We drove out to the Otago Peninsula with stunning scenery across to Dunedin and across the harbour. The Royal Albatross Centre was rapidly packing up with tourists and the only way to see the birds we were informed was by a guided walk. Seeing as it was cold and windy and Tony didnt want to spend too much time on his feet we decided to explore for ourselves and low and behold we found a free
Being Forward
Vietnamese people are much more forward than Cambodians. This can be good and bad. My first morning in Saigon and going for a wander. The moto and tour touts and beggars are a bit more pushy than Cambodia but not too bad but I go and sit in the park to look at the map away from them. Then a couple of students ask if they can talk to me and practice their English. We chat about a range of th
Dickie shot My Tiger
Mooched around town yesterday afternoon visiting the market outside of the twon walls. Lots of brightly coloured turbans saris fruit and bowls. Not to mention the plastic tat that seems to characterise markets the world over. On the way back to the hote spent some time sat at a rooftop cafe the Taragarh in front of me the tangled little pastel and biscuit hued streets below punctuated every
More Insights into Seoul
This was my time to get caught up on evaluating the homework for my great students preparing for this weeks class sessions and enjoying my new found past time of Hanji Painting. I will begin this week on Tuesday as I had ended my last blog with my return from Thailand journey notes ending on Monday. Our lovely Korean roomate took great care of Matt while I was away. I think he may be getting a
A few random videos I never got around to posting…and why you haven’t heard from me. haha.
Hey AllIt's definately been a while since I last posted. This is partly due to my Chinese homework as it exponentially increased in the past few weeks. And well I'll admit that my interest in the Chinese language unfortunately took a dive recently and left me wondering why I came here. Yeah that was scary. But after much thinking I feel like I'm much more levelheaded about it now. Alt
The final weeks. Dalat to Saigon
Its been a long journey and good finish. We were on the move enjoying our last days so it was tough for me to sit down and recap. So here is the much delayed conclusion to my blog.From Hoi An Iwe bordered another Iron lung for our journey to notorious Nha Trang. This was Amber's first night bus in Vietnam and so I tried to prepare her as best I could read muscle relaxers and sleeping pills
A Modern Conflict
Sunday March 6th 2011Java SeaLatitude 5 degrees 15 minutes south Longitude 112 degrees 28 minutes southI am struck by the complete paradox that is the Indonesian Island of Lombok. Much less developed than the neighboring island of Bali Lombok is still rural and primitive. A lot of the people there live in abject poverty. Some dont even have or use money they simply trade the rice they
2 Months
Wow It's hard to believe I've been here two months and haven't posted in 1 month. I think I'm starting to get the hang of things. It's still been bitterly cold and I know that there's a lot more to do when it gets warm out. So I decided to write this entry on the bus on my way into Seoul. It's my first trip by myself into Seoul and I ended up getting on a bus I've never taken before because it
Day 29 Auckland
Heute Morgen war das Wetter besser als gestern. Also habe ich beschlossen heute auf den Skytower zu steigen und den Skywalk 360 zu genieen. Der Skywalk ist ein ein Meter breiter Giterrost der in 192 Meter Hhe um den Turm herum fhrt. Der Rost hat keine Gelnder so das man ein Auffanggurt bekommt und dann frei um den Turm gehen kann. Wir waren vier Personen und unsere Fhrerin. Von einer P
Your Excellencies Special International Guests from QSA
Our itinerary was rearranged before we came so we could be in Pursat for their IWD celebration and trade fair. We were told we needed to dress properly ie. long trousers and shoulder coverings and that Jane was giving a speech on behalf of QSA but little did we know what was in store. We arrived at the DWA centre at 4 and was told they would take us to the fair. Then suddenly our buses were p
Writer’s Block
Hello folksJust thought I would write a few words in case anyone is still worrying about me. I am ok but suffering a case of writers block in addition to not having had much access to the internet. We that's me Marilyn Terry and Angela have had a good week at Wnaka Lake a lovely resort...so being in the hot tub and the beautiful scenery quite a lot of wine has helped us in the aftermath of th
Bujagali Falls 2
Today I took a walk downstream to look at the fallsI left the campsite and went through the main gate at the entrance to the falls where you have to pay 3000Ugandan Shillings about 80p and walked towards the river firstly i walked down to a small area that sticks out just above the falls where there was some local people doing their washing and fishing I then walked back up to the roadtra
Van rustige dorpjes in Laos naar ‘vrouwen’ en tempels met piemels
Na afscheid te hebben genomen van Laos was het ook al snel tijd om afscheid te nemen van Rob eerst nog een paar daagjes Thailand. De overgang van Vieng Phouka in Laos naar Chiang Rai was enorm. Ook al is Chiang Rai een van de kleinere steden in Thailand het is nog steeds groter dan de meeste steden in Laos. Overal druk verkeer billboards luide muziek De cultuurschok werd al helemaal groot
Harassing Dolphins Tarsiers and Nemo Involuntarily
Sometimes when faced with big problems and major decisions to make its nice to take a breather. Get away from it all to postpone the inevitable and think. So I went away to Bohol. Supposedly to think and meditate on the things that I'm going to lose and how to start all over again but I was too busy to do that But somehow its all clear now. Now I know what to do.We were picked up by the driver
Working it in HK
Not alot of time to take pictures when you are working 6 days a week but here are a few snaps from Brett's 3 weeks in Hong Kong. Don't worry there will be more to come since he is due back in HK after a quick week and a half jaunt to Sydney. The trip was a bit of a deja vu trip since it was almost a year ago that we were both in Hong Kong last year for the first skatepark. This time Brett was do
5 March the sky at night fur seals and a load of boulders
Forgot to mention on previous entry a clear sky here at night here is nothing short of breathtaking. The stars appear so much closer and clearer and you can actually see other galaxies with what appears to be gases around them. Onto today and we woke up to a cold grey start and ducks spuddling outside the van. One thing weve noticed while over here is how many old caravans are still functio
Topical NSAIDs
I have a mental basket of drugs that I suspect may be placebos. In that basket were the topical versions of non-steroidal anti-inflammatory drugs (NSAIDs). When the first products were commercially marketed over a decade ago, I found the clinical evidence unconvincing, and I suspected that the modestly positive effects were probably due to simply rubbing the affected area, or possibly due to the effects of the cream or vehicle itself. Frankly, I didn’t think these products worked. So when I recently noticed a topical NSAID appear for sale as an over-the-counter treatment for muscle aches and pains (seemingly only in Canada, for now), I was confident it would make a good case study in bad science.
It’s not that I’m partial to the oral NSAIDs. Yes, they’re among the most versatile, and probably most well-loved drugs in our modern medicine cabinet. They offer good pain control, reduce inflammation and can eliminate fever. We start using it in our sick and feverish infants, through childhood and adulthood for the aches and pains of modern life, and into our later years for the treatment of degenerative disease like osteoarthritis, which affects pretty much everyone as we age. An astonishing 17 million Americans use NSAIDs on a daily basis, and this number is expected to grow as the population ages. In the running groups I frequent, ibuprofen has the affectionate nickname “Vitamin I”, where it’s perceived as an essential ingredient for dealing with the consequences of training.
But NSAIDs have a long list of side effects. Not only do they cause stomach ulcers and bleeding by damaging the gastrointestinal mucosa, there are heart risks, too. It was the arrival (and departure) of the drugs Bextra and Vioxx that led to documentation of the potential for cardiovascular toxicity. And now there’s data to suggest that these effects are not limited to the “COX-2″ drugs – almost all NSAIDs, including the old standbys we have used for years, seem capable of raising the risks of heart attacks and strokes.
So despite my initial skepticism, I took another look at the topical NSAIDs. The data were not what I expected.
The use of NSAIDs
ASA (acetylsalicylic acid, Aspirin) the prototypical NSAID, traces its origin back to willow bark, a natural source of salicylate. All NSAIDs work the same way, interrupting the production of inflammatory and pain-related hormones called prostaglandins. Since ASA’s introduction in 1897, more than two dozen chemically related drugs have come to market. They’re now among the commonly used drugs used worldwide, playing a crucial role in pain management. Given the ubiquity of acute pain conditions, as well as chronic conditions like osteoarthritis, it’s estimated that 1 in 20 physician visits are related to prescriptions for NSAIDs. In general, all NSAIDS have equivalent efficacy at the population level, though individual response, and side effects, can vary between drugs. The discovery of different forms of cyclooxygenase enzymes led to new drugs that targeted COX-2 (at sites of inflammation) rather than COX-1 (which is involved with the stomach mucosa. Inhibit COX-2 rather than COX-1, the thinking went, and you could get the antinflammatory action of a traditional NSAID without the gastrointestinal toxicity. However, as the COX-2 saga demonstrated, effects can include the creation of a significant prothrombic effect – with devastating consequences.
The Risks of NSAIDs
Prescription drugs can and do cause significant morbidity, leading to frequent hospital admissions. While we may think nothing of popping a few ibuprofen now and then, NSAIDs have been linked to about 30% of drug-related hospital admissions, and it’s estimated that 12,000-16,000 Americans die annually as a result of gastrointestinal bleeding caused by NSAIDs.
Stomach bleeding and ulcers are a consequence of an NSAID’s mechanism of action – their effect on prostaglandins. The lining of the gut is weakened, and stomach and duodenal ulcers result. Even very low doses of ASA have been documented to have measurable effects on the mucosal lining of the gastrointestinal tract. The risks of gastrointestinal toxicity are significantly increased in the elderly, in those on high doses of NSAIDs, and when combined with other drugs (e.g., steroids) that suppress normal stomach protection.
The cardiovascular risks of NSAIDs became well documented following the worldwide withdrawal of rofecoxib (Vioxx) and international examinations of the cardiovascular risks of the entire category of drugs. Data have now emerged to convincingly establish that most NSAIDs (except ASA) are associated with an increased risk of cardiovascular events. Chronic (routine) consumption of most drugs is linked to small but real increases in heart attacks and stroke. These effects may be a consequence of interference with the beneficial effects of ASA (Aspirin), direct negative cardiovascular effects, and exacerbations of fluid balance, leading to heart failure.
When it comes to cardiovascular risks, not all NSAIDs are the same. A recently published network meta-analysis summarizes the differences, and the overall risks. Both traditional NSAIDs, like naproxen, ibuprofen, and diclofenac, as well as the COX-2 selective NSAIDs, like celecoxib (Celebrex) and rofecoxib (Vioxx) were studied. Happily for those that use over-the-counter anti-inflammatories only occasionally: naproxen seems to be the safest among the NSAIDs, with little to no increase in risk, and ibuprofen’s elevated risk seems limited to regular doses of 1200mg per day or more. So for the individual consumer, when do the risks outweigh the benefits of NSAIDs? Ultimately this comes down to an individual consideration of reasons for use, risk factors, and expected benefits.
To be clear, the absolute cardiovascular risks of NSAIDs, on an individual level, are low, compared to the other side effects of NSAIDs. They seem to cause three or more excessive events like heart attacks and stroke events, per 1000 patients, per year. Compare this to the 20-40 per 1000 per year that may have a (sometimes fatal) stomach bleed, a risk that’s 4x that of non-users. Still, their risk profile suggests that a consideration of their risk and benefits is warranted, particularly when they’re being contemplated in people with preexisting cardiovascular disease. On balance, when treating short-term conditions, the incremental risk in patients without cardiovascular disease is probably very low. Still, it seems prudent to use safer alternatives first (when possible) and if using NSAIDs, considering the lowest possible dose for the shortest possible duration.
Topical NSAIDs: The evidence
Over the past two decades, evidence has emerged to demonstrate that topical versions of NSAIDs are well absorbed through the skin and reach therapeutic levels in synovial fluid; muscle, and fascia. With topical use, little drug actually circulates in the plasma, leading to levels that are a fraction of comparable oral doses. As adverse events from NSAIDs are largely dose-related, it’s expected (thought not as well documented) that serious side effects should be minimized.
For chronic conditions like osteoarthritis, the data are of fair quality and are persuasive. The National Institutes for Health and Clinical Excellence osteoarthritis guidelines provides a nice summary of the trials. Studies varied by site of osteoarthritis (knee, hand, hip, etc), the type of NSAID studied, the regimen, and trial design. On balance, there’s good evidence to show that topical NSAIDs are clinically- and cost-effective for short term (< 4 weeks) use, especially when pain is localized. Topical and oral versions seem to be similarly effective under these circumstances, and there there’s a significant reduction in non-serious adverse events with topical products. While there’s no conclusive evidence to demonstrate a reduction of serious adverse events, they’re expected to be better than oral products, given the blood levels are much lower. What impressed me is that topical NSAIDs are recommended as a preferred treatment before oral NSAIDs. And given many taking oral NSAIDs need to take stomach protecting drugs like omeprazole, the topical products, while more expensive than their oral versions, may actually be more cost-effective overall.
A Cochrane review from 2010 is equally positive about the treatment of acute pain conditions. Forty-seven trials were included in their analysis that considered topical NSAIDs for strains, sprains, and overuse-type injuries. Compared to placebo, topical NSAIDs were evaluated to be effective, with few side effects, with a number needed to treat (NNT) of 4.5. About 6 or 7 out of 10 users can expect to achieve pain control with a topical NSAID, compared to 4 with a placebo. Side effects are comparable to placebo. And given systemic absorption is lower, the serious toxicity we associate with NSAIDs should be lessened, too. Not bad.
Given there’s no long-term data with topical NSAIDs, the evidence doesn’t give us enough insight to understand the risk profile beyond a few weeks. Consequently it seems reasonable to try using topical products instead of oral products, particularly for intermittent, rather than chronic, pain conditions. While compounding pharmacies have made topical versions of NSAIDs for years, there’s little information on effectiveness and safety of these products. As commercial formulations are supported with pharmacokinetic and clinical studies demonstrating efficacy, they are the preparations of choice.
Conclusion
NSAIDs, which already had a bad side effect profile, cause more harm then we thought. Evidence has emerged to demonstrate that topical NSAIDs are effective for many conditions that might otherwise require oral therapies. There’s little evidence to demonstrate that topical NSAIDs are effective for some types of pain, like back pain, headache, or neuropathic pain. But based on what’s now known about the cardiovascular toxicity of NSAIDs, it’s likely that topical products provide a superior risk/benefit perspective for regular and occasional users. The Cochrane review points out that topical NSAIDs are widely accepted in some parts of the world, but not in others. The reasons why are not clear. But having read the evidence, I’ve changed my opinion. And when I’m recovering from my next marathon, I’ll think about reaching for a topical NSAID, instead of that comforting bottle of vitamin I.
References
Haroutiunian, S., Drennan, D., & Lipman, A. (2010). Topical NSAID Therapy for Musculoskeletal Pain Pain Medicine, 11 (4), 535-549 DOI: 10.1111/j.1526-4637.2010.00809.x
Massey T, Derry S, Moore RA, & McQuay HJ (2010). Topical NSAIDs for acute pain in adults. Cochrane database of systematic reviews (Online) (6) PMID: 20556778
Solomon DH. Up-to-Date: Nonselective NSAIDs: Overview of adverse effects; Nonselective NSAIDs: Overview of adverse effects. From Up-To-Date (Database on the Internet).
Trelle, S., Reichenbach, S., Wandel, S., Hildebrand, P., Tschannen, B., Villiger, P., Egger, M., & Juni, P. (2011). Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis BMJ, 342 (jan11 1) DOI: 10.1136/bmj.c7086
Of SBM and EBM Redux. Part IV, Continued: More Cochrane and a little Bayes
OK, I admit that I pulled a fast one. I never finished the last post as promised, so here it is.
Cochrane Continued
In the last post I alluded to the 2006 Cochrane Laetrile review, the conclusion of which was:
This systematic review has clearly identified the need for randomised or controlled clinical trials assessing the effectiveness of Laetrile or amygdalin for cancer treatment.
I’d previously asserted that this conclusion “stand[s] the rationale for RCTs on its head,” because a rigorous, disconfirming case series had long ago put the matter to rest. Later I reported that Edzard Ernst, one of the Cochrane authors, had changed his mind, writing, “Would I argue for more Laetrile studies? NO.” That in itself is a reason for optimism, but Dr. Ernst is such an exception among “CAM” researchers that it almost seemed not to count.
Until recently, however, I’d only seen the abstract of the Cochrane Laetrile review. Now I’ve read the entire review, and there’s a very pleasant surprise in it (Professor Simon, take notice). In a section labeled “Feedback” is this letter from another Cochrane reviewer, which was apparently added in August of 2006, well before I voiced my own objections:
The authors’ state that they: “[have] clearly identified the need for randomised or controlled clinical trials assessing the effectiveness of Laetrile or amygdalin for cancer treatment.” This is to fail completely to understand the nature of oncology research in which agents are tested in randomized trials (“Phase III”) only after they have been successful in Phase I and II study. There was a large Phase II study of laetrile (N Engl J Med. 1982 Jan 28;306(4):201-6) which the authors of the review do not cite, they merely exclude as being non-randomized. But the results of the paper are quite clear: there was no evidence that laetrile had any effect on cancer (all patients had progression of disease within a few months); moreover, toxicity was reported. To expose patients to a toxic agent that did not show promising results in a single arm study is clinical, scientific and ethical nonsense.
I would like to make a serious recommendation to the Cochrane Cancer group that no reviews on cancer are published unless at least one of the authors either has a clinical practice that focuses on cancer or actively conducts primary research on cancer. My recollection when the Cochrane collaboration was established was that the combination of “methodologic” and “content” expertise was essential.
Wow! That letter makes several of the same arguments that we’ve made here: that for both scientific and ethical reasons, scientific promise (including success in earlier trials) ought to be a necessary pre-requisite for a large RCT; that the 1982 Moertel case series was sufficient to disqualify Laetrile; and that EBM, at least in this Cochrane review, suffers from “methodolatry.” It also brings to mind Steven Goodman’s words:
An important problem exists in the interpretation of modern medical research data: Biological understanding and previous research play little formal role in the interpretation of quantitative results. This phenomenon is manifest in the discussion sections of research articles and ultimately can affect the reliability of conclusions. The standard statistical approach has created this situation by promoting the illusion that conclusions can be produced with certain “error rates,” without consideration of information from outside the experiment.
…
This method thus facilitated a subtle change in the balance of medical authority from those with knowledge of the biological basis of medicine toward those with knowledge of quantitative methods, or toward the quantitative results alone, as though the numbers somehow spoke for themselves.
Perhaps most surprising about the ‘Feedback’ letter is the identity of its author: Andrew Vickers, a biostatistician who wrote the Center for Evidence-Based Medicine’s “Introduction to evidence-based complementary medicine.” I’ve complained about that treatise before in this long series, observing that
There is not a mention of established knowledge in it, although there are references to several claims, including homeopathy, that are refuted by things that we already know.
Well, Dr. Vickers may not have considered plausibility when he wrote his Intro to EBCM, but he certainly seems to have done so when he wrote his objection to the Cochrane Laetrile review. Which is an appropriate segue to a topic that Dr. Vickers hints at (“content expertise”), perhaps unintentionally, in the letter quoted above: Bayesian inference.
Bayes Revisited
A few years ago I posted three essays about Bayesian inference: they are linked below (nos. 2-4). The salient points are these:
- Bayes’s Theorem is the solution to the problem of inductive inference, which is how medical research (and most science) proceeds: we want to know the probability of our hypothesis being true given the data generated by the experiment in question.
- Frequentist inference, which is typically used for medical research, applies to deductive reasoning: it tells us the probability of a set of data given the truth of a hypothesis. To use it to judge the probability of the truth of that hypothesis given a set of data is illogical: the fallacy of the transposed conditional.
- Frequentist inference, furthermore, is based on assumptions that defy reality: that there have been an infinite number of identically designed, randomized experiments (or other sort of random sampling), without error or bias.
- Bayes’s Theorem formally incorporates, in its “prior probability” term, information other than the results of the experiment. This is the sticking point for many in the EBM crowd: they consider prior probability estimates, which are at least partially subjective, to be arbitrary, capricious, untrustworthy, and—paradoxically, because it is science that is ignored in the breach—unscientific.
- Nevertheless, prior probability matters whether we like it or not, and whether we can estimate it with any certainty or not. If the prior probability is high, even modest experimental evidence supporting a new hypothesis deserves to be taken seriously; if it is low, the experimental evidence must be correspondingly robust to warrant taking the hypothesis seriously. If the prior probability is infinitesimal, the experimental evidence must approach infinity to warrant taking the hypothesis seriously.
- Frequentist methods lack a formal measure of prior probability, which contributes to the seductive but erroneous belief that “conclusions can be produced…without consideration of information from outside the experiment.”
- The Bayes Factor is a term in the theorem that is based entirely on data, and is thus an objective measure of experimental evidence. Bayes factors, in the words of Dr. Goodman, “show that P values greatly overstate the evidence against the null hypothesis.”
I bring up Bayes again to respond to Prof. Simon’s statements, recently echoed by several readers, that people may differ strongly in what they consider plausible, and that it is not clear how prior probability estimates might be incorporated into formal reviews. I’ve discussed these issues previously (here and here, and in recent comments here and here), but it is worth adding a point or two.
First, it doesn’t really matter that people may differ strongly in what they consider plausible. What matters is that they commit to some range of plausibility—in public and with justifications, in the cases of authors and reviewers, so that readers will know where they stand—and that everyone understands that this matters when it comes to judging the experimental evidence for or against a hypothesis.
An example will explain these points. Wayne Jonas was the Director of the US Office of Alternative Medicine from 1995 until its metamorphosis into the NCCAM in 1999. He is the co-author, along with Jennifer Jacobs, of Healing with Homeopathy: the Doctors’ Guide (©1996), which unambiguously asserts that ultra-dilute homeopathic preparations have specific effects. Yet Jonas is also the co-author (with Klaus Linde) of a 2005 letter to the Lancet that includes this statement, prefacing his argument that homeopathy, already subjected to hundreds of clinical trials, has not been disproved and deserves further trials:
We agree that homoeopathy is highly implausible and that the evidence from placebo-controlled trials is not robust.
Bayes’s theorem shows that Jonas can’t have it both ways. Either he doesn’t really agree that homeopathy is highly implausible (which seems likely, unless he changed his mind between 1996 and 2005—oops, he didn’t); or, if he does, he needs to recognize that his statement quoted above is equivalent to arguing that the homeopathy ‘hypothesis’ has been disproved, at least to an extent sufficient to discourage further trials.
Next, does it matter that we can’t translate qualitative statements of plausibility to precise quantitative measures? Does this mean that prior probability, in the Bayesian sense, is not applicable? I don’t think so, and neither do many scientists and statisticians. Even “neutral” or “non-informative” priors, when combined with Bayes factors, are more useful than P values (see #7 above). “Informative” priors—estimated priors or ranges of priors based on existing knowledge—are both useful and revealing: useful because they show how differing priors affect the extent to which we ought to revise our view of a hypothesis in the face of new experimental evidence (see #5 above); and revealing of where authors and others really stand, and of the information that those authors have used to make their estimates.
I believe that frequentist statistics has allowed Dr. Jonas and other “CAM” enthusiasts to project a posture of scientific skepticism, as illustrated by Jonas’s own words quoted above, without having to accept the consequences thereof. If convention had compelled him to offer a prior high enough to warrant further trials of homeopathy, Dr. Jonas would have revealed himself as credulous and foolish.
Finally, there is no reason that qualitative priors can’t be translated, if not precisely then at least usefully, to estimated quantitative priors. Sander Greenland, an epidemiologist and a Bayesian, explains this in regard to household wiring as a possible risk factor for childhood leukemia. First, he argues that there are often empirical bases for estimating priors:
…assuming (an) absence of prior information is empirically absurd. Prior information of zero implies that a relative risk of (say) 10100 is as plausible as a value of 1 or 2. Suppose the relative risk was truly 10100; then every child exposed >3 mG would have contracted leukaemia, making exposure a sufficient cause. The resulting epidemic would have come to everyone’s attention long before the above study was done because the leukaemia rate would have reached the prevalence of high exposure, or ~5/100 annually in the US, as opposed to the actual value of 4 per 100,000 annually; the same could be said of any relative risk >100. Thus there are ample background data to rule out such extreme relative risks.
The same could be said for many “CAM” methods that, while not strictly subjects of epidemiology per se, have generated ample experimental data (see homeopathy) or have been in use by enough people for enough time to have been noticed for substantial deviations from typical outcomes of universal diseases, should such deviations exist (see “Traditional [insert ethnic group here] Medicine”).
Next, Greenland has no problem with non-empirically generated priors, because these are revealing as well:
Many authors have expressed extreme scepticism over the existence of an actual magnetic-field effect, so much so that they have misinterpreted positive findings as null because they were not ‘statistically significant’ (e.g. UKCCS, 1999). The Bayesian framework allows this sort of prejudice to be displayed explicitly in the prior, rather than forcing it into misinterpretation of the data.
By “misinterpretation,” Greenland is arguing not that the “positive findings” of epidemiologic studies have proven the existence of a magnetic field effect, but that the objections of extreme skeptics must be made explicit: it is their presumed, if unstated, prior probability estimates that justify their conclusions about whether or not there is an actual magnetic field effect associated with childhood leukemia; it is not the data collection itself. Prior probability estimates put people’s cards on the table.
I recommend the rest of Greenland’s article, which is full of interesting stuff. For example, he doesn’t agree that “objective” Bayesian methods, using non-informative priors (see my point #7 above) are more useful than frequentist methods, since they are really doing the same thing:
…frequentist results are what one gets from the Bayesian calculation when the prior information is made negligibly small relative to the data information. In this sense, frequentist results are just extreme Bayesian results, ones in which the prior information is zero, asserting that absolutely nothing is known about the [question] outside of the study. Some promote such priors as ‘letting the data speak for themselves’. In reality, the data say nothing by themselves: The frequentist results are computed using probability models that assume complete absence of bias and so filter the data through false assumptions.
All for now. In the next post I’ll discuss another Cochrane review that has some pleasant surprises.
…
*The Prior Probability, Bayesian vs. Frequentist Inference, and EBM Series:
1. Homeopathy and Evidence-Based Medicine: Back to the Future Part V
2. Prior Probability: The Dirty Little Secret of “Evidence-Based Alternative Medicine”
3. Prior Probability: the Dirty Little Secret of “Evidence-Based Alternative Medicine”—Continued
4. Prior Probability: the Dirty Little Secret of “Evidence-Based Alternative Medicine”—Continued Again
5. Yes, Jacqueline: EBM ought to be Synonymous with SBM
6. The 2nd Yale Research Symposium on Complementary and Integrative Medicine. Part II
7. H. Pylori, Plausibility, and Greek Tragedy: the Quirky Case of Dr. John Lykoudis
10. Of SBM and EBM Redux. Part I: Does EBM Undervalue Basic Science and Overvalue RCTs?
11. Of SBM and EBM Redux. Part II: Is it a Good Idea to test Highly Implausible Health Claims?
12. Of SBM and EBM Redux. Part III: Parapsychology is the Role Model for “CAM” Research
13. Of SBM and EBM Redux. Part IV: More Cochrane and a little Bayes
14. Of SBM and EBM Redux. Part IV, Continued: More Cochrane and a little Bayes
Placebo Effect for Pain
It has long been recognized that there are substantial multifactorial placebo effects that create real and illusory improvements in response to even an inactive treatment. There is a tendency, however (especially in popular discussion), to oversimplify placebo effects – to treat them as one mind-over-matter effect for all outcomes. Meanwhile researchers are elucidating the many mechanisms that go into measured placebo effects, and the differing magnitude of placebo effects for different outcomes.
For example, placebo effects for pain appear to be maximal, while placebo effects for outcomes like cancer survival appear to be minimal.
A recent study sheds additional light on the expectation placebo effect for pain. The effect is, not surprisingly, substantial. However it does not extrapolate to placebo effects for outcomes other than pain, and the results of this very study give some indication why. From the abstract:
The effect of a fixed concentration of the ?-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain).
What they found was that the positive expectation group reported twice the analgesic effect as the no expectation group, and the negative expectation group reported no analgesic effect. This is a dramatic effect, but not surprising.
There are systems in the brain that specifically alter the perception of pain. Mood, expectation, and attention all affect the perception of pain. This makes evolutionary sense, since pain is meant to be a warning system for tissue damage or disease, and so needs to have an acute grip on our attention. At the same time, there are circumstances when we may need to function despite our pain, or when it would be adaptive to habituate to chronic pain. There are therefore mechanisms in the brain that function to enhance and draw our emotional attention to pain, and others that function to inhibit pain.
It also needs to be noted that, broadly speaking, there are two components to pain. There is the origin and transmission of the pain signal, which is perceived as any tactile sensation. But then there is a specific emotional component to pain which occurs in the brain – that processing which makes pain hurt, that makes it into an emotionally negative experience. These two components can be separated. Narcotics, for example, are especially good at blocking the emotional component of pain, so that at times patients on opiates may report that they feel the pain but it does not bother them. Additionally, while withdrawing from narcotics the emotional component of pain in enhanced – patients may have what appears to be an exaggerated emotional response to even minor pain.
Therefore – since there is a built in system for modulating pain in response to both the physical and emotional environment, it makes sense that this system can be manipulated with physical and emotional inputs. If you make a patient feel better emotionally or decrease their stress or anxiety, their perception of pain will decrease, or at least it will not bother them as much (or, more precisely, their reporting of pain will decrease). This is why multi-disciplinary pain clinics often include psychological therapy as part of the overall approach.
This study demonstrates that expectation itself can have a dramatic effect on pain perception. They further elucidate, with fMRI analysis, the neuroanatomy that underlies this effect.
These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus.
This finding support prior research:
Further PET studies with dopamine D2/D3 receptor-labeling radiotracer demonstrate that basal ganglia including NAC are related to placebo analgesic responses. NAC dopamine release induced by placebo analgesia is related to expectation of analgesia. These data indicate that the aforementioned brain regions and neurotransmitters such as endogenous opioid and dopamine systems contribute to placebo analgesia.
The fMRI shows us where the effect is, and the PET scanning additionally shows us that dopamine is the important neurotransmitter involved in this effect.
What I would have loved to have seen in this study (perhaps this will be part of a follow up) is the same three treatment arms with a placebo treatment. This would enable us to directly compare the relative size of the expectation effect to the opiate effect. There are other questions as well. How much variation is there in the magnitude of this effect from person to person? Does the expectation effect habituate over time? Is the magnitude the same for different kinds of pain?
Conclusion
This study reinforces prior research indicating that there are built-in neurological mechanisms that modulate the perception and emotional content of pain. The study gives us further information about the exact brain structures involved in this effect. The authors conclude:
We propose that it may be necessary to integrate patients’ beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.
They should have added “for pain.” This study says nothing about other treatment effects for which there does not exist a target system for symptom modulation. This error is distressingly common, especially in the translation of such research to the public. Pain is uniquely amenable to manipulation through mood and expectation. This does not predict that any other symptom or disease state can be so manipulated.
This situation is analogous to stress and heart disease. The heart is specifically susceptible to the physiological effects of emotional stress. Stress reduction, therefore, decreases, for example, the risk of heart attack. This does not mean, however, that stress reduction will therefore decrease the risks of any disease or adverse outcome.
All too often, however, people speak of “the placebo effect” as if it is one effect, equal for all outcomes. This notion is then supported with hand-waving explanations about self-healing. But the research is actually quite clear. There are many placebo effects. Expectation is only one effect among many, and many of these effects are illusory – they create the false appearance of improvement where none exists (like regression to the mean or observational bias). Further, when speaking of the expectation effect we must be careful not to falsely extrapolate this effect from one outcome (like pain) to others.
This and other studies show that the brain is hardwired to modulate pain based upon expectation. There is no reason to think that this effect translates to other subjective symptoms, let alone objective outcomes like survival.
But I do agree with the authors to the extent that this and other studies do suggest that practitioners should seek to ethically maximize the benefits of positive expectation when treating pain. This should not, of course, violate the principles of honesty or informed consent. But putting a positive spin on the potential of a pain intervention is therapeutic. This does not justify, in my opinion, using a known placebo intervention (unless the patient was informed that it was a placebo or a treatment without any biological activity), because otherwise this would involve unethical deception (and could also create and reinforce unscientific beliefs in patients that could result in harm downstream). Further, as this study shows, you can get a sizable placebo effect from physiologically effective treatments.
Questioning the Annual Pelvic Exam
A new article in the Journal of Women’s Health by Westhoff, Jones, and Guiahi asks “Do New Guidelines and Technology Make the Routine Pelvic Examination Obsolete?”
The pelvic exam consists of two main components: the insertion of a speculum to visualize the cervix and the bimanual exam where the practitioner inserts two fingers into the vagina and puts the other hand on the abdomen to palpate the uterus and ovaries. The rationales for a pelvic exam in asymptomatic women boil down to these:
- Screening for Chlamydia and gonorrhea
- Evaluation before prescribing hormonal contraceptives
- Screening for cervical cancer
- Early detection of ovarian cancer
None of these are supported by the evidence. Eliminating bimanual exams and limiting speculum exams in asymptomatic patients would reduce costs without reducing health benefits, allowing for better use of resources for services of proven benefit. Pelvic exams are necessary only for symptomatic patients and for follow-up of known abnormalities.
Screening for Chlamydia and Gonorrhea
Screening for Chlamydia in young women is evidence-based: it reduces the rate of pelvic inflammatory disease. New tests are available (on urine and self-administered vaginal swabs) that do not require a pelvic exam by a doctor. They are sensitive and cost-effective. Supporting references are listed in the article.
Hormonal Contraception
Doctors used to require pelvic exams before they would dispense prescriptions for oral contraceptives. This was never shown to be necessary; no findings from these exams influenced the decision to issue a prescription. One concern, the possibility of a pre-existing pregnancy, can’t be entirely ruled out by a pelvic exam; but the risk can be minimized by starting the pills after a normal menstrual period. Now all the major guidelines (from the FDA, WHO, ACOG, Planned Parenthood, etc.), specify that a pelvic exam is not required for hormonal contraception.
Cervical Cancer Screening
Pap smears have been proven effective in reducing morbidity and mortality from cervical cancer. Speculum exams are necessary to obtain specimens for Pap smears, but Pap smears need not be done annually and speculum exams need not be accompanied by bimanual exams. Current recommendations are to begin screening at age 21 and to re-screen at intervals of 2-3 years. New technology currently in development may eventually allow for equivalent screening without a pelvic exam.
Ovarian Cancer
The evidence shows that bimanual exams are useless for detecting ovarian cancer, and they are no longer recommended for this purpose.
Other Benefits/Risks of Pelvic Exams
While other conditions such as fibroids, ovarian cysts, and yeast infections can be detected by examining asymptomatic women, there is no evidence that early diagnosis improves outcomes. Over-screening for cervical cancer has been shown to lead to harm. Findings on pelvic exams can be false positives and can lead to unnecessary interventions.
“U.S. rates of ovarian cystectomy and hysterectomy are more than twice as high as rates in European countries, where the use of the pelvic examination is limited to symptomatic women.”
Is It Time to Abandon the Annual Pelvic Exam?
Yes, I think so. The existing evidence indicates that omitting it in asymptomatic women would not affect health outcomes. This article is representative of a growing consensus in the medical community, especially in other countries; but many US doctors are still doing annual pelvic exams. I suspect (just my opinion) that they are afraid of looking stupid or getting sued if they miss something, or are clinging to what they were taught to do out of inertia. Meanwhile, science-based doctors are leaning away from annual physical exams in general. As this website says,
The annual physical exam is beloved by many people and their doctors. But studies show that the actual exam isn’t very helpful in discovering problems. Leading doctors and medical groups have called the annual physical exam “not necessary” in generally healthy people.
Even in patients being followed for diagnosed diseases, the physical exam sometimes degenerates into a token ritual. I’ve noticed that although I have no heart or lung symptoms, my own doctors like to check my lungs at every visit by putting the stethoscope on four spots (right, left, front and back) for one breath each, and to check my heart by applying the stethoscope briefly to one spot. I tolerate it because I know it makes them feel better, but I consider it totally useless.
Admittedly, there is a human element involved: hands-on interactions and the perception of “doing something” can be reassuring and can enhance the doctor/patient relationship. But can’t a caring clinician attain those same benefits within the realm of science-based medicine? A doctor’s time is better spent on proven health screening measures and in educating and counseling patients than in carrying out nonproductive rituals.
