The Siege of Breda is one of the most graphic events of the Eighty Years War (also known as the Dutch War of Independence).
Under the orders of Spanish general Ambrogio Spinola, the walled city of Breda in what is now the Netherlands was besieged by the Spanish army for more than eleven months. So extreme were conditions inside the town for the 7,000 soldiers defending the town that they soldiers began dying of scurvy due to the lack of fresh fruit and vegetables. Though curable through simple nutrition, scurvy is potentially deadly for anyone whose diet is low in Vitamin C and the Dutch soldiers were no exception. Along with problems stemming from malnutrition, the long siege also led to a critical shortage in various medications, including medications for relieving pain (primarily opium and laudanum). To solve this problem, the garrison commander Justin of Nassau (a son of William of Orange), hit on a cunning plan.
Working with the city's doctors, Justin had the doctors provide their patients with a powerful new medicine that he reportedly managed to smuggle in from the mysterious East. The medicine was so strong that only a few drops in a gallon of water would clear up their symptoms. The soldiers were impressed that their commander had managed to get them this medicine despite the risks and expense involved. Except, of course, that the "medicine" in this case was nothing more than a mixture of wormwood, camomile, and camphor, carefully placed into small phials, which Justin provided to the doctors. While available reports stated that "they took the medicine eagerly and grew well rapidly", there are likely limits to how well the power of suggestion could work in preventing the symptoms of scurvy. Certainly men continued to die and only 3,500 Dutch soldiers were still alive by the time Justin surrendered the town.
Though medical doctors had long observed that patient belief had a powerful effect on the body and how they responded to medical treatment, the first formal investigation into what would be called "the placebo effect" would not be until the early 19th century. The word "placebo" is Latin for "I will please" and actually comes from a Latin translation of the Bible. British physician John Haygarth published what would be the first treatise on the placebo effect when he investigated that medical effectiveness of a popular cure of the time known as "Perkins tractors." Invented by American physician Elisha Perkins, these "tractors" consisted of two 3-inch metal rods made of steel and brass. By using the tractors to "draw off the noxious electrical fluid that lay at the root of suffering", Perkins claimed to be able to cure a wide variety of illnesses, including rheumatism and arthritis. 
Even though conventional medical doctors were quick to denounce Perkins' invention as sheer quackery, many patients reported getting significant pain relief from the treatments and John Haygarth decided to investigate further. Alarmed at the growing popularity of Perkins tractors among his patients in Bath, Haygarth dem0nstrated that patients could get the same pain relief from rods made of virtually any substance and that they were unable to tell the difference between fake tractors and the "real" ones. He also noted that some patients actually got worse instead of better which suggested that imagination could cause as well as cure disease.
What mattered most was the credibility of the doctor (famous doctors were more likely to get positive results than obscure ones) as well as how credulous the patients were. The best results appeared to come from both the doctor and the patient believing in the power of the medical treatment. He prophetically commented that: "medical practitioners of good understanding, but of various dispositions of mind, feel different degrees of skepticism in the remedies they employ. One who possesses, with discernment, the largest portion of medical faith, will be undoubtedly of greatest benefit to his patients."
As Haygarth observed in his 1800 paper Of the Imagination as a Cause and as a Cure of Disorders of the Body, what really caused pain relief was the belief that patients were getting an apparently effective treatment. Haygarth concluded in his paper that his results showed "to a degree which has never been suspected, what powerful influence upon diseases is produced by mere imagination". While his research into the power of belief would be largely overlooked by medical historians (he is mainly remembered as a pioneer in smallpox inoculation), he is still the first physician to raise questions about the placebo effect which have haunted discussions of alternative medical treatments ever since.
At the same time that John Haygarth was making his groundbreaking observations on the power of positive belief in relieving pain, the influence of Franz Mesmer and his disciples was also being felt across Europe and North America. Despite attempts by skeptics such as Benjamin Franklin and Antoine Lavoisier to debunk Mesmer's work, mesmerists would ply their trade for decades afterward and physicians often had trouble understanding how they were accomplishing their apparently miraculous cures.
Along with mesmerism, the early 19th century was also seeing a rise of interest in homeopathy. Based on the "like cures like" doctrine of Samuel Hahnemann, homeopathic practitioners began offering their treatments for various illnesses with only anecdotal evidence from satisfied patients to prove that it even worked. The first formal clinical trial to test the effectiveness of homeopathic medicine was carried out in Russia in 1832. Not coincidentally, it was also the first clinical trial to use a placebo in medical research. Tests comparing homeopathic medicine with placebo pills made of flour paste showed no real difference in medical effectiveness. After publishing these results, the term "placebo effect" became well-known to medical researchers across Europe and North America (though homeopathic medicine seems not to have been seriously derailed by the findings).
In another informal test of the placebo effect, French physician Albert Matthieu informed many of his tuberculosis patients at the Hopital Andral in Paris of a powerful new treatment for tuberculosis that had recently been discovered in Germany. This new treatment, which he dubbed "antiphymose" was supposed to yield wonderful results in people suffering from tuberculosis and the news quickly spread with patients demanding that the drug be tested on them. After a time, Matthieu began conducting clinical trials which the drug he had supposedly received from Germany. All patients receiving antiphymose injections were carefully tested on a regular basis to see if their weight and temperature changed as a result of the new treatment.
According to the results, antiphymose had a powerful effect on tuberculosis patients receiving the injections. Not only did the patients gain weight but their chronic fever was reduced as well. Some gained as much as three kilograms of weight while other symptoms such as persistent coughing and insomnia improved as well. When the antiphymose injections stopped, the old symptoms returned as well and patients quickly lost the weight they had gained before. Only afterward did Matthieu reveal that there was no such treatment as antiphymose. What they had received was simply sterilized water and saline. The record fails to record how the patients responded to being deceived, even in a good cause.
While the placebo effect is an acknowledged part of modern medicine (and the driving force behind most alternative medical treatments), the power of the placebo continues to influence how many patients respond to treatment. As patients and doctors alike believe that a treatment will work, patients tend to recover faster than they might do otherwise. When a newer (and more expensive) drug comes out however, the drug it replaces often performs less well in research because doctors are less confident in how it will help patients. Research has shown that simply changing the size and colour of a pill can be enough to change its apparent effectiveness.
But how exactly does the placebo effect work? Research into using placebos for pain suggests that increased endorphin levels and reduced cholecystokinin production in the brain may lead to placebo-induced pain relief. A 1978 study showed that the opioid antagonist naloxone can block endorphins and prevent the placebo effect from occurring. These results only appear to apply to pain relief however.
But, the power of belief can also play a role in worsening symptoms as well. Much like the placebo effect, nocebos (coming from the Latin phrase for "I will harm") can have a powerful effect on health by making many medical conditions worse and may even play a role in "voodoo deaths" linked to curses. Various proposed explanations for the placebo (and nocebo) effect include suggestion, operant and classical conditioning, cognitive dissonance, the Hawthorne effect, and expectancy effects though they are all largely based on speculation. All that we can say for certain is that the exact mechanism for the placebo and nocebo effects are (still) unknown.
Is there such a thing as a placebo-responder personality? While some researchers have attempted to link patient responding to placebos to suggestibility or other personality traits, the results have been largely inconclusive. In studies observing how subjects respond to placebos over multiple trials, no consistent pattern has been identified. In other words, the same subjects who respond to placebos in one trial may not respond in later trials or vice versa. It is also difficult to decide exactly what the placebo effect can affect. Though most research into placebo use focuses on pain relief, some studies suggest that belief in placebos can accomplish much more, including relieving swelling and changing serum cortisol levels. The extent to which the placebo effect can relieve symptoms can range from no effect at all to total relief in some cases.
In identifying the different factors that can make placebos effective, researchers have identified the following:
- The nature of the intervention - the more intrusive the intervention, the more effective the placebo effect seems to be. "Sham surgery" (skin incisions without an actual operation) seems to be at least partially effective in relieving symptoms for most patients receiving it. Placebo injections also appear more effective than placebo pills with the more discomfort associated with the sham treatment, the better. Treatments that are more "exotic", i.e., involving complicated technology or a radical new medical technique also seems to increase the effectiveness of the placebo.
- The credibility of the one providing the treatment - Doctors with a high degree of status showing strong belief in their treatment are more likely to have a positive effect on their patients. Also, therapists showing warmth and empathy to their patients will get better results on average.
- Patient expectation - If the patient is involved in the treatment and has developed a sense of trust in the doctor and the treatment being received, the placebo effect is likely to be stronger.
- The nature of the complaint - Though most placebo research has focused on pain relief, a wide range of other symptoms appear to be affected by belief as well. Biofeedback research suggests that many physiological functions can be consciously controlled although it is still unknown whether some complaints or disorders may be more "placebo prone" than others.
- The treatment setting - A 1994 clinical study found that therapeutic setting was the only significant predictor for nocebo effects, i.e., patients in some clinical centres were more likely to experience adverse reactions to a placebo than patients in other centres. This suggests that even the location where treatment is received may play a role in whether the placebo effect occurs.
It is also important to understand that simply observing patients improving after taking a placebo cannot be considered evidence for a placebo effect at work. According to Edward Ernst and his colleagues, evidence for a "true placebo effect" needs to rule out other factors that might be contributing to patients getting better. This can include natural recovery from illness, regression towards the mean, patient bias, or other time-related factors that researchers failed to take into account. In other words, simply seeing a patient improve does not mean that a placebo effect is occurring although this "perceived placebo effect" is often confused with the real effect. To make medical research even more complicated, proving that a treatment is really effective means showing that the positive benefits are greater than what could be accounted for by the true and perceived placebo effects.
In a real sense, the placebo effect is a part of all medical treatments, whether intended or not. Many of the factors that make the placebo effect more powerful are also used by caring health professionals to reassure patients and make them more confident that the treatment will be effective. That same confidence also plays a role in the perceived benefits that patients being treated with alternative medicine often experience and which, in turn, are taken as "proof" of their effectiveness. Virtually every practitioner of alternative medicine can produce anecdotes provided by apparently grateful clients. Though these glowing anecdotes can seem convincing to people desperate for a cure, there are always limits to what can be accomplished by belief alone.
While there are certainly colourful stories of the placebo effect at work, relying on placebos to treat patients often invokes a critical problem in medical ethics. Is it permissible for doctors to lie to their patients, even in a good cause? And can practitioners of alternative medicine be considered to be providing a valuable service to patients if the placebo effect makes the treatment more effective than it might otherwise be?
There are still too many unanswered questions about how and why placebos work despite the enormous amount of research that has been done to date. Though the placebo effect has a long and venerable history, it remains a mystery in many ways. And perhaps it always will be.
