Nocebo - Part 2

I have been waiting for this paper (1) to come out for the past 6 months.  I posted on the very interesting nocebo effect in antidepressant trials and why it was so interesting and in the process learned that the lead author - Seetal Dodd had a paper being reviewed on the nocebo effect in bipolar trials.  That paper finally came out and I had the pleasure of reading it and presenting it here.

As a brief refresher, the nocebo effect is an adverse drug experience or worsening based on taking placebo or inactive medication in a clinical trial.  At the clinical level, it can also be an unrealistic reaction to a medication based on  similar response.  Any researcher who has participated in clinical trials that all breaking the protocol and allow the subject to be informed about whether they were taking active drug or placebo has probably observed this effect.  Clinicians commonly see it as an improbable reaction to a medication or in some cases multiple medications.  It is an important phenomenon because it blurs the results of clinical trials by making it seem that there is less difference between placebo and the active drug being studied.  It also may lead to the rate of actual adverse events due to the study drug being underestimated.

For the purpose of this study the nocebo response is defined as any a treatment emergent adverse events (TEAE) or clinical worsening in people treated with a placebo. That involves collecting data on both TEAEs and rating mania and depression.

The data used in this study was from a randomized placebo controlled clinical trial of olanzapine monotherapy for bipolar disorder versus placebo and several comparators (haloperidol, valproate, olanzapine-fluoxetine combination [OFC]).  The trials occurred between 1996 and 2007.  There were a total of 9 studies and 7 were published.

Only data for the patients randomized to placebo (N = 1185/4680) were used for the purpose of this study and meta-analysis.  866/1185 or 68% experienced  (TEAE) and 4.6% discontinued the study due to a TEAE.  Typical rating scales for mania and depression were used to rate symptoms. TEAEs were significant ranging from 3% to 11.8% of the placebo treated group.  Headache, insomnia , somnolence, anxiety, nausea, diarrhea, irritability, and agitation all occurred in over 5% of the placebo treated patients.  Median time to report the TEAE was 16 days with the longest time of 37 days.

Apart from the TEAEs, a significant number of the placebo treated patients experienced clinical worsening as noted on the rating scales for depression (321 or 27%), mania (585 or 49%), or global function (278 or 23%).

The 806 patients reporting TEAEs reported a total of 1,119 nocebo events.

TEAEs were associated with not being treatment naive, being obese, being located in the US, and participating in an earlier study.  There were no significant difference based on gender or smoking status.

A major limitation of the study is that it is not possible to detect if clinical worsening is a nocebo effect or and the effect of worsening illness.

In their discussion the authors point out that the evidence is that the nocebo effect is significant in clinical trials.  Of all of the possible correlates they studied they di not find any that were useful to predict who might be a nocebo responder.   They discussed some psychological theories and in a couple of additional papers discuss the putative neurobiological underpinnings of both the placebo and nocebo effect.  Certainly any effect that leads to 4.5% or placebo treated patients discontinuing the study is significant.  Until the nocebo effect is better characterized we probably do not have an adequate estimate of the side effect profiles.  The authors describe is as similar to the placebo response as "an expected consequence of exposure to therapy."

The nocebo response may be less clear in looking at the therapeutic effects of medication.  I think it is good to remember that true nocebo/placebo effects are estimated on the placebo response.  In other words a 20% placebo response rate means that 20% of the actively treated group also responded to placebo.  Hence, if 68% of the placebo treated group experience TEAEs and 4.5% discontinue the study on that basis - what happened when those number are applied to the actively treated group?  It would generally mean less subject carried forward in an intent-to-treat analysis and and a more favorable side effect profile if the nocebo responders could be accurately identified. A good place to start to look for more accurate numbers and methods of identification may be in large scale medicine studies looking at an identifiable quantitative endpoint like blood pressure.  The nocebo effect is easier to sort out with a medication that has a clear effect on a more easily measured parameter.

Clinicians are left with estimating the likelihood of a TEAE or nocebo response based on the likelihood of a patient exhibiting a particular side effect.  A low likelihood of a particular presentation is fairly frequent in clinical practice and continuing the medication in those circumstances often comes down to clinical necessity.  As an example, the patient has a vague TEAE, but learns from the physician that there are no other medications that can be prescribed for the problem.

Nocebo responses are certainly out there.  Clinically we can be more specific until there is better research guidance on what to do about it.  I have had conversations with many people who were interested in the placebo response or why a particular pattern of responding to a therapeutic intervention may have been established.     



George Dawson, MD, DFAPA


References:

1: Dodd S, Walker AJ, Brnabic AJM, Hong N, Burns A, Berk M. Incidence and characteristics of the nocebo response from meta-analyses of the placebo arms of clinical trials of olanzapine for bipolar disorder. Bipolar Disord. 2018 Jun 21. doi: 10.1111/bdi.12662. [Epub ahead of print] PubMed PMID: 29926533.

Attributions:

Figure at the top is stock photo from Shutterstock per their licensing agreement by kasezo entitled:

Stock illustration ID: 284558927 conceptual 3d design of false pill.( placebo and nocebo effect.red and green colored version)

The Nocebo Effect In Antidepressant Trials

Early in my career I was an assistant to principle investigators who were doing clinical trials of drugs to treat generalized anxiety disorder, major depression, schizophrenia, and Alzheimer's Disease.  My job was top screen patients, do medical histories and physical examination, and follow them throughout the research protocol.  That is not an easy job.  The difficult part is making sure that the research patients are not getting any medical complications from a new and experimental drug in addition to assessing any possible therapeutic effects.

One of the main complications was the nocebo effect.  With all of the hype about placebo effects with antidepressants, I have always found it curious that few mention the nocebo and how it affects clinical research.  In those early days it was possible to break the blind and if research subjects withdrew from the protocol to let them know if they were taking active drug or placebo.   An adverse reaction to placebo is the nocebo effect.  It was common in these protocols for research subjects to either stop the protocol due to adverse effects or describe severe side effects while they were taking placebo.

One of the main problems I encountered with this effect in clinical trials that is an even bigger problem today is loss of research subjects who terminated early due to nocebo effects.  In the example I gave the patients developed significant side effects in response to a placebo, but people can also develop dramatic side effects to the active research medication.  Whether they are more likely to get the effect from active drug or an active placebo over the active study drug has not been actively studied.  These are critical questions because FDA trials now require and Intent To Treat Analysis for clinical trials.  That means all of the research subjects who did not complete the protocol for whatever reason need to be included in the analysis.  That becomes a problem when any subject has not been treated with the active drug - both in terms of true response but also side effects reporting.  All FDA package inserts contain detailed information on medication side effects.  Today in many cases there is a side effect comparison between active drug and placebo. Nocebo related data can skew the side effect data reported in the package inserts.    

I always thought that antidepressant trials were the ideal setting to study nocebo effects and came across a paper two years ago that does that (1).  That time frame over the last two years was an interesting one.  We saw all of the speculations about the release of the DSM-5 in the summer of 2015.  Much of that speculation involved sensational articles in the media suggesting that antidepressant medications did not work or ate least were no better than the placebo effect. Further speculation suggested that pharmaceutical manufacturers and the American Psychiatric Association (via the DSM-5) had an interest in broadening the market for antidepressants and increasing their use. At no point did any of the critics suggest that their may be a serious problem with clinical trials based on the nocebo effect.  And most interestingly, many of the critics in non-professional forum complained mostly about the side effects of these medications.  In some cases they described these medications as very dangerous.

The paper in reference 1 looks only at people receiving placebo in a pooled sample of placebo-arm data from 20 industry-sponsored multi-site randomized clinical trials of antidepressant medication in the treatment of acute major depression.  Adverse event data was recorded for all 20 clinical trials.  Adverse events (AE) can be pre-existing nonspecific somatic symptoms.  Treatment emergent adverse events (TEAE) were events that occurred or worsened during placebo treatment.  The adverse events were obtained by open ended questioning and in clinical trials from that period (1993-2010) were listed on standard forms.  Five endpoints were studied including any AE, any treatment related AE, any severe AE, any serious AE resulting in discontinuation from the study, and discontinuation form the study for any reason.  Worsening of clinical symptoms was also measured and defined as any increase in the depression rating score on any scale used for that particular study.

The main results included:

1.  TEAEs from placebo were reported in 1,569/2,457 or 63.9% of the study participants.

2.  11.2% (274) of the participants had worsening depression rating scores during the placebo treatment.

3.  4.7% (115) of the participants discontinued the study due to an AE during the placebo treatment.     

Just considering those results and nothing more illustrates the nocebo problem with current state-of-the-art clinical trials technology.  If 63.9% of the placebo-treated subjects experience side effects - what does that translate to in terms of subjects taking the active drug getting side effects unrelated to that drug?  Although untreated depression might be expected to worsen - how much of that is nocebo modulated and how much crosses over to the active drug.  A significant number of people dropped out of the trial due to the nocebo effect.  The main results suggest that in randomized placebo controlled trials of efficacy and safety - the nocebo effect is substantial.  Since the observed TEAEs and percentage of research subjects worsening on placebo was substantial - extension to TEAEs, worsening, and dropping out in clinical practice could be expected.  That would be a very difficult problem to research due to a lack of standardization across practices.

The authors did not stop with those results.  They looked at additional variable to see if there was any evidence to confirm either of the two major hypotheses about the nocebo effect.  The first is a conditioning hypothesis.  In this effect, prior exposure results in the expectation of an associated effect.  They cite as an example, women receiving chemotherapy for breast cancer and how an associated stimulus led to more nausea in the conditioned group (4).  In this case they looked at previous treatment with antidepressants as a possible conditioning effect and did not find any significant associations.

The other major hypothesis regard the nocebo effect is an expectation hypothesis.  They cite an example where a sample of college students were given inert placebo and told that it was an herbal supplement for cognitive enhancement (5).  They were provided with a fictitious list of potential benefits and side effects.  Symptoms were endorsed by most students but the students who believed that they received the active supplement endorsed more symptoms suggesting that their expectation of supplement and effect affected their perception.  They found some support that previous treatment with Hypericum perforatum (St. John's Wort) may have been associated with a greater likelihood of reporting TEAEs and suggest that users of complementary medications may be more suspect of medical pharmacotherapy.

The paper is a fairly concise review of demographic and neurobiological factors associated with the nocebo effect.  On the neurobiological side they cite the work of Enck, et al (6).  Elman and Borsook (7) have an interesting paper that looks at addiction, pain, and several common substrates of the placebo and nocebo effects.             

The take home message for me is what I have known for over a decade at this point. Current clinical trials technology in psychiatry and medicine is general is very primitive.  The evidence-based movement has had its day if this is the kind of evidence they are considering.  Why would anyone expect much more than a mild to moderate effect from a medication used for heterogeneous disorders when the true effect of the medication is significantly affected by two factors that are never measured?  This suggests areas for improvements in clinical trials that could render much of what has been collected so far - obsolete.

A final observation comes to mind and that is a phenomenon that I wrote about on this blog many years ago.  People with little to no expertise in psychiatry or medicine don't hesitate to criticize the field.  A good example would be people who have never treated a single case of depression much less thousands of cases who do a meta-analysis and claim that antidepressants are placebos.  I don't recall any of these critics in the popular press considering the limitations of clinical trials.  Without that basic consideration any theory that fits the apparent data can apply.

What would be useful at this point would be detailed analyses of the placebo arm of all clinical trials and a discussion of how these effects might bias the data.  Actual interventions to quantify or eliminate these effects in future trials is the next step.  These are more practical steps than hoping for mythical large clinical trials with slightly more sophisticated clinical trials technology that epidemiologists and the Cochrane Collaboration routinely recommend.         


George Dawson, MD, DFAPA

References:

1: Dodd S, Schacht A, Kelin K, Dueñas H, Reed VA, Williams LJ, Quirk FH, Malhi GS, Berk M. Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials. J Clin Psychiatry. 2015 Jun;76(6):702-11. doi: 10.4088/JCP.13r08858. PubMed PMID: 26132671.

2:  Gupta SK. Intention-to-treat concept: A review. Perspectives in Clinical Research. 2011;2(3):109-112. doi:10.4103/2229-3485.83221.

3:   Interactions between brain and spinal cord mediate value effects in nocebo hyperalgesia” by A. Tinnermann, S. Geuter, C. Sprenger, J. Finsterbusch, C. Büchel in Science. Published online October 5 2017 doi:10.1126/science.aan122

4:  Bovbjerg DH, Redd WH, Jacobsen PB, Manne SL, Taylor KL, Surbone A, Crown JP,Norton L, Gilewski TA, Hudis CA, et al. An experimental analysis of classically conditioned nausea during cancer chemotherapy. Psychosom Med. 1992 Nov-Dec;54(6):623-37. PubMed PMID: 1454956.

5: Link J, Haggard R, Kelly K, Forrer D. Placebo/nocebo symptom reporting in asham herbal supplement trial. Eval Health Prof. 2006 Dec;29(4):394-406. PubMed PMID: 17102062.

6: Enck P, Benedetti F, Schedlowski M. New insights into the placebo and nocebo responses. Neuron. 2008 Jul 31;59(2):195-206. doi: 10.1016/j.neuron.2008.06.030. Review. PubMed PMID: 18667148.

7: Elman I, Borsook D. Common Brain Mechanisms of Chronic Pain and Addiction. Neuron. 2016 Jan 6;89(1):11-36. doi: 10.1016/j.neuron.2015.11.027. Review. PubMed PMID: 26748087.



Attributions:

Figure at the top is stock photo from Shutterstock per their licensing agreement by kasezo entitled:

Stock illustration ID: 284558927   conceptual 3d design of false pill.( placebo and nocebo effect.red and green colored version)

Language and the Nocebo Effect

Arthur Barsky wrote an article in this week's JAMA entitled "The Iatrogenic Potential of the Physician's Words."  Dr. Barsky is one of those authors I have been reading over the past 20 years.  He is a psychiatrist and an expert on psychosomatic medicine.  Like a number of authors, when I see his name - I just read the article. It is automatic.  This article is brief but it contains a lot of wisdom about how communication with patients can affect the expected outcome of medical treatment.  There are several points in the article that just jump out at you if you are an experienced clinician and have followed many patients.

The single most important sentence in the article starts the second paragraph:

"Somatic symptoms and underlying disease do not have a fixed, invariable, one-to-one equivalence."  Physicians of course are trained to see a multitude of presentations of illness.  Influenza is a good example.  The majority of people are more ill than if they have the common cold, but a significant number are critically ill and dying.  For example in 2016, the CDC estimated that about 24.6 million people got the flu, 308,000 were hospitalized, and 11,995 died.  Theoretically there are a number of people with few or no symptoms who can still spread the virus.  There are a significant number of factors in both the disease vector and the host that determine a wide array of outcomes.  Infectious diseases provide the most straightforward example or variability in symptoms, underlying illnesses and outcome.

With the chronic complex, polygenic illnesses that require ongoing medical care the situation is less clear.  In this case we have a patient who is constantly updating their assessment of their problems, symptoms, and state of their illness.  They make similar determinations about any medicine or treatment that their physician wants them to take. A significant part of that determination is based on the information that they obtain from their physician or other sources and more importantly how it is presented.  From a psychiatric perspective it should be presented as neutral as possible, but patients vary greatly in their reactions to even fairly dry information.  As an example, I typically provide patients with MedlinePlus information on their medications.  I consider these documents to present all of the essential unbiased information.  It is still common to encounter people who tell me: "Don't give me that doctor! I know if I read it I will get every side effect that is listed!"  I honor their request and reassure them that they can call me if there are any problems.

Dr. Barsky focuses on the informed consent aspect of treatment and how the information presented can affect the patients reaction to the treatment.  He gives examples of men warned about the sexual side effects of beta blockers getting roughly twice as much sexual dysfunction and back pain patients undergoing spine imaging having more pain, functional impairment and physician visits.  Psychiatry has the additional burden of many more vocal critics promoting the side effect burden of medications, often to the point that it seems like there was a conspiracy to "cover them up".  That results in patients in the office complaining about what they have read online, even before the informed consent discussion begins.

There is a discussion of the nocebo effect or adverse effects to placebo treatment that does not receive enough discussion within medicine.  I had early familiarity with this phenomenon from my work with clinical trials of pharmaceuticals (antidepressants, anxiolytics, antipsychotics).  In each case the active drug was compared to placebo and patients were followed closely.  In those days we were allowed to break the blind to tell patients if they were on active drug or placebo.  The first time I encountered the nocebo effect, I was treating a young man with an experimental anxiety medication.  He bitterly complained of many side effects initially and at the second or third visit said that he could no longer stand it.  He needed to be taken off the medication because it was making him extremely ill.  I broke the blind and told him that he was taking an inert placebo.  He was somewhat embarrassed but the symptoms resolved during the time he was sitting in my office.  Since then I have seen the nocebo effect hundreds of time in clinical practice.  Many of the predisposed claim a high sensitivity or allergy to multiple medications and warn me ahead of time that they need to start on the lowest possible dose of medication.  Even then it is dicey.

Over the years that led me to develop a uniform informed consent decision designed to minimize the nocebo effect.  I think it is fairly straightforward to provide all of the relevant information in a manner that transmits both the side effect but also the likelihood of developing the side effect to the patient.  Worst case scenarios are never avoided.  For example, I always warn people on serotonergic medications about the risk of serotonin syndrome and the fact that it can be lethal.  I also let them know that the chances of developing serotonin syndrome are very low.  I use the same approach for tardive dyskinesia and other tardive syndromes, diabetes mellitus, cardiac arrhythmias, metabolic syndrome, seizures, neutropenia and agranulocytosis, and neuroleptic malignant syndrome.  But also give them an estimate of how likely it is that they will develop that side effect or how often I have seen the side effect in 30 years of practice.  That approach seems to have the expected effect on false positive reports of these symptoms and in fact I am much more likely to notice threshold symptoms (hypophonia, micrographia, etc) than the people who I warn about the side effects.

A second tier of symptoms surrounds the issues of sexual side effects and weight gain.  A significant number of people are averse to trying any medication that might result in either side effect.  That can occur even when they want to take the medication.  In that situation it is useful to have a comprehensive reference that described the entire range of side effects in clinical trials for specific medications and present the facts.  The facts will generally illustrate that the side effect of concern is not universal by any means and can be addressed if it happens in the case of sexual side effects or proactively (at least in some cases) in the case of increased appetite and weight gain.

Given the long list of potential side effects, reassurance that they will be assessed and a plan put in place to address them is the best approach to informed consent.  The other discussion that most people find reassuring is that I have a low threshold for stopping a medication that causes any side effect that a patient finds distressing.  During residency I had the experience of stopping an antidepressant medication that a patient had been on for 5 years.  He was complaining primarily of a flu-like syndrome and headaches.  After that medication was stopped those symptoms cleared up entirely.  Since that incident, I routinely advice patients that I don't advise that they try to "get used to" medications and that I would prefer we just stop a medication if it is causing problems and try a different approach where possible.

Barsky invokes viscerosomatic amplification as a likely cause of information affecting symptom perception.  He provides a very interesting supplement outlining a process whereby both benign but noticeable bodily sensations and disease symptoms of varying intensity are biased by information provided by the physician leading to a feedback loop of increasing anxiety, vigilance, and reactivity.  Psychiatrists used to treating anxiety disorders are probably very familiar with this mechanism.  I routinely ask those patients if they have cardiac awareness.  Are they aware of their heart beating as they lay awake in bed at night waiting to fall asleep?  Is it more intense than that - like their entire body is pulsating?  What is their theory of what is happening?  Are they concerned that there is something wrong with their heart?  That phenomenon suggests that anxiety plays a significant role in selective attention and hypervigilance that is internally focused.  It also suggests a major role for temperament and personality factors in the hypervigilance process since so many patients experience the anxiety at that level.     

Concrete steps to minimize the symptom amplification process are discussed and they logically follow the proposed mechanism.  The meaning to the patient of the symptoms needs to be explored.  Education can be provided about both the nocebo effect and the amplification process.  I typically use my research vignette for the nocebo discussion.  The purported evolutionary aspects of anxiety and how it results in theories including somatic theories is a good starting point.  The article suggests that "contextualized informed consent" can be useful or a method not enumerating "benign, nonspecific symptoms" with the patient's consent.  This is often a practical matter given the length of rare and nonspecific symptoms included in package inserts these days.  If the patient present with what I consider to be a rare side effect, I will look it up during the session, give them a ballpark estimate of how common it was in the clinical trials and discuss other potential causes.

The article also points out that side effects can also point to problems in the physician-patient relationship.  Psychiatrists who are training in therapeutic neutrality often encounter difficulties with dependent patients who frequently present as not tolerating any medication or suggestion.

In addition to typical prescription scenarios this dynamic applies to other important clinical scenarios.  Treating acute and chronic pain is a case in point.  There is probably no better example of patient expectations based on physician advice than this prescribing relationship.  If opioids are involved the scenario is complicated by a medication that reinforces its own use.  The physician discussing medication response can bias the patient in the direction of dose escalation in the context of what is perceived as an incomplete response to pain when chronic pain does not respond completely to opioid analgesia.

In many cases entire illnesses are the result of problematic information supplied by physicians.  Cases of chronic Lyme disease and the extremes that many of these patients go to including the application of devices that constitute medical quackery is another example.  The best approach in these cases is to discuss the patient's theory of their current symptoms and how anxiety amplifies these symptoms.  At that point an alternate more plausible theory for their distress can be discussed and it often results in significant improvement if not resolution of symptoms. 

I can't recommend this brief article by Dr. Barsky enough.  It should be read and understood by all psychiatric trainees and practicing psychiatrists.  These concepts are critical to both discussions with patients about a treatment plan in order to avoid iatrogenic effects and to make sense out of somatization. 
     


George Dawson, MD, DFAPA   

         
Reference:

1: Barsky AJ. The Iatrogenic Potential of the Physician's Words. JAMA. 2017 Dec 26;318(24):2425-2426. doi: 10.1001/jama.2017.16216. PubMed PMID: 29090307.


Attributions:

Figure at the top is stock photo from Shutterstock per their licensing agreement by kasezo entitled:

Stock illustration ID: 284558927   conceptual 3d design of false pill.( placebo and nocebo effect.red and green colored version)



            

Placebo - Nocebo Implications For Psychiatric Research and Clinical Care

The words popped up this week in two separate journals that I read regularly.  In the New England Journal of Medicine, there was an opinion piece on Placebo Effects in Medicine.   In the Journal of Clinical Psychiatry there was an article on Nocebo Effects in the Treatment of Major Depression.  Most people are familiar with the definition of placebo, or an apparent therapeutic effect from an otherwise inert medication or therapeutic intervention.  Even though the nocebo effect has been known for some time, it is less familiar.  A nocebo effect is an apparent adverse reaction to an inert substance.  I first became aware of it about 30 years ago as a clinical investigator working on a double blind placebo controlled study of an experimental anxiolytic medication.  In that study, the blind could be broken and the research subject informed of whether they were receiving active drug or placebo.  I had to inform several distressed subjects that they were receiving placebo after they insisted on stopping the study due to medication side effects.  In clinical practice, nocebo effects are also apparent typically as adverse reactions to low doses of medication or very atypical responses to medication.  In clinical practice, the determination is always probabilistic because placebos can't be given.

In the nocebo paper (1),  the authors analyze treatment-emergent adverse events (TEAEs) in 1,565 or 2,457 placebo treated participants in 20 industry sponsored, randomized, placebo controlled trials of duloxetine.  There were 16 different study designs typically in terms of length.  The Hamilton Depression Rating Scale (HDRS) was the primary outcome measure in 17 of the trials.  The authors looked at worsening ratings of depression score,  TEAEs, and discontinuation rates.  The authors hypothesized that prior conditioning by previous treatments (especially within the same class of drug) and negative expectations regarding treatment might predict nocebo responses.  They could find no  results to support either of these theories.  

The nocebo response has clear implications for interpreting the results of clinical trials in psychiatry and clinical practice.  Nocebo has really not been a term in the discussion, even by some authors who have basically declared that there is no antidepressant response (3).  Practically all of the naysayers doing meta-analyses to prove that antidepressants don't work don't include any discussion of it in their work.  All that you hear is that there is really no difference or not much difference between active drug and placebo.  What if 10% of the worsening depressive symptoms and 5% of the dropouts were due to a nocebo response?  That is a significant proportion of the trial subjects carried forward in an intent-to-treat design.

Should nocebo response rates be calculated for all clinical trials?  I think that they should and that data should be collected in a standardized manner as a part of clinical trials redesign in psychiatry.

What happens in clinical practice?  If a patient tells me that he or she is cutting up the lowest dose of a medication into sixteenths and can only tolerate 1/16 at a time due to side effects, I am not going to tell them to gradually titrate the dose up by sixteenths.  I know that this is probably a nocebo response, and it will likely occur with other medications.  I tell them to stop whatever they are doing immediately and we will try something else.  That could be a treatment focus on insomnia, supportive psychotherapy, exercise, meditation, relaxation techniques, mindfulness approaches -  anything but that medication.  If a patient tells me that they are basically "allergic to everything" my approach is the same.  I have no interest in prescribing a medication that makes a patient feel worse, irrespective of the purported clinical phenomenon.  Often, the patient's response is surprise.  Many people with these reactions are accustomed to physicians anguishing with them over the fact that they "cannot take any medication" and going through all of the excruciating misadventures associated with that nocebo response.  I certainly don't.  There are many other approaches and many other doctors who they can see.  One of the behaviors that I have observed in this population is a tendency to seek out complementary medicine providers where there is a risk that nocebo responders will find other treatments that may be more expensive with no proven efficacy in the context of improved tolerability.  There is also a tendency for non-psychiatrists to "kick the can down the road" and tell the patient experiencing a nocebo response that they have a psychiatric problem and need to see a psychiatrist.  I think it is useful to discuss the placebo and nocebo effects with patients and provide them with as much detail as possible.  I tend to focus on what is known rather than speculative neurobiology, especially in any conversation about endorphins.  Endorphins have already been excessively hyped as being associated with the "high" associated with exercise but the evidence is weak (4).

The opinion piece on placebo effects (2) is an interesting contrast.  One of the authors of this piece is associated with the Program in Placebo Studies & Therapeutic Encounter (PiPS).  A white paper on their web site describes their observations about the placebo effect and an action plan to conduct further research and a possible introduction of it as an action plan in medicine.  In the opening paragraphs they allude to the theoretical neurobiology of placebo effects including the early genetics of placebo responders.  They summarize three major findings of current research on placebo effects.  The first is that they are not curative.  The best example of this was the placebo effects with asthmatics.  Their subjective symptoms are relieved but their forced expiratory volume in one second (FEV_1.0) - stays the same.  The same is true of placebo in cancer treatment where the side effects of treatment improve but there are no changes in tumor size.  The second is the expectation effect, best illustrated by an example the authors give having to do with rizatriptan - a standard migraine medication.  If the active drug is labeled "placebo" the results are no better than placebo.  If the active drug is correctly labeled the antimigraine effect increases by 50%.  They list a number of medications with similar expectation effects.  Lastly, they touch on the nocebo effect as "the psychosocial factors that promote therapeutic placebo effects also have the potential to cause adverse consequences."  In a clinical trial of finasteride for benign prostatic hypertrophy, patients informed of sexual side effects report them at three times the rate of men who have not been informed.  They quote the statistic that 4-26% of placebo treated patients in clinical trials discontinue the study due to perceived side effects.  The philosophical aspects of this commentary are probably the most interesting.  The authors correctly point out that the placebo effect has pejorative connotations.  There is perhaps no better example than in psychiatry.  They suggest a further understanding and application of the various facets of this response to create a better therapeutic alliance with patients and alleviate their suffering.

This is a fascinating area of psychiatry.   I am generally compulsive about informed consent in general and more so in high risk situations.  For the highest risk warnings that I give patients - serotonin syndrome, tardive dyskinesia, agranulocytosis, cardiovascular complications, seizures, renal failure, and liver failure - I have never seen a nocebo effect.  That may have to do with the clear objective markers of these problems or the fact that I describe them as rare complications.  On the issue of sexual side effects, I clearly explain what they are and give people the exact numbers from clinical trials.  When it comes to explanations about medication side effects, the one that leads to the most problems is increased appetite and weight gain.  Even though that side effect is common with medications that psychiatrists prescribe, people tend to flee from it independent of the statistics and how much weight they have recently lost or gained due to either the primary psychiatric diagnosis or substance use.  It seems that most people who are likely to be nocebo responders, are well known before it gets to the informed consent stage.  In the initial evaluation stages they have clear histories of not be able to tolerate much of anything and the side effects described are very atypical.  

Another area where placebo-nocebo comes into play is when the primary disorder has been treated and a patient presents with the idea that the "medication has lost its effect".  There are papers written on this effect and some give statistics about how often it occurs.  In my experience, these outcomes are most often not due to a medication, but prevailing psychosocial factors and/or substance use.  Clarifying and addressing those issues frequently leads to better outcomes than changing medications or adding another one.  In many way it seems that some elements of a placebo response are an antidote to psychosocial stressors that affect medication responses.

Translating life into a medication mediated process needs to be averted at all costs.  




George Dawson, MD, DFAPA


References:

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4: Harbach H, Hell K, Gramsch C, Katz N, Hempelmann G, Teschemacher H.Beta-endorphin (1-31) in the plasma of male volunteers undergoing physical exercise. Psychoneuroendocrinology. 2000 Aug;25(6):551-62. PubMed PMID: 10840168.


Attribution:

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