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2.13 Placebo and Nocebo

Lowell Ackerman, DVM, DACVD, MBA, MPA, CVA, MRCVS

Global Consultant, Author, and Lecturer, MA, USA

BASICS

2.13.1 Summary

The concept of placebo is well known in human medicine, but it often does not get the same sort of respect when it comes to the use of medications in animals. It might be inferred that pets are the best “blinded” controls when it comes to therapeutics since pets do not know if they are being administered active medications, and yet since it is pet owners that ultimately report on what works and what doesn't, placebo is an important topic in veterinary medicine as well.

2.13.2 Terms Defined

Nocebo: A negative type of placebo effect in which being informed that there could be adverse effects associated with a therapy increases the likelihood that adverse effects will be experienced and reported.

Placebo: The beneficial effect perceived for a product without actual physiological impact.

MAIN CONCEPTS

The placebo effect is well recognized in human medicine, but it was once believed that animals could not cognitively appreciate that a medication would be of benefit to them and react accordingly. However, there are several reasons why this line of reasoning may not be correct.

A lot of work has been done on the placebo effect, including the concept of honest placebos (patients or caregivers know something is a placebo but they discern benefit regardless). It's an important concept in veterinary medicine, not because the animals can be fooled but because the owners may identify responses as positive. In our pet‐specific forum, it is important to realize that just because a pet responded, this does not mean that we made the correct diagnosis and selected the appropriate medication in all cases. We also need to account for placebo and nocebo in animals.

2.13.3 Caregiver Placebo Effect

While animals may not be able to directly perceive benefits from placebo therapies, the same cannot be said of the caregivers who are administering the medications and/or assessing its effects. This includes veterinarians, who are often eager for their interventions to have documentable success. In fact, the caregiver placebo effect may be evident around 30–40% of the time regarding subjective evaluations, such as for lameness in dogs and cats.

2.13.4 The Hawthorne Effect

Another manifestation of caregiver placebo effect can be seen as a feature of being enrolled in a study, or receiving an intervention perceived as new and potentially exciting – known as the Hawthorne effect. With the extra attention potentially shown by veterinary staff, and more scrutiny and monitoring, it is quite possible that pet owners will have expectation‐based placebo effects. Conceivably, they may approach their pet in a more positive manner, spend more time praising and having physical contact with it, and pets can respond to that increased attention.

If studies in human medicine are any indication, the placebo effect can also be enhanced if clients are told a medication is hard to get or expensive; the color of the tablet can also affect degree of perceived benefit. All of this supports the contention that a placebo is more than just an inert substance without physiological effects, even if those effects cannot be completely explained.

2.13.5 Regression to the Mean

When treating chronic problems, such as arthritis, allergies, inflammatory bowel disease, and others, there tends to be a progressive nature to the diseases, but attitudes and clinical signs tend to wax and wane over time – there are good days and bad days.

When patients are having “bad days” and are clinically at their worst, this is the most likely time when clients are going to be most receptive to trying something new. Since waxing and waning of clinical signs is typical, it is also not unusual that a percentage of patients will be better following the administration of anything – be it a legitimate therapy or a placebo – just because that is the fluctuating nature of chronic disease.

In other cases, even though chronic problems are by their very definition “chronic,” there can be much larger cycles that can explain observed changes from placebo. For example, with atopic dermatitis, pets may be worst during peak pollination periods for specific allergens. During the worst periods of such pollination, owners are more likely to be desperate for new treatment alternatives. However, intense pollination periods tend to be relatively short‐lived, so in some instances the allergen load may actually have diminished significantly on its own and the clinical benefits should really be attributed to this discontinuation of intense pollination. Just because a pet gets better on a therapy does not mean that the primary effect can be attributed to the medication.

2.13.6 Honest Placebo

One very interesting aspect of placebo studies is that sometimes they can still provide benefits even if the patient/client knows they are administering placebos. This is known as the honest placebo effect. Thus, human researchers for several years have been conducting open‐label placebo studies where patients know they are receiving placebo, and still documenting benefit. We know that for some clients, there is an expectation that they will receive at least some sort of medication for whatever problem their pet might have. In fact, even some veterinarians might feel the need to dispense something for a client in need, even if there is not a specific medical indication. For example, sometimes clients request antibiotics for a pet when it is sick, even if there is no indication of bacterial involvement. Sometimes owners (and veterinarians) just want to feel like they are doing “something,” and a percentage will report success with this “something.”

2.13.7 Nocebo Effect

The nocebo effect is an interesting phenomenon in which people have negative expectations about something and that alone is enough to make them perceive an ill effect. This may account in part for people who believe that certain vaccines have deleterious effects or that certain foods are more responsible for allergies and insensitivities than would otherwise be statistically reasonable. Adverse effects to food and vaccines certainly exist and are well documented in animals, but many more people harbor beliefs about potential adverse effects than can be justified by scientific likelihood.

EXAMPLES

Mrs Jansen brought Meili, her 2‐year‐old spayed female shih tzu, to ABC Animal Hospital for persistent scratching, especially around her face and ears. Mrs Jansen seemed to think the problem was most likely due to a food allergy, since the problem started a few weeks after a new commercial diet was introduced and she noticed that the diet included gluten, which she herself was avoiding.

In consultation with the veterinary team, Mrs Jensen agreed to commence an elimination diet trial for a minimum of eight weeks, and if there was any question of effect, she was willing to continue for a total of 12 weeks. She was given the option of either a commercial hypoallergenic diet or a home‐made recipe with novel ingredients, and she thought she would have better control with the home‐made diet. An allergy medication was dispensed to be used for the first two weeks of the trial just to give Meili some relief, and then would be discontinued for the remainder of the dietary trial.

Meili was presented eight weeks later and was substantially improved. Mrs Jansen was happy that she was able to stick to the home‐made diet, even though it was more work that she was doing in addition to food preparation for her other family members. She also lamented why pet food companies were able to sell foods with such ingredients that were capable of making pets sick.

Dr Green congratulated Mrs Jansen on her ability to persevere for the entire dietary trial, but had one other request just to conclusively determine a cause‐and‐effect relationship. He didn't want Mrs Jansen to have to cook for Meili forever, or to try diet after diet to find an acceptable commercial option, so he asked if she would be prepared to try one other scientific trial – reintroduce the original diet to see how long it took for the clinical signs to start to recur. After all, if the problem was really the diet, they should be able to induce the clinical signs with reintroduction of the offending allergen(s), and then make them quickly go away again by stopping the diet once again. Once they had conclusively established the diet as the culprit, they would commence challenge feeding to determine which ingredient(s) were actually problematic.

Mrs Jansen was a bit unsure of the process, and didn't want Meili to suffer, but she agreed to the trial realizing that she could reverse any ill effects quickly, and that it would appease Dr Green's scientific curiosity so they could get on with more permanent solutions. However, with challenge feeding, Mrs Jansen was surprised that Meili did not get worse when she reintroduced the original diet, even after she had fed it for a full two weeks. She even fed Meili some bread and pasta, the gluten content of which she was sure would aggravate Meili's condition … but it didn't. Dr Green explained that the likelihood was that Meili was allergic to certain pollens which were prevalent during the period when she was symptomatic, and perhaps food was not playing a major role after all. He praised Mrs Jansen for her willingness to explore the complexity of Meili's condition, provided her with information on atopic dermatitis, and asked her to track Meili's clinical signs on a calendar and if major problems recurred, they would have some documentation to compare with allergy test results to determine the most likely allergens implicated.

TAKE‐AWAYS

 Don't be fooled – the placebo effect is evident in animals.

 Caregivers are responsible for judging the impact of interventions on clinical issues and their impressions can be influenced.

 Simply enrolling in a study or taking part in a therapeutic trial can influence the perception of benefit. This is known as the Hawthorne effect.

 Most chronic conditions tend to wax and wane over time, and sometimes medication benefits can be attributed to times when clinical signs would be waning regardless.

 People can be influenced to expect that certain interventions are likely to have bad effects, even if not likely. This is known as the nocebo effect.

MISCELLANEOUS

Recommended Reading

1 Conzemius, M.G. and Evans, R.B. (2012). Caregiver placebo effect for dogs with lameness from osteoarthritis. J. Am. Vet. Med. Assoc. 241 (10): 1314–1319.

2 Gruen, M.E., Dorman, D.C., and Lascelles, B.D.X. (2017). Caregiver placebo effect in analgesic clinical trials for cats with naturally occurring degenerative joint disease‐associated pain. Vet. Rec. 180 (19): 473.

3 McKenzie, B. (2018). What is a placebo? Animals receiving inert treatments may show improvement due to causes other than direct placebo effects. http://veterinarypracticenews.com/what‐is‐a‐placebo

4 McKenzie, B.A. (2019). Placebos for Pets? The Truth about Alternative Medicine in Animals. England: Ockham Publishing, Newmachar, Scotland.

5 Munkevics, M., Munkevica, S. (2017). Why does placebo work on dogs and cats? http://pet‐happy.com/why‐does‐placebo‐work‐on‐pets

6 Sifferlin, A. (2018). Placebo's new power. Time Magazine 3/10: 65–69.