. Celocoxib is the only of the COX-2 inhibitors available in the US, though there is real concern of increased cardiovascular problems, esp at the higher doses (which were the ones that worked)
  • Several studies looking at adverse cardiovascular effects of NSAIDs have found that diclofenac (which I’ve read in the past has a higher COX-2/COX-1 inhibition, though not sure this is true) is the worst. (Naproxen is usually found to be the best, high dose ibuprofen is not so good. See, for example, Prescrire Int. 2016 25 (167): 14; or PLoS Med 2011; 8(9): e1001098)

So, what does this all mean??

  • As mentioned in several blogs, there is typically a significant placebo effect of pain meds, often on the order of 20-30% (though one interesting study found, not surprisingly, that people who had positive expectation of treatment had a much higher placebo response than those with negative expectations (see Science Translational Medicine 2011; 70(3):70ra14). And, in this study, subjects exposed to experimental heat pain ​but had a negative expectancy​ did have some benefit from an infusion of a m-opioid agonist remifentanil; but, when they thought the infusion had stopped, they had a full restoration of pain intensity.
  • So, though the network meta-analysis showed not much effect of acetaminophen, or even lower dose ibuprofen of naproxen, if the patient expects some benefit, they may well respond (which means: to a large extent this benefit may depend on how well/enthusiastically we can present the options – i.e., we may be able to enhance the effectiveness of an intervention by providing a very positive vibe).
  • And the many adverse effects of high dose diclofenac (used a lot in Europe), naproxen or ibuprofen, which have a higher likelihood of benefit in RCTs, may be avoided by using even low-dose acetaminophen
  • I still use a lot of non-systemic treatments first. Exercise/PT is a mainstay. Topicals often work (e.g. topical capsaicin, lidocaine, or topical dicofenac). Injections often work well (though I leave intra-articular hip injections to specialists who can use ultrasound-directed injections), and they work well at many different sites (A-C joint, hand joints, etc.).
  • And, in the final analysis, I do sometimes use lower-potency opiates (e.g. tramadol, codeine), even in elderly people who either experience or at higher risk of experiencing adverse effects of long-term NSAIDs (e.g. heart failure, bad hypertension, higher risk of GI bleed, renal insufficiency) and who are not at risk of abusing or diverting them, or having them taken by a younger family member. Unfortunately, as we age we tend to have the combination of more pain and more adverse effects of meds. And I realize that, as clinicians, we all have different prescribing thresholds, but many of my older patients are barely able to get around/function because of pain, and they really do tolerate and function well on low doses of less potent opioids (I also realize this is a tad heretical in the current anti-opioid atmosphere…)

Primary Care Corner with Geoffrey Modest MD: New CDC Guidelines for Opiate Prescribing

25 Mar, 16 | by EBM

By Dr. Geoffrey Modest

The CDC recently came out with their formal guidelines on when to initiate or continue prescribing opiates (see!documentDetail;D=CDC-2015-0112-0002​ ). Of note, it is commented on many times in the publication about the lack of high-quality trials, but that there was an urgency to develop these guidelines given the increasing risks of opioid misuse/adverse effects, and that the “contextual evidence” reviews, complementary information that assists in the translation of clinical research into recommendations, “provides indirect evidence and should be interpreted accordingly”.


  1. Nonpharmacologic therapy and nonopioid meds are preferred for chronic pain; and if opioids are used, they should be combined with these interventions as appropriate. There are minimal data supporting chronic opiate benefits, so hard to recommend given their known risks, except for this little caveat in the guidelines: “no study of opioid therapy versus placebo, no opioid therapy, or nonopioid therapy for chronic pain evaluated long-term (>1 year) outcomes related to pain, function, or quality of life. Most placebo-controlled randomized trials were ≤ 6 weeks in duration”. So, no data really. There is a comment that it’s okay for end-of-life care (commenting that “evidence of long-term opioid therapy for chronic pain outside of end-of-life care remains limited”), which does suggest there may be benefit (and, I’m not sure what the real difference in subjective pain is, comparing those at end-of life and those not). My point is that there are basically no data, that in my experience there are patients with really bad chronic pain who pretty clearly benefit from opiates and sometimes higher doses, and this puts us providers in a bind. There is no question to me that trying nonpharmacologic therapy is really important (PT, weight loss in those with knee pain etc., massage/manipulation, psych therapy and esp. cognitive behavioral therapy, exercise…., and combinations of these). And that non-opioid therapies often help (acetaminophen, etc… though I am concerned that prolonged NSAID use has its very real problems for the GI tract, kidneys, and heart especially, and significant mortality), but I should add that some of these drugs (e.g. salsalate, trilisate) are off the Medicare-approved list for unknown reasons, are much more benign, but in my experience sometimes work really well. And local steroid injections often give reasonably long-term relief (e.g. joint injections, trigger point injections) in my experience, as well as other adjuvant meds such as tricyclics, anticonvulsants (pregabalin, gabapentin, carbamazepine), and SNRIs. I would further reinforce avoiding opiates unless really needed, the above often work, and it is clear that opioids do have significant harms (abuse/overdoses, MIs, car accidents…)


  1. Before starting opioids for chronic pain, prescribers should establish realistic treatment goals with patients in terms of pain and function, including discontinuing them if benefits do not outweigh risks. This applies to pain lasting >3 months or past the time of normal tissue healing


  1. Before starting and periodically during opioid therapy, clinicians should discuss risks and realistic benefits of continued use, as well as the patient and provider responsibilities for managing therapy. This includes safety issues, which might be uncovered by looking at the prescription drug monitoring program (PDMP). Again, the issue is: unknown benefit (i.e., not studied, though the patient may attest to the benefit) but clear risks (and there are data showing that patients who have multiple providers prescribing the opioids are at increased risk). And contextual evidence suggest that many patients do not understand the safety issues.


  1. When starting opioids, use immediate-release ones, not the extended-release ones. The latter have likely increased potential for overdose, and, as I have mentioned in earlier blogs, there really are no data showing that long-acting ones are better, either more effective or safer. Also, if you decide to switch from short to long-acting and are switching opioids, remember that there is incomplete cross-tolerance, so the dose of the long-acting med should be reduced. Also, given the above, they recommend NOT giving long-acting along with short-acting opiates (this is pretty different from the old model: give long-acting to get steady state of opiates, then short-acting for “breakthrough” pain). Also given the [actually not-so-scientific] data finding more deaths with methadone, that should not be the first agent to use for a long-acting one.


  1. Use the lowest effective dose of opiates. And especially if increasing the dose to >50 morphine milligram equivalents (MME)/day. And generally “should avoid increasing the dosage to ≥​​ 90 MME/day”. One interesting contradiction is that methadone maintenance programs often have people above 100mg methadone/day (that is, >300 MME) for the long-term. In fact I have a chronic pain patient who is in a methadone program and on 70mg for the past many years. Given the presumed benefit of TID dosing of methadone for chronic pain, I appealed to the Medicaid program in Massachusetts so I could give him 70mg of methadone in divided doses at the health center but was unable to get approval for more than 60mg, the Medicaid max. However, I was told I could give him 60mg of methadone and an almost unlimited amount of oxycodone along with it (?!?). The dosage restriction suggested above, as pointed out in prior blogs, comes from ecological data showing that those on higher doses (e.g. >100 MME/day) have higher risk of overdoses and deaths. But, again, there are NO (as in, zero) randomized controlled studies looking at the benefits of higher vs lower doses. And I certainly have some chronic pain patients who are on high doses for a long time and who are very willing to take risks in order to get “better pain relief and function”, from their perspective (part of the issue in those requiring higher MME’s is that they may have genetic variants in mu receptors and need higher doses to get an effect– see past blogs as listed at the end). Also, we should consider giving naloxone kits to patients on opioids in case there is an overdose, esp. if they are on higher doses of opiates.


  1. Chronic opiate use begins with acute pain therapy. We should also give the lowest dose possible and shortest duration of immediate-release opiates. (And ERs should not blithely prescribe opiates). “3 days or less will often be sufficient; more than 7 days will rarely be needed”. The 3-day suggestion is largely “expert opinion”, though there was a study in patients with acute low back pain showing that there was usually a significant decrease in pain by the 4th day. And another one I blogged on recently (see blogs below) not finding that opiates were in fact better than nonopiates for acute low back pain. And the guidelines reinforce not giving ER/LA preparations for acute pain.


  1. Evaluate benefits and harms within 1-4 weeks of starting opiates and at least every 3 months thereafter, more frequently if a history of substance use disorder, of overdose,  if taking ≥​​ 50 MME/d, or if taking other CNS depressants. There may be utility to using validated scales to assess function, pain control and quality of life (e.g. PEG scale–Pain average, interference with Enjoyment of life, and interference with General activity). The recommended rate of tapering doses is not clear, some suggesting rapid tapers over 2-3 weeks in those with severe adverse events (e.g. overdose), others recommend slower tapers at 10%/week.


  1. Before starting and periodically thereafter, evaluate risk factors for opioid-related harms. Include considering offering naloxone
  • Patients with disordered breathing: the issue is opiate-related respiratory depression. Those with moderate-to-severe sleep-disordered breathing should probably not have opiates
  • Pregnant women: avoid initiating opiates during pregnancy, since they are associated with stillbirth, poor fetal growth, pre-term delivery, neonatal opioid withdrawal syndrome and birth defects. And for those pregnant and on opiates chronically, be careful about tapering (risks to patient and fetus if patient goes into withdrawal). Also a potential issue with breast-feeding: neonatal toxicity and death have been reported when mothers take codeine
  • Patients with renal or hepatic insufficiency — use more caution and increased monitoring, given decreased processing/clearing of drugs
  • >65 yo: opiates may be more dangerous, given reduced renal function. Also, more opiate-related confusion.
  • Mental health issues: untreated depression could lead to overdoses (suicide, or confusion). Anxiety treated with benzos adds toxicity when given together with opiates. And, though not mentioned in the recommendations, those under stress or not sleeping well experience more pain (i.e., best to try to help with underlying issues here)
  • Patients with substance use disorders — illicit drugs and alcohol increase likelihood of opioid-related overdose deaths
  • And, consider giving naloxone to those who are at higher risk of overdose


  1. Review the PDMP to see if patient is receiving high dose opiates or other meds that put him/her at higher risk. This should be done at least every 3 months. (Though I would add that there are a few problems here: the pharmacy data are not updated as quickly as they should be; navigating the website is not easy and one has to click on the same patient many times if they list different addresses; hard to get data on patients who go to other states for opiates or gets them through the VA system; and it really takes a lot of time doing so in a busy primary care session (the issue of chronic pain management really is, to me, the poster-child for team-based care: a clinician just does not have the time to do everything, especially since we typically have so many complex medical and psychosocial issues to take of in mostchronic pain patients. A team-approach with nursing and others involved in the voluminous paper work, checking PDMP, calling patients back for urine tests/pill counts, etc., is really essential to practicing high quality care).


  1. Check urine drug screen prior to starting opiates, and “consider” doing them at least annually thereafter. These are important for a variety of reasons, including patient safety


  1. Avoid prescribing opiates if patients are on benzodiazepines. Based on a lot of observational data, but as pointed out in some prior blogs, those on benzos by themselves may have underlying psych conditions which have significant mortality associated. But the opiates and benzos in combo are likely to produce more respiratory depression. In stopping the benzos, very important to taper slowly (e.g. decrease dose not more than 25% every 1-2 weeks)


  1. Arrange treatment for patients with opioid use disorder (e.g. with methadone or buprenorphine as meds; in combination with behavioral therapies). I believe that all of us who prescribe buprenorphine are very impressed with the results in the majority of patients… I really feel it is one of the few interventions I do which really give patients back their lives. And, given the huge benefits and significantly decreased risks of buprenorphine, I can see no reason why nurse practitioners/physician assistants/medical residents should not be able to prescribe buprenorphine, both because it is so effective in so many people, and, also, ironically, these providers are allowed to prescribe much more potentially dangerous meds anyway (oxycontin, methadone etc.)


So, my bottom line is that there is no doubt that opioids can be dangerous both to the patient and society (through diversion, availability in the streets, overdoses, crime), with cited statistics of 165,000 people dying from overdoses related to opioid pain medication in the US from 1999-2014, and >420,000 ED visits related to opioid pain relievers in 2011. And this danger is very likely increased with higher doses of opiates, or their combos with other meds (e.g. benzos). But there really are very little scientific data to inform these guidelines, making it hard for us in the trenches to accept the “expert opinion” when we have patients in front of us with inadequately treated chronic pain and severe functional impairment from that pain. And, I think, pain is pain, whether it is in cancer patients, those at the end-of-life, or those who fall off a ladder. So, I am a strong advocate for pretty much all of the above guidelines, especially trying to avoid opiates whenever possible, using adjunctive therapies including injections, trying to avoid benzos, giving the lowest opiate dose possible, educating patients on risks and benefits (And emphasizing that the benefit of opiates is rarely complete or near-complete pain relief). And I have even had several patients come off chronic opiates, some having been on them for years. But, there is no question in our practice, this issue of treating chronic pain is remarkably common and remarkably difficult (and remarkably hard to do in the context of a brief primary care visit, where we also deal with their depression/psych issues, hypertension, homelessness or other profound social issues, diabetes, illicit drug use, domestic violence, ……..). And there is no question to me that some patients do need higher doses of opiates to function, whether they have cancer or not.


A couple of other comments on the guidelines:


  • The estimates of the risk of opioid addiction are lower than previously believed/promulgated: in pain clinic settings, the rate of addiction is 2-14%. In primary care settings in patients on chronic opioids it is 3-26%.
  • Although methadone has been singled out as a particularly bad actor, and now requires more stringent prior authorization by Massachusetts Medicaid, the actual data are not so clear: several observational studies (e.g. Oregon Medicaid) found no increased risk of death or overdose, and a VA study found lower overall risk with methadone, despite the concern about prolongation of QTc intervals. another recent study did find increased risk of overdose with methadone, with “twice as many single-drug deaths as any other prescription opioid”


For other blogs: shows that teens given legit prescribed opiates are more likely to misuse opiates later in life. There are also studies in adults having cataract surgery or varicose vein stripping, finding that those still using opioids within 7 days of surgery had higher risk of use after 1 year (cannot show causal relationship in this type of study, but does raise the potential benefit of avoiding or minimizing opioid use unless absolutely necessary, even for short-term acute pain) finding unclear benefit of giving opiates which includes many of my comments about the lack of studies on opiates and the risks of developing strict guidelines in their absence (many more comments than above)​ which looks at some genetic variants (e.g. in the mu receptor) and their effects on individual’s drug use

Primary Care Corner with Geoffrey Modest MD: FDA Response to Prescription Opioid Abuse

17 Feb, 16 | by EBM

By Dr. Geoffrey Modest

The FDA published a “proactive response to prescription opioid abuse” in New Engl J Med (see$db.getCUSTOMERID()&jspc=$db.getSPECIALTY(). This article reflects the direction they plan to follow:


  • In the course of one year, 100 million people in the US suffer from pain; 9-12 million have chronic or persistent pain. All should benefit from pain relief
  • But, there are increasing issues of addiction, diversion, and death (19,000 overdose deaths in 2014)
  • Around 300 million opioid prescription are now written annually in the US


  • They asked the National Academy of Medicine (NAM, used to be the Institute of Medicine) to help develop a regulatory framework for opioid review, approval, and monitoring, one which balances the individual’s need for pain control with the broader public health/societal issues (this process will take a pretty long time)
  • The FDA’s Science Board will meet in March to discuss the role of meds in pain management, development of alternative pain meds, and post-marketing surveillance (as a means to address the more immediate concerns)
  • Special focus will be on extended-release or long-acting opioids, including extensive post-marketing research (11 mandated studies) around safety concerns. Also manufacturers of these long-acting preparations will be subject to a Risk Evaluation and Mitigation Strategy (REMS) requiring them to fund voluntary CME courses around these products. The FDA will also require mandatory provider education
  • Support the development of abuse-deterrent formulations of opioids, as well as countermeasures (e.g. naloxone, intranasal or via auto-injector) and ways to improve their access
  • Prioritize the development of non-opioid alternatives for pain relief
  • For children, focus on making sure that evidence-based medicine is used to identify appropriate indications and dosing, with a focus on safe and effective opioid prescribing, and reduce use for inappropriate indications. The Pediatric Advisory Committee will address specifics
  • They acknowledge the elephant in the room: “the field of chronic pain treatment is strikingly deficient in …scientific evidence … to assess the risk and benefits of intended use of medical products”, and that a key lesson learned by the FDA is the need for continued research. The risks are clear, and there are reasonable data on the benefits of non-opioids. But not a lot of data on the long-term benefit of opioids themselves

For older blogs on chronic pain management and opiates, see This includes a rather striking blog on the use of appropriate provider-prescribed opiates in kids (e.g., post-surgery) and their subsequent opioid misuse (these were kids who had a low pretest probability of doing so).

The blog/critique of the CDC recommendations of Dec 2015 (which are being reviewed because of lots of negative public feedback — see: . Though I should add that the FDA noted in the current article that they are “supporting the CDC’s Guidelines for Prescribing Opioids for Chronic Pain”).

Primary Care Corner with Geoffrey Modest MD: 2 Blogs in 1 — Kratom, and Repeated Opioid Overdoses

5 Jan, 16 | by EBM

By Dr. Geoffrey Modest

A couple of recent articles relating to opioid dependence.

  1. The NY Times had an article on kratom, a natural product sometimes used for opiate withdrawal but  is itself addictive (see​). A few points from the article:
  • They highlight a few cases of individuals trying to recover from heroin addictions by taking kratom, which relieved the withdrawal symptoms but led to addiction to kratom, with cravings, taking increasing quantities over time, and severe withdrawal symptoms. And there is a “large epidemic in Florida.”
  • Kratom is natural plant (mitragyna speciosa, a tropical decidKratom_leaf_2uous and evergreen tree which reaches up to 30 ft tall, from Southeast Asia, esp from Indochina and Malaysia), marketed as a “natural painkiller”. It functions as a mu-opioid receptor agonist. And its metabolites are NOT DETECTED on using drug screening. It was first used in Southeast Asia as a substitute for opium when that was not available, and is typically ingested by chewing the raw leaf. [Also used by laborers to give energy and as mood enhancer/painkiller (sounds like cocaine use by field workers???, though this was not in the article]
  • And, of course, the FDA cannot regulate it since it is a “dietary supplement”. Though in 2014 the FDA did ban the import and seized a shipment of 25,000  pounds in Los Angeles. However, it is just a “drug of concern” for the FDA and not a controlled substance. It is also making its way into the country with the label “not for human consumption”, and non-alcoholic bars sell kratom as a drink, often without it being explicitly on the menu, with the article noting bars in Colorado, New York and North Carolina, “as well as other states.”​

A brief internet review by me shows many, many suppliers of kratom, with many different strains/names of kratom products, provided as a powder/leaf/extract/tea bags /capsules, and costs about $10-16/ounce. With free shipping and discounts on higher quantities ($220/pound)… Though it is illegal to ship to a few states (Indiana, Tennessee, Vermont, and Wyoming). It is still more expensive than street opium, leading some to revert to heroin. And, there is even an American Kratom Association…

  1. The annals of internal med article looked at patients with nonfatal opioid overdoses (ODs), the rate of subsequent opioid prescriptions, and the rate of repeated overdoses (see doi:10.7326/M15-0038). Details:
  • They accessed the Optum database, a complete inpatient, outpatient, and pharmacy claims database from all 50 US states, which included 50 million commercially enrolled patients from 2000-2012
  • 2848 noncancer patients who had nonfatal OD on initial presentation (mean age 44, 40% male, daily opioid dose of <50mg/d MED in 33%/ 50-100 mg in 22%/ >100 mg in 46%, mean daily MED was 152-164 MED/ peaking at 187 on the day before OD, 56% were on benzos in past 90 days, 59% with “mental health diagnosis” within 90 days of OD, 88% on opioids for extremity pain/with an array of other painful sites, 51% from the south/24% midwest/20% west/6% east). [MED=morphine-equivalent dose]
  • Patients were followed from 90 days prior to initial OD until either: a second OD event, disenrollment from plan, age >65 (Medicare eligible), 2 years after initial OD.
  • Results:
    • Mean follow-up of 299 days
    • 30 days after the initial OD, the mean MED dose decreased to 118 mg/d, and remained in the 111-131 range over the 2 years of follow-up
    • In the follow-up period, 2597 patients (91%) received 1 or more opioid prescriptions
      • On days 31-60 after OD, 70% were on active opioid prescriptions on any given day, which trended down to 64% at the end of the 2 years
      • Opioid discontinuation after the OD was in 10% on the highest MED doses, 15% in the moderate dose group and 14% in lowest dose group
      • Patients largely stayed in the same opioid dose category from before to after the initial OD, with 31-36% being in the high dose group
    • A primary care provider was identified in 76% of the patients, and in 61% it was the same person before and after the OD. 30% of patients switched to a new provider after the OD.
    • In the post-OD period:
      • 58% got some benzos, and in those with active benzo prescribing this was more common in those who continued getting opioids
      • 7% got buprenorphine
      • 75 (n=212) had a repeated OD, which was highest in the group on large dose opioids (17%), less so with moderate dose (15%) , and no clear difference between those on low-dose and not on any (9% and 8%). these translate into HRs (vs not getting subsequent opioids):
        • Low-dose, 1.13 (0.69-1.85), non-significant
        • Moderate dose, 1.89 (1.18-3.04), i.e. an 89% increase
        • High dose, 2.57 (1.72-3.85), i.e. a 157% increase
        • ​And, overall in those with active benzo prescribing, 1.74 (1.31-2.32), a 74% increase
      • ​Subsequent medical claims for drug withdrawal treatment (n=267, 9%) were highest in those on large doses opioids, lowest in moderate, and in-between for low or none.

So, these articles bring up several issues:

  • We as providers should be aware of the kratom issue, since this appears to be an addictive opioid, readily available, not-so-expensive, which does not show up on our usual tox screens. and the substance is a dietary supplement, not monitored by anyone (e.g. FDA) for quality, consistency of preparation etc. and could easily have added drugs (fentanyl??, others??) and variable potencies and the potential for increasing concerns about addiction and ODs
  • The second article raises lots of issues. Clearly there is an inherent issue of OD with patients who are on opioids, and these may well be higher in those with “mental health diagnoses”, on benzos or on higher opioid doses (and, by the way, may be higher in those in chronic pain anyway). But other issues of concern include:
    • The remarkable lack of a coherent system of health care in the US, with general lack of communication between providers. It is not clear from this retrospective database scouring how many patients had a primary care provider (which I would imagine is more than the 76% of claims which documented one, since these patients did receive regular prescriptions for the opioids), or how many of the primary care providers even knew about the OD happening (which certainly places the patient at a higher risk of a subsequent OD).
    • And, yet again, the bottom line issue remains of how to treat patients with chronic pain who only get relief from opioids, in an environment where we as health care providers do not have adequate clinical studies assessing the actual benefit vs risks of opioids and especially at higher doses (for an array of my past blogs and comments on this issue see
    • And, it is easy to look at these studies such as above and conclude that opioids are “not safe”, or that we should just follow the recommendations of the CDC or other organizations (by the way, the recent CDC guidelines were retracted because of public outcry about the lack of studies — see above link for review of the guidelines).
    • But it is really different as a primary care provider who has a patient in front of him/her who has disabling chronic pain and is not able to function even close to normally, who seems to get great relief from opioids in terms to returning to a much more functional state, who may even need high MED dosages to get that response, and who is willing to take the risks of adverse outcomes to maintain this functionality (and we do give out lots of other drugs which potentially – and actually – cause very serious harms, where it seems that the benefits warrant prescribing them). I think that this brings up another issue about recommendations overall — they tend to be formulated by researchers in the field who are somewhat removed from the day-to-day practice of us guys in primary care, and it is pretty easy to make recommendations which are not so relevant to taking care of actual patients (i.e., making recommendations from aggregate data and “expert opinion” may not be particularly helpful in figuring out what to do with the patient in front of you. Especially if these recommendations do not reflect real practice situations but come from heads of specialty groups who in fact have not a lot of real patient experience).
    • That all being said, there are no doubt safety issues with opioids. We need to explore all avenues to avoid or minimize their use (ancillary therapies, meds, etc.), we should identify those at highest risk of harm and make sure they are plugged into appropriate programs to minimize that risk (e.g., it seems reasonable to me to require those with psych issues to be in counseling or medical treatment for these issues), and we really need an overall system which allows for easy, pretty seamless flow of information between providers and one not limited by needing the same electronic medical record in all institutions.

EBM blog homepage

Evidence-Based Medicine blog

Analysis and discussion of developments in Evidence-Based Medicine Visit site

Creative Comms logo

Latest from Evidence-Based Medicine

Latest from EBM