Joyce Krekels
Some time ago, I went to the RAMS symposium ‘Placebo effect: The Mind as Medicine’, where professor Andrea Evers and PhD student Judith Tekampe from Leiden University spoke about positive (placebo) and negative (nocebo) treatment effects that occur as a result of a patient’s expectations and beliefs about the effect of a certain treatment or its side effects (1). This urged me to dig a little bit deeper into the placebo effect and how it can be applied in the clinic. Remarkably, placebo and nocebo effects are seen in almost every condition and physiological response system, such as in immune and endocrine functioning (1). But how can we use these effects as a treatment?
Let’s start with a few factors that can influence the impact of the placebo effect. Among others, the doctor-patient relationship and the phrasing of the doctor matters in this case. Research conducted by Howe et al. showed an enhancement of the placebo effect when the doctor appeared warm and competent compared to when a doctor appeared cold and incompetent(2). Also, the type (injected or orally), size and colour (blue, red or green) of the medication that is given, affects the impact of the placebo effect (3, 4). In addition, there might even be a role for genetics where it, more specifically, can influence the response to neurotransmitters such as in the dopamine, endocannabinoid and opioid pathways (5, 6).
Currently, evidence in cardiovascular medicine suggests that a placebo might reduce symptoms and possibly autonomic responses such as hypertension, congestive heart failure, paroxysmal atrial fibrillation and vasovagal syncope (7). Especially for relieving anxiety (and the response of the autonomic nervous system to anxiety and stress) and pain, placebo effects can possibly be very substantial (7). In an already older study from Levine et al., it is already shown that if patients are told that a painkiller is injected after extraction of the third molar, with what is actually a saline solution, this works as potent as a dose of 6-8 mg of morphine (8). This also holds for other painkillers, such as tramadol and buprenorphine (7). In the dermatological field, research towards chronic itch in patients with psoriasis, atopic dermatitis and chronic idiopathic urticaria, showed that itching can be considerably reduced by placebo effects (9). Also, research in this field showed that learned (conditioned) immune functioning is possible, whereby conditioning to antihistamines or cyclosporine led to relieve of subjective rhinitis symptoms, allergic skin reactions and induces changes in effector immune functions when researchers provoked allergic reactions in participants who had a house-dust mite allergy (1, 10).
As more researchers have been debating the mechanisms of placebo and nocebo effects and how we can use this optimally in clinical practice for years, recent research focuses more on the use the of these effects on therapy outcomes in clinical practice. Still, the most challenging aspects of this research are that some studies are insufficiently powered to account for the impact of these effects. However, there is increasing attention for research on the placebo and nocebo effect, for example at the international SIPS conference that will be held in Leiden for the second time (www.sipsconference.com), including research on the complex interplay of neurobiological and psychological factors, or the ethical considerations that need to be dealt with. Despite this, research on placebo effects may change the medication dose description by pharmacological conditioning, the way we feel about both pharmacological and non-pharmacological treatment, and train doctors to exploit the placebo effect by, for example, improving the doctor-patient relationship and being aware of the phrasing they use.
[1] Evers AW. Using the placebo effect: how expectations and learned immune function can optimize dermatological treatments. Exp Dermatol. 2017;26(1):18-21.
[2] Howe LC, Goyer JP, Crum AJ. Harnessing the placebo effect: Exploring the influence of physician characteristics on placebo response. Health Psychol. 2017;36(11):1074-82.
[3] Bhugra D, Ventriglio A, Till A, Malhi G. Colour, culture and placebo response. Int J Soc Psychiatry. 2015;61(6):615-7.
[4] Peerdeman KJ, Tekampe J, van Laarhoven AIM, van Middendorp H, Rippe RCA, Peters ML, et al. Expectations about the effectiveness of pain- and itch-relieving medication administered via different routes. Eur J Pain. 2018;22(4):774-83.
[5] Sheldon R, Opie-Moran M. The Placebo Effect in Cardiology: Understanding and Using It. Can J Cardiol. 2017;33(12):1535-42.
[6] Hall KT, Loscalzo J, Kaptchuk TJ. Genetics and the placebo effect: the placebome. Trends Mol Med. 2015;21(5):285-94.
[7] Benedetti F. Placebo effects: from the neurobiological paradigm to translational implications. Neuron. 2014;84(3):623-37.
[8] Levine JD, Gordon NC, Smith R, Fields HL. Analgesic responses to morphine and placebo in individuals with postoperative pain. Pain. 1981;10(3):379-89.
[9] van Laarhoven AIM, van der Sman-Mauriks IM, Donders ART, Pronk MC, van de Kerkhof PCM, Evers AWM. Placebo effects on itch: a meta-analysis of clinical trials of patients with dermatological conditions. J Invest Dermatol. 2015;135(5):1234-43.
[10] Goebel MU, Meykadeh N, Kou W, Schedlowski M, Hengge UR. Behavioral conditioning of antihistamine effects in patients with allergic rhinitis. Psychother Psychosom. 2008;77(4):227-34.