Placebo

A Placebo’s Role in Modern Health Care 

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Perceived ethics can stand in the way of the positive effects of the use of placebos for healing patients.

A Placebo’s Role in Modern Health Care 

Modern medicine prides itself on its evidence-based approach, where doctors and hospitals choose treatments based not on faith or hearsay, but hard science.

What if our faith in medicine can be scientifically shown to have a significant therapeutic effect?

Enter the Placebo

Generally understood as the illusion of treatment, a placebo often takes the form of a sugar pill masquerading as a genuine drug.

A placebo has no discernible pharmacological value, and yet research has shown that when patients take placebos, their symptoms improve.

This effect works so well that drug trials are often built around it. When evaluating new pharmaceuticals, researchers routinely compare one group of people who receive the actual drug, with another group who receives a placebo. It’s only when new drugs and procedures can outperform this placebo effect that they can be deemed legitimately effective.

To many, the idea that patients can find relief through the power of suggestion smacks of quackery—but the evidence of this phenomenon is undeniable. Just consider is supported by the vast number of drug studies that use placebo controls in their trials. In this way, placebos are the most thoroughly tested medical interventions ever.

It’s not just fake pills—placebo surgeries have also shown a surprising amount of success.

Despite all this evidence, most doctors or hospitals would never even consider using placebos on their patients. However, since researchers already use placebos to test the effectiveness of new medicines, why don’t we harness this mysterious (and no-cost) effect for direct healing?

That’s the aim of a new book, “The Power of Placebos,” by Jeremy Howick, a professor of empathic health care at the University of Leicester.

According to Mr. Howick, the last 20 years of research in particular has shown that placebos at least deserve a supporting role in modern medicine. His book offers practical ideas on how doctors can use them in practice to improve health outcomes.

“The placebo effect can boost the effect of whatever else we’re doing, and in some cases, it has the best benefit-to-harm ratio,” Mr. Howick said. “But all that knowledge is being stuck in the walls of academia. It’s got to break out from those walls to help patients.”

In one recent study published in The Lancet journal, researchers from the University of Sydney compared an opioid (morphine) with a placebo in two groups of patients suffering acute low back or neck pain.

After six weeks, the group given actual opioids showed about the same level of pain relief as those in the placebo group. However, the opioid group saw a far greater risk of drug misuse, which can include addiction and intoxication.

An Honest Placebo

Many studies show placebos can be effective, but the predominant notion is that playing a trick on patients by administering a fake drug is unethical. That’s why placebos are still largely relegated to drug trials.

But according to Mr. Howick, this prevailing wisdom has it all backward.

“Not only are they ethical in routine practice, but placebo effects, which don’t always require a pill, are an ethical requirement in clinical practice, and the opposite is true for clinical trials,” he said.

Placebo-controlled trials are the gold standard for drug testing, but Mr. Howick believes they’re often not the best choice. Consider this example: Since the 1990s, doctors have known that steroids can prevent death in about 20 percent of people with alcoholic liver disease. But in the early 2000s, when a new drug was created to treat alcoholic liver disease, this medicine was measured against a placebo, not steroids.

According to Mr. Howick, building a study around such a comparison puts subjects in the placebo group at a greater risk of death, and that doesn’t make sense either.

“When you buy a new car, you’re looking at a side-by-side comparison—Toyota versus Ford. Why the difference in drug trials? We should test the best thing against all the known alternatives, not how it compares against a placebo,” he said.

While this opinion has its merits, it also has its critics, who say that testing a drug against another drug can create uncertainty if there are concerns about the original drug’s clinical trial. In other words, if the original drug isn’t all that effective, as in the case of some antidepressants, then testing against it doesn’t necessarily provide a clear picture of a new drugs effectiveness. Testing against a placebo at least isolates a drug’s effectiveness from the influence of the patient’s effect.

It’s typically considered unethical for a doctor to prescribe placebos because they are generally understood as a kind of deception. Even if a patient might improve from a placebo, it isn’t right to lie.

However, lying isn’t necessary to get the placebo effect to work. In 2016, Ted Kaptchuk, director of the program for placebo studies at Beth Israel Deaconess Medical Center and professor of medicine at Harvard Medical School, conducted a study where participants were given a medicine bottle labeled “placebo pills” with directions to take two capsules twice daily.

Because they knew they were receiving placebos in the study, subjects expressed suspicion about the phony treatment. But these “honest” or “open” placebos performed so well that many subjects believed they must have been given a real drug. Several participants asked for a placebo prescription after the study was over.

According to Mr. Howick, as long as doctors use honest placebos, the ethical issue vanishes.

“I think it’s crazy not to use placebos,” he said. “In fact, if the outcome is better, it’s unethical to not do that.”

Placebos Through the Ages

It’s not clear how long doctors have understood the placebo concept, but Mr. Howick believes that ancient doctors may have relied on bedside manner to exert an effect on their patients.

The word placebo didn’t find its way into medical jargon until the late 1700s and the meaning was a bit different than it is today. Back then, placebos weren’t used for drug trials but referred to any kind of dummy pill that could be used to satisfy a patient’s demand for a prescription even if a doctor had nothing to offer.

This is why the word placebo comes from a Latin root which means “I shall please.”

Over time, our understanding of placebos went from a fake pill used to placate patients, to a mysterious technique that could relieve symptoms using the power of suggestion. This modern understanding of placebos comes primarily from Dr. Henry K. Beecher, a Harvard Medical School graduate who became chief of anesthesia at Massachusetts General Hospital in 1936, and the world’s first chair of anesthesia at Harvard University in 1941.

Dr. Beecher’s interest in placebos is said to come from his time serving in World War II. The story goes that Dr. Beecher ran out of morphine, so he was forced to turn to placebos. Despite the switch, his patients still experienced pain relief.

Beecher’s seminal article, “The Powerful Placebo,” published in the December 1955 edition of the Journal of the American Medical Association looked at 15 different trials examining a variety of diseases. According to Dr. Beecher, 35 percent of 1,082 patients experienced relief from their ailment just from taking a placebo.

How They Work

So what force was behind the phenomenon that Dr. Beecher witnessed? One journal article from the 1990s critical of Dr. Beecher’s findings offered numerous explanations for the placebo effect: “Spontaneous improvement, fluctuation of symptoms, regression to the mean, additional treatment, conditional switching of placebo treatment, scaling bias, irrelevant response variables, answers of politeness, experimental subordination, conditioned answers, neurotic or psychotic misjudgment, psychosomatic phenomena, misquotation, etc.,” but certainly not some medicinal power of suggestion.

Mr. Howick says the science of the last 20 years has given us a better idea of how the placebo effect may work. The human body already contains within it the power to heal itself. Placebos just offer a little positive push to help the process.

“If you get a cut, your body heals itself,” Mr. Howick said. “Your body also has its own pharmacy to create serotonin, melatonin, dopamine, endorphins. Communication can help induce those positive things,” he said.

Consider just one aspect of our physiology: the stress response. Research has repeatedly shown that chronic stress is hard on our bodies and a major contributor to chronic disease.

However, if a doctor is talking to you with empathy, care, and understanding, even before he writes a prescription, your stress response may begin to subside. Since stress can impact the immune system, Mr. Howick says these expressions of empathy may actually boost our immunity.

”That being said, the effect is small, on average. But to put it into context, the average effect of most drugs is also small,” he said.

Limits and Dangers of the Placebo Effect

Although Mr. Howick strongly supports doctors employing honest placebos with their patients, he doesn’t recommend replacing every facet of modern medicine.

“If you get in a car accident you want the latest technology. If someone is having an anaphylactic shock, you give them an adrenaline shot,” he said. “Those situations, however, are thankfully the exception rather than the rule. Placebos can boost the effectiveness for some things, including moderate pain, depression, and anxiety.”

Once modern medicine is sold on the idea of placebos, a big part of using them effectively will come from understanding how this power of suggestion can work. While placebos show potential for healing, they can also harm.

Strange as it may sound, placebos can produce unwanted side effects. Researchers who issue informed consent forms as part of the drug trial process may include a number of symptoms patients can experience with the genuine drug. However such informed consent may even cause a placebo group to report adverse events.

This dark side of placebos is known as the nocebo effect, which comes from the Latin verb “I shall harm,” meaning the outcome of the effect is a negative one. Because the Hippocratic oath requires doctors “do no harm,” few researchers have examined the effects of nocebos.

However, available evidence suggests that the nocebo effect is even stronger than the placebo effect. According to Mr. Howick, this is part of our survival mechanism.

“We’re hard-wired to avoid things that are dangerous more than we are to seek pleasure. If you avoid danger, you stay alive,” he said.

The nocebo effect can destroy a patient’s confidence in health care professionals and the treatments they provide. This means that even if doctors never use placebos in their practice, they should at least strive to avoid triggering a nocebo effect.

This is harder than you might expect. A review of nocebo studies published in 2016 reports that “The verbal and nonverbal communications of physicians contain numerous unintentional negative suggestions that may trigger a nocebo response.”

Mr. Howick says what’s most important is that doctors understand how much their bedside manner can influence their patients’ health. While this may require a bit more time spent with each patient, it may mean more successful treatments and better health outcomes.

“I think there should be a major shift in the health care system,” he said. “We need more in-depth communication with patients. We need to shift towards a system where doctors are reimbursed for how much value they provide, not how many tests and treatments they give.”

Pembrolizumab in combination with chemotherapy improves progression free survival for women with advanced or recurrent endometrial cancer

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NRG Oncology Phase III clinical trial, NRG-GY018, evaluating pembrolizumab in combination with standard of care chemotherapy (carboplatin and paclitaxel) met its primary endpoint of progression free survival (PFS) for the treatment of patients with stage III-IV or recurrent endometrial carcinoma, regardless of mismatch repair status. A pre-specified interim analysis, conducted by an independent Data Monitoring Committee, demonstrates that pembrolizumab in combination with chemotherapy has a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone in both study cohorts, mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR). The full results of this trial will be presented at an upcoming scientific conference.

NRG-GY018, a randomized, blinded, placebo-controlled study, accrued 819 women with stage III-IV or recurrent endometrial cancer. Two independent cohorts were evaluated, patients with endometrial cancers that are dMMR and patients with endometrial cancers that are pMMR. Patients were randomly assigned to receive pembrolizumab combined with carboplatin and paclitaxel (for a planned six, 3-week cycles), followed by pembrolizumab maintenance (for up to fourteen, 6 week cycles) or placebo combined with carboplatin and paclitaxel, followed by placebo maintenance.

Patients with advanced stage or recurrent endometrial cancer, the most common type of gynecologic cancer in the U.S., face a poor prognosis with limited treatment options. This is particularly notable in patients who progress after prior platinum-based adjuvant therapy with disease not amenable to curative surgery or radiation. In this study, pembrolizumab in combination with carboplatin and paclitaxel resulted in a statistically significant and clinically meaningful improvement in PFS in both the dMMR and pMMR study populations. We look forward to presenting these exciting findings at an upcoming scientific congress.”

Ramez Eskander, MD, of the University of California San Diego Moores Cancer Center and the Principal Investigator of the NRG-GY018 trial

This project was supported by the NRG Oncology Operations grant U10CA180868 and the NRG Oncology SDMC grant U10CA180822 from the National Cancer Institute (NCI), part of the National Institutes of Health and conducted by the NCI National Clinical Trials Network. Funding and support were also received from Merck & Co., Inc. through a Cooperative Research and Developmental Agreement with NCI. NRG-GY018 was conducted with funding supplemental to the CRADA from Merck in an Agreement between Merck and The GOG Foundation d/b/a NRG Oncology Philadelphia East.

Why placebo pills work even when you know they’re a placebo

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In 2014, the American footballer Marshawn Lynch – a former NFL running back nicknamed ‘Beast Mode’ because he bulldozed and ran over would-be tacklers – signed an endorsement deal with Skittles. This was more than business. To Lynch, Skittles aren’t just Skittles. Since he was young, the button-shaped candies have been his secret weapon.

As a rising football star in high school, Lynch was often struck by anxiety in advance of his games. It was often so extreme it caused an intense upset stomach. Young Lynch tried several over-the-counter remedies, but nothing seemed to work. Then one day, his mother, Delisa Lynch, told him that Skittles would settle his stomach. Not only that, but she said the Skittles would also make him play better: ‘They’re going to make you run fast, and they’re going to make you play good.’ And, somehow, they did.

No offence to Skittles lovers, but there’s nothing special about them. They’re mostly sugar, corn syrup and artificial flavours. Yet, throughout his college football and illustrious NFL career, Lynch held on to the belief that Skittles helped his game, and he always ate them before taking the field. You might assume that the Skittles were, for him, just a silly pre-game ritual. But by eating the Skittles and believing that they helped improve his performance, Lynch was taking advantage of a very real phenomenon: the placebo effect.

The placebo effect occurs when someone experiences a benefit due primarily to the belief that something they are doing – taking a medication, engaging in a ritual, or getting treatment – will have a beneficial effect. Placebos are far more powerful than most people realise. They’ve been shown in research trials to help reduce anxiety, depression, pain, asthma, the motor symptoms of Parkinson’s disease, and recovery from osteoarthritis of the knee. It’s worth noting that these benefits aren’t just seen in terms of how people feel, although that alone is important, but also in terms of measurable physiological improvements.

The power of the placebo effect is such that new drugs are required to demonstrate that they have additional benefits, above and beyond a placebo, before they can go to market. Most drug and behavioural intervention trials fail this test – not because the drugs or interventions don’t work, but because the placebo effect is so strong.

Even though the placebo pills contained no active ingredients, and despite the patients knowing they’d been taking placebos, they reported fewer IBS symptoms

Given that placebos are such a powerful treatment on their own, we might ask ourselves: why are they not being used as a treatment more widely?

One of the biggest barriers is an ethical dilemma. On the one hand, placebos are highly effective for certain symptoms and conditions, and can have a real therapeutic effect. On the other hand, to benefit from placebos, the predominant thinking has been that people need to be misled into believing they’re taking an active treatment. Since most medical authorities worldwide have agreed – for good reasons – that lying to patients isn’t a best practice, this reliance on deception has prevented the widespread use of placebos as treatments in and of themselves.

But what about the case of Marshawn Lynch? Of course, he knows that Skittles don’t really have magical powers. He also knows the actual ingredients of Skittles can’t make him run faster or play better. And yet, he continues taking them, believing in and apparently enjoying their beneficial effects.

Lynch’s experience reflects an emerging research trend to study the possible beneficial effects of placebos given without deception, also known as ‘open-label placebos’ or ‘non-deceptive placebos’. In a foundational study in 2010, researchers at Harvard Medical School randomised patients experiencing irritable bowel syndrome (IBS) symptoms into either an open-label placebo group or a no-treatment control group – and crucially, all the patients knew which group they were in. The researchers told patients in the open-label placebo group that the placebo effect is powerful, that the body can respond automatically to taking placebo pills (similar to the classic conditioning example of Pavlov’s dogs, who salivated at the sound of the dinner bell), that a positive attitude helps but is not required, and that it is vital to take the pills faithfully for the entire 21-day study period, regardless of their belief in the pills. By the end of the study, even though the placebo pills contained no active ingredients, and despite the patients knowing they’d been taking placebos, they reported fewer IBS symptoms and more improvement in overall quality of life than patients in the no-treatment control group.

This paradigm of giving non-deceptive placebo pills as treatment has been repeated, including a recent replication of the benefit for IBS, while other trials have shown benefits for patients with ADHD and hay fever. Unsurprisingly, further research suggests that open-label placebos can also work in non-clinical settings. Together with colleagues, one of us (Darwin) showed in 2020 that an open-label placebo nasal spray reduced the distress provoked by looking at emotionally upsetting images. Like Lynch’s Skittles, the open-label placebo we used helped our volunteers manage their feelings and anxiety, an effect that was even visible in their electrical brain activity.

So what’s really going on here? It’s not the sugar pill itself that leads to these changes in psychology and physiology, and it’s not magic either. Research in medicine and psychology on both traditional and open-label placebos suggests several mechanisms at play.

Patients who also took the open-label placebo pills consumed approximately 30 per cent less daily morphine in the days after surgery

One is people’s expectations, or the positive belief that a treatment might have beneficial effects. In open-label placebo studies, including Darwin’s nasal spray study mentioned above, people are often told that a belief in the placebo isn’t necessary, but they are encouraged to keep an open mind. Some of the clinical studies have involved volunteers for whom many other treatments have failed, and so they have added reason to hope that this experimental, slightly unorthodox treatment might work for them. Emerging research suggests that this belief might be partially responsible for the benefits. For example, a study one of us (Kari) ran as part of her PhD showed that open-label placebos led to a reduction in allergic response from a histamine skin-prick test, but only for those volunteers who believed strongly in the beneficial power of placebos.

Another possible mechanism is conditioning, in which the body learns to associate beneficial effects with an action or ritual. Many of us have had repeated experiences of taking pills that help reduce our symptoms – ibuprofen for a headache, NyQuil for a cold, or Pepto Bismol for an upset stomach. Over time, the body may learn to associate taking a pill with symptom relief. So the very act of taking a pill itself can catalyse the body’s own capacity for healing.

This conditioning is sometimes done explicitly in research with open-label placebos. In one clinical study, researchers asked patients recovering from spine surgery to pair their active pain medication with open-label placebos and also to take the placebo pills on their own. The placebo pills began exerting their own pain relief. Compared with the control group who received treatment as usual, patients who also took the open-label placebo pills consumed approximately 30 per cent less daily morphine in the days after surgery.

There are also other, less well-studied mechanisms that may be at play in open-label placebo effects. For example, when someone starts taking a treatment – placebo or not – they often begin paying closer attention to their own minds and bodies. Most conditions and symptoms fluctuate over time. For example, when we are experiencing a headache, even if we don’t take any medication or other action, the severity of that headache will naturally decrease over time. People who take open-label placebo pills may hope for improvement, making them more attuned to times when their symptoms subside. Other research shows that medical rituals – whether that’s taking a pill, getting an injection, or merely having a cup of tea and taking a hot bath – can evoke both expectations for healing and a conditioned response. Thus, the act of taking pills faithfully can become a healing medical ritual in and of itself.

The pharmaceutical industry has no incentive to promote this kind of medication over patented, privatised medications

Now that we are seeing an accumulation of evidence that open-label placebos might be helpful, researchers and clinicians are starting to think about how to apply them in practice to benefit patients. For certain conditions, particularly those such as IBS that have already been studied, open-label placebos could be an effective treatment on their own. As the American footballer Marshawn Lynch has known for years, and new research is demonstrating, open-label placebos could also be used for reducing stress and anxiety to help people get in the zone before exams or games. And as research continues combining open-label placebos with existing medications, we may find them useful for tapering or decreasing doses of medications that have side-effects, such as pain medications or medications for disorders such as ADHD.

Current and future research is continuing to shed light on which conditions open-label placebos might be best-suited to. As the field grows, a debate must follow: will open-label placebos ever become part of mainstream medicine? Is it better to focus efforts on convincing doctors (and patients) that open-label placebos can be effective, or should we better understand the mechanisms of open-label placebo effects and try to harness those mechanisms in conjunction with active medications and treatments, such as by boosting patient expectations? Will open-label placebos ever be more than a semi-fringe last resort for conditions and patients for whom most other treatments have failed?

Of no small consideration is the fact that, with little money to be made from prescribing sugar pills, the influential pharmaceutical industry has no incentive to promote this kind of medication over patented, privatised medications and treatments. In many ways, research on open-label placebos is still in its infancy. The next 10 years may determine the ultimate impact of this research. As the field progresses, one of us (Darwin) plans to continue to investigate and optimise open-label placebo effects on stress, anxiety and depression in both clinical and non-clinical settings.

On an individual level, while taking open-label placebos – or Skittles – isn’t a substitute for seeking medical advice or treatment, if you’re trying to be like Marshawn Lynch, you could begin to think about how you might use open-label placebos in your own life. As a starting point, when you take a real medication, such as Tylenol (paracetamol), you could try to boost some of the relevant mechanisms – such as expectations and conditioning – for example, by reminding yourself of the benefits you expect. You could consider using some of your own open-label placebos for minor issues that don’t require medical intervention, such as aches and minor pains, stress and anxiety, difficulty sleeping, or mild upset stomach. You can drink tea (reminding yourself that lots of herbal teas do actually contain active healing ingredients), take a hot bath (which can also have medical benefits), or do other rituals that help you feel better while deliberately focusing on their healing benefits. Try finding your own version of an open-label placebo to help you in times of need. The science says it just might work.

Vitamin D-calcium supplement effect on tibia similar to that of placebo

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U.S. Army recruits taking a daily calcium and vitamin D supplement during basic training had no change in tibial microarchitecture compared with placebo, according to study data published in Bone.

“A calcium and vitamin D fortified food product prevented increases in biochemical markers of bone resorption, but there were no significant changes in tibial density or microarchitecture in men and women after military training,” Erin Gaffney-Stomberg, PhD, RD, division chief of the combat feeding division at the U.S. Army Research Institute of Environmental Medicine in Natick, Massachusetts, and colleagues wrote. “In addition, markers of bone formation increased, and parathyroid hormone decreased equally in both groups over the course of training.”

Vitamin D Pills

Researchers conducted a randomized controlled trial of 50 male and 50 female U.S. Army recruits aged 17 to 42 years in basic training at Fort Jackson in South Carolina between April and June 2015. Participants had not been pregnant or breastfeeding in the 6 months before the study and had no self-reported history of endocrine or bone-modifying disorders, kidney disease, renal calculi or glucocorticoid prescription within 2 years. Participants were randomly assigned to an intervention group receiving a snack bar fortified with 1,000 mg of calcium and 1,000 IU of vitamin D daily, or a control group receiving a placebo snack bar. A background questionnaire was conducted at baseline to obtain demographic information. Anthropometric measurements and fasting blood samples were collected at baseline and at an 8-week follow-up. High-resolution peripheral quantitative CT was conducted at baseline and follow-up to measure density, microarchitecture and strength at the distal metaphyseal and diaphyseal regions of the tibia.

There were 93 recruits who completed the study, including 45 in the supplement group and 47 in the placebo group. At 8 weeks, increases in total volumetric bone mineral density, trabecular volumetric BMD, trabecular number, trabecular thickness, and trabecular bone volume/total volume, and a decrease in trabecular separation were observed for all participants. Women had changes in all bone parameters, and men had a change in all parameters except for trabecular number and separation.

All participants experienced increases in stiffness and failure load at the distal metaphyseal site, with no significant difference between the supplement and placebo groups. Stiffness and failure load did not change among women, but men had increases in stiffness of 1.3% and failure load of 3.4% at 8 weeks compared with baseline. (P < .05).

Increases in cortical perimeter and cortical volumetric BMD were observed in both groups at 8 weeks compared with baseline, but there were no other parameter changes at the diaphyseal site. Women experienced a decrease in cortical porosity and cortical volumetric BMD at 8 weeks, but there was no difference between the supplement and placebo groups. Men in both groups had an increase in cortical perimeter and decrease in cortical volumetric BMD at 8 weeks. Small increases in stiffness and failure load at the diaphyseal site were observed in women for both groups, but not in men.

“These results indicate that bone density and microarchitecture were not impacted by calcium and vitamin D supplementation at the doses tested,” the researchers wrote. “However, post hoc power analysis indicated that the current study achieved 35.8% power to detect a difference by group, and 106 volunteers per group would be required to detect a statistically significant difference if one exists. Thus, underpowering cannot be excluded as a possibility.”

The researchers said studies powered to examine stress fracture outcomes along with bone density and microarchitecture changes at varying doses of calcium and vitamin D are needed to better understand the effects of supplementation. They said future studies should also involve diverse groups of participants and take place during different times of the year.

Seizure Drug May Help in MS Eye Disease

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Phenytoin shows promise for slowing neurodegeneration in optic neuritis.

The seizure drug phenytoin may improve degenerative eye disease in patients with multiple sclerosis, researchers reported.

In a small phase II study, MS patients with optic neuritis who were on the drug had better preservation of retinal thickness and macular volume than those on placebo, although visual outcomes were similar.

The findings by Raj Kapoor, MD, of the National Hospital for Neurology and Neurosurgery in London, and colleagues are to be reported at theAmerican Academy of Neurology annual meetingnext week. An abstract for the late-breaking study was released Thursday.

Some early studies have shown that the partial blockade of voltage-gated sodium channels may be neuroprotective. Phenytoin being a sodium channel blocker, as well as a drug with an established safety record, Kapoor and colleagues randomized 86 MS patients with acute optic neuritis to the agent at 4 mg/kg/day or to placebo for 3 months.

They measured retinal nerve fiber layer (RNFL) thickness and macular volume at baseline and 6 months using optical tomography. They also measured visual function via logMAR, low contrast acuity, and color perception, along with optic nerve imaging and visual evoked potentials.

The primary outcome was RNFL thickness in the affected eye at 6 months.

Ultimately, five patients were lost to follow-up, so 81 were assessed for the intention-to-treat comparison.

Kapoor and colleagues found that patients in the phenytoin group had 30% less damage to the nerve fiber layer compared with placebo, with RNFL thickness that was 7.15 mcm higher in the drug group (P=0.02).

The volume of the macula was 34% higher in those on phenytoin compared with placebo, with a 0.20 mm3 greater volume among patients in the active group (P=0.005).

However, there were no differences in visual outcomes between the two groups.

Still, they concluded that phenytoin protects the RNFL and the macula from neurodegeneration in acute optic neuritis, raising the possibility that blockage of voltage-gated sodium channels may be neuroprotective in relapses of MS in general.

Kapoor said in a statement that if the findings are confirmed in larger studies, it may lead to a treatment to prevent nerve damage and blindness in MS.

 Shlomo Shinnar, MD, PhD, of Montefiore Medical Center in New York, who was not involved in the study, was not immediately convinced of the utility of the drug in this condition.

“Over the years, phenytoin has been reported to have a wide range of effects in a variety of disorders. Most have not been confirmed,” Shinnar said in an email to MedPage Today.

He agreed with Kapoor that the result needs confirmation in a more definitive study. In addition, he noted that the lack of a difference in actual vision means that the clinical significance of the finding remains unclear.

“As we continue to search for disease modifying/neuroprotective agents, our enthusiasm for preliminary findings is tempered by a long history of promising agents that subsequently more definitive trials did not find to be effective,” Shinnar said.

Vedolizumab as Induction and Maintenance Therapy for Crohn’s Disease.

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BACKGROUND

The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn’s disease is unknown.

METHODS

In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab therapy (300 mg) in adults with active Crohn’s disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52.

RESULTS

At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn’s Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%).

CONCLUSIONS

Vedolizumab-treated patients with active Crohn’s disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab.

Source: NEJM

Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension.

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Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial.

METHODS

We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension.

RESULTS

A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P=0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia.

CONCLUSIONS

Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study.

Source: NEJM

 

Patients’ Attitudes About Placebo Treatments.

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Most patients thought placebo treatment was acceptable, but they wanted to know about it after the fact.
In a 2008 survey, more than half of randomly selected U.S. internists and rheumatologists reported they had recommended a placebo treatment (most of the placebos were “active” placebos: e.g., over-the-counter analgesics, vitamins, sedatives, antibiotics) at least once in the past year In contrast, we know little about patients’ views of this practice. In this telephone survey of 853 adult members of a large California health plan who had been seen by primary care providers for chronic conditions during the previous 6 months, investigators determined patients’ attitudes about placebos. The surveyed people were told that “placebo treatments can be sugar pills or other treatments used to create a placebo effect.” Placebo effect was defined as “getting better not because of the treatment itself, but because of an expectation of benefit.”

Nearly all respondents (97%) believed a person’s mind can affect his or her health. Most (85%) believed that a clinician speaking positively about a treatment can influence a patient’s response to that treatment. Two thirds (69%) believed placebos can produce physical changes in the body. Most (83%) believed placebos are only effective if a patient is unaware that he or she is receiving a placebo. Overall, three quarters (76%) believed clinicians recommending placebo treatment was acceptable if such treatment would benefit and not harm patients; in contrast, 22% of respondents thought clinicians should never recommend placebos. Respondents valued transparency about placebo treatments: Most (75%) believed if a placebo treatment worked and a patient inquired about the medicine, the clinician should tell the patient it was a placebo.

COMMENT

In this study, most surveyed patients expressed favorable views of placebos. Nonetheless, one fifth of respondents regarded placebos as unacceptable, and most valued transparency about use of placebos. The authors appropriately recommend that clinicians engage with patients “to discuss their values and attitudes about the appropriateness of [placebo treatments] in the context of clinical decision making.”

Source: NEJM

 

Patients’ attitudes about the use of placebo treatments: telephone survey.

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Abstract

Objective To examine the attitudes of US patients about the use of placebo treatments in medical care.

Design One time telephone surveys.

Setting Northern California.

Participants 853 members of Kaiser Permanente Northern California, aged 18-75, who had been seen by a primary care provider for a chronic health problem at least once in the prior six months.

Results The response rate was 53.4% (853/1598) of all members who were eligible to participate, and 73.2% (853/1165) of all who could be reached by telephone. Most respondents (50-84%) judged it acceptable for doctors to recommend placebo treatments under conditions that varied according to doctors’ level of certainty about the benefits and safety of the treatment, the purpose of the treatment, and the transparency with which the treatment was described to patients. Only 21.9% of respondents judged that it was never acceptable for doctors to recommend placebo treatments. Respondents valued honesty by physicians regarding the use of placebos and believed that non-transparent use could undermine the relationship between patients and physicians.

Conclusions Most patients in this survey seemed favorable to the idea of placebo treatments and valued honesty and transparency in this context, suggesting that physicians should consider engaging with patients to discuss their values and attitudes about the appropriateness of using treatments aimed at promoting placebo responses in the context of clinical decision making.

Discussion

The opinions of US patients have been missing from debates over the use of placebo treatments in clinical practice and deliberate efforts by physicians to enhance patient care by promoting placebo responses. Our data show that patients are open to the idea of placebo treatments. Most (50-84%) judged it acceptable for doctors to recommend placebo treatments under conditions that varied according to the doctor’s level of certainty about the benefits of the treatment, the purpose of the treatment (for example, to address a patient’s need to receive a treatment), and the transparency with which the treatment was described to patients. Fewer than a quarter stated that it was never acceptable for doctors to recommend placebo treatments. In addition, many respondents indicated a willingness to try placebo treatments in different scenarios. This is generally compatible with trends reported in previous patient surveys in other countries regarding willingness to try placebo treatments.16 17 18 20

Our findings also underscore the importance of honesty and trust in the prescription of placebo treatments. Respondents indicated that the use of placebo treatments could have a negative impact on the doctor-patient relationship if patients learnt that a doctor had recommended a placebo to placate patient’s expectations for treatment–especially if it did not work. Respondents said that doctors should be honest about an intervention being a placebo treatment when patients ask specific questions about the treatment, and they disagreed about whether it is acceptable for physicians to call a placebo treatment “real medicine.” Interestingly, some respondents thought that doctors should not disclose that a treatment is a placebo if it is working, suggesting some support for the non-transparent use of placebo treatments, a finding not reported in previous surveys.

Although clinical practice guidelines recommend against the use of placebo treatments to mollify patients,10 most participants in this survey judged their use to be acceptable to address patients’ need to feel like they received some treatment. Patients did, however, specify limits on how far physicians should go to placate patients, with over 90% judging it inappropriate for doctors to prescribe antibiotics for a cold, even when patients ask for it. Yet recent surveys suggest that a small proportion of physicians would indeed prescribe antibiotics to some patients in this situation, and that they had done so at least once within the past year.4 21 Taken together, these findings hint at a disconnect between clinical practice guidelines, patients’ opinions, and physicians’ practices that should be further explored.

Although our data indicate a general acceptance of placebo treatments by patients, responses to different questions about the effectiveness of such treatments varied. While most thought when asked directly that placebo treatments are only effective when patients do not know they are receiving them, the responses to the more nuanced scenarios indicated a general acceptance of transparently prescribed “open” placebo treatments—both a belief that they are effective (62%) and a willingness to take them (61-65%). This discrepancy prompts questions about how well patients understand the concept of placebo treatments in general and whether providing additional detail in the scenarios adds to their understanding such that their answers to the corresponding questions are more accurate.

The study sample was representative of the population of Northern California but may not be representative of US patients in general. Our sample was more highly educated (≥44% college graduates) than the general population, had health insurance coverage through Kaiser Permanente Northern California, and had seen a physician within the past six months for a chronic medical condition. Although we constructed our definition of placebo treatments based on feedback from focus groups and pretest interviews, respondents may none the less have variable or limited understandings of the concepts of the placebo effect and placebo treatments. This is perhaps not surprising, given the variable understandings of these concepts among the placebo research community.5In view of the widespread variability in definitions and conceptions of placebo in the literature, we endeavored to employ a pragmatic definition of the placebo effect in our questionnaire that would be useful in the context of a patient survey. While there may be some vagueness and ambiguity in the concept of placebo treatments, the pattern of survey responses and our experience in exploring placebo treatments with focus groups indicate that patients are able to understand the difference between treatments that work on the basis of their inherent pharmacologic properties and those that may produce benefit primarily by means of positive expectations. We observed some variability in answers to analogous questions that were asked in different ways (for example, directly versus in contextualized scenarios), and it is difficult to know which formulation of the questions is likely to reflect attitudes more accurately. Furthermore, the survey captures patients’ opinions about a series of plausible hypothetical scenarios rather than actual behaviors and experiences.

Researchers of one study have argued that models of shared decision making need to include conversations between physicians and patients about the role of the placebo effect in clinical care,22 and clinical practice guidelines leave the door open for the use of placebo treatments when presented to patients transparently.10 Researchers of another study further suggest that attitudinal data can help develop and foster the use of effective and non-deceptive placebo treatment techniques.20 That many patients in this survey seem favorable to the idea of placebo treatments suggests that physicians should consider engaging with patients to discuss their values and attitudes concerning the appropriateness of using placebos in the context of clinical decision making. Such conversations could allow physicians to determine which patients might be open to the use of placebo treatments and could help physicians tailor their description of placebo treatments according to patients’ preferences and level of understanding. Further research is needed to determine how physicians can optimally promote placebo responses in clinical practice and to guide the appropriate use of placebo treatments.

What is already known on this topic

  • The use of placebo treatments by physicians in clinical practice has been documented in recent surveys
  • Attitudinal surveys in other countries suggest that patients are open to the use of placebo treatments in specific circumstances
  • This study provides data on US patients’ attitudes about the use of placebo treatments in clinical practice
  • These data suggest that many patients are favorable to the idea of placebo treatments

What this study adds

 

Source: BMJ

 

‘Most family doctors’ have given a patient a placebo drug.

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Most family doctors have given a placebo to at least one of their patients, survey findings suggest.

In a poll, 97% of 783 GPs admitted that they had recommended a sugar pill or a treatment with no established efficacy for the ailment their patient came in with.

The PLOS One study authors say this may not be a bad thing – doctors are doing it to help, not to deceive patients.

The Royal College of GPs says there is a place for placebos in medicine.

But they warn that some sham treatments may be inappropriate and could cause side effects or issues such as drug resistance.

For example, one of the placebo treatments identified in the study was antibiotics for suspected viral infections.

 “Start Quote

This is not about doctors deceiving patients”

Dr Jeremy HowickThe study’s co-author

Antibiotics are powerless against viruses and doctors are told not to use them.

About one in 10 of the GPs in the study said they had given a patient a sugar pill or an injection of salty water rather than a real medicine at some time in their career.

One in 100 of them said they did this at least once a week.

‘Offering reassurance’

Almost all of the GPs said they had provided patients with treatments, like supplements, probiotics and complementary medicines, that were unproven for their medical condition. Three-quarters said they offered unproven treatments on a daily or weekly basis.

Dr Jeremy Howick, co-author of the study that was carried out by the University of Oxford and the University of Southampton, said: “This is not about doctors deceiving patients.

The power of placebo

The placebo effect – when the patient feels better despite taking a medicine with no active ingredient – can be surprisingly strong.

One study even found patients with irritable bowel syndrome reported improvements despite knowing they were taking a dummy pill.

And its not just pills, fake acupuncture has been shown to reduce the severity of headaches and migraines.

The effect is based on the patient’s expectation of a cure and seems to work best for subjective measures such as pain.

The size, colour, and branding of placebo treatments have all been shown to influence ‘effectiveness’.

The placebo is the backbone of medical research enabling doctors to distinguish between real and expected or perceived effects of treatment.

But when it comes to their use in general medicine some believe their use can damage the doctor-patient relationship.

The question is whether the patient minds as long as they have their ‘cure’.

“The study shows that placebo use is widespread in the UK, and doctors clearly believe that placebos can help patients.”

The GPs in the study said they used placebos either because patients requested treatment or to reassure patients.

Half said they told their patients that the therapy had helped other patients without specifically telling them that they were prescribing a placebo.

Dr Clare Gerada, chairwoman of the Royal College of GPs, said it was perfectly acceptable to use a placebo as long as it did not cause harm and was not expensive.

“Lots of doctors use them and they can help people.

“If you think about it, a kiss on the cheek when you fall over is a placebo.

“But there are risks. Not all of the placebo treatments that the researchers looked at in this study are inert. If you take too many vitamins, for example, some can cause harm.”

She said fobbing off patients with an ineffectual treatment was never acceptable. “But admitting to your patient that you do not know exactly what is going on, but that a therapy might help is.”

Source:BBC