Practical Pointers - February 2006

I hope you will find Practical Pointers interesting and helpful. The complete content of all issues for the past 5 years can be accessed at www.practicalpointers.org

Richard T. James Jr, M.D.

Editor/Publisher.

HIGHLIGHTS AND EDITORIAL COMMENTS FEBRUARY 2006

Begin Consideration of Both Biomedical and Psychosocial Causes at the Onset of A New Consultation

2-1 SOMATIZATION: A Joint Responsibility of Doctor and Patient

Most studies of somatization focus on patients’ characteristics. There is a widespread belief that inappropriate symptomatic treatment has to be attributed to patients’ beliefs that symptoms are caused by physical disease, their insistence on biomedical intervention, and their denial of psychosocial needs. The possibility that doctors play a part has been largely ignored.

A detailed analysis of general practice patients with unexplained symptoms found that physical interventions were proposed more often by doctors than by patients. Almost all patients provided clues to their psychological needs. Most doctors suggested that one or more physical diseases might be present. The authors conclude that the explanation for the high level of physical intervention in these patients lies in doctors’ responses rather than patients’ demands.

Some studies show that most doctors adapt their biomedical interventions at least partly to presumed patient preferences. They may overestimate their patients’ wishes in this regard, particularly regarding prescriptions and referrals.

The mantra “First of all, do no harm” seems to be replaced by “First of all, don’t miss a medical diagnosis”.

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Primary care clinicians—Do you agree that we are partly responsible for the overuse of tests and consultation—not only for patients with suspected somatization,, but for patients in general ?

These patients are indeed suffering. How best can primary care clinicians help them? I believe mainly by listening to the patient. The art of medicine is indeed long and difficult.

Device Outperforms Pill

2-2 SHAM DEVICE VERSUS INERT PILL: Randomized Trial Of Two Placebo Treatments

This trial, in patients with arm pain, investigated whether a sham acupuncture needle had a greater placebo effect than an inert pill.

Participants (n = 119) were community dwellers who had arm pain due to repetitive use that had lasted

at least 3 months despite treatment. All had pain scores of 3 or more on a 10-point pain scale.

Randomized to 1) acupuncture with a sham device twice a week for 6 weeks, and 2) an inert placebo pill once daily for 8 weeks.

Pain scores and the symptom severity scale decreased significantly more in the sham group than in the pill

group.(-0.33 vs -0.15; and -0.007 vs -0.05) (In the sham acupuncture group, the downward slope in the 10-point pain scale each week was significantly steeper than the downward slope in the placebo pill group.)

Differences in grip strength and arm function were not significant.

Nocebo effects were totally different in the two groups, and clearly mimicked the information given at

informed consent. Sham acupuncture subjects were told that their pain might be temporarily aggravated: placebo pill subjects were told that they might experience sleepiness, dry mouth, dizziness, and restlessness. One quarter to one third of subjects reported such adverse effects. “Our findings contribute to the debate on the influence of information provided at informed consent and subsequent reported adverse effects.” “We found that reported side effects perfectly mirrored the information provided to participants.”

“Placebo effects seem to be malleable, and depend on the behaviors embedded in medical rituals.”

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The same group commented in 1998 “No longer is it sufficient for a therapy to work; it must be better than placebo.”

Placebos are both fascinating and powerful. Indeed, I believe at times the placebo effect is the primary care clinician’s best friend. I would not discourage placebo use in a patient who perceives benefit—provided the placebo is not harmful and does not preclude other therapy of proven benefit.

Although we may argue about whether it is ethical to prescribe a placebo, I believe many, if not most, primary care clinicians will occasionally prescribe a drug for which they have little or no expectation of pharmacologic benefit.

To assess the power of the placebo effect, it is necessary to compare a group of patients who receive

no-treatment and no-placebo, with a group receiving a placebo.

A part of the effect of all active drugs is due to the placebo effect.

The strength of the placebo depends on its form (as in this study), the enthusiasm and belief of the clinician, and the culture and belief of the patient. If 1000 patients are given a placebo, and 1) 500 enthusiastically and conscientiously take it, and 2) 500 patients take it irregularly, without complying with the regular schedule, outcomes in group 1) will be better than in group 2).

There is no doubt that totally (pharmacologically) inactive substances can produce demonstrable effects on brain function. Inert pills and devices can have harmful (nocebo) effects.

“First New Insulin Delivery System since The Discovery Of Insulin In The 1920s”. But use with reservations.

2-3 INHALED INSULIN APPROVED IN EUROPE AND UNITED STATES

An inhaled form of human insulin (Exubera) has been approved for treatment of both type 1 and type 2 diabetes.

This brief comment lists some cautions. It is contraindicated in smokers. It is not recommended for patients with asthma, bronchitis and emphysema. It has been associated with increases in cough, dyspnea, sinusitis, and pharyngitis. And is also associated with a small mean decrease in FEV1.

There are concerns about erratic absorption. It may fail to control postprandial glucose as well as subcutaneous insulin.

It may be especially indicated for patients “who absolutely refuse to take shots”.

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I believe primary care clinicians should wait for a year or two of observation of use in the general population before prescribing it.

Is this the final word on calcium + vitamin D supplementation to reduce risk of fracture ?

2-4 CALCIUM PLUS VITAMIN D SUPPLEMENTATION AND RISK OF FRACTURES IN OLDER WOMEN

This trial tested the hypothesis that calcium + vitamin D (C + D) supplementation, begun at an advanced age in women, would lower risk of hip fractures and other fractures as compared with placebo.

The Women’s Health Initiative recruited over 36 000 postmenopausal women age 50 to 79 (mean age = 62 at baseline). All were living in the community and were considered healthy.

Randomized to: 1) 1000 mg calcium + 400 IU vitamin D daily, or 2) placebo.

Bone mineral density was greater in the calcium + vitamin D group at year 7 by 1%.

Fracture rate overall* Ca + D Placebo

Hip 175 199

Vertebral 181 197

Forearm of wrist 565 557

Total 2102 2158

(*Intention-to-treat. No statistical difference between groups.)

Among women who were adherent (ie, took at least 80% of their study medication), C + D supplementation

resulted in a 29% reduction in hip fracture—68 in the C + D group vs 99 in the placebo group (95% confidence interval = 0.52-0.97—statistically significant).

“The trial demonstrated that calcium with vitamin D supplementation diminishes bone loss at the hip, but the

observed 12 percent reduction in the incidence of hip fracture (the primary outcome) was not statistically significant.” “It is plausible that there was a benefit only among women who adhere to the study treatment.” Only 59% of women were still taking the intended dose of the study medication at the end of the trial.

Although the statistically null primary effect argues against recommending universal calcium with

vitamin D supplementation, the findings provided evidence of a positive effect of calcium with vitamin D on bone health in older postmenopausal women

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I would amend the conclusion to state that calcium and vitamin D supplementation did not significantly reduce hip fracture when begun at age 62. I would not expect much reduction in fractures in women when C + D supplementation is begun long after the menopause. Intakes of C and D are almost universally deficient in the USA at all ages. Efforts to develop and maintain healthy bone structure are a life-time endeavor. Primary care clinicians should ensure their patients achieve adequate intakes beginning in childhood.

The benefit/harm-cost of C + D supplementation is, I believe, very high. Entering menopause with healthy bones will reduce hip fractures and alleviate the frequency of disabling kyphosis which plagues many older women.

No Benefit; No Harm

2-5 CONJUGATED EQUINE ESTROGENS AND CORONARY HEART DISEASE The Women’s Health Study

Recent randomized trials of hormone replacement therapy (HRT) with conjugated equine estrogens (CEE) + medroxyprogesterone reported no protection against coronary heart disease (CHD), and may have increased risk.

This associated, but separate, trial considered women who had experienced a hysterectomy and were eligible to receive unopposed CEE . This is the final report of the trial.

Randomized over 10 000 women (mean age = 64) to; 1) unopposed CEE 0.625 mg daily, or

2) placebo.

At 7 years, 201 coronary events occurred in the CEE group, vs 217 in the placebo group. (No clinical or statistical difference.)

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This study is important. It applies to the many women who have undergone hysterectomy whose menopausal symptoms are disturbing. It was reported without editorial comment as the last article in this issue of Archives. I believe it deserved wider distribution. Estrogens-alone did not lead to excess CVD risk.

Observational studies long reported that HRT protected against cardiovascular disease. This, it finally turned out, was due to the bias of the “healthy user”.

The original reports of WHI studies ^1,2 (CEE + progestin) were widely distributed and caused much comment. They refuted the long-held view that HRT would protect against cardiovascular disease. The main conclusion was that HRT should not be used to prevent CVD.

Many doctors then discontinued prescribing CEE + progestin. And many women stopped taking it (despite continuing menopausal symptoms), and despite the low excess risk of cardiovascular events over 5 years.

Associated With Significant Deficits in Cognitive Functioning

2-6 NON-DEGENERATIVE MILD COGNITIVE IMPAIRMENT IN ELDERLY PEOPLE AND USE OF ANTICHOLINERGIC DRUGS

Dysfunction of the cholinergic system has a detrimental effect on cognitive performance. The anticholinergic agent, scopolamine, reduces hyppocampal activation, and, when given to young adults, produces cognitive defects characteristic of aging-related changes, rather than dementia.

Drug consumption in elderly people is high. Many commonly prescribed drugs have anticholinergic effects (antiemetics, antispasmodics, bronchodilators, antiarrhythmic drugs, antihistamines, analgesics, antihypertensives, antiparkinsonian agents, corticosteroids, skeletal muscle relaxants, ulcer drugs, and psychotropic drugs). These are likely to have a more toxic effect in an aging brain because of increased permeability of the blood-brain barrier, slower metabolism and drug elimination, and polypharmacy.

Doctors commonly fail to associate cognitive dysfunction in elderly people with anticholinergic agents. They also underestimate anticholinergic toxicity, and prescribe such drugs at high doses. An increasing number of such compounds are available without prescription.

This study tested whether drug-induced anticholinergic burden is associated with cognitive dysfunction.

Of the 372 subjects, 51 (14%) were taking at least one anticholinergic drug at baseline. None were taking acetylcholinesterase inhibitors. At the end of the year, 30 of 51 were still taking the drugs regularly.

Compared with the 297 non-users, the 30 continuing users had poorer performance on reaction time, attention, memory, visuospatial construction, and language tasks. 80% were classified as having mild cognitive impairment, compared with 35% of non-users.

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This is an important contribution. I was not aware that so many drugs have anticholinergic activity. I believe also that few primary care clinicians are aware of them.

Before assuming that your patient has early dementia from Alzheimer’s disease and prescribing a acetylcholinesterase inhibitor, consider if any drug you are prescribing could be related to beginning “dementia”.

The message applies to many other drugs used in geriatric practice. Many carry unsuspected and undetected adverse effects in some individuals. Primary care clinicians should be constantly aware that adverse drug effects may occur more frequently in the elderly, and may present in diverse ways. Continually ask—could any drug I prescribed adversely affect this patient? Or is any non-prescription drug?

I hope a follow-up study will measure effects of discontinuing these drugs.

Is Melatonin Ineffective?

2-7 EFFICACY AND SAFETY OF EXOGENOUS MELATONIN FOR SECONDARY SLEEP DISORDERS AND SLEEP DISORDERS ACCOMPANYING SLEEP RESTRICTION

Melatonin is classified as a “dietary supplement”¹. It is available without a prescription.

This systematic review assessed efficacy and safety of melatonin for managing secondary sleep disorders and sleep restriction.

A. Secondary sleep disorders:

Sleep onset latency (amount of time between lying down to sleep and onset of sleep): Six trials (97 participants) showed no evidence that melatonin had an effect on sleep onset latency. The combined estimate favored melatonin by a mean of 13 minutes. However, the confidence interval = -27 to 0.9 minutes, and thus did not quite reach the 0.05 significance level. Heterogeneity between studies was substantial. When one outlier which favored placebo was eliminated, the result became statistically significant (CI = -26 min to – 8 min)

Other efficacy outcomes: Six trials showed a significant effect favoring melatonin. (Weighted mean difference = 1.9%; confidence interval = 0.5 to 3.3) “However, the effect seems not to be clinically important.”²

B. Sleep restriction:

Sleep onset latency: Nine trial produced a combined estimate that favored melatonin, but was not statistically significant. Mean difference = -1 minute; confidence interval = -2.7 min to 0.3 min.

Other efficacy outcomes: For sleep efficiency (time spent in bed asleep), the combined estimate

from 5 trials showed no statistically significant difference between melatonin and placebo. Weighted mean difference = 0.5%; confidence interval = -0.6% to 1.6%

Safety over 3 months or less:

The most commonly reported adverse effects were headache, dizziness, nausea, and drowsiness. The occurrence of these outcomes did not differ between groups.

Conclusion of the meta-analysis: “There is no evidence that melatonin is effective in treating secondary sleep disorders, or sleep disorders accompanying sleep restriction such as jet lag or shift work disorder.”

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This is a sophisticated statistical study. I congratulate the investigators on their diligence. Is it the last word on melatonin? I think not.

1“Dietary supplements” are not standardized, are not pure, and may by adulterated. Although melatonin is

classified as a “dietary supplement”, it is an exception. It is a simple, defined chemical entity which may permit standardization of purity and dose. The dose may have to be established on a person-to-person basis. The various studies cited did not use a standardized form and dose of melatonin.

2 Clinical effectiveness must be judged on the basis of response by an individual patient, not on p values, not on

confidence intervals. Patients know nothing about p values. There will always be outliers from the mean response. For some subjects, melatonin was associated with shortening the time to go to sleep and lengthening the time spent asleep. Undoubtedly, there is a large placebo effect of melatonin. But, in view of its safety, if my patient judged his sleep to be improved by the melatonin, I would not dispute his observation or/NOR discourage him from taking it. If a patient who had never taken melatonin expressed a desire to try it, I would not discourage her. I would suggest she purchase it in a national drug store chain, not by mail or over the Internet. My pharmacy sells 3 mg melatonin at $13 for 240 tablets.

A new drug for insomnia has been released by the FDA—ramelteon (Rozerem). It is a melatonin agonist, targeting two melatonin receptors in the brain. 1) MT1 receptor is thought to regulate sleepiness, and 2) MT2 receptor is thought to help the body shift between phases of day and night. It has been reported to modestly decrease the time it takes to reach persistent sleep and to modestly increase the total sleep time. It is available as 8 mg tablets.

Purity and dosage is regulated by the FDA. It is classified as a non-scheduled drug. The information provided by the company (Takeda, Japan) claims there is no risk of abuse or dependence. Withdrawal effects have not been reported.

Compared with melatonin: 1) ramelteon may have the advantage of being certified as pure and with an established dose, 2) ramelteon has the disadvantage of a shorter time of use by the general population. Some adverse effects may yet appear.

(Information gleaned from the internet via GOOGLE.)

Is Melatonin Legal Fiction?

2-8 DOES MELATONIN HELP PEOPLE SLEEP?

(This editorial comments and expands on the preceding article.)

“In North America, melatonin is a popular wonder drug which has legal status and a ‘nutritional’ supplement, although that is legal fiction.” As a result, it is not regulated as a medicine, and is advertised and sold widely—in pharmacies, health food shops, and on the internet. Millions of people use it mostly because they believe it will help them sleep.

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The Dietary Supplement Health and Education Act, passed by the US Congress (1994), prevents the FDA from monitoring the quality and safety of “dietary supplements” before marketing. Supplements do not have to be dietary components.

The great majority of nostrums advertised and promoted to the general public by charlatans are taken by millions and are indeed legal fiction. They are not “nutritional” and they are not “supplements”. They are not standardized. They are not pure. Many are purposely adulterated. Melatonin may be an exception. It is a simple, defined chemical entity which may permit standardization of purity and dose. The dose may have to be established on a person-to-person basis. The various studies cited in the article did not use a standardized form and dose of melatonin. Used properly, as for jet lag, melatonin should be taken at the time night begins at the place of destination.

Combined G and C May Be Effective In the Subgroup with Moderate-To-Severe Pain.

2-9 GLUCOSAMINE, CHONDROITIN SULFATE, AND THE TWO IN COMBINATION FOR PAINFUL KNEE ARTHRITIS

This randomized, double-blind, placebo-controlled trial compared glucosamine sulfate (G), chondroitin (C), both, celecoxib, and placebo for 6 months in over 1500 patients with knee osteoarthritis.

Product selection: The study was conducted under an investigational new drug application. As such,

C and G were subject to pharmaceutical regulation by the FDA. Ingredients were tested for purity, potency and quality. ¹

Primary outcome = a 20% decrease in pain from baseline to 24 weeks based on a pain score.

Overall, for all randomized patients, C and G were not significantly better than placebo in reducing knee pain

by 20%. Change in WOMAC pain score for placebo = -86 points; for G + C = -100 points.

The rate of response to placebo was high (60% reported a decrease in pain of 20% or more). As compared with placebo, the rate of response to G was 4% higher. And the rate of response to C was 5% higher. The rate of response to both C and G combined was 10% higher. (Not statistically significant.)

Overall, response to celecoxib was 10% higher than to placebo. And response time was much faster than for

C and G.

For patients with moderate-to-severe pain, the rate of response to C + G combined was significantly

higher than for placebo (79% vs 54%). Change in mean WOMAC pain scores from baseline to end of

follow=-up = -123 points in the placebo group vs -153 points in the C + G group. (Statistically significant.)

For patients with moderate-to-severe pain, G +C was associated with a greater reduction in pain than

celecoxib: - 177 points vs - 153 points.

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A 20% reduction in pain seems a very modest goal.

1 This is unusual. Most studies of “dietary supplements” do not screen products so carefully. This study was detailed, carefully crafted, executed, and analyzed from a statistical standpoint.

2 Does lack of “statistical” significance preclude a prescription? I believe not. There will always be patients whose response to treatment deviates from the mean, either less favorably or more favorably. Response to C + G must be evaluated in an individual patient.

Would I prescribe C + G for a patient with OA pain? I would prescribe acetaminophen first. In view of the safety of C +G, I would mention the combination as a possibility for the patient to consider—at least to try.

I would suggest they purchase the preparation at a national-chain pharmacy rather than by mail or on the internet. I believe it would be more likely to be as labeled.

Although primary care clinicians may not admit it, I believe many do indeed rely on the placebo effect, at least accept it when a patient reports improvement.

At my pharmacy, G (1500 mg)+ c (1200 mg) costs $32 for 120 tablets. At times, it is on sale at about half price. Celebrex 200 mg costs $ 3.19 each

A Promising Anticoagulant. Long-Term Efficacy Not Established.

2-10 EFFICACY AND SAFETY OF FONDAPARINUX FOR THE PREVENTION OF VENOUS THROMBOEMBOLISM IN OLDER ACUTE MEDICAL PATIENTS

“Most patients who die from pulmonary embolism (PE) as a complication of being admitted to hospital are medical patients.” Around 10% of deaths are due to PE.

Fondaparinux (Arixtra; Glaxco SmithKline) is a synthetic, selective inhibitor of factor Xa. It effectively reduces postoperative venous thromboembolism (VTE) after orthopedic surgery.

This study determined the short-term efficacy and safety of fondaparinux in older, acutely ill medical inpatients. Randomized within 48 hours to: 1) fondaparinux, or 2) placebo.. Doses were given subcutaneously daily (2.5 mg fondaparinux or 0.5 mg saline).

A. Primary efficacy outcome for first 15 days only:

Fondaparinux Placebo

Any VTE 18 29

Proximal deep vein thrombosis 5 7

Distal deep vein thrombosis 13 22

Fatal PE 0 5

Total 18/321 (5.6%) 34/323 (10.5%)

(NNT to prevent one VTE = 20.)

B. Symptomatic VTE up to day 32:

Fondaparinux Placebo

Symptomatic deep vein thrombosis 0 0

Non-fatal pulmonary embolism 1 4

Fatal pulmonary embolism 3 7

Ten additional cases of PE occurred during follow-up after day 15—4 in the fondaparinux group, 6 in the

placebo group. (Three in the fondaparinux group were fatal.).

Major bleeding occurred in one patient in each group. (0.2%) ¹

Two thirds of the clinically apparent events and half of the fatal PE were observed after the initial 6 to 14 day

study period. This supports the need to evaluate extended prophylaxis in medical patients.²

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I abstracted this article mainly to introduce what may become a major breakthrough. Two new oral Xa inhibitors are in the works.

1 If the risk of major bleeding is indeed lower with fondaparinux, it would be a major benefit. Watch

for further studies.

2 Note that the study focused on outcomes over 2 weeks only. The risk of VTE in these very ill older

patients extends far beyond. The investigators note that VTE occurred frequently after the study period. Some were fatal. The question remains: How long must fondaparinux be continued in these medical patients? And for how long? . Duration of therapy for only 2 weeks adds relatively little overall protection.

Look For Early Signs Of Sepsis: Leg Pains, Cold Hands and Feet (Despite Fever) , Abnormal Skin Color

2-11 CLINICAL RECOGNITION OF MENINGOCOCCAL DISEASE IN CHILDREN AND ADOLESCENTS

Meningococcal disease (MD) is a rapidly progressive infection of global importance. MD is initially misdiagnosed. The infection can progress from initial symptoms to death within hours. Diagnosis must be made as early as possible. The diagnosis often depends on textbook descriptions of classic features such as hemorrhagic rash, meningism, and impaired consciousness. These signs appear late in the course of the disease.

This study determined the frequency and time of onset of clinical features of MD. Questionnaire obtained data from parents and primary care records for the course of illness before hospital admission in 448 children age 16 and younger with MD. (103 were fatal.)

Calculated the number of hours from the onset of illness to the initial consultation, and to hospital admission

(or to death before admission).

Most children had only non-specific symptoms in the first 4 to 6 hours, but were close to death by 24 hours.

Three quarters of children had early symptoms of sepsis.

In all age groups, the first specific clinical features were signs of sepsis—leg pain, cold hands and feet, and/or abnormal skin color (pallor or mottling). Most of these symptoms appeared at a median time of 8 hours—before the first medical contact. This was much earlier than the median time to hospital admission (19 hours).

Classical symptoms of rash, meningism, and impaired consciousness appeared late. (median onset = 13

to 22 hours).

“We believe our evidence is sufficiently robust to argue that we need a diagnostic paradigm shift.”

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The article reported that 50% of children were referred to the hospital at the first consultation. These clinicians were sharp!

Primary care physicians in the UK have been encouraged to carry penicillin in their bags, and to administer it immediately and empirically to children who appear very ill as efforts to admit to the hospital are begun. The benefit/harm-cost ratio of this approach may be high. It may be life-saving.

I would add another non-specific early sign—does the child appear very ill?

In a career, an individual primary care clinician may never encounter a patient with MD early enough to suspect and act on the possibility of MD. If the occasion arises, recognition may be life-saving.

Does a High Intake of Chocolate Reduce Risk of Death?

2-12 COCOA INTAKE, BLOOD PRESSURE, AND CARDIOVASCULAR MORTALITY

This study estimated intake of cocoa from the habitual consumption of cocoa-containing foods, and evaluated whether intake was inversely related to BP and CVD and all-cause mortality in a cohort of elderly men.

Used data of 470 elderly men (mean age at baseline = 72). All were free of chronic diseases at baseline (1985).

Assessed habitual food consumption by dietary history at 5-year intervals. This included consumption of cocoa-containing foods. Chocolate confectionary contributed about 2/3 of the total cocoa intake.

Ascertained causes of death during 15 years of follow-up.

Mean blood pressure highest tertile of cocoa use vs lowest tertile of use:

A. Mean systolic was 3.7 mmHg lower.

B. Mean diastolic was 2.1 mmHg lower.

Tertiles of cocoa intake

Lowest (0.5 g/d) Middle (0.5-2.25 g/d) Highest (> 2.3 g/d)

No of subjects 165 149 156

Cocoa median g/d 0 0.92 4.2

Relative risk (RR) of death:

A Cardiovascular death (CVD): highest tertile compared with lowest tertile of cocoa use = 0.50.

B. All-cause mortality: highest tertile vs lowest tertile of cocoa use = 0.53.

(* These RRs resulted from a model which adjusted for 19 possible confounders. RTJ)

“In the present study, usual daily cocoa intake was inversely related to blood pressure.”

“In prospective analysis, usual cocoa intake was associated with a 45% to 50% lower risk of cardiovascular

and all-cause death.”

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The results are provocative, but unrealistic. I doubt the investigators really believe that cocoa is related to a 50% reduction in mortality. The observational study assumed many adjustments for possible confounding variables. It followed a relatively small number of subjects.

I can visualize a report in the lay press—“Chocolate reduces risk of death by 50%”. Conflicting reports of medical studies result in an increasingly skeptical public.

ABSTRACTS FEBRUARY 2006

Begin Consideration of Both Biomedical and Psychosocial Causes at the Onset of A New Consultation

2-1 SOMATIZATION: A Joint Responsibility of Doctor and Patient

Patients with unexplained symptoms are common. They are often portrayed as “difficult” and “heartsink”, a burden to the doctor as well as to the health care system. They show resistance to psychological explanations of their suffering and are always in quest of biomedical cause. This results in excessive use of heath-care services and risks of iatrogenic harm.

A recent study claims that the doctor is often responsible for the disproportionate levels of somatic interventions in these patients. A detailed analysis of general practice patients with unexplained symptoms found that physical interventions were proposed more often by doctors than by patients. Almost all patients provided clues to their psychological needs. Most doctors suggested that on or more physical disease might be present. The authors conclude that the explanation for the high level of physical intervention in these patients lies in doctors’ responses rather than patients’ demands.

Further analysis of the interviews did reveal that, although doctors did indeed propose biomedical interventions, about two thirds also proposed non-medical explanations. And about 70% of patients proposed some biomedical intervention. Both were active in advocating biomedical interventions.

The truth is that both patient and doctor have a preoccupation with finding biomedical causes; patients because of fear of serious diseases, and doctors because of professional pride and fear of missing a medical diagnosis with potential judicial consequences. The mantra “First of all, do no harm” seems to be replaced by “First of all, don’t miss a medical diagnosis”.

“There is a certain tension between these two guiding principles.”

The editorialists conclude that a solution may lie in a comprehensive approach right from the start in which a biomedical track and a psychosocial track are jointly explored. This may give the patient confidence that all biomedical needs are rightly addressed while at the same time the floor is open for discussing psychological issues. Most patients are willing to discuss psychological issues at the beginning of a new illness episode, but not after all medical examinations have failed. At that point, a psychological explanation is experienced as a second-rate explanation by which many patients feel offended and humiliated.

Lancet February 11, 2006; 367: 452-54 “Comment”, editorial, first author J M Bensing, Netherlands Institute for Health Services Research, Utrecht.

2-2 SHAM DEVICE VERSUS INERT PILL: Randomized Trial Of Two Placebo Treatments.

A National Institutes of Health conference declared that understanding how placebo effects are modulated is an urgent priority. Devices are thought to have enhanced placebo effects.

This trial, in patients with arm pain, investigated whether a sham device (a validated sham acupuncture needle) had a greater placebo effect than an inert pill.

Conclusion: The sham device had greater effects than the placebo pill.

STUDY

1. A single-blind, randomized-controlled trial compared sham acupuncture device vs placebo pill.

2. Participants (n = 119) were community dwellers who had arm pain (due to repetitive use) that had lasted at least 3 months despite treatment. All had pain scores of 3 or more on a 10-point pain scale.

3. Randomized to 1) acupuncture with a validated sham device twice a week for 6 weeks, and 2) an inert placebo pill once daily for 8 weeks.

4. The sham device looks exactly like a real acupuncture needle. When the needle is “inserted into the skin” participants think they see needle penetration and feel needle penetration pain. But the needle has a blunt tip, and retracts into a hollow shaft handle.

5. Main outcome measure = arm pain measured on a 10-point scale. Secondary outcomes = symptoms on a symptom severity scale, function measured on a function scale, and grip strength.

RESULTS

1. Pain scores and the symptom severity scale decreased significantly more in the sham group than in the pill group (-0.33 vs -0.15; and -0.007 vs -0.05). (In the sham acupuncture group, the downward slope in the 10-point pain scale each week was significantly steeper than the downward slope in the placebo pill group.)

2. Differences in grip strength and arm function were not significant.

3. Nocebo effects were totally different in the two groups and clearly mimicked the information given at informed consent. Sham acupuncture subjects were told that their pain might be temporarily aggravated: placebo pill subjects were told that they might experience sleepiness, dry mouth, dizziness, and restlessness. One quarter to one third of subjects reported such adverse effects.

DISCUSSION

1. Recent mechanism studies of placebo treatments have shown that placebo effects go beyond spontaneous fluctuations in symptoms (ie, beyond the natural evolution of disease, spontaneous remission, and regression to the mean).

2. Many studies have been accompanied by deceptive expectations—ie, subjects being told that the placebo was a “potent pain medication”.

3. “If spontaneous remission alone accounted for our findings, the type of placebo should have made no difference, and we should not have been able to detect a difference between the device and pill.”

4. That the differential placebo effect was confined to self-reported measures (and not grip strength) suggests the effect that may be confined to subjective outcomes.

5. “Our findings contribute to the debate on the influence of information provided at informed consent and subsequent reported adverse effects.” “We found that reported side ef