Placebo/nocebo effects

Describe a double blind RCT which assessed what happened if the words in patient leaflets regarding side effect commonality were changed

(Webster et al, 2018) 203 healthy volunteers compared standard wording vs positively framed wording (1 in 10 will be effected vs 90% wont be affected by...) Rare became very rare etc. standard wording patients = more likely to report side effects than positively worded information, so this condition significantly reduced the nocebo effect - R=0.66. (only 9 participants guessed placebo - even removing them the effect remained) This was within healthy volunteers - Now looking to expand research into a clinical population with real medication

Describe positive framing as a potential way of reducing nocebo risk whilst not compromising ethical guidelines

- 70% of patients receiving a drug for the first time read at least some of the patient information leaflet (PIL) (Raynor et al. 2007) - The side-effects section is the part most commonly read by patients good place to intervene (in the medication leaflet - to reduce the nocebo effect) A study to assses whether patients understood the terms, rare common etc. was conducted based on patient leaflets - (n=1,003) - Randomised to mild (e.g. headache) or severe (e.g. seizure) side-effects information given to patients. found people don't understand risk as they think it is more likely to happen than it is regardless of descriptive leaflet group. suggests we are not describing side effects incidence well.

What are the requirements for classical conditioning to occur?

- CS needs to reliably predict US - More pairings = stronger effect - More powerful US = stronger effect - Intermittent schedule of pairings = harder to extinguish - Works for any effects that an active agent can generate - Pairing needs to have happened

What are the main implications associated with placebos requiring the use of deception?

- Damages doctor-patient relationship? - Damages reputation of medicine? - Benevolent paternalism? - Can and does result in lawsuits BUT is this deception? - "this substance is known to significantly reduce pain"

What are the issues with current methods of reducing ethical dillemma associated with minimising noecbo risk in practice

- Still faces criticism of reducing informed consent/patient autonomy - Explaining the nocebo effect could be problematic - patients might not seek medical advice when they have a serious side effect/allergic reaction (if genuine side effect)

What are the main critiques of the current theories for nocebo effects?

- There is not 'one theory fits all' (same issue in placebo effects) - Expectation theory cannot explain how nocebo effects can be induced through non-conscious processes - Classical conditioning cannot explain nocebo responses to exposure that we have not had experience with before (conditioning requires prior pairing) - There are many different 'nocebo effects' which have different mechanisms of action

Describe the prevalence for the clinical use of placebos despite ethical issues

- USA (1999) - 59% of physicians 'familiar' with their use - Denmark (2003) - 48% of GPs have used placebos multiple times in last year (positive suggestion and non essential tech exam = blood test or scan when not clinically needed = most frequent)

Describe expectations as a possible explanation for nocebo effects

Again expectations can be generated from: Prior experience Information from trusted sources e.g. patient information sheets, what we read/see in the media (drastic cases etc. have strong effect on nocebo), family/friends - Social observation e.g. higher expectations if someone else you can see also develops symptoms On a large scale = mass psychogenic illness (Wessely, 1987) - e.g. in schools when a girl faints on a hot day and then 3 or more also faint, then spreads throughout the school. e.g. Sham exposure to electromagnetic fields (Szemerszky et al. 2010)

Myers et al, 1987 evidence of nocebo effect in a drug trial

Altering the information sheet, alters the symptoms - 3 centres trialled (one forgot to include gastro side effects) and because they didn't have these side effects there were less drop outs in this centre

Describe research which has shown how expectations of a drug's effect (and the resulting placebo effect) can knock out the active effects of a drug

Bingel et al, 2011 - Participants exposed to heat pain and given strong painkiller Told to expect analgesia, hyperalgesia (increased pain) or given no expectations Positive expectations double the strength of the drug (expected the pain relief) Negative expectations abolish the effect (people in the hyperalgesia group given the painkiller were no better able to withstand the pain than those in the no expectation condition where not given the drug) Self-report and MRI data

Give examples of studies using classical conditioning as a possible explanation for nocebo effects

Chemotherapy and nausea (Stockhurst et al., 2007) Food intolerance (e.g. some link with gluten intolerance with having too much bread one day and feeling bloated and this happening over time to develop and intolerance) van den Bergh et al. (1995) (in healthy participants)

Describe a study looking at What happens if we deprive a treatment of its placebo effect?

Colloca et al., 2004 - Open (patients know about it) vs hidden administration of 10mg morphine in postoperative patients Results: 1- High pain after surgery, morphine after 1.5 hours - those who don't know about morphine take longer to report pain relief effects vs those who knew. Stopping the drug- quicker increase in pain for those who knew the drug has been stopped. When the patient is completely unaware that a treatment is being given, the treatment is less effective than when it is given overtly in accordance with routine medical practice. The difference between open and hidden administrations is thought to represent the placebo component of the treatment, even though no placebo has been given. The decreased effectiveness of hidden treatments indicates that knowledge about a treatment affects outcome and highlights the importance of the patient-provider interaction. In addition, by use of covert administration, the efficacy of some treatments can be assessed without the use of a placebo and associated ethical issues.

Describe the study of wind turbine syndrome (Pierpoint, 2009) as an example of nocebo effects

Communities reporting disturbed sleep and headaches etc. when wind farms erected, found correlation between side effect reporting and how often they saw media reports on them (rather than close proximity to them)

In order to overcome the ethical dilemma of informed consent etc. vs nocebo risk in practice what can be done?

Contextualised informed consent (Wells & Kaptchuk, 2012) - doctor takes into account the individual patients and decides what information to give based on what they are like as a person - its paternalistic and puts a lot on the doctors. Explaining the nocebo effect (Crichton & Petrie, 2015) - patients still get all side effect info but are aware of the potential for the nocebo effect Emphasize treatment benefit (Heisig et al., 2015) - take the attention away from the side effects and putting it more on the positives (perhaps even framing the side effects as a sign that the drug is working...?)

What is the main clinical implication of knowledge about nocebo effects

Dillemma: Whether to tell patients about all side effects in line with informed consent etc. (so increasing risk of nocebo) or limit side effect information to enhance wellbeing (but reduce informed consent and patient autonomy)

How are expectations generated?

Direct experience (e.g. medication has worked in the past so should work again) Explicit information from others (especially trusted sources) - e.g. doctors, parents etc. Implicit information from others (doctor's confidence, doctor-patient relationship) - e.g. non-verbal cues Observation (social observational learning) - see someone else have benefit from a medication, or in the media, may impact own experience of it Individual differences (optimism, suggestibility...)

How do expectations work in terms of the placebo effect?

Direct, unmediated effects (Stewart-Williams, 2004) Expectations of arousal likely to be arousal provoking thereby directly causing the expected effect (e.g. expecting a stimulant may make you feel stimulated in itself) Indirect effects (Emotional change) Positive expectations increase sense of control and predictability (doing something about your condition) - e.g. via Decreased worry and stress (e.g. effect on immune system from less stress) Indirect effects (Perceptual change; Ross & Olsen, 1981) Look for, notice and recall information that meets expectations and Interpret ambiguous information in manner consistent with expectations - Ignore inconsistent information (or explain it in an alternative way)

Describe the use of placebo in surgery trials (example being from McCrae et al, 2004)

Double-blind sham surgery controlled trial (Parkinsons patients) to determine the effectiveness of transplanting human embryonic dopamine neurons into brains of patients with Parkinson's on quality of life 1 year later Patients randomly assigned to receive the transplant or sham surgery (still have surgery, just not the embryo transplant) Regardless of condition they were assigned to, those who thought they received the transplant reported better QoL scores (perhaps surprising they got the ethical approval given risks of anaesthetic etc.)

Describe the use of placebo in drug trials

Early 1900's: placebos start to be used more regularly to control for suggestion and other, non-drug, effects Placebo effects are a nuisance Response rates can be as high as 30-50% (Enck et al., 2011) - where the placebo makes them feel better despite having no reason to Aim is to develop drugs that have more of an effect (higher response rate) than that of a placebo

What are three core proposed psychological mechanisms of action for the placebo effect?

Expectance, classical conditioning, (psychological characteristics), there are also biological ones

Critique the main theory of placebo effect

Expectation theory cannot explain placebo effects generated through nonconscious processes Conditioning leads to stronger placebo effects as such placebo effects seem to be multifaceted - Lots of different components of 'the placebo effect' so perhaps a mistake to lump them all together

What are the main explanations for nocebo effects

Expectations Classical conditioning Misattribution (not for placebo) Individual differences

How can the placebo effect of treatments be enhanced?

Explore and manage patient expectations Create expectation of improvement Maintain trust 'Concerned optimism' - empathise with patient but at the same time optimistic they will improve Consider effects when transitioning between drugs (for your patient) - Brand name to generic (effectiveness and side effects may increase)

What are the 2 types of expectancy

Hypothetical expectancy (paracetamol cures headaches), categorical expectancy (Ive taken paracetamol. my headache will go)

Give some key findings about placebos

Improve health and cause side-effects, at the same time Mimic active drugs (Shapiro, 1970) - Two pills are better than one - Big pills are better than small ones (more medicine expected?) - Injections are better than pills (idea that it gets into bloodstream quicker) Follow cultural norms (Blackwell et al., 1972; Luchelli et al., 1978) - Red, yellow or orange pills = stimulants (report increased heart rate, jittery etc.) - Green, blue or purple pills = sedatives (report feeling drowsy etc.) Branded placebos work better than unbranded ones (Faasse et al., 2015) Expensive placebos are better than cheap ones (Espay et al., 2015) Placebo effects can be localised - placebo cream reduces pain only in the finger it is applied to (Montgomery & Kirsch, 1996)

Describe expectations within placebo effects

Large body of work suggests that strength of expectation is associated with strength of placebo effect (Finnis et al., 2010) - by assessing strength of expectation before taking the placebo and then looking at the effect of the placebo Accounts for anything you can form an expectation about, including positive, negative and localised effects Can knock out the effect of an active drug

Summarise nocebo effect

Nocebo's may explain many medication side effects Need to develop ways to reduce nocebo effects without reducing informed consent

What can both medication side effects and nocebo effects lead to

Non-adherence Reduced quality of life (vs just dealing with the existing medical condition) Costs the NHS billions! (e.g. people turning up to GP with symptoms, being prescribed extra meds to counteract for these effects etc.) BUT only 10.9% of reported adverse reactions to commonly prescribed drugs are clearly attributable to the medication - suggest most effects are non-specific and may be attributable to a nocebo effect Many side effects are not always related to the physiological action of the medication (Faasse & Petrie, 2013) These are thought to occur due to the nocebo effect (Barsky et al. 2002)

Is gluten intolerance a nocebo effect?

Non-celiac gluten sensitivity (Biesierkierski et al., 2013) study - Study compared celiac disease patients and self-reported intolerance and cycled them through different levels of gluten in the diet. There was no difference in any gluten group for the self-reported patients

Give some example nocebo effect symptoms

Pain, sweating, nausea, headaches, gastrointestinal symptoms

Define placebo effect

Placebo effect is the improvement/positive outcome that is experienced after exposure to the sham

What are the main examples of nocebo effects given in the lecture

Placebo overdose (Reeves et al., 2007) Conditioning nocebo effects in rats (Ader & Cohen, 1975 Wind turbine syndrome (Pierpont, 2009) The dump that wasn't there (Maugh, 1982) Non-celiac gluten sensitivity (Biesierkierski et al., 2013) Idiopathic environmental intolerance - e.g. being allergic to computer signals, overhead power signals, Wi-F - Electromagnetic sensitivity Rubin et al. (2006) EM signals - headaches, not sleeping etc.

Describe a study into the nocebo effect related to electromagnetic sensitivity (Rubin et al, 2006)

Rubin et al, 2006 Tested whether people who report bring sensitive to mobile phone signals have more symptoms when exposed to a pulsing mobile phone signal than when exposed to a sham signal (phone strapped to head) 60 "sensitive" and 60 "control" participants Double-blind, randomised trial There was no difference between the conditions in terms of symptom (headache) severity so no effect of condition. Suggests that the negative expectations of these signals have caused the symptoms and not the signals themselves...?

Describe a study which concluded that homeopathic intervention offers positive health changes to patients with a wide variety of chronic conditions

Spence et al. (2005) Assessed health changes in routine homeopathic care for patients with chronic conditions (natural alternative: so treating like with like where a fever may be treated with spices etc.) Observational study of 6544 patients during a 6 year period Health outcomes measured on a 7 point likert type scale 70.7% reported positive health changes 50.7% recorded their improvement as better or much better

Give an example of a study of the placebo effect showing the real-world implications of it

Sport doping: Benedetti et al. 2007 Athletes given intramuscular opioid injections on training days to enhance pain endurance. Saline injection on day of competition improves performance, with no trace of a drug present. - real world implications for sporting events performances (evidence for either type of theory potentially?)

Describe miss-attribution as an explanation for nocebo effects

Symptoms are common in everyday life (e.g. pain or breathlessness) Easy to misattribute an unrelated symptom to an exposure if both occur at a similar time

Define nocebo effect

The experience of unpleasant symptoms in response to a sham or inert exposure First documented in 1896

Summarise the placebo effect

There is no one "placebo effect" - there are several different placebo effects Main mechanisms involve expectation and conditioning We use the placebo effect all the time. The trick is knowing how to enhance it, and to do so ethically

Describe the process of classical conditioning

Unconditioned stimulus (US) causes unconditioned response (UR) Repeatedly pair US with conditioned stimulus (CS) Eventually CS will cause a response like the UR, called Conditioned Response (CR) e.g. Pavlov's dogs

What is the main implication of enhancing the placebo effect in practice (forgetting about ethical implications)

We could reduce use of drugs with side-effects - Reduce narcotic use by 30% post-op -Reduced chemotherapy doses in lupus

Describe the study of Placebo overdose (Reeves et al, 2007) as an example of the nocebo effect

clinical trial of a drug for depression - 1 patient in placebo trial overdoses on the placebo drug and BP drops, he faints etc. but then he's told he only took placebo and is fine

Describe the study of conditioning nocebo effects in rats (Ader and Cohen, 1975) as an example of the nocebo effect

got rats to drink water sweetened with sacharine solution and also put an immunosuppressant. They learned to associate the sugar taste with feeling unwell. Afterwards, presented with simple saccharine solution and immunosuppressant effects found and rats still died due to the conditioned effect.

Limitations of findings about homeopathy benefits from Spence et al, 2005

important to think about the other factors that may have been going on that could also be used to explain these positive effects, as not a controlled trial - e.g. behavioural factors such as diet, other health treatments - medication etc. alongside this, change in attitude may affect positive thinking Spontaneous improvement • Regression to the mean (i.e. normal fluctuation) • Selection bias at start • Recall bias of earlier symptoms (recalling the negative ones more) • Demand characteristics (what the researcher wants to find)

Describe the study of the dump that wasn't there (Maugh, 1982) as an example of the nocebo effect

people thought there was a chemical leak and people began reporting breathing difficulties, rashes etc. - but environmental protection agency found nothing wrong - symptoms resolve on their own

Give a study example of misattribution leading to nocebo effects

pesticide spraying (Petrie et al., 2005) - surveyed people in the area about e.g. health anxiety before widespread spraying, then also after and asked if any side effects after spraying reported - number of symptoms at baseline was strongest predictor of number reported after the spraying happened

Describe the nocebo effect within drug trials

~25% of patients in the placebo arm of a clinical trial will experience the side effects associated with the real medicine (Barsky et al. 2002) - as patients don't usually know which condition they are assigned to in such trials Typically warned about these in the information sheet (so have the knowledge of what the medication could cause and may experience it anyway)

According to Webster et al. (2016) what individual differences are associated with nocebo effects based on their links with ease of generating expectations

• Pessimism (effect of personality) • Perceived sensitivity to medicines (amplifies effects) • Somatisation • Negative affect • Modern health worries (e.g. worries about technology)