Review articleThe placebo effect and randomized trials: analysis of conventional medicine
Section snippets
Learning from the placebo effect: past popular conventional medical trials
There are a variety of conventional medical treatments or prescription drugs that are currently popular with patients. Clinicians and especially patients should be reminded of the original results from the clinical trials that allowed these agents to be approved by the Food and Drug Administration (FDA) or that have been demonstrated since the time of approval. This seems especially true when it comes to the placebo effect observed in these same trials. A variety of medical conditions and their
Allergies/asthma
Allergic rhinitis affects approximately 1–2 of every 10 Americans [6]. It is a condition with a high prevalence, but it is also interesting that patients seem to get some relief with a placebo during randomized trials. A trial of approximately 200 individuals who were exposed to ragweed pollen in an environmental exposure unit was recently conducted [7]. Cetirizine (Zyrtec) demonstrated a 36.7% and loratadine (Claritin) a 15.4% mean reduction in total symptoms. The placebo group demonstrated a
Alopecia in men and women
There are probably few greater overt and tangible examples of the importance of measuring the placebo effect than when observing the results of some prescription medications for alopecia (premature baldness/hair loss).
One of the first medications approved for hair loss in men and women was minoxidil (Rogaine) which is currently sold as an over the counter medication but initially was only available by prescription. In women, approximately 30–45% of participants in randomized trials experienced
Benign prostatic hyperplasia
Currently, there are several drugs that are widely used for the treatment of benign prostatic hyperplasia (BPH). Doxazosin (Cardura), Finasteride (Proscar), tamsulosin (Flomax), and terazosin (Hytrin) are just some of the agents that are FDA approved for BPH. All of these agents share similar features when it comes to analyzing the data that enabled these drugs to achieve FDA approval. They were not only significantly more effective than placebo, but the placebo effect in most of these cases
Cholesterol levels
Some agents have dramatic placebo effects, especially in trials with subjective outcomes, whereas others tend to have little to no response, especially in trials with objective outcomes (i.e., serum studies). Statin drugs (HMG-CoA reductase inhibitors) have been become the gold-standard prescription medications for the reduction of elevated cholesterol levels (hypercholesterolemia) in men and women. In general, because of the large number of FDA-approved statins, they tend to be compared with
Depression or social anxiety
Numerous agents have been approved for the treatment of depression by the FDA. Some of the more popular include the selective serotonin reuptake inhibitors (SSRIs) and venlafaxine (Effexor). Randomized clinical trials found that a large number of patients in these trials experienced a placebo effect. For example, data from eight randomized, double-blind trials of major depressive disorder were analyzed [23]. Over 800 patients taking venlafaxine, and approximately 750 total patients taking
Erectile dysfunction
Erectile dysfunction (ED) is the persistent inability to achieve or maintain an erection necessary for sexual performance. It has many etiologies and is estimated to affect as many as 30 million men in the United States alone [26]. This condition is associated with increasing age and a variety of available treatments currently exist [27], [28], [29]. Several years ago, the first effective oral treatment for ED, sildenafil (Viagra), was approved by the FDA. An evaluation of past clinical trials
Gastroesophageal reflux disease and related conditions
Gastroesophageal reflux disease (GERD) is characterized by the symptoms of indigestion and/or heartburn [36]. Prescription drugs for this and some of its related conditions are some of the largest-selling and prescribed drugs in the United States. Two of the more popular agents are lansoprazole (Prevacid) and omeprazole (Prilosec). Some of the many randomized trials have revealed a fairly large placebo response. One hundred and seventy nine patients were evaluated in a 2-week study of
Hot flashes
Vasomotor hot flashes are experienced by women during menopause and by women and even men who have undergone some form of hormone-deprivation treatment [42], [43], [44]. This is a symptom which is subject to some bias because it is generally self-reported by the patient in clinical studies. Therefore, large placebo responses should be expected in these trials. Megestrol acetate (Megace) has been a mainstay of treatment for hot flashes. Previous large trials have demonstrated that approximately
Osteoporosis
Bisphosphonates have become popular prescription medications for the prevention of osteoporosis. This type of treatment demonstrates placebo results similar to those observed with cholesterol-lowering drugs (statins) because researchers are measuring internal markers or observing imaging tests (objective outcomes) to determine effectiveness rather than using patient symptoms (subjective outcomes). In these cases, it is probably difficult to measure a strong placebo response (if any) because
Pain management
Pain or the relief of pain from various conditions is with little doubt subject to subjective bias, so researchers would expect a fairly strong placebo response in these trials [4]. For example, sumatriptan (Imitrex) is a commonly used FDA-approved prescription for the relief of pain associated with migraine headaches. Trials have demonstrated that 67–71% of patients receiving this drug can experience relief versus 22–33% with placebo [51]. It is noteworthy in some of these studies that a
Weight loss
Obesity rates have dramatically increased in the United States and other countries in the past several years [54], [55]. Effective interventions besides lifestyle changes are becoming an option for patients with extreme obesity. For example, the recently FDA-approved drug orlistat (Xenical), a lipase inhibitor, has been found to be somewhat effective for weight loss compared with placebo [56], [57]. However, it is interesting that occasionally when dealing with a somewhat objective measurement
Conclusion
Randomized controlled trials with a variety of conventional medical options have not only revealed the superiority of some of these agents versus placebo, but they also revealed that the placebo response is quite notable by itself. Whether researchers are examining the effects of allergy, alopecia, BPH, depression, ED, weight loss, or other treatments, the placebo effect is quite tangible. Table 1 is a partial summary of the unique and variable placebo responses demonstrated in some previous
References (62)
- et al.
Cetirizine, loratadine, or placebo in subjects with seasonal allergic rhinitis: effects after controlled ragweed pollen challenge in an environmental exposure unit
J Allergy Clin Immunol
(1998) Double-blind, placebo-controlled evaluation of topical minoxidil in extensive alopecia areata
J Am Acad Dermatol
(1987)Androgenetic alopecia: treatment results with topical minoxidil
J Am Acad Dermatol
(1987)- et al.
Measuring reversal of hair miniaturization in androgenetic alopecia by follicular counts in horizontal sections of serial scalp biopsies: results of finasteride 1 mg treatment of men and postmenopausal women
J Investig Dermatol Symp Proc
(1999) - et al.
Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia
J Am Acad Dermatol
(2000) - et al.
Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study
J Urol
(1994) - et al.
Efficacy and safety of fixed-dose oral sildenafil in the treatment of erectile dysfuction of various etiologies
Urology
(1999) - et al.
Symptoms in gastro-oesophageal reflux disease
Lancet
(1990) - et al.
A placebo-controlled dose-ranging study of lansoprazole in the management of reflux esophagitis
Am J Gastroenterol
(1998) - et al.
Venlafaxine in management of hot flashes in survivors of breast cancer: a randomized controlled trial
Lancet
(2000)
Efficacy and safety of etodolac and naproxen in patients with osteoarthritis of the knee: a double-blind, placebo-controlled study
Clin Ther
Demonstration to medical students of placebo responses and non-drug factors
Lancet
The powerful placebo effect: fact or fiction?
J Clin Epidemiol
Is there logic in the placebo?
Lancet
What can randomized controlled trials tell us about nutrition and cancer prevention?
CA Cancer J Clin
A note on placebo
Ann J Pharm
The powerful placebo
JAMA
The importance of placebo effects in pain treatment and research
JAMA
Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey
JAMA
Allergic rhinitis update: epidemiology and natural history
Allergy Asthma Proc
The placebo effect in asthma drug therapy trials: a meta-analysis
J Asthma
Androgenetic alopecia in the female. Treatment with 2% topical minoxidil solution
Arch Dermatol
Use of topical minoxidil therapy for androgenetic alopecia in women
Int J Dermatol
Treatment of female androgenetic alopecia with minoxidil 2%
Int J Dermatol
Australian trial of minoxidil and placebo in early male pattern baldness
Australas J Dermatol
Finasteride: a review of its use in male pattern hair loss
Drugs
Tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist. A meta-analysis of two randomized, placebo-controlled, multicentre studies in patients with benign prostatic obstruction (symptomatic BPH). European Tamsulosin Study Group
Eur Urol
Placebo therapy of benign prostatic hyperplasia: a 25-month study. Canadian PROSPECT Study Group
Br J Urol
Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group
N Engl J Med
A multicenter, placebo-controlled, dose-ranging study of atorvastatin
J Cardiovasc Pharmacol Ther
Comparative efficacy study of atorvastatin vs. simvastatin, pravastatin, lovastatin and placebo in type 2 diabetic patients with hypercholesterolaemia
Diabetes Obes Metab
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The sweetest pill to swallow: How patient neurobiology can be harnessed to maximise placebo effects
2013, Neuroscience and Biobehavioral ReviewsCitation Excerpt :It is preferable to utilise the interaction-enhanced pharmacology concept proposed here to enhance the effectiveness of the drug therapy. Since placebo and placebo effects are often linked to more psychosomatic ailments, it is not surprising that symptoms such as migraine (Bendtsen et al., 2003; Clayton et al., 2005; de Craen et al., 2000; Diener, 1999; Ferrari et al., 2001; Henry et al., 1995; Macedo et al., 2006; Tfelt-Hansen et al., 1995), insomnia (Fratello et al., 2005; McCall et al., 2003; Walsh et al., 2000), irritable bowel syndrome (Kaptchuk et al., 2009; Kelley et al., 2009; Vase et al., 2003, 2005; Verne et al., 2003), gastric disturbances (Bernstein, 2006; Enck and Klosterhalfen, 2005; Musial et al., 2007) and genitourinary disorders (Bradford and Meston, 2007; Fink et al., 2002; McConnell et al., 1998; Mondaini et al., 2007; Moyad, 2002; Nickel, 1998; van Leeuwen et al., 2006) have been found to respond well to placebos. Most of the above disorders manifest themselves as painful conditions, and as we have seen, the mode of action of placebo – in addition to its effectiveness – in pain relief has been well established.
Therapeutic Strategies for Managing BPH Progression
2006, European Urology, SupplementsPrevention and treatment of erectile dysfunction using lifestyle changes and dietary supplements: What works and what is worthless, part I
2004, Urologic Clinics of North AmericaCitation Excerpt :Newer oral agents approved in other countries that may gain FDA approval for ED also have observed placebo responses of 25% to 41% [62]. Many of the best-selling and popular dietary supplements are for conditions that also have observed high placebo response rates (eg, BPH, depression, ED, hair loss, pain) in clinical studies [63–65]. The FDA recently approved two new oral-prescribed agents for ED, vardenafil and tadalafil [8], which may spark an increase in the advertising and promotion of novel and untested ED dietary supplements.