Was thalidomide a placebo hypnotic?

Six decades ago the world learned that thalidomide, a seemingly non-toxic sedative and hypnotic, caused severe birth defects including the flipper-like deformity of the arms known as phocomelia. When thalidomide was tested against placebo by the trialist Louis Lasagna in 1960 (while the drug was banned from the U.S. marketplace), he found the 100-mg dosage equivalent to placebo, as well as greatly inferior to the 200-mg dosage, in producing sleep. Even as these findings were made known, a 100-mg dose of thalidomide was in general use as a sleep aid for pregnant women. It appears that unbeknownst to themselves, an untold number of pregnant women around the world who were prescribed thalidomide incurred the risks of a teratogen in return for the benefits of a sugar pill.

From blocked flows to suppressed emotions: the life of a trope.

Internal blockages and build-ups cause disease: traditionally, this principle seemed intuitive both to professionals and the laity, explained conditions as diverse as melancholy and scurvy (among many others), and justified the use of evacuative treatments to get rid of noxious matter. With the collapse of humoral medicine and the establishment of the concept of specific causation, one might have expected time-honoured tropes of obstruction to die off. They did not die off, but moved with the times and adapted to new conditions. Emphasis swung from the noxious character of retained substances to the harms of suppressed urges and emotions-harms including disabling maladjustments as a result of sexual inhibition, and cancer as a result of emotional inhibition. In both cases the causal mechanisms resemble traditional blockages. Theories of noxious inhibitions or psychological blocks, which have a familiar and perhaps even intuitive sound because they have so much history behind them, can easily lead patients into fanciful methods of prevention and treatment.

The Weight of a Term: "Substantial Evidence" and Buried Data.

When Congress amended the Food, Drug, and Cosmetic Act in 1962 to ensure the efficacy of drugs before they reach the market, it imposed a standard of evidence distinctly weaker than the reasonable one of preponderance. The difference is material. Some drugs now on the market may or may not have a preponderance of trial evidence of efficacy. An obstacle to a finding of efficacy is the well-known nemesis of drug makers with a definite interest in favorable trials: the placebo effect. Trials where the placebo effect runs high are vulnerable to negative findings, and trials with such findings all too often find their way to burial sites like regulatory archives. Publication bias-the preferential reporting of positive findings-has been abetted by a regulatory standard that does not require a preponderance of evidence and discounts negative trials, provided only that two trials show positive results.

Active Surveillance for the Management of Localized Prostate Cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement.

PURPOSE: To endorse Cancer Care Ontario's guideline on Active Surveillance for the Management of Localized Prostate Cancer. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines developed by other professional organizations. METHODS: The Active Surveillance for the Management of Localized Prostate Cancer guideline was reviewed for developmental rigor by methodologists. The ASCO Endorsement Panel then reviewed the content and the recommendations. RESULTS: The ASCO Endorsement Panel determined that the recommendations from the Active Surveillance for the Management of Localized Prostate Cancer guideline, published in May 2015, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the Active Surveillance for the Management of Localized Prostate Cancer guideline with added qualifying statements. The Cancer Care Ontario recommendation regarding 5-alpha reductase inhibitors was not endorsed by the ASCO panel. RECOMMENDATIONS: For most patients with low-risk (Gleason score ≤ 6) localized prostate cancer, active surveillance is the recommended disease management strategy. Factors including younger age, prostate cancer volume, patient preference, and ethnicity should be taken into account when making management decisions. Select patients with low-volume, intermediate-risk (Gleason 3 + 4 = 7) prostate cancer may be offered active surveillance. Active surveillance protocols should include prostate-specific antigen testing, digital rectal examinations, and serial prostate biopsies. Ancillary radiologic and genomic tests are investigational but may have a role in patients with discordant clinical and/or pathologic findings. Patients who are reclassified to a higher-risk category (Gleason score ≥ 7) or who have significant increases in tumor volume on subsequent biopsies should be offered active therapy.

Can I Author Myself? The Limits of Transformation.

Narrative medicine is predicated on the importance of narrative to human life. Although that in itself is not controversial, an extension of this principle that has sprung up in narrative psychiatry--namely, that by coming to imagine a different life story one can become a different person--ought to be. One reason one cannot remake one's life in the image of a story is that life is not to be mistaken for a story in the first place. The seminal study of psychotherapy, Persuasion and Healing, although recommending that the demoralized absorb more uplifting stories about themselves, appears to recognize some limit to the possibility of modeling life on story. The same study likens therapeutic stories to placebos, but as it happens, placebos themselves have their limits, alleviating symptoms but not curing or "healing." In order for someone to become a different person through the agency of the placebo effect, it would have to be more robust than it is. The argument that life follows narrative is an ironic one for a discipline devoted to narrative to make, given the salience in the tradition of the novel, from Don Quixote forward, of works that explore the fallacies of that presumption. In keeping with its attention to narrative, this article challenges the use of a short story by Chitra Divakaruni as an illustration of the principles of narrative psychiatry.

Montaigne on Medicine: Insights of a 16th-Century Skeptic.

Michel de Montaigne (1533-1592) viewed the medicine of his time with a well-merited skepticism and had remarkable insight into its best resource, the placebo effect. Because less separates biomedicine from its Early Modern counterpart than commonly supposed, Montaigne still has much to tell us about the workings of this potent variable. When people improve as a result of surgery that did not take place, or for that matter sicken as a result of fumes that elude detection, they behave much like their counterparts in Montaigne's world. But doctors as well as patients are subject to errors of perception and inference. It was the goal of correcting misleading impressions by more reliable knowledge that led mid-20th-century investigators of the placebo effect to propose the sort of methodologically demanding trials through which drugs are now run before being brought to market. Montaigne's awareness of the weak foundations of claimed knowledge, prominently including medical knowledge, was central to his philosophy of the human.

Deceit and transparency in placebo research.

Studies designed to elicit the full strength of the placebo effect differ from those in which the placebo effect represents a nuisance factor to be accounted for in order to establish the efficacy of a treatment. In the latter, informed consent is the rule; in the first, while consent may be informed in some narrow sense of the word, deception is common. However, the trickery of placebo experimentation goes beyond straightforward lies to include the use of crafty ambiguities, half-truths, and deliberate omissions in scripts read to the subjects of these studies. As words come to resemble therapeutic agents in their own right, it is only to be expected that researchers would methodically exploit verbal effects to evoke the responses they are looking for. Even experiments in which placebo is disclosed as placebo have used language in leading and misleading ways. Such studies are conducted in the hope of yielding results that might translate into clinical practice, but it should be noted that good clinical practice has a placebo value of its own--that is, confers a benefit over and beyond the specific effects of treatments--even if nothing like a sugar pill is administered.

Placebo: the lie that comes true?

Over the decades of experimentation on the placebo effect, it has become clear that it is driven largely by expectation, and that strong expectations of efficacy are more likely to give rise to the experience of benefit. No wonder the placebo effect has come to resemble a self-fulfilling prophecy. However, this resemblance is considerably exaggerated. The placebo effect does not work as strongly as it is advertised to do in some efforts to elicit it. Half-truths about the placebo effect are now in circulation, reinforced by a number of other equivocations that it seems to attract. As the deceptive use of placebos has fallen into discredit, the use of half-truths and exaggerations-neither of which is technically a deception-becomes an ever more inviting possibility. However, there are risks and costs associated with the half-truth that the doctor possesses the power to make his or her words come true by the alchemy of the placebo effect.

Do no harm: a case in point.

The principle of avoiding harm, though still cited here and there in the literature, is regarded by many as a bit of antiquarianism with no relevance to actual medical practice and decision-making. But while treatment necessarily entails trading off risks against benefits, it is not so easy to defend harm caused in the name of prevention. Drugs intended for preventive use by the general population must meet high standards of safety-that is, they should not harm. This principle came to the fore in a recent meeting of an FDA Advisory Committee tasked with deciding whether or not to recommend two drugs for the prevention of prostate cancer. As the transcript of this charged meeting shows, the principle of avoiding harm is far from an inert doctrine without application to medicine.

Uninformed consent: mass screening for prostate cancer.

While medicine may agree in principle that cancer screening requires informed consent, such consent is not, in fact, common practice. In the case of prostate-cancer screening this means that men in large numbers undergo PSA testing with little understanding of its liabilities -- in particular, that it may or may not decrease mortality, often detects cancer of questionable significance, and may lead to unnecessary surgery. Given that prostate cancer is known to be overtreated and that family history is a risk factor, it follows that a man diagnosed with prostate cancer, even if it is of no clinical significance, automatically promotes his son into the high-risk category; and given that those so categorized are subject to heightened medical surveillance and that the more diligently medicine searches for prostate cancer the more likely it is to find it, it follows that the sons of men diagnosed as a result of PSA testing are at risk of being overdiagnosed (and overtreated) precisely because their father was. Twenty years into the PSA revolution, its generational consequences have not been discussed in the medical literature.

What's wrong with chemoprevention of prostate cancer?

When prostate-specific antigen (PSA) testing was introduced, proponents expected it to cut prostate-cancer mortality and did not expect it to unleash an epidemic of unnecessary treatments. Now that evidence of a mortality benefit remains unclear while evidence of overtreatment in undeniable, there is understandable interest in reducing the human costs of the PSA system. Two related drugs, finasteride and dutasteride, both proven to reduce the incidence of prostate cancer and the "risk of diagnosis," are being promoted accordingly. However, if not for the flaws of the PSA system the use of these drugs for purposes of prevention would lose its rationale. Not only are the drugs in this sense dependent on a faulty system, but their own mortality benefits are as speculative as PSA's-in addition to which, they introduce new risks.

From medicine to psychotherapy: the placebo effect.

If placebos have been squeezed out of medicine to the point where their official place in in clinical trials designed to identify their own confounding effect, the placebo effect nevertheless thrives in psychotherapy. Not only does psychotherapy dispose of placebo effects that are less available to medicine as it becomes increasingly technological and preoccupied with body parts, but factors of the sort inhibiting the use of placebos in medicine have no equivalent in psychology. Medicine today is disturbed by the placebo effect in a way psychotherapy is not. Psychotherapy does not have to grapple with such a disconcerting paradox as successful sham surgery, and unlike those physicians who once pretended to treat the patient's body while actually attempting to treat the mind, the psychotherapist can treat the mind in all frankness. Perhaps it is because psychotherapy is less burdened by doubts about the placebo effect that it was able to come to its aid when it was orphaned by medicine. It is vain to expect something with so long a history as the placebo effect to disappear from the practices of healing.

To feel what others feel: two episodes from 18th century medicine.

In the late 18th century two medical fashions--Mesmerism in France and the Perkins 'tractor' in the USA and England--appealed to the principle that a single universal force acts on all of us and is responsible for health and illness. This principle served both fashions well, as it made it all the easier for those who came within their force fields to experience the sort of sensations that other subscribers to the fashion also seemed to feel. The first research on what is now known as the placebo effect was in connection with these two movements. The propensity to feel what we suppose or imagine that others like us feel remains even now one of the channels of the placebo effect.

The power of rhetoric: two healing movements.

Though we might suppose that our sensations are unaffected by the talk around us, the rhetoric surrounding a treatment can in fact color the experience of those having the treatment. So it is with both Eye Movement Desensitization and Reprocessing (EMDR) and the 18th-century therapy that has been cited as its predecessor: mesmerism. In both cases, rhetoric itself is conscripted into the service of therapeutic ends. Reports of cures are advertised and celebrated in a way that builds the expectation and feeds the experience of more of the same. Precisely because they are rooted in and speak to their time and place, however, the efficacy of these therapies may be limited. An investigation of the kinship between the two healing movements - and the driving force of a movement is nothing other than rhetoric - throws light on possibly social sources of therapeutic efficacy.

Use of 5-alpha-reductase inhibitors for prostate cancer chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline.

PURPOSE To develop an evidence-based guideline on the use of 5-alpha-reductase inhibitors (5-ARIs) for prostate cancer chemoprevention. METHODS The American Society of Clinical Oncology (ASCO) Health Services Committee (HSC), ASCO Cancer Prevention Committee, and the American Urological Association Practice Guidelines Committee jointly convened a Panel of experts, who used the results from a systematic review of the literature to develop evidence-based recommendations on the use of 5-ARIs for prostate cancer chemoprevention. Results The systematic review completed for this guideline identified 15 randomized clinical trials that met the inclusion criteria, nine of which reported prostate cancer period prevalence. CONCLUSION Asymptomatic men with a prostate-specific antigen (PSA)

Use of 5alpha-reductase inhibitors for prostate cancer chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline.

PURPOSE: To develop an evidence-based guideline on the use of 5-alpha-reductase inhibitors (5-ARIs) for prostate cancer chemoprevention. METHODS: The American Society of Clinical Oncology (ASCO) Health Services Committee (HSC), ASCO Cancer Prevention Committee, and the American Urological Association Practice Guidelines Committee jointly convened a Panel of experts, who used the results from a systematic review of the literature to develop evidence-based recommendations on the use of 5-ARIs for prostate cancer chemoprevention. RESULTS: The systematic review completed for this guideline identified 15 randomized clinical trials that met the inclusion criteria, nine of which reported prostate cancer period prevalence. CONCLUSION: Asymptomatic men with a prostate-specific antigen (PSA)