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Placebo

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: Another Blog on the Power of Placebos

14 Apr, 16 | by EBM

By Dr. Geoffrey Modest

Again, I was dusting off old medical articles and saved another from the recycle bin, this one revealing that the profound effect of medication adherence (whether a med or placebo) leads to improved outcomes (see Lancet2005; 366: 2005). The CHARM trials (all published in the September 3, 2003 issue of Lancet) were a multinational set of trials from 618 sites in 26 countries, enrolling adult patients with symptomatic heart failure (NYHA class II-IV): the CHARM-Alternative trial had patients with low left ventricular ejection fraction (LVEF ≤​40%) who did not tolerate an ACE-inhibitor; the CHARM-Added trial had patients with LVEF ≤40 and taking an ACE-I; and the CHARM-Preserved included patients with a preserved LVEF (i.e. >40%) with or without ACE-I. All were randomized to candasartan vs placebo. Overall, each of these studies found efficacy for candasartan (though in the CHARM-Preserved​ one it was limited to a decrease of 16% for heart failure hospital admissions; the others showed benefit in cardiovascular deaths of about 20% as well as heart failure admissions of 17-39%). But in the current study, done by the CHARM investigators, they looked at the effect of good medication adherence and clinical outcomes.

Details:

  • 7599 patients with heart failure (69% men, 45% NYHA class II/52% class III, 71% had recent heart failure admission, mean LVEF in those with systolic dysfunction was 29% and in the study with preserved LVEF was 54%), median follow-up of 38 months
  • Results, controlling for a variety of parameters, including age, sex, LVEF, NYHA class, number of meds, smoking, blood pressure:
  • 89% of the patients were “good adherers” (patients taking >80% of their assigned meds, whether candasartan or placebo); 11% were <80% med adherent
  • Good adherence was associated 35% decrease in all-cause mortality [HR 0.65 (0.57-0.75), p<0.001]
  • There was NO DIFFERENCE if patients were in the candasartan vs placebo wing!!
    • For candasartan, good adherers had a 34% decrease in all-cause mortality [HR 0.66 (0.55-0.81), p<0.001]
    • For placebo, good adherers had a 36% decrease in all-cause mortality [HR 0.64 (0.53-0.78), p<0.001]

So, what does this mean???

  • There may well be very important differences in those who take their meds regularly vs those who don’t. This study did control for the anticipated demographic and medical differences (blood pressure, etc.) which could explain this variance. But there certainly may be very important other variables not controlled for, including psychosocial variables (e.g. depression, social isolation, life stressors, etc.) that could affect clinical outcomes.
  • But, given the limitations of this retrospective analysis, are there other possible explanations?
  • Candasartan and perhaps all angiotensin receptor blockers really don’t do much and really are no better than placebo, and we have been hoodwinked yet again. Though, of note, other studies (e.g. the Coronary Drug Project and the Beta Blocker in Heart Attack Trial) also found lower mortality in those adherent to placebos, though this was not found in the Lipids Research Clinics Primary Prevention Trial.
  • ​Poor medication adherence to candasartan could also mean poor adherence to other meds or therapies that are even more important clinically.
  • The people who take their meds regularly are probably the subgroup more likely to have positive expectations about treatment and are more likely to have a placebo response. Since one of the recent emails has not yet been posted on the website, I will excerpt a relevant section: “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 Medcine 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.​”i.e., this study found that even with continued infusion of a potent opiate in those with negative expectation of benefit, they reported lack of effect when they thought the infusion stopped….)​
  • So, are there practical implications for this study?
    • ​My (anecdotal) experience is that patients take their meds more consistently when I present the value of the med more enthusiastically. And I think there are important ways to involve patients more in their care and improve medication adherence (e.g., making sure that we incorporate the patient’s own approach to care to the extent we think appropriate or at least not harmful, making sure the patient understands and can verbalize him/herself what the goals of treatment are, asking the patient what their concerns are — which ironically may be increased when they see TV ads which highlight the potential adverse effects of meds, having a check-in visit or phone call to see if there are any problems with the meds, involving the patient more in self-care—e.g. checking their own blood pressure at the pharmacy, making sure there are no obstacles to care — insurance copays, etc. etc.)
  • But, of course, I have no data to show that any of these interventions would equalize the effects of placebo vs active meds as in the study, though I do think they at least help reinforce the general therapeutic effect of a strong clinician-patient relationship​.

Also regarding placebos, a recent blog (http://blogs.bmj.com/ebm/2015/05/07/primary-care-corner-with-geoffrey-modest-md-placebo-genetics-and-the-placebome/ ) notes that there may well be a strong role for genetics in determining the placebo response.​​

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 doi.org/10.1016/ 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.

Details:

  • 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.

Results:

  • 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: Low Back Pain Treatment per AHRQ Review

17 Mar, 16 | by EBM

By Dr. Geoffrey Modest

The agency for healthcare research and quality (AHRQ) just published an evaluation of the literature on noninvasive treatments for low back pain (LBP), looking at both pharmacologic and nonpharmacologic approaches (see https://www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=2192 ).

Details:

  • As we know only too well, LBP is really common. 84% of adults will have LBP at some time, and >25% have had it within the past 3 months
  • 1998 US health care expenditures were $90 billion, not including the rather large indirect costs of lost work productivity, etc.
  • Those with acute LBP (up to 4 weeks) typically have rapid improvement. Those with subacute (4-12 weeks) tend to have slower improvement, and those with chronic (>12 weeks) often do not get much more improvement and account for much of the costs of LBP treatment
  • Predictors of chronicity: psych comorbidities, maladaptive coping strategies (e.g. fear avoidance: avoiding activities because they fear they will make things worse), catastrophizing (e.g., anticipating the worst possible LBP outcome), presence of nonorganic symptoms (without physiologic basis), high baseline functional impairment, and low general health status. [By the way, we used to suggest that people with low back pain have strict bedrest, to the point of using urinals at the bedside, for 1-2 weeks. This was subsequently found to be incorrect and counterproductive/harmful, and I would imagine would reinforce the “maladaptive coping strategies” noted. I wonder if we created more chronic LBP by our older incorrect advice???]
  • Imaging: big issues of false attribution — degenerative changes, facet joint arthropathy, bulging or herniated discs are really common in people with and without [And, in my experience, I have had several patients with very severe lumbar spinal stenosis both by symptoms and by really awful looking MRIs, who have spontaneously gotten dramatically better, in a few cases becoming asymptomatic without any treatment]
  • 156 publications met the inclusion criteria of AHRQ, most in patients with nonradicular LBP
  • Results:
    • Pharmacologic therapies:
      • Acute and subacute LBP:
        • NSAIDs, opioids (only studied: buprenorphine patch), and skeletal muscle relaxants were associated with small effects on pain (vs placebo).
        • NSAIDs were associated with small effects on function
        • Acetaminophen and systemic steroids had no benefit vs placebo
      • Chronic LBP:
        • NSAIDs and tramadol had moderate effects on pain, vs placebo
        • Opioids, duloxetine, and benzos had small effects on pain
        • NSAIDs, opioids, tramadol, and duloxetine had small effects on function
        • Tricyclics had no effect (though older studies did show small benefit), and there were not enough data to determine if gabapentin on pregabalin helped; evidence was inconsistent on opioids vs NSAIDs
      • Radicular symptoms
        • Limited data, but no difference in pain or function with systemic steroids vs placebo. One study found that benzos delayed return to work. Insufficient evidence for gabapentin or pregabalin
      • Harms of therapies: overall not very well reported
    • Nonpharmacologic therapies: (limited studies overall)
      • Acute LBP
        • Spinal manipulation, heat, massage, low-level laser therapy are associated with some benefit vs sham treatments or no intervention/usual care
        • Exercise, massage, and heat had moderate effect on pain and function
        • The data on using ice/cold packs is insufficient for a recommendation [though, in my experience, many patients do find it helpful]
      • Chronic LBP:
        • Exercise, yoga, tai chi; psychological therapies (especially restoration or cognitive-behavioral therapies); multidisciplinary rehab; acupuncture; spinal manipulation; and low-level laser therapy have small to moderate effect for improving pain or function
      • ​Evidence for taping, electrical muscle stimulation, passive physical modalities had too little data; one study on ultrasound or TENS showed no benefit vs sham ultrasound/TENS

So, these assessments raise several issues:

  • Systematic reviews and meta-analyses have one really large limitation: they only include those studies which were actually done. I.e., even though some meds may work, or different doses of meds than those studied may work, they get no support in the review if they were never tested in a formal study. And, for better or worse, much of what we do in medicine does not have the support of rigorous studies.
  • In the studies included in the systematic reviews (which include onlymethodologically “good” studies), several may yield the “no benefit” designation if the drug was no better than placebo. But many placebos get reasonable responses, on the order of 20-30% often, so suggesting acetaminophen, for example, has helped several of my patients feel better and be able to function through perhaps the very real “placebo” effect (for more on the placebo effect, see http://blogs.bmj.com/ebm/2015/05/07/primary-care-corner-with-geoffrey-modest-md-placebo-genetics-and-the-placebome/ for a discussion of the genetics, or http://blogs.bmj.com/ebm/2014/11/18/primary-care-corner-with-geoffrey-modest-md-placebo-for-coughs-in-kids-and-an-adult-perspective/​ for a couple of examples).
  • One currently very hot topic is the use of opioids for chronic low back pain. And it is a really important issue given their attendant huge social costs (addiction, overdoses, etc.) and is particularly relevant given the large numbers of people on chronic opioids for chronic LBP (one of the most common reasons for chronic opioid prescribing). But for acute low back pain, there are only 2 studies (of “low” stength-of-evidence), using only buprenorphine patches and showing a small effect on pain relief. And only 4 studies showing moderate effect on the pain of chronic LBP. I’m not sure how that squares with several of my patients who derive significant benefit even though I really have no doubt that they are taking the meds regularly and have real, functionally-disabling pain that we are treating. And there are no really good trials looking at opioids vs NSAIDs or other drugs, or even what dose of opioids is adequate for pain relief
  • More invasive procedures were not included in this review. And, for example, well-designed studies suggest that epidural injections do not help radicular back pain. But I have certainly had several patients who were in constant pain and unable to function well, who have gotten very dramatic and durable relief from injections. Is that a placebo effect?? Maybe. But it really restored function and basically eliminated their pain, so I will continue to prescribe it when all else fails, and typically before a referral for surgery

So, as with many medical papers, this one sheds some light but largely raises the many lacunes in our knowledge base, ones that we really need answered to practice high quality, appropriate care. (I hate to say the usual caveat after pretty much all editorials in the major medical journals, but “further studies should be done….”)​

Primary Care Corner with Geoffrey Modest MD: Placebo genetics and the “placebome”

7 May, 15 | by EBM

By: Dr. Geoffrey Modest

-A new article just came out of the Program in Placebo Studies in Boston that link the “placebo effect” to specific genes in the newly-defined “placebome” (see here), also noted in a more popular forum

Background, promoting the concept that placebo effects are legitimate biological responses to environmental cues:

–studies on placebos have dated back decades. Old studies have found red placebos and those in capsule form to be more effective. Another found that blue placebos are more effective for sleep, across cultures (though, per NPR, not so only for males but not females in Italy, where blue perhaps evokes images of their national soccer league and may increase arousal).

–other old studies have found that in some patients pain could be suppressed by placebo, equivalent to up to 8mg of morphine, and blocked by the opioid receptor antagonist naloxone

In this setting, this article explores what is known about the genetic component of the placebo response, noting that behavioral/personality assessments have had limited success in predicting placebo response.

–A very large limitation in assessing the placebo response is the lack of NTC (no-treatment control) trials. Just as we compare active drugs with placebo to assess the added effect of the active drug, we need to compare placebo to NTC to see if placebo has additional effects over doing nothing (thereby accounting for “regression-to-the-mean” as well as other changes in the natural history). As a real-world example I use in my lipid talk, there was a study of hyperlipidemic patients with elevated ALT levels put on a statin, compared to hyperlipidemic patients with normal ALT put on a statin, but they also had a 3rd group with elevated ALT given no statin: results were that there was an increase in ALT in the first group on statin, as compared to those in the 2nd group with baseline normal ALT, which suggested that statins in the setting of an elevated ALT are associated with higher ALT levels. But in fact there was no difference between the 1st and 3rd groups, suggesting that there is enough variability in ALT values in those with an elevated ALT that the statin actually had no additional effect on ALT levels…).

–There are several studies suggesting that there is a “placebome“, areas of the genome which may predispose individual patients to a placebo response:

–much of the research has assessed areas of the genome that affect the opioid (pain suppression) and dopamine (reward) systems.

–pain studies have found that those patients with more profound placebo response have higher opioid and dopamine receptor activation; patients with higher pain sensation with placebo had decreased signaling in both systems

–several studies have looked at genetic polymorphisms of the catechol-O-methyltranserase gene (COMT is responsible for dopamine metabolism), finding in different studies that homozygotes for a less-active allele (a common polymorphism in the population, varies with ethnicity/race but is in 20-25% in the Causasian population) have higher levels of dopamine in the prefrontal cortex; patients with this polymorphism and irritable bowel syndrome had the greatest placebo response; a pain study found increasing placebo-induced pain suppression in those with increasing numbers of this allele; and, conversely, in those with high levels of the “normal” allele, there were more nocebo effects (adverse effects from the placebo). Similar results were found with variants of the monoamine oxidase A polymorphisms (MAO-A metabolizes monoamines, including dopamine and serotonin), where people with a particular polymorphism had decreased MAO-A activity and higher basal dopamine levels; and, in patients with clinical depression who had this polymorphism and were given placebo vs one of 3 selective serotonin reuptake inhibitors (SSRIs), they had a higher placebo response. A study of genetic variations of dopamine beta-hydroxylase (converts dopamine to norepinephrine) has found that patients with alcohol dependence who had this polymorphism did better with placebo and worse on naltrexone. Other studies have looked at variations in the mu opioid receptor, finding variability in placebo-induced pain perception. There are also some data on placebo response variability with endocannabinoid and seratonergic signaling genetic variants.

I don’t mean to overplay this, but I do think this article raises a few interesting points:

–there is utility in having a no-treatment control in studies, to help control for clinical variability in symptoms over time, and making it easier to tease out a placebo effect.

–identifying those with genetic variants associated with less placebo response could, at some point in the future, lead to needing smaller studies to determine medication efficacy

–identifying those with more profound placebo response could lead to more effective non-medical (or placebo) interventions

–it is important to be aware that in those instances with known high placebo-response (eg depression, irritable bowel), it is much harder to assess drug efficacy, with results biased to null even if the medication were really effective in those patients genetically predisposed to minimal placebo response (more likely to be an issue in smaller trials). Awareness of placebo-sensitive genotypes might be particularly useful in these cases.

–there may be important gene-drug-placebo effects.  There is the potential that in some patients with specific genetic pro-placebo polymorphisms and given an active drug, they may then get both the drug effect as well as the placebo effect, and these 2 effects could interact with each other in different ways: eg, these placebo effects could significantly augment or compete with the drug effect (especially if the drug and placebo focus on the same target in the body). The point here is that even the active drug’s effects may be very different in those predisposed to a placebo effect than those not, and that the placebo and drug effects are not necessarily simply additive.​ The above example of alcohol dependence/naltrexone may indicate an adverse placebo-drug interaction.

Primary Care Corner with Geoffrey Modest MD: Placebo for coughs in kids, and an adult perspective

18 Nov, 14 | by EBM

An interesting article found that placebo was more effective than no treatment in kids with cough (see doi:10.1001/jamapediatrics.2014.1609). This was a 13 month study in 2 outpatient pediatric practices of kids aged 2-47 months who had nonspecific acute cough of less than 7 days. Parents were given surveys the day before and after the allotted treatment, which was either pasteurized agave nectar, caramel-colored placebo (each given 30 minutes prior to bedtime), or “no treatment”. All parents were instructed in routine care of the child: hydration, saline nasal spray, and use of acetaminophen/ibuprofen as needed (ie, the “no treatment” group did get treatment, just not a teaspoon of “meds”). The survey assessed cough frequency, cough severity, congestion severity, rhinorrhea severity and the cough effect on child and parent sleep.

Results:​

–119 children completed the study, mean age 23 months, 50% female, 87% white non-Hispanic.

–No difference in any of these outcomes between administering agave nectar or placebo (though agave nectar was nonsignificantly better on all outcomes)

–Significant differences between either one of these two treatments and “no treatment” for all of the above outcomes, all with p<0.05

–Subgroup analysis suggested that the effects of agave nectar over placebo were somewhat more pronounced in those under 1 year old, though nonsignificant (but only 30 kids <1yo)

Agave

So, background is that acute cough is a remarkably common outpatient complaint in kids and a common reason for a healthcare visit, with nocturnal cough disturbing sleep in 88% of children and 72% of parents. Given current valid concerns about adverse events with medications as well as their unclear efficacy in young children (eg antihistamines, decongestants, antitussives), providers have limited medication options. There are some studies showing efficacy of honey, but that should not be used in kids <1yo for concerns about botulism. in above study, they chose agave nectar, since it sort of tastes like honey (though no data that it really works), does have some anti-inflammatory properties (as does honey), but lacks honey’s anti-oxidant effects.​

So, this article does suggest that placebo has a role for cough in kids (there was an analysis in 2002 suggesting that 85% of the treatment response in adults with cough was attributable to placebo effect). This is really not so surprising. There is an obvious interconnection between an individual’s clinical condition and their psychosocial state. to me, perhaps the most obvious example is the therapeutic effect of the provider-patient relationship itself. Many patients derive tremendous benefit without specific treatment. There are a slew of articles on the placebo effect, showing both the dramatic efficacy of placebo, the relatively frequent adverse effects as well, and effect even studies where the patients benefited even if aware that they were taking a placebo. there was an interesting article I ran across last year on this but, one of my favorite articles in the medical literature was an analysis of the CHARM trial, a placebo controlled trial of candasartan in patients with congestive heart failure (see Lancet 2005; 366: 2005–11), which found that those patients who adhered well to their treatment did well and had a lower all-cause mortality, and it didn’t matter whether they were assigned to candasartan or to placebo — ie, people who took their assigned medicine (who were probably more open to having a good effect from that medicine and perhaps more open to “taking care of themselves”) had similarly lower mortality independent of whether their assignment was to “active” medication or not…..

Geoff

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