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Words to the wise: 4 secrets of successful pharmacotherapy
The therapeutic success of any medication depends on the interaction between its specific biochemical effects and nonspecific factors.1 Therefore, clinical trial designers may view the placebo effect as undesirable, but it can be a valuable response that improves outcomes in medical practice. As Freud stated: “Expectation colored by hope and faith is an effective force with which we have to reckon…in all our attempts at treatment and cure.”2
This article describes how experienced clinicians make use of the placebo effect and three other powerful, nonspecific elements of successful pharmacotherapy.
Any effect attributable to a pill or potion that does not originate from its specific pharmaceutical properties is known as the placebo effect.3 Its clinical value has been trivialized, in part because of misconceptions (TABLE 1). For example, the placebo effect is commonly believed to be short-lived; in fact, it can last a long time.4
In practice, our goal is to enhance the placebo effect to maximize a desirable therapeutic outcome (TABLE 2).5 Therefore, before I prescribe a medication, I tell my patient that I have selected a particular medication because I have had good results with it in many other patients and I believe it will work well for her, too.
Too often, physicians feel pessimistic about a medication’s potential therapeutic result, and communicate that pessimism. What the patient hears is: “There’s nothing else I can do for you; why not try this medication, even though I don’t believe it’s going to work.” This may create a negative placebo effect6—termed the “nocebo” effect— which gives the patient a negative expectation about the treatment’s outcome. The patient internalizes the physician’s statement and belief, and lives out this negative expectation.
TABLE 1
Correcting misconceptions about the placebo effect4
| Misconception | What the evidence shows |
|---|---|
| Placebo effects are short-lived | The placebo effect has been documented to last for a long time |
| Only complaints of psychological origin respond to placebo | Changes after placebo have been documented for most symptoms, including those originating from somatic disease |
| Placebo responders and nonresponders are distinctly different | There is no difference between placebo responders and nonresponders |
| The placebo effect is only about one third of the total therapeutic effect | The placebo effect can be as much as 100% of the total therapeutic effect |
| Only about one third of the population responds to placebo | The placebo response is context-dependent, and may include more than 90% of the patient population |
Strategies to enhance the placebo effect5
| Develop a sustained therapeutic partnership with the patient |
| Listen effectively and verify that she feels listened to |
| Provide comprehensible explanations of health problems therapeutically tailored to her needs and personality style |
| Show empathy, care, and concern for her as a person |
| Enhance her sense of control and mastery over her predicament |
CASE 1: Predicting positive results
Mrs. A. J. is a 38-year-old mother of two. She has symptoms of anxiety and depression, crying spells, poor appetite, and insomnia.
After taking a detailed history and examination, I recommend treatment with a combination of counseling and the antidepressant mirtazapine. I tell Mrs. A. J. that this medication has very good potential to help her recover. I also inform her that improved sleep and appetite may well be the first effects she’ll experience—even accompanied by restored hope and optimism. I then give her an appointment for the following week.
When Mrs. A. J. comes for the follow-up appointment, she reports improvement in appetite, sleep, and mood—as predicted.
Even though studies of antidepressants rarely show mood improvement within the first 7 days, it is not unusual to hear patients report feeling less depressed within days after they start a new antidepressant. The drug’s specific chemical effects on the brain may not be sufficient to explain this phenomenon; the explanation for such improvement probably lies in nonspecific effects, such as the patient expecting that this medication will make her feel better. The placebo effect can occur as soon as a patient starts a medication. Experienced clinicians understand the placebo effect’s power and harness it for their patients.
Conditioned responses
Many biologic responses can be associated with visual, auditory, tactile, olfactory, and gustatory stimuli. Nonconditioned physiologic responses paired with conditioned stimuli induce the same biologic effects as a drug. Evidence supporting this phenomenon includes successful conditioning of the immune system.7-10 Conditioned responses—as demonstrated in glycemia regulation10 and with psychopharmacology11—also can enhance the desirable results of pharmacotherapy.
CASE 2: A soothing drink
Ms. L. G. is a 24-year-old single college student who complains of irritability, short temper, and anxiety associated with obsessive worries about her health and her studies. Her symptoms become significantly worse before her menstrual period. Repeated diagnostic workups and pelvic examinations by her ObGyn have all been unremarkable.
At the beginning of this visit, Ms. L. G. is short of breath and looks anxious and worried. The nurse offers her a cup of tea; she asks for water instead, and is asked to bring it into the consultation-therapy room.
After a comprehensive interview and mental status examination, I recommend treatment with a combination of cognitive behavior therapy (CBT) and medication. Considering Ms. L. G.’s history of treatment with other medications, we agree to start treatment with sertraline. We review the potential benefits and therapeutic expectations of alleviating her symptoms of anxiety and obsessive worries. She is also told that she can expect an improvement in mood.
I then give her a sample of 50-mg sertraline and ask her to take it right there in the office, sipping from the glass of water. As she swallows, I compliment her on her wise decision to start treatment. She thanks me for being attentive to her needs. She is instructed to call me in 1 week, even if she feels better, and report changes in her condition.
Seven days later, Ms. L. G. calls to report significant improvement in her symptoms. She reports no side effects.
Often, patients come to my office feeling thirsty. My staff or I offer them a glass of water or a cup of tea. As patients sip, they swallow and incorporate the liquid into their body. At the same time, I use verbal interventions to make them feel listened to and understood. They internalize this emotional experience in connection with swallowing the liquid.
Later, when swallowing the new medication as instructed, the patient again experiences the positive therapeutic effect that was internalized in the physician’s office.
The power of suggestion
It has been shown that the power of suggestion can positively—or negatively—affect treatment outcome.12,13 In practice, most clinicians give unintentional suggestions by how and what they communicate to the patient.
We make predictions about the patient’s disease in terms of progress, severity of symptoms, and expected treatment outcomes, including possible side effects. The patient consciously and subconsciously internalizes these predictions, and then exhibits the outcome predicted by the medical expert. This is compatible with Watzlawick’s principle that the prediction of an event may lead to events fulfilling the prediction.14 In practice, be aware of the power in your words and body language and learn to use them wisely to enhance the positive outcome of pharmacotherapy.
CASE 3: Predicting improvement
Mrs. J. C., 48 years old, has had premenstrual dysphoric disorder (PMDD) and fibromyalgia for many years. She describes to me how specialists have tried to alleviate her depression and chronic pain. Follow-up questioning reveals that, whenever she received a new prescription, the physician would alert her to all the possible side effects and instruct her to call the office if she developed a problem with the new medication.
Invariably, Mrs. J. C. would call as instructed and describe side effects she developed with the new medication. Often, the physician would discontinue the medication, depriving her of benefits she might have obtained later.
My approach is different. Although I answer all of Mrs. J. C.’s questions about potential side effects, I also emphasize this prescription’s potential benefits—improved sleep, appetite, thoughts, and mood. I tell her she may experience improved sleep before improved mood. I then make a request: “Promise to call me by Tuesday next week, even if you begin to feel better?”
When Mrs. J. C. calls to report her status, she mentions that she is sleeping better and has begun to feel better during the day.
This vignette illustrates the importance of suggesting to the patient a positive outcome of pharmacotherapy associated with a particular action (calling the physician’s office to report results). When the patient promised to call, she internalized the suggestion that calling would be associated with feeling better—and that is what happened. Contrast that with saying to her: “Call me if you have a problem with any of these side effects,” which gives her a suggestion to report a problem.
The suggestion effect also can be used to reframe a predictable side effect as a positive sign that indicates the beginning of change leading to recovery (see “Using suggestion to reframe initial side effects as positive signs”).
Ms. M. K. is 34 years old and unmarried. She suffers chronic tension headaches associated with anxiety, depression, and insomnia. Numerous diagnostic workups have been negative.
After taking a detailed history, I decide to prescribe amitriptyline. I tell Ms. M. K. about this medication’s potential benefits and side effects, including the common one of dry mouth, which often occurs before a patient experiences a therapeutic effect. I tell Ms. M .K. that dry mouth will be a sign for her that the medication has begun to work, and the beneficial effect will soon follow. I instruct her to call my office and report when the sensation of dry mouth has begun.
In pharmacotherapy, side effects may appear before patients experience a medication’s beneficial or therapeutic effects. Patients’ initial experience often determines whether or not they will continue taking a prescribed medication. I know that Ms. M. K. may stop taking amitriptyline—as she has done with other medications—if she has uncomfortable side effects at the outset.
Instructing a patient to expect a specific side effect (such as dry mouth with amitriptyline) and associating it with a future therapeutic benefit sets up a roadmap of expectations: She knows that her experience is compatible with the physician’s prediction. For Ms. M. K., I reframed the side effect as a positive sign that recovery has begun, with more positive changes to come.
Participatory pharmacotherapy
Many patients seek ownership in making decisions about their treatment and medications. In participatory pharmacotherapy, patients provide you with data and valuable information—family history, personal medical history, experience with treatment—and inform you about which medications worked best. You invite patients to predict how they see themselves getting better and into recovery.
Based on this information and your knowledge, training, and experience, you and the patient jointly create a treatment plan that includes tailored pharmacotherapy. The next case illustrates the use of participatory pharmacotherapy to enhance treatment.
CASE 4: All in the family
Mrs. B. R., age 52, suffers from diabetic polyneuropathy, with tingling, numbness, and pain in her legs, feet, and hands. These symptoms are associated with anxiety, sadness, and worry. A detailed history reveals that these symptoms persist even though her blood glucose level has been in the target range and she has already achieved her goal of weight control with proper diet and exercise.
Mrs. B. R. then reports to me that her cousin, who has the same diagnosis, recently started to take venlafaxine with very good results. She asks me if we can consider this medication as part of her treatment.
I compliment Mrs. B. R. for her knowledge of her condition and her cousin’s treatment results. She responds by elaborating on her readings about venlafaxine on the Web and how convinced she is that this medication will help her as it helped her cousin.
I also reassure Mrs. B. R. that, together, we will make decisions about what medications to use and what to avoid based on her experiences. Her input into this process of choosing the best medications for her is valuable and will also be considered in future situations. She smiles and thanks me for considering her suggestions.
Inviting patients to be partners in diagnosing their illness and formulating a treatment plan improves the likelihood of a successful therapeutic alliance; adherence with prescribed medication; and the best possible outcome of pharmacotherapy.
Not all patients are candidates for participatory pharmacotherapy (TABLE 3), but many respond well. Avoid medications that the patient has already found unhelpful, ineffective, or associated with intolerable side effects. If possible, choose medications that the patient associates with a positive experience or expectation, based on family and personal history.
In patients with a defiant-oppositional personality, consider framing the treatment decision as a choice between two equally efficacious medications. This gives the patient the sense of control in choosing her medication, which is jointly monitored.
Related resources See Dr. Torem’s accompanying reading list
TABLE 3
Choosing patients for participatory pharmacotherapy
| Good candidates | Exclusionary qualities |
|---|---|
| Adults | Children, adolescents, and prison inmates |
| No history of alcoholism or drug addiction | Alcohol dependence or drug addiction |
| Average or above-average intelligence | Below-average intelligence |
| Intact cognitive function | Cognitive deficits, such as dementia |
| Not psychotic | Actively psychotic |
| Good comprehension of diagnosis and treatment | Poor comprehension of diagnosis and treatment |
| Therapeutic alliance is present | Therapeutic alliance is absent |
| Personality style or disorder with a need to be in control of treatment, such as obsessive–compulsive personality | Passive, dependent personality style or disorder (these patients may view a participatory approach as reflecting the physician’s lack of confidence) |
Benedetti F. Placebo Effects: Understanding the Mechanisms in Health and Disease. New York, NY: Oxford University Press; 2009.
Brody H. The Placebo Response: How You Can Release the Body’s Inner Pharmacy for Better Health. New York, NY: HarperCollins Publishers; 2000.
Ernst E. Placebo: new insights into an old enigma. Drug Discov Today. 2007;12:413–418.
Kradin R. The Placebo Response and the Power of Unconscious Healing. New York, NY: Routledge, Taylor & Francis Group; 2008.
Raz A, Raikhel E, Anbar RD. Placebos in medicine: knowledge, beliefs, and patterns of use. McGill J Med. 2008;11:206–211.
Spiro H. The Power of Hope: A Doctor’s Perspective. New Haven, Conn: Yale University Press; 1998.
Thompson WG. The Placebo Effect and Health: Combining Science & Compassionate Care. Amherst, NY: Prometheus Books; 2005.
Torem MS. Hypnotherapeutic techniques in the treatment of hyperemesis gravidarum. Am J Clin Hypn. 1994;37:1–11.
Torem MS. Psychopharmacology for office gynecology. In: Curtis MG, Hopkins MP, eds. Glass’s Office Gynecology. Baltimore, Md: Williams & Wilkins; 1999:519–548.
1. Frank JD, Frank JB. Persuasion and Healing. Baltimore, Md: The Johns Hopkins University Press; 1991.
2. Freud S. The Complete Psychological Works of Sigmund Freud. Strachey J, trans-ed. Toronto, Ontario, Canada: Hogarth Press; 1953.
3. Wolf S. The pharmacology of placebos. Pharmacol Rev. 1959;11:689-704.
4. Ernst E. Placebo: new insights into an old enigma. Drug Discov Today. 2007;12:413-418.
5. Brody H. The placebo response: recent research and implications for family medicine. J Fam Pract. 2000;49:649-654.
6. Spiegel H. Nocebo: the power of suggestibility. Prev Med. 1997;26(5 Pt 1):616-621.
7. Ader R, Cohen N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science. 1982;215:1534-1536.
8. Ader R. The role of conditioning in pharmacotherapy. In: Harrington A, ed. The Placebo Effect: An Interdisciplinary Exploration. Cambridge, Mass: Harvard University Press; 1997:138-165.
9. Olness K, Ader R. Conditioning as an adjunct in the pharmacotherapy of lupus erythematosus. J Dev Behav Pediatr. 1992;13:124-125.
10. Stockhorst U, Mahl N, Krueger M, et al. Classical conditioning and conditionability of insulin and glucose effect in healthy humans. Physiol Behav. 2004;81:375-388.
11. Wolf S. Effect of suggestion and conditioning on the action of chemical agents in human subjects—the pharmacology of placebos. J Clin Invest. 1950;29:100-109.
12. Lown B. The verbal conditioning of angina pectoris during exercise testing. Am J Cardiol. 1977;40:630-634.
13. Lown B. Introduction. In: Cousins N. The Healing Heart. New York, NY: W.W. Norton; 1983:11-28.
14. Watzlawick P. If you desire to see, learn how to act. In: Nardone G, Watzlawick P, eds. The Art of Change: Strategic Therapy and Hypnotherapy Without Trance. San Francisco, Calif: Jossey-Bass; 1993:1-16.
The therapeutic success of any medication depends on the interaction between its specific biochemical effects and nonspecific factors.1 Therefore, clinical trial designers may view the placebo effect as undesirable, but it can be a valuable response that improves outcomes in medical practice. As Freud stated: “Expectation colored by hope and faith is an effective force with which we have to reckon…in all our attempts at treatment and cure.”2
This article describes how experienced clinicians make use of the placebo effect and three other powerful, nonspecific elements of successful pharmacotherapy.
Any effect attributable to a pill or potion that does not originate from its specific pharmaceutical properties is known as the placebo effect.3 Its clinical value has been trivialized, in part because of misconceptions (TABLE 1). For example, the placebo effect is commonly believed to be short-lived; in fact, it can last a long time.4
In practice, our goal is to enhance the placebo effect to maximize a desirable therapeutic outcome (TABLE 2).5 Therefore, before I prescribe a medication, I tell my patient that I have selected a particular medication because I have had good results with it in many other patients and I believe it will work well for her, too.
Too often, physicians feel pessimistic about a medication’s potential therapeutic result, and communicate that pessimism. What the patient hears is: “There’s nothing else I can do for you; why not try this medication, even though I don’t believe it’s going to work.” This may create a negative placebo effect6—termed the “nocebo” effect— which gives the patient a negative expectation about the treatment’s outcome. The patient internalizes the physician’s statement and belief, and lives out this negative expectation.
TABLE 1
Correcting misconceptions about the placebo effect4
| Misconception | What the evidence shows |
|---|---|
| Placebo effects are short-lived | The placebo effect has been documented to last for a long time |
| Only complaints of psychological origin respond to placebo | Changes after placebo have been documented for most symptoms, including those originating from somatic disease |
| Placebo responders and nonresponders are distinctly different | There is no difference between placebo responders and nonresponders |
| The placebo effect is only about one third of the total therapeutic effect | The placebo effect can be as much as 100% of the total therapeutic effect |
| Only about one third of the population responds to placebo | The placebo response is context-dependent, and may include more than 90% of the patient population |
Strategies to enhance the placebo effect5
| Develop a sustained therapeutic partnership with the patient |
| Listen effectively and verify that she feels listened to |
| Provide comprehensible explanations of health problems therapeutically tailored to her needs and personality style |
| Show empathy, care, and concern for her as a person |
| Enhance her sense of control and mastery over her predicament |
CASE 1: Predicting positive results
Mrs. A. J. is a 38-year-old mother of two. She has symptoms of anxiety and depression, crying spells, poor appetite, and insomnia.
After taking a detailed history and examination, I recommend treatment with a combination of counseling and the antidepressant mirtazapine. I tell Mrs. A. J. that this medication has very good potential to help her recover. I also inform her that improved sleep and appetite may well be the first effects she’ll experience—even accompanied by restored hope and optimism. I then give her an appointment for the following week.
When Mrs. A. J. comes for the follow-up appointment, she reports improvement in appetite, sleep, and mood—as predicted.
Even though studies of antidepressants rarely show mood improvement within the first 7 days, it is not unusual to hear patients report feeling less depressed within days after they start a new antidepressant. The drug’s specific chemical effects on the brain may not be sufficient to explain this phenomenon; the explanation for such improvement probably lies in nonspecific effects, such as the patient expecting that this medication will make her feel better. The placebo effect can occur as soon as a patient starts a medication. Experienced clinicians understand the placebo effect’s power and harness it for their patients.
Conditioned responses
Many biologic responses can be associated with visual, auditory, tactile, olfactory, and gustatory stimuli. Nonconditioned physiologic responses paired with conditioned stimuli induce the same biologic effects as a drug. Evidence supporting this phenomenon includes successful conditioning of the immune system.7-10 Conditioned responses—as demonstrated in glycemia regulation10 and with psychopharmacology11—also can enhance the desirable results of pharmacotherapy.
CASE 2: A soothing drink
Ms. L. G. is a 24-year-old single college student who complains of irritability, short temper, and anxiety associated with obsessive worries about her health and her studies. Her symptoms become significantly worse before her menstrual period. Repeated diagnostic workups and pelvic examinations by her ObGyn have all been unremarkable.
At the beginning of this visit, Ms. L. G. is short of breath and looks anxious and worried. The nurse offers her a cup of tea; she asks for water instead, and is asked to bring it into the consultation-therapy room.
After a comprehensive interview and mental status examination, I recommend treatment with a combination of cognitive behavior therapy (CBT) and medication. Considering Ms. L. G.’s history of treatment with other medications, we agree to start treatment with sertraline. We review the potential benefits and therapeutic expectations of alleviating her symptoms of anxiety and obsessive worries. She is also told that she can expect an improvement in mood.
I then give her a sample of 50-mg sertraline and ask her to take it right there in the office, sipping from the glass of water. As she swallows, I compliment her on her wise decision to start treatment. She thanks me for being attentive to her needs. She is instructed to call me in 1 week, even if she feels better, and report changes in her condition.
Seven days later, Ms. L. G. calls to report significant improvement in her symptoms. She reports no side effects.
Often, patients come to my office feeling thirsty. My staff or I offer them a glass of water or a cup of tea. As patients sip, they swallow and incorporate the liquid into their body. At the same time, I use verbal interventions to make them feel listened to and understood. They internalize this emotional experience in connection with swallowing the liquid.
Later, when swallowing the new medication as instructed, the patient again experiences the positive therapeutic effect that was internalized in the physician’s office.
The power of suggestion
It has been shown that the power of suggestion can positively—or negatively—affect treatment outcome.12,13 In practice, most clinicians give unintentional suggestions by how and what they communicate to the patient.
We make predictions about the patient’s disease in terms of progress, severity of symptoms, and expected treatment outcomes, including possible side effects. The patient consciously and subconsciously internalizes these predictions, and then exhibits the outcome predicted by the medical expert. This is compatible with Watzlawick’s principle that the prediction of an event may lead to events fulfilling the prediction.14 In practice, be aware of the power in your words and body language and learn to use them wisely to enhance the positive outcome of pharmacotherapy.
CASE 3: Predicting improvement
Mrs. J. C., 48 years old, has had premenstrual dysphoric disorder (PMDD) and fibromyalgia for many years. She describes to me how specialists have tried to alleviate her depression and chronic pain. Follow-up questioning reveals that, whenever she received a new prescription, the physician would alert her to all the possible side effects and instruct her to call the office if she developed a problem with the new medication.
Invariably, Mrs. J. C. would call as instructed and describe side effects she developed with the new medication. Often, the physician would discontinue the medication, depriving her of benefits she might have obtained later.
My approach is different. Although I answer all of Mrs. J. C.’s questions about potential side effects, I also emphasize this prescription’s potential benefits—improved sleep, appetite, thoughts, and mood. I tell her she may experience improved sleep before improved mood. I then make a request: “Promise to call me by Tuesday next week, even if you begin to feel better?”
When Mrs. J. C. calls to report her status, she mentions that she is sleeping better and has begun to feel better during the day.
This vignette illustrates the importance of suggesting to the patient a positive outcome of pharmacotherapy associated with a particular action (calling the physician’s office to report results). When the patient promised to call, she internalized the suggestion that calling would be associated with feeling better—and that is what happened. Contrast that with saying to her: “Call me if you have a problem with any of these side effects,” which gives her a suggestion to report a problem.
The suggestion effect also can be used to reframe a predictable side effect as a positive sign that indicates the beginning of change leading to recovery (see “Using suggestion to reframe initial side effects as positive signs”).
Ms. M. K. is 34 years old and unmarried. She suffers chronic tension headaches associated with anxiety, depression, and insomnia. Numerous diagnostic workups have been negative.
After taking a detailed history, I decide to prescribe amitriptyline. I tell Ms. M. K. about this medication’s potential benefits and side effects, including the common one of dry mouth, which often occurs before a patient experiences a therapeutic effect. I tell Ms. M .K. that dry mouth will be a sign for her that the medication has begun to work, and the beneficial effect will soon follow. I instruct her to call my office and report when the sensation of dry mouth has begun.
In pharmacotherapy, side effects may appear before patients experience a medication’s beneficial or therapeutic effects. Patients’ initial experience often determines whether or not they will continue taking a prescribed medication. I know that Ms. M. K. may stop taking amitriptyline—as she has done with other medications—if she has uncomfortable side effects at the outset.
Instructing a patient to expect a specific side effect (such as dry mouth with amitriptyline) and associating it with a future therapeutic benefit sets up a roadmap of expectations: She knows that her experience is compatible with the physician’s prediction. For Ms. M. K., I reframed the side effect as a positive sign that recovery has begun, with more positive changes to come.
Participatory pharmacotherapy
Many patients seek ownership in making decisions about their treatment and medications. In participatory pharmacotherapy, patients provide you with data and valuable information—family history, personal medical history, experience with treatment—and inform you about which medications worked best. You invite patients to predict how they see themselves getting better and into recovery.
Based on this information and your knowledge, training, and experience, you and the patient jointly create a treatment plan that includes tailored pharmacotherapy. The next case illustrates the use of participatory pharmacotherapy to enhance treatment.
CASE 4: All in the family
Mrs. B. R., age 52, suffers from diabetic polyneuropathy, with tingling, numbness, and pain in her legs, feet, and hands. These symptoms are associated with anxiety, sadness, and worry. A detailed history reveals that these symptoms persist even though her blood glucose level has been in the target range and she has already achieved her goal of weight control with proper diet and exercise.
Mrs. B. R. then reports to me that her cousin, who has the same diagnosis, recently started to take venlafaxine with very good results. She asks me if we can consider this medication as part of her treatment.
I compliment Mrs. B. R. for her knowledge of her condition and her cousin’s treatment results. She responds by elaborating on her readings about venlafaxine on the Web and how convinced she is that this medication will help her as it helped her cousin.
I also reassure Mrs. B. R. that, together, we will make decisions about what medications to use and what to avoid based on her experiences. Her input into this process of choosing the best medications for her is valuable and will also be considered in future situations. She smiles and thanks me for considering her suggestions.
Inviting patients to be partners in diagnosing their illness and formulating a treatment plan improves the likelihood of a successful therapeutic alliance; adherence with prescribed medication; and the best possible outcome of pharmacotherapy.
Not all patients are candidates for participatory pharmacotherapy (TABLE 3), but many respond well. Avoid medications that the patient has already found unhelpful, ineffective, or associated with intolerable side effects. If possible, choose medications that the patient associates with a positive experience or expectation, based on family and personal history.
In patients with a defiant-oppositional personality, consider framing the treatment decision as a choice between two equally efficacious medications. This gives the patient the sense of control in choosing her medication, which is jointly monitored.
Related resources See Dr. Torem’s accompanying reading list
TABLE 3
Choosing patients for participatory pharmacotherapy
| Good candidates | Exclusionary qualities |
|---|---|
| Adults | Children, adolescents, and prison inmates |
| No history of alcoholism or drug addiction | Alcohol dependence or drug addiction |
| Average or above-average intelligence | Below-average intelligence |
| Intact cognitive function | Cognitive deficits, such as dementia |
| Not psychotic | Actively psychotic |
| Good comprehension of diagnosis and treatment | Poor comprehension of diagnosis and treatment |
| Therapeutic alliance is present | Therapeutic alliance is absent |
| Personality style or disorder with a need to be in control of treatment, such as obsessive–compulsive personality | Passive, dependent personality style or disorder (these patients may view a participatory approach as reflecting the physician’s lack of confidence) |
Benedetti F. Placebo Effects: Understanding the Mechanisms in Health and Disease. New York, NY: Oxford University Press; 2009.
Brody H. The Placebo Response: How You Can Release the Body’s Inner Pharmacy for Better Health. New York, NY: HarperCollins Publishers; 2000.
Ernst E. Placebo: new insights into an old enigma. Drug Discov Today. 2007;12:413–418.
Kradin R. The Placebo Response and the Power of Unconscious Healing. New York, NY: Routledge, Taylor & Francis Group; 2008.
Raz A, Raikhel E, Anbar RD. Placebos in medicine: knowledge, beliefs, and patterns of use. McGill J Med. 2008;11:206–211.
Spiro H. The Power of Hope: A Doctor’s Perspective. New Haven, Conn: Yale University Press; 1998.
Thompson WG. The Placebo Effect and Health: Combining Science & Compassionate Care. Amherst, NY: Prometheus Books; 2005.
Torem MS. Hypnotherapeutic techniques in the treatment of hyperemesis gravidarum. Am J Clin Hypn. 1994;37:1–11.
Torem MS. Psychopharmacology for office gynecology. In: Curtis MG, Hopkins MP, eds. Glass’s Office Gynecology. Baltimore, Md: Williams & Wilkins; 1999:519–548.
The therapeutic success of any medication depends on the interaction between its specific biochemical effects and nonspecific factors.1 Therefore, clinical trial designers may view the placebo effect as undesirable, but it can be a valuable response that improves outcomes in medical practice. As Freud stated: “Expectation colored by hope and faith is an effective force with which we have to reckon…in all our attempts at treatment and cure.”2
This article describes how experienced clinicians make use of the placebo effect and three other powerful, nonspecific elements of successful pharmacotherapy.
Any effect attributable to a pill or potion that does not originate from its specific pharmaceutical properties is known as the placebo effect.3 Its clinical value has been trivialized, in part because of misconceptions (TABLE 1). For example, the placebo effect is commonly believed to be short-lived; in fact, it can last a long time.4
In practice, our goal is to enhance the placebo effect to maximize a desirable therapeutic outcome (TABLE 2).5 Therefore, before I prescribe a medication, I tell my patient that I have selected a particular medication because I have had good results with it in many other patients and I believe it will work well for her, too.
Too often, physicians feel pessimistic about a medication’s potential therapeutic result, and communicate that pessimism. What the patient hears is: “There’s nothing else I can do for you; why not try this medication, even though I don’t believe it’s going to work.” This may create a negative placebo effect6—termed the “nocebo” effect— which gives the patient a negative expectation about the treatment’s outcome. The patient internalizes the physician’s statement and belief, and lives out this negative expectation.
TABLE 1
Correcting misconceptions about the placebo effect4
| Misconception | What the evidence shows |
|---|---|
| Placebo effects are short-lived | The placebo effect has been documented to last for a long time |
| Only complaints of psychological origin respond to placebo | Changes after placebo have been documented for most symptoms, including those originating from somatic disease |
| Placebo responders and nonresponders are distinctly different | There is no difference between placebo responders and nonresponders |
| The placebo effect is only about one third of the total therapeutic effect | The placebo effect can be as much as 100% of the total therapeutic effect |
| Only about one third of the population responds to placebo | The placebo response is context-dependent, and may include more than 90% of the patient population |
Strategies to enhance the placebo effect5
| Develop a sustained therapeutic partnership with the patient |
| Listen effectively and verify that she feels listened to |
| Provide comprehensible explanations of health problems therapeutically tailored to her needs and personality style |
| Show empathy, care, and concern for her as a person |
| Enhance her sense of control and mastery over her predicament |
CASE 1: Predicting positive results
Mrs. A. J. is a 38-year-old mother of two. She has symptoms of anxiety and depression, crying spells, poor appetite, and insomnia.
After taking a detailed history and examination, I recommend treatment with a combination of counseling and the antidepressant mirtazapine. I tell Mrs. A. J. that this medication has very good potential to help her recover. I also inform her that improved sleep and appetite may well be the first effects she’ll experience—even accompanied by restored hope and optimism. I then give her an appointment for the following week.
When Mrs. A. J. comes for the follow-up appointment, she reports improvement in appetite, sleep, and mood—as predicted.
Even though studies of antidepressants rarely show mood improvement within the first 7 days, it is not unusual to hear patients report feeling less depressed within days after they start a new antidepressant. The drug’s specific chemical effects on the brain may not be sufficient to explain this phenomenon; the explanation for such improvement probably lies in nonspecific effects, such as the patient expecting that this medication will make her feel better. The placebo effect can occur as soon as a patient starts a medication. Experienced clinicians understand the placebo effect’s power and harness it for their patients.
Conditioned responses
Many biologic responses can be associated with visual, auditory, tactile, olfactory, and gustatory stimuli. Nonconditioned physiologic responses paired with conditioned stimuli induce the same biologic effects as a drug. Evidence supporting this phenomenon includes successful conditioning of the immune system.7-10 Conditioned responses—as demonstrated in glycemia regulation10 and with psychopharmacology11—also can enhance the desirable results of pharmacotherapy.
CASE 2: A soothing drink
Ms. L. G. is a 24-year-old single college student who complains of irritability, short temper, and anxiety associated with obsessive worries about her health and her studies. Her symptoms become significantly worse before her menstrual period. Repeated diagnostic workups and pelvic examinations by her ObGyn have all been unremarkable.
At the beginning of this visit, Ms. L. G. is short of breath and looks anxious and worried. The nurse offers her a cup of tea; she asks for water instead, and is asked to bring it into the consultation-therapy room.
After a comprehensive interview and mental status examination, I recommend treatment with a combination of cognitive behavior therapy (CBT) and medication. Considering Ms. L. G.’s history of treatment with other medications, we agree to start treatment with sertraline. We review the potential benefits and therapeutic expectations of alleviating her symptoms of anxiety and obsessive worries. She is also told that she can expect an improvement in mood.
I then give her a sample of 50-mg sertraline and ask her to take it right there in the office, sipping from the glass of water. As she swallows, I compliment her on her wise decision to start treatment. She thanks me for being attentive to her needs. She is instructed to call me in 1 week, even if she feels better, and report changes in her condition.
Seven days later, Ms. L. G. calls to report significant improvement in her symptoms. She reports no side effects.
Often, patients come to my office feeling thirsty. My staff or I offer them a glass of water or a cup of tea. As patients sip, they swallow and incorporate the liquid into their body. At the same time, I use verbal interventions to make them feel listened to and understood. They internalize this emotional experience in connection with swallowing the liquid.
Later, when swallowing the new medication as instructed, the patient again experiences the positive therapeutic effect that was internalized in the physician’s office.
The power of suggestion
It has been shown that the power of suggestion can positively—or negatively—affect treatment outcome.12,13 In practice, most clinicians give unintentional suggestions by how and what they communicate to the patient.
We make predictions about the patient’s disease in terms of progress, severity of symptoms, and expected treatment outcomes, including possible side effects. The patient consciously and subconsciously internalizes these predictions, and then exhibits the outcome predicted by the medical expert. This is compatible with Watzlawick’s principle that the prediction of an event may lead to events fulfilling the prediction.14 In practice, be aware of the power in your words and body language and learn to use them wisely to enhance the positive outcome of pharmacotherapy.
CASE 3: Predicting improvement
Mrs. J. C., 48 years old, has had premenstrual dysphoric disorder (PMDD) and fibromyalgia for many years. She describes to me how specialists have tried to alleviate her depression and chronic pain. Follow-up questioning reveals that, whenever she received a new prescription, the physician would alert her to all the possible side effects and instruct her to call the office if she developed a problem with the new medication.
Invariably, Mrs. J. C. would call as instructed and describe side effects she developed with the new medication. Often, the physician would discontinue the medication, depriving her of benefits she might have obtained later.
My approach is different. Although I answer all of Mrs. J. C.’s questions about potential side effects, I also emphasize this prescription’s potential benefits—improved sleep, appetite, thoughts, and mood. I tell her she may experience improved sleep before improved mood. I then make a request: “Promise to call me by Tuesday next week, even if you begin to feel better?”
When Mrs. J. C. calls to report her status, she mentions that she is sleeping better and has begun to feel better during the day.
This vignette illustrates the importance of suggesting to the patient a positive outcome of pharmacotherapy associated with a particular action (calling the physician’s office to report results). When the patient promised to call, she internalized the suggestion that calling would be associated with feeling better—and that is what happened. Contrast that with saying to her: “Call me if you have a problem with any of these side effects,” which gives her a suggestion to report a problem.
The suggestion effect also can be used to reframe a predictable side effect as a positive sign that indicates the beginning of change leading to recovery (see “Using suggestion to reframe initial side effects as positive signs”).
Ms. M. K. is 34 years old and unmarried. She suffers chronic tension headaches associated with anxiety, depression, and insomnia. Numerous diagnostic workups have been negative.
After taking a detailed history, I decide to prescribe amitriptyline. I tell Ms. M. K. about this medication’s potential benefits and side effects, including the common one of dry mouth, which often occurs before a patient experiences a therapeutic effect. I tell Ms. M .K. that dry mouth will be a sign for her that the medication has begun to work, and the beneficial effect will soon follow. I instruct her to call my office and report when the sensation of dry mouth has begun.
In pharmacotherapy, side effects may appear before patients experience a medication’s beneficial or therapeutic effects. Patients’ initial experience often determines whether or not they will continue taking a prescribed medication. I know that Ms. M. K. may stop taking amitriptyline—as she has done with other medications—if she has uncomfortable side effects at the outset.
Instructing a patient to expect a specific side effect (such as dry mouth with amitriptyline) and associating it with a future therapeutic benefit sets up a roadmap of expectations: She knows that her experience is compatible with the physician’s prediction. For Ms. M. K., I reframed the side effect as a positive sign that recovery has begun, with more positive changes to come.
Participatory pharmacotherapy
Many patients seek ownership in making decisions about their treatment and medications. In participatory pharmacotherapy, patients provide you with data and valuable information—family history, personal medical history, experience with treatment—and inform you about which medications worked best. You invite patients to predict how they see themselves getting better and into recovery.
Based on this information and your knowledge, training, and experience, you and the patient jointly create a treatment plan that includes tailored pharmacotherapy. The next case illustrates the use of participatory pharmacotherapy to enhance treatment.
CASE 4: All in the family
Mrs. B. R., age 52, suffers from diabetic polyneuropathy, with tingling, numbness, and pain in her legs, feet, and hands. These symptoms are associated with anxiety, sadness, and worry. A detailed history reveals that these symptoms persist even though her blood glucose level has been in the target range and she has already achieved her goal of weight control with proper diet and exercise.
Mrs. B. R. then reports to me that her cousin, who has the same diagnosis, recently started to take venlafaxine with very good results. She asks me if we can consider this medication as part of her treatment.
I compliment Mrs. B. R. for her knowledge of her condition and her cousin’s treatment results. She responds by elaborating on her readings about venlafaxine on the Web and how convinced she is that this medication will help her as it helped her cousin.
I also reassure Mrs. B. R. that, together, we will make decisions about what medications to use and what to avoid based on her experiences. Her input into this process of choosing the best medications for her is valuable and will also be considered in future situations. She smiles and thanks me for considering her suggestions.
Inviting patients to be partners in diagnosing their illness and formulating a treatment plan improves the likelihood of a successful therapeutic alliance; adherence with prescribed medication; and the best possible outcome of pharmacotherapy.
Not all patients are candidates for participatory pharmacotherapy (TABLE 3), but many respond well. Avoid medications that the patient has already found unhelpful, ineffective, or associated with intolerable side effects. If possible, choose medications that the patient associates with a positive experience or expectation, based on family and personal history.
In patients with a defiant-oppositional personality, consider framing the treatment decision as a choice between two equally efficacious medications. This gives the patient the sense of control in choosing her medication, which is jointly monitored.
Related resources See Dr. Torem’s accompanying reading list
TABLE 3
Choosing patients for participatory pharmacotherapy
| Good candidates | Exclusionary qualities |
|---|---|
| Adults | Children, adolescents, and prison inmates |
| No history of alcoholism or drug addiction | Alcohol dependence or drug addiction |
| Average or above-average intelligence | Below-average intelligence |
| Intact cognitive function | Cognitive deficits, such as dementia |
| Not psychotic | Actively psychotic |
| Good comprehension of diagnosis and treatment | Poor comprehension of diagnosis and treatment |
| Therapeutic alliance is present | Therapeutic alliance is absent |
| Personality style or disorder with a need to be in control of treatment, such as obsessive–compulsive personality | Passive, dependent personality style or disorder (these patients may view a participatory approach as reflecting the physician’s lack of confidence) |
Benedetti F. Placebo Effects: Understanding the Mechanisms in Health and Disease. New York, NY: Oxford University Press; 2009.
Brody H. The Placebo Response: How You Can Release the Body’s Inner Pharmacy for Better Health. New York, NY: HarperCollins Publishers; 2000.
Ernst E. Placebo: new insights into an old enigma. Drug Discov Today. 2007;12:413–418.
Kradin R. The Placebo Response and the Power of Unconscious Healing. New York, NY: Routledge, Taylor & Francis Group; 2008.
Raz A, Raikhel E, Anbar RD. Placebos in medicine: knowledge, beliefs, and patterns of use. McGill J Med. 2008;11:206–211.
Spiro H. The Power of Hope: A Doctor’s Perspective. New Haven, Conn: Yale University Press; 1998.
Thompson WG. The Placebo Effect and Health: Combining Science & Compassionate Care. Amherst, NY: Prometheus Books; 2005.
Torem MS. Hypnotherapeutic techniques in the treatment of hyperemesis gravidarum. Am J Clin Hypn. 1994;37:1–11.
Torem MS. Psychopharmacology for office gynecology. In: Curtis MG, Hopkins MP, eds. Glass’s Office Gynecology. Baltimore, Md: Williams & Wilkins; 1999:519–548.
1. Frank JD, Frank JB. Persuasion and Healing. Baltimore, Md: The Johns Hopkins University Press; 1991.
2. Freud S. The Complete Psychological Works of Sigmund Freud. Strachey J, trans-ed. Toronto, Ontario, Canada: Hogarth Press; 1953.
3. Wolf S. The pharmacology of placebos. Pharmacol Rev. 1959;11:689-704.
4. Ernst E. Placebo: new insights into an old enigma. Drug Discov Today. 2007;12:413-418.
5. Brody H. The placebo response: recent research and implications for family medicine. J Fam Pract. 2000;49:649-654.
6. Spiegel H. Nocebo: the power of suggestibility. Prev Med. 1997;26(5 Pt 1):616-621.
7. Ader R, Cohen N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science. 1982;215:1534-1536.
8. Ader R. The role of conditioning in pharmacotherapy. In: Harrington A, ed. The Placebo Effect: An Interdisciplinary Exploration. Cambridge, Mass: Harvard University Press; 1997:138-165.
9. Olness K, Ader R. Conditioning as an adjunct in the pharmacotherapy of lupus erythematosus. J Dev Behav Pediatr. 1992;13:124-125.
10. Stockhorst U, Mahl N, Krueger M, et al. Classical conditioning and conditionability of insulin and glucose effect in healthy humans. Physiol Behav. 2004;81:375-388.
11. Wolf S. Effect of suggestion and conditioning on the action of chemical agents in human subjects—the pharmacology of placebos. J Clin Invest. 1950;29:100-109.
12. Lown B. The verbal conditioning of angina pectoris during exercise testing. Am J Cardiol. 1977;40:630-634.
13. Lown B. Introduction. In: Cousins N. The Healing Heart. New York, NY: W.W. Norton; 1983:11-28.
14. Watzlawick P. If you desire to see, learn how to act. In: Nardone G, Watzlawick P, eds. The Art of Change: Strategic Therapy and Hypnotherapy Without Trance. San Francisco, Calif: Jossey-Bass; 1993:1-16.
1. Frank JD, Frank JB. Persuasion and Healing. Baltimore, Md: The Johns Hopkins University Press; 1991.
2. Freud S. The Complete Psychological Works of Sigmund Freud. Strachey J, trans-ed. Toronto, Ontario, Canada: Hogarth Press; 1953.
3. Wolf S. The pharmacology of placebos. Pharmacol Rev. 1959;11:689-704.
4. Ernst E. Placebo: new insights into an old enigma. Drug Discov Today. 2007;12:413-418.
5. Brody H. The placebo response: recent research and implications for family medicine. J Fam Pract. 2000;49:649-654.
6. Spiegel H. Nocebo: the power of suggestibility. Prev Med. 1997;26(5 Pt 1):616-621.
7. Ader R, Cohen N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science. 1982;215:1534-1536.
8. Ader R. The role of conditioning in pharmacotherapy. In: Harrington A, ed. The Placebo Effect: An Interdisciplinary Exploration. Cambridge, Mass: Harvard University Press; 1997:138-165.
9. Olness K, Ader R. Conditioning as an adjunct in the pharmacotherapy of lupus erythematosus. J Dev Behav Pediatr. 1992;13:124-125.
10. Stockhorst U, Mahl N, Krueger M, et al. Classical conditioning and conditionability of insulin and glucose effect in healthy humans. Physiol Behav. 2004;81:375-388.
11. Wolf S. Effect of suggestion and conditioning on the action of chemical agents in human subjects—the pharmacology of placebos. J Clin Invest. 1950;29:100-109.
12. Lown B. The verbal conditioning of angina pectoris during exercise testing. Am J Cardiol. 1977;40:630-634.
13. Lown B. Introduction. In: Cousins N. The Healing Heart. New York, NY: W.W. Norton; 1983:11-28.
14. Watzlawick P. If you desire to see, learn how to act. In: Nardone G, Watzlawick P, eds. The Art of Change: Strategic Therapy and Hypnotherapy Without Trance. San Francisco, Calif: Jossey-Bass; 1993:1-16.
Words to the wise: 4 secrets of successful pharmacotherapy
Any medication’s therapeutic success depends on the interaction between its specific biochemical effects and nonspecific factors.1 Thus, clinical trial designers may view the placebo effect as undesirable, but it can be a valuable response that improves treatment outcomes in clinical practice. As Freud stated, “Expectation colored by hope and faith is an effective force with which we have to reckon…in all our attempts at treatment and cure.”2
This article describes how experienced clinicians make use of the placebo effect and 3 other powerful, nonspecific elements of successful pharmacotherapy.
The placebo effect
The placebo effect is any effect attributable to a pill or potion that does not originate from its specific pharmacologic properties.3 Its clinical value has been trivialized, in part because of misconceptions (Table 1). For example, the placebo effect is commonly believed to be short-lived, whereas in fact it can last a long time.4
In clinical practice, our goal is to enhance the placebo effect to maximize a desirable therapeutic outcome (Table 2).5 Therefore, before I prescribe a medication, I tell my patient that I have selected a particular medication because I have had good results with it in many other patients and I believe it will work well for him or her, too.
Too often, doctors feel pessimistic about a medication’s potential therapeutic result and communicate this pessimism. What the patient hears is, “There’s nothing else I can do for you; why not try this medication, even though I don’t believe it’s going to work.” This may create a negative placebo effect6—termed the “nocebo” effect—which gives the patient a negative expectation about the treatment’s outcome. The patient internalizes the doctor’s words and lives out this negative expectation.
Table 1
Correcting misconceptions about the placebo effect
| Misconception | What the evidence shows |
|---|---|
| Placebo effects are short-lived | The placebo effect has been documented to last for a long time |
| Only complaints that are psychologically originated respond to placebo | Changes after placebo have been documented for most symptoms, including those originating from somatic diseases |
| Placebo responders are distinctly different from nonresponders | There is no difference between placebo responders and nonresponders |
| The placebo effect is only about one-third of the total therapeutic effect | The placebo effect can be up to 100% of the total therapeutic effect |
| Only about one-third of the population responds to placebo | The placebo response is context-dependent and may include >90% of the patient population |
| Source: Reference 4 | |
Clinical strategies to enhance the placebo effect
| |
| Source: Reference 5 | |
CASE REPORT: Predicting positive results
Mr. B, age 42, has a history of recurrent depression associated with severe insomnia, poor appetite, significant weight loss, and psychosocial withdrawal with feelings of hopelessness. After I take a detailed history and do a mental status examination, I suggest that he be treated with cognitive-behavioral therapy (CBT) and mirtazapine.
Even though studies of antidepressants rarely show mood improvements within the first 7 days, it is not unusual to hear patients report feeling less depressed within days after they start a new antidepressant. Although the drug’s specific chemical effects on the brain may not be sufficient to explain this phenomenon, the explanation probably lies in nonspecific effects—such as the patient expecting that this medication will make him feel better.
The placebo effect can occur as soon as a patient starts a medication. Experienced clinicians understand the placebo effect’s power and harness it to benefit their patients.
Conditioned responses
Many biological responses can be associated with visual, auditory, tactile, olfactory, or gustatory stimuli. Nonconditioned physiologic responses paired with conditioned stimuli induce the same biological effects of a drug. Evidence supporting this phenomenon includes successful conditioning of the immune system.7-10 Conditioned responses—as demonstrated in glycemia regulation10 and with psychopharmacology11—also can enhance the desirable results of pharmacotherapy.
CASE REPORT: A soothing drink
Ms. L, a 22-year-old college student, suffers from obsessive-compulsive disorder associated with anxiety and depression. She arrives at the appointment hurried and worried that she might be late. She is short of breath and looks stressed. The nurse offers Ms. L a cup of tea or water. She chooses a glass of water and is asked to bring it into her session.
Following a comprehensive interview and mental status examination, I recommend CBT plus medication. Considering Ms. L’s medication history, we agree to start treatment with sertraline. We review its potential benefits and expectations that it will reduce her anxiety, alleviate her ruminating obsessive worries, and improve her mood. I give her a 50-mg sample and inform her that some patients experience positive effects soon after taking the medication. I then ask her to take the first pill, using her glass of water. She does so and thanks me for being attentive to her needs.
I instruct her to call within 1 week and report on her condition, even if she feels better. Seven days later she reports that she is feeling better and is looking forward to her next appointment. She reports no side effects.
Often patients come to my office feeling thirsty. My staff or I offer them a glass of water or a cup of tea. As patients sip from the cup, they swallow and incorporate the liquid into their bodies. At the same time, I use verbal interventions to make them feel listened to and understood. They internalize this emotional experience in connection with swallowing the liquid.
Later, when swallowing the new medication as instructed, the patient re-experiences the positive therapeutic effect that was internalized in the doctor’s office.
The power of suggestion
The power of suggestion has been shown to positively or negatively affect treatment outcomes.12,13 In practice, most clinicians give unintentional suggestions by how and what they communicate to the patient.
CASE REPORT: Predicting improvement
Mrs. J, age 48, has had dysthymic disorder and fibromyalgia for many years. She describes how various specialists have tried to alleviate her depression and chronic pain. Follow-up questions reveal that whenever she received a new prescription the physician would alert her to all the possible side effects and instruct her to call the office if she developed a problem with the new medication.
Invariably, Mrs. J would call as instructed and describe side effects she developed with the new medication. Often the doctor would discontinue the medication, depriving Mrs. J of benefits she might have derived later.
When Mrs. J calls to report on her status, she mentions that she is sleeping better and has begun to feel better during the day. She says that her husband told her she has started to smile again.
This vignette illustrates the importance of suggesting to the patient a positive outcome of pharmacotherapy associated with a particular action (calling the doctor’s office to report results). When the patient promised to call, she internalized the suggestion that calling would be associated with feeling better—and that is what happened. This intervention contrasts with saying to the patient, “Call me if you have a problem with any of these side effects,” which gives the patient a suggestion to call and report a problem.
The suggestion effect also can be used to reframe a predictable side effect as a positive sign that indicates the beginning of change leading to recovery (Box).
Ms. M, age 32 and single, has an anxiety disorder associated with bipolar depression. She has discontinued several psychotropics because of uncomfortable side effects, such as constipation.
After taking a detailed history, I decide to prescribe quetiapine. I tell Ms. M about this medication’s potential benefits and side effects. One common side effect is dry mouth, which often occurs before patients experience therapeutic effects.
I inform Ms. M that a dry mouth will be her sign that the medication has begun to work, and beneficial effects—such as improved sleep, reduced anxiety, and improved mood—will soon follow. I then instruct her to call my office and report when she experiences a dry mouth.
Discussion. In pharmacotherapy, side effects may appear before patients experience a medication’s beneficial/therapeutic effects. Patients’ initial experience often determines whether or not they will continue taking a prescribed medication. I know Ms. M may stop taking quetiapine—as she has done with other medications—if she initially has uncomfortable side effects.
Instructing patients to expect a specific side effect (such as a dry mouth with quetiapine) and associating it with a future therapeutic benefit sets up a road map of expectations. They know their experience is compatible with the doctor’s predictions. For Ms. M, I reframed the side effect as a positive sign that recovery has begun, with more positive changes to come.
Participatory pharmacotherapy
Many patients seek ownership in making decisions about their treatment and medications. In participatory pharmacotherapy, patients provide you with data and valuable information—such as family history, personal medical history, and experience with treatment—and inform you about which medications worked best and which did not work. You invite patients to predict how they see themselves getting better and into recovery.
CASE REPORT: All in the family
Mr. A, age 28 and single, has been diagnosed with a bipolar mood disorder. As part of a detailed family history, he reports that his maternal grandfather, mother, and a maternal uncle were diagnosed with mood swings and were successfully treated with medications, specifically lithium. He states that he believes he has the same condition.
I compliment Mr. A for being so well informed about his grandfather and uncle and educate him about mood stabilizers’ benefits in bipolar disorder. I tell him about the finding that if lithium has helped his relatives, it will probably help him as well.
I also reassure Mr. A that, in deciding what medications to avoid and what medications to use, I will consider his experience with specific antidepressants that did not help him. He thanks me for considering his suggestion about what medication to use for him.
- a successful therapeutic alliance
- adherence with prescribed medications
- the best possible outcome with pharmacotherapy.
In patients with a defiant-oppositional personality, consider framing the treatment decision as a choice between 2 equally efficacious medications. This gives the patient the sense of control in choosing his or her own medication, which is jointly monitored.
Table 3
Choosing patients for participatory pharmacotherapy
| Good candidates | Exclusionary qualities |
|---|---|
| Adults | Children, adolescents, and prison inmates |
| No history of alcoholism or drug addiction | Alcohol dependence or drug addiction |
| Average and above intelligence | Below-average intelligence |
| Intact cognitive function | Cognitive deficits, such as dementia |
| Not psychotic | Actively psychotic |
| Good comprehension of diagnosis and treatment | Poor comprehension of diagnosis and treatment |
| Therapeutic alliance is present | Therapeutic alliance is absent |
| Personality style or disorder with a need to be in control of treatment, such as obsessive-compulsive personality | Passive, dependent personality style or disorder; these patients may view a participatory approach as the doctor’s lack of confidence |
- Brody H. The placebo response: how you can release the body’s inner pharmacy for better health. New York, NY: HarperCollins Publishers; 2000.
- Spiro H. The power of hope: a doctor’s perspective. New Haven, CT: Yale University Press; 1998.
- Ernst E. Placebo: new insights into an old enigma. Drug Discov Today 2007;12:413-8.
- Lithium • Eskalith, Lithobid
- Mirtazapine • Remeron
- Quetiapine • Seroquel
- Sertraline • Zoloft
Dr. Torem reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Frank JD, Frank JB. Persuasion and healing. Baltimore, MD: The Johns Hopkins University Press; 1991.
2. Freud S. The complete psychological works of Sigmund Freud. Strachey J, trans-ed. Toronto, Ontario, Canada: Hogarth Press; 1953.
3. Wolf S. The pharmacology of placebos. Pharmacol Rev 1959;11:689-704.
4. Ernst E. Placebo: new insights into an old enigma. Drug Discov Today 2007;12:413-8.
5. Brody H. The placebo response: recent research and implications for family medicine. J Fam Pract 2000;49:649-54.
6. Spiegel H. Nocebo, the power of suggestibility. Prev Med 1997;26:616-21.
7. Ader R, Cohen N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 1982;215:1534-6.
8. Ader R. The role of conditioning in pharmacotherapy. In: Harrington A, ed. The placebo effect: an interdisciplinary exploration. Cambridge, MA: Harvard University Press; 1997;138-65.
9. Olness K, Ader R. Conditioning as an adjunct in the pharmacotherapy of lupus erythematosus. J Dev Behav Pediatr 1992;13:124-5.
10. Stockhorst U, Mahl N, Krueger M, et al. Classical conditioning and conditionability of insulin and glucose effect in healthy humans. Physiol Behav 2004;81:375-88.
11. Wolf S. Effect of suggestion and conditioning on the action of chemical agents in human subjects—the pharmacology of placebos. J Clin Invest 1950;29:100-9.
12. Lown B. The verbal conditioning of angina pectoris during exercise testing. Am J Cardiol 1977;40:630-4.
13. Lown B. Introduction. In: Cousins N. The healing heart. New York, NY: W.W. Norton; 1983:11-28.
14. Watzlawick P. If you desire to see, learn how to act. In: Nardone G, Watzlawick P, eds. The art of change San Francisco, CA: Jossey-Bass; 1993:1-16.
Any medication’s therapeutic success depends on the interaction between its specific biochemical effects and nonspecific factors.1 Thus, clinical trial designers may view the placebo effect as undesirable, but it can be a valuable response that improves treatment outcomes in clinical practice. As Freud stated, “Expectation colored by hope and faith is an effective force with which we have to reckon…in all our attempts at treatment and cure.”2
This article describes how experienced clinicians make use of the placebo effect and 3 other powerful, nonspecific elements of successful pharmacotherapy.
The placebo effect
The placebo effect is any effect attributable to a pill or potion that does not originate from its specific pharmacologic properties.3 Its clinical value has been trivialized, in part because of misconceptions (Table 1). For example, the placebo effect is commonly believed to be short-lived, whereas in fact it can last a long time.4
In clinical practice, our goal is to enhance the placebo effect to maximize a desirable therapeutic outcome (Table 2).5 Therefore, before I prescribe a medication, I tell my patient that I have selected a particular medication because I have had good results with it in many other patients and I believe it will work well for him or her, too.
Too often, doctors feel pessimistic about a medication’s potential therapeutic result and communicate this pessimism. What the patient hears is, “There’s nothing else I can do for you; why not try this medication, even though I don’t believe it’s going to work.” This may create a negative placebo effect6—termed the “nocebo” effect—which gives the patient a negative expectation about the treatment’s outcome. The patient internalizes the doctor’s words and lives out this negative expectation.
Table 1
Correcting misconceptions about the placebo effect
| Misconception | What the evidence shows |
|---|---|
| Placebo effects are short-lived | The placebo effect has been documented to last for a long time |
| Only complaints that are psychologically originated respond to placebo | Changes after placebo have been documented for most symptoms, including those originating from somatic diseases |
| Placebo responders are distinctly different from nonresponders | There is no difference between placebo responders and nonresponders |
| The placebo effect is only about one-third of the total therapeutic effect | The placebo effect can be up to 100% of the total therapeutic effect |
| Only about one-third of the population responds to placebo | The placebo response is context-dependent and may include >90% of the patient population |
| Source: Reference 4 | |
Clinical strategies to enhance the placebo effect
| |
| Source: Reference 5 | |
CASE REPORT: Predicting positive results
Mr. B, age 42, has a history of recurrent depression associated with severe insomnia, poor appetite, significant weight loss, and psychosocial withdrawal with feelings of hopelessness. After I take a detailed history and do a mental status examination, I suggest that he be treated with cognitive-behavioral therapy (CBT) and mirtazapine.
Even though studies of antidepressants rarely show mood improvements within the first 7 days, it is not unusual to hear patients report feeling less depressed within days after they start a new antidepressant. Although the drug’s specific chemical effects on the brain may not be sufficient to explain this phenomenon, the explanation probably lies in nonspecific effects—such as the patient expecting that this medication will make him feel better.
The placebo effect can occur as soon as a patient starts a medication. Experienced clinicians understand the placebo effect’s power and harness it to benefit their patients.
Conditioned responses
Many biological responses can be associated with visual, auditory, tactile, olfactory, or gustatory stimuli. Nonconditioned physiologic responses paired with conditioned stimuli induce the same biological effects of a drug. Evidence supporting this phenomenon includes successful conditioning of the immune system.7-10 Conditioned responses—as demonstrated in glycemia regulation10 and with psychopharmacology11—also can enhance the desirable results of pharmacotherapy.
CASE REPORT: A soothing drink
Ms. L, a 22-year-old college student, suffers from obsessive-compulsive disorder associated with anxiety and depression. She arrives at the appointment hurried and worried that she might be late. She is short of breath and looks stressed. The nurse offers Ms. L a cup of tea or water. She chooses a glass of water and is asked to bring it into her session.
Following a comprehensive interview and mental status examination, I recommend CBT plus medication. Considering Ms. L’s medication history, we agree to start treatment with sertraline. We review its potential benefits and expectations that it will reduce her anxiety, alleviate her ruminating obsessive worries, and improve her mood. I give her a 50-mg sample and inform her that some patients experience positive effects soon after taking the medication. I then ask her to take the first pill, using her glass of water. She does so and thanks me for being attentive to her needs.
I instruct her to call within 1 week and report on her condition, even if she feels better. Seven days later she reports that she is feeling better and is looking forward to her next appointment. She reports no side effects.
Often patients come to my office feeling thirsty. My staff or I offer them a glass of water or a cup of tea. As patients sip from the cup, they swallow and incorporate the liquid into their bodies. At the same time, I use verbal interventions to make them feel listened to and understood. They internalize this emotional experience in connection with swallowing the liquid.
Later, when swallowing the new medication as instructed, the patient re-experiences the positive therapeutic effect that was internalized in the doctor’s office.
The power of suggestion
The power of suggestion has been shown to positively or negatively affect treatment outcomes.12,13 In practice, most clinicians give unintentional suggestions by how and what they communicate to the patient.
CASE REPORT: Predicting improvement
Mrs. J, age 48, has had dysthymic disorder and fibromyalgia for many years. She describes how various specialists have tried to alleviate her depression and chronic pain. Follow-up questions reveal that whenever she received a new prescription the physician would alert her to all the possible side effects and instruct her to call the office if she developed a problem with the new medication.
Invariably, Mrs. J would call as instructed and describe side effects she developed with the new medication. Often the doctor would discontinue the medication, depriving Mrs. J of benefits she might have derived later.
When Mrs. J calls to report on her status, she mentions that she is sleeping better and has begun to feel better during the day. She says that her husband told her she has started to smile again.
This vignette illustrates the importance of suggesting to the patient a positive outcome of pharmacotherapy associated with a particular action (calling the doctor’s office to report results). When the patient promised to call, she internalized the suggestion that calling would be associated with feeling better—and that is what happened. This intervention contrasts with saying to the patient, “Call me if you have a problem with any of these side effects,” which gives the patient a suggestion to call and report a problem.
The suggestion effect also can be used to reframe a predictable side effect as a positive sign that indicates the beginning of change leading to recovery (Box).
Ms. M, age 32 and single, has an anxiety disorder associated with bipolar depression. She has discontinued several psychotropics because of uncomfortable side effects, such as constipation.
After taking a detailed history, I decide to prescribe quetiapine. I tell Ms. M about this medication’s potential benefits and side effects. One common side effect is dry mouth, which often occurs before patients experience therapeutic effects.
I inform Ms. M that a dry mouth will be her sign that the medication has begun to work, and beneficial effects—such as improved sleep, reduced anxiety, and improved mood—will soon follow. I then instruct her to call my office and report when she experiences a dry mouth.
Discussion. In pharmacotherapy, side effects may appear before patients experience a medication’s beneficial/therapeutic effects. Patients’ initial experience often determines whether or not they will continue taking a prescribed medication. I know Ms. M may stop taking quetiapine—as she has done with other medications—if she initially has uncomfortable side effects.
Instructing patients to expect a specific side effect (such as a dry mouth with quetiapine) and associating it with a future therapeutic benefit sets up a road map of expectations. They know their experience is compatible with the doctor’s predictions. For Ms. M, I reframed the side effect as a positive sign that recovery has begun, with more positive changes to come.
Participatory pharmacotherapy
Many patients seek ownership in making decisions about their treatment and medications. In participatory pharmacotherapy, patients provide you with data and valuable information—such as family history, personal medical history, and experience with treatment—and inform you about which medications worked best and which did not work. You invite patients to predict how they see themselves getting better and into recovery.
CASE REPORT: All in the family
Mr. A, age 28 and single, has been diagnosed with a bipolar mood disorder. As part of a detailed family history, he reports that his maternal grandfather, mother, and a maternal uncle were diagnosed with mood swings and were successfully treated with medications, specifically lithium. He states that he believes he has the same condition.
I compliment Mr. A for being so well informed about his grandfather and uncle and educate him about mood stabilizers’ benefits in bipolar disorder. I tell him about the finding that if lithium has helped his relatives, it will probably help him as well.
I also reassure Mr. A that, in deciding what medications to avoid and what medications to use, I will consider his experience with specific antidepressants that did not help him. He thanks me for considering his suggestion about what medication to use for him.
- a successful therapeutic alliance
- adherence with prescribed medications
- the best possible outcome with pharmacotherapy.
In patients with a defiant-oppositional personality, consider framing the treatment decision as a choice between 2 equally efficacious medications. This gives the patient the sense of control in choosing his or her own medication, which is jointly monitored.
Table 3
Choosing patients for participatory pharmacotherapy
| Good candidates | Exclusionary qualities |
|---|---|
| Adults | Children, adolescents, and prison inmates |
| No history of alcoholism or drug addiction | Alcohol dependence or drug addiction |
| Average and above intelligence | Below-average intelligence |
| Intact cognitive function | Cognitive deficits, such as dementia |
| Not psychotic | Actively psychotic |
| Good comprehension of diagnosis and treatment | Poor comprehension of diagnosis and treatment |
| Therapeutic alliance is present | Therapeutic alliance is absent |
| Personality style or disorder with a need to be in control of treatment, such as obsessive-compulsive personality | Passive, dependent personality style or disorder; these patients may view a participatory approach as the doctor’s lack of confidence |
- Brody H. The placebo response: how you can release the body’s inner pharmacy for better health. New York, NY: HarperCollins Publishers; 2000.
- Spiro H. The power of hope: a doctor’s perspective. New Haven, CT: Yale University Press; 1998.
- Ernst E. Placebo: new insights into an old enigma. Drug Discov Today 2007;12:413-8.
- Lithium • Eskalith, Lithobid
- Mirtazapine • Remeron
- Quetiapine • Seroquel
- Sertraline • Zoloft
Dr. Torem reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Any medication’s therapeutic success depends on the interaction between its specific biochemical effects and nonspecific factors.1 Thus, clinical trial designers may view the placebo effect as undesirable, but it can be a valuable response that improves treatment outcomes in clinical practice. As Freud stated, “Expectation colored by hope and faith is an effective force with which we have to reckon…in all our attempts at treatment and cure.”2
This article describes how experienced clinicians make use of the placebo effect and 3 other powerful, nonspecific elements of successful pharmacotherapy.
The placebo effect
The placebo effect is any effect attributable to a pill or potion that does not originate from its specific pharmacologic properties.3 Its clinical value has been trivialized, in part because of misconceptions (Table 1). For example, the placebo effect is commonly believed to be short-lived, whereas in fact it can last a long time.4
In clinical practice, our goal is to enhance the placebo effect to maximize a desirable therapeutic outcome (Table 2).5 Therefore, before I prescribe a medication, I tell my patient that I have selected a particular medication because I have had good results with it in many other patients and I believe it will work well for him or her, too.
Too often, doctors feel pessimistic about a medication’s potential therapeutic result and communicate this pessimism. What the patient hears is, “There’s nothing else I can do for you; why not try this medication, even though I don’t believe it’s going to work.” This may create a negative placebo effect6—termed the “nocebo” effect—which gives the patient a negative expectation about the treatment’s outcome. The patient internalizes the doctor’s words and lives out this negative expectation.
Table 1
Correcting misconceptions about the placebo effect
| Misconception | What the evidence shows |
|---|---|
| Placebo effects are short-lived | The placebo effect has been documented to last for a long time |
| Only complaints that are psychologically originated respond to placebo | Changes after placebo have been documented for most symptoms, including those originating from somatic diseases |
| Placebo responders are distinctly different from nonresponders | There is no difference between placebo responders and nonresponders |
| The placebo effect is only about one-third of the total therapeutic effect | The placebo effect can be up to 100% of the total therapeutic effect |
| Only about one-third of the population responds to placebo | The placebo response is context-dependent and may include >90% of the patient population |
| Source: Reference 4 | |
Clinical strategies to enhance the placebo effect
| |
| Source: Reference 5 | |
CASE REPORT: Predicting positive results
Mr. B, age 42, has a history of recurrent depression associated with severe insomnia, poor appetite, significant weight loss, and psychosocial withdrawal with feelings of hopelessness. After I take a detailed history and do a mental status examination, I suggest that he be treated with cognitive-behavioral therapy (CBT) and mirtazapine.
Even though studies of antidepressants rarely show mood improvements within the first 7 days, it is not unusual to hear patients report feeling less depressed within days after they start a new antidepressant. Although the drug’s specific chemical effects on the brain may not be sufficient to explain this phenomenon, the explanation probably lies in nonspecific effects—such as the patient expecting that this medication will make him feel better.
The placebo effect can occur as soon as a patient starts a medication. Experienced clinicians understand the placebo effect’s power and harness it to benefit their patients.
Conditioned responses
Many biological responses can be associated with visual, auditory, tactile, olfactory, or gustatory stimuli. Nonconditioned physiologic responses paired with conditioned stimuli induce the same biological effects of a drug. Evidence supporting this phenomenon includes successful conditioning of the immune system.7-10 Conditioned responses—as demonstrated in glycemia regulation10 and with psychopharmacology11—also can enhance the desirable results of pharmacotherapy.
CASE REPORT: A soothing drink
Ms. L, a 22-year-old college student, suffers from obsessive-compulsive disorder associated with anxiety and depression. She arrives at the appointment hurried and worried that she might be late. She is short of breath and looks stressed. The nurse offers Ms. L a cup of tea or water. She chooses a glass of water and is asked to bring it into her session.
Following a comprehensive interview and mental status examination, I recommend CBT plus medication. Considering Ms. L’s medication history, we agree to start treatment with sertraline. We review its potential benefits and expectations that it will reduce her anxiety, alleviate her ruminating obsessive worries, and improve her mood. I give her a 50-mg sample and inform her that some patients experience positive effects soon after taking the medication. I then ask her to take the first pill, using her glass of water. She does so and thanks me for being attentive to her needs.
I instruct her to call within 1 week and report on her condition, even if she feels better. Seven days later she reports that she is feeling better and is looking forward to her next appointment. She reports no side effects.
Often patients come to my office feeling thirsty. My staff or I offer them a glass of water or a cup of tea. As patients sip from the cup, they swallow and incorporate the liquid into their bodies. At the same time, I use verbal interventions to make them feel listened to and understood. They internalize this emotional experience in connection with swallowing the liquid.
Later, when swallowing the new medication as instructed, the patient re-experiences the positive therapeutic effect that was internalized in the doctor’s office.
The power of suggestion
The power of suggestion has been shown to positively or negatively affect treatment outcomes.12,13 In practice, most clinicians give unintentional suggestions by how and what they communicate to the patient.
CASE REPORT: Predicting improvement
Mrs. J, age 48, has had dysthymic disorder and fibromyalgia for many years. She describes how various specialists have tried to alleviate her depression and chronic pain. Follow-up questions reveal that whenever she received a new prescription the physician would alert her to all the possible side effects and instruct her to call the office if she developed a problem with the new medication.
Invariably, Mrs. J would call as instructed and describe side effects she developed with the new medication. Often the doctor would discontinue the medication, depriving Mrs. J of benefits she might have derived later.
When Mrs. J calls to report on her status, she mentions that she is sleeping better and has begun to feel better during the day. She says that her husband told her she has started to smile again.
This vignette illustrates the importance of suggesting to the patient a positive outcome of pharmacotherapy associated with a particular action (calling the doctor’s office to report results). When the patient promised to call, she internalized the suggestion that calling would be associated with feeling better—and that is what happened. This intervention contrasts with saying to the patient, “Call me if you have a problem with any of these side effects,” which gives the patient a suggestion to call and report a problem.
The suggestion effect also can be used to reframe a predictable side effect as a positive sign that indicates the beginning of change leading to recovery (Box).
Ms. M, age 32 and single, has an anxiety disorder associated with bipolar depression. She has discontinued several psychotropics because of uncomfortable side effects, such as constipation.
After taking a detailed history, I decide to prescribe quetiapine. I tell Ms. M about this medication’s potential benefits and side effects. One common side effect is dry mouth, which often occurs before patients experience therapeutic effects.
I inform Ms. M that a dry mouth will be her sign that the medication has begun to work, and beneficial effects—such as improved sleep, reduced anxiety, and improved mood—will soon follow. I then instruct her to call my office and report when she experiences a dry mouth.
Discussion. In pharmacotherapy, side effects may appear before patients experience a medication’s beneficial/therapeutic effects. Patients’ initial experience often determines whether or not they will continue taking a prescribed medication. I know Ms. M may stop taking quetiapine—as she has done with other medications—if she initially has uncomfortable side effects.
Instructing patients to expect a specific side effect (such as a dry mouth with quetiapine) and associating it with a future therapeutic benefit sets up a road map of expectations. They know their experience is compatible with the doctor’s predictions. For Ms. M, I reframed the side effect as a positive sign that recovery has begun, with more positive changes to come.
Participatory pharmacotherapy
Many patients seek ownership in making decisions about their treatment and medications. In participatory pharmacotherapy, patients provide you with data and valuable information—such as family history, personal medical history, and experience with treatment—and inform you about which medications worked best and which did not work. You invite patients to predict how they see themselves getting better and into recovery.
CASE REPORT: All in the family
Mr. A, age 28 and single, has been diagnosed with a bipolar mood disorder. As part of a detailed family history, he reports that his maternal grandfather, mother, and a maternal uncle were diagnosed with mood swings and were successfully treated with medications, specifically lithium. He states that he believes he has the same condition.
I compliment Mr. A for being so well informed about his grandfather and uncle and educate him about mood stabilizers’ benefits in bipolar disorder. I tell him about the finding that if lithium has helped his relatives, it will probably help him as well.
I also reassure Mr. A that, in deciding what medications to avoid and what medications to use, I will consider his experience with specific antidepressants that did not help him. He thanks me for considering his suggestion about what medication to use for him.
- a successful therapeutic alliance
- adherence with prescribed medications
- the best possible outcome with pharmacotherapy.
In patients with a defiant-oppositional personality, consider framing the treatment decision as a choice between 2 equally efficacious medications. This gives the patient the sense of control in choosing his or her own medication, which is jointly monitored.
Table 3
Choosing patients for participatory pharmacotherapy
| Good candidates | Exclusionary qualities |
|---|---|
| Adults | Children, adolescents, and prison inmates |
| No history of alcoholism or drug addiction | Alcohol dependence or drug addiction |
| Average and above intelligence | Below-average intelligence |
| Intact cognitive function | Cognitive deficits, such as dementia |
| Not psychotic | Actively psychotic |
| Good comprehension of diagnosis and treatment | Poor comprehension of diagnosis and treatment |
| Therapeutic alliance is present | Therapeutic alliance is absent |
| Personality style or disorder with a need to be in control of treatment, such as obsessive-compulsive personality | Passive, dependent personality style or disorder; these patients may view a participatory approach as the doctor’s lack of confidence |
- Brody H. The placebo response: how you can release the body’s inner pharmacy for better health. New York, NY: HarperCollins Publishers; 2000.
- Spiro H. The power of hope: a doctor’s perspective. New Haven, CT: Yale University Press; 1998.
- Ernst E. Placebo: new insights into an old enigma. Drug Discov Today 2007;12:413-8.
- Lithium • Eskalith, Lithobid
- Mirtazapine • Remeron
- Quetiapine • Seroquel
- Sertraline • Zoloft
Dr. Torem reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
1. Frank JD, Frank JB. Persuasion and healing. Baltimore, MD: The Johns Hopkins University Press; 1991.
2. Freud S. The complete psychological works of Sigmund Freud. Strachey J, trans-ed. Toronto, Ontario, Canada: Hogarth Press; 1953.
3. Wolf S. The pharmacology of placebos. Pharmacol Rev 1959;11:689-704.
4. Ernst E. Placebo: new insights into an old enigma. Drug Discov Today 2007;12:413-8.
5. Brody H. The placebo response: recent research and implications for family medicine. J Fam Pract 2000;49:649-54.
6. Spiegel H. Nocebo, the power of suggestibility. Prev Med 1997;26:616-21.
7. Ader R, Cohen N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 1982;215:1534-6.
8. Ader R. The role of conditioning in pharmacotherapy. In: Harrington A, ed. The placebo effect: an interdisciplinary exploration. Cambridge, MA: Harvard University Press; 1997;138-65.
9. Olness K, Ader R. Conditioning as an adjunct in the pharmacotherapy of lupus erythematosus. J Dev Behav Pediatr 1992;13:124-5.
10. Stockhorst U, Mahl N, Krueger M, et al. Classical conditioning and conditionability of insulin and glucose effect in healthy humans. Physiol Behav 2004;81:375-88.
11. Wolf S. Effect of suggestion and conditioning on the action of chemical agents in human subjects—the pharmacology of placebos. J Clin Invest 1950;29:100-9.
12. Lown B. The verbal conditioning of angina pectoris during exercise testing. Am J Cardiol 1977;40:630-4.
13. Lown B. Introduction. In: Cousins N. The healing heart. New York, NY: W.W. Norton; 1983:11-28.
14. Watzlawick P. If you desire to see, learn how to act. In: Nardone G, Watzlawick P, eds. The art of change San Francisco, CA: Jossey-Bass; 1993:1-16.
1. Frank JD, Frank JB. Persuasion and healing. Baltimore, MD: The Johns Hopkins University Press; 1991.
2. Freud S. The complete psychological works of Sigmund Freud. Strachey J, trans-ed. Toronto, Ontario, Canada: Hogarth Press; 1953.
3. Wolf S. The pharmacology of placebos. Pharmacol Rev 1959;11:689-704.
4. Ernst E. Placebo: new insights into an old enigma. Drug Discov Today 2007;12:413-8.
5. Brody H. The placebo response: recent research and implications for family medicine. J Fam Pract 2000;49:649-54.
6. Spiegel H. Nocebo, the power of suggestibility. Prev Med 1997;26:616-21.
7. Ader R, Cohen N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 1982;215:1534-6.
8. Ader R. The role of conditioning in pharmacotherapy. In: Harrington A, ed. The placebo effect: an interdisciplinary exploration. Cambridge, MA: Harvard University Press; 1997;138-65.
9. Olness K, Ader R. Conditioning as an adjunct in the pharmacotherapy of lupus erythematosus. J Dev Behav Pediatr 1992;13:124-5.
10. Stockhorst U, Mahl N, Krueger M, et al. Classical conditioning and conditionability of insulin and glucose effect in healthy humans. Physiol Behav 2004;81:375-88.
11. Wolf S. Effect of suggestion and conditioning on the action of chemical agents in human subjects—the pharmacology of placebos. J Clin Invest 1950;29:100-9.
12. Lown B. The verbal conditioning of angina pectoris during exercise testing. Am J Cardiol 1977;40:630-4.
13. Lown B. Introduction. In: Cousins N. The healing heart. New York, NY: W.W. Norton; 1983:11-28.
14. Watzlawick P. If you desire to see, learn how to act. In: Nardone G, Watzlawick P, eds. The art of change San Francisco, CA: Jossey-Bass; 1993:1-16.