Placebo effects using putatively active compounds have been used since antiquity
to soothe the pain and suffering of patients. While the placebo effect wasn’t known
centuries ago, the efficacy of these ‘treatments', now known to be inert or ineffective,
could be attributed to the placebo effect. A placebo is a treatment whose efficacy is
attributed not to the inert substance itself, but due to the patient’s subconscious
internalization of a therapeutic benefit derived from the medical environment in which
the inert compound was administered. It is emphasized that the patient’s response to the
medical environment is the treatment when the inert placebo elicits a biological
response. As a therapeutic modality, placebo-therapeutic observations are the result of
subconscious beliefs of the patient. The stronger the belief in the placebo’s therapeutic
benefit, the more likely the placebo will be successful. Sometimes the placebo effect can
be as effective, or even more effective than the treatment itself. This can explain why
obsolete treatments such as snake oil, trepanning, and bloodletting may have had some
degree of efficacy when used historically; for instance, when some people (responders)
believed that snake oil would cure them, the placebo effect may have changed that
individual’s internal physiology, biochemistry, and other such factors.
A 2019 study by Brutcher et al showed that placebo creams with no activity were
effective in treating laser-induced pain. This study clearly demonstrated that the placebo
effect caused a significant and remarkable degree of pain relief. In this study, patients
were exposed to three equally inert creams that were applied to their skin. They were
told, or taught, that one cream was inactive, another had mild activity, and the other had
strong activity in preventing laser light induced pain. While keeping the laser light
intensity constant at a painful dose of irradiation, they challenged the area where the skin
creams were applied. The patients then self-reported their pain levels and relief. The
‘control’ placebo had negligible effect on the patients’ pain, the ‘weak’ placebo elicited
light pain relief, and the ‘strong’ placebos showed marked pain relief.
The placebo effect providing pain relief is known as placebo analgesia. This
response to placebos is virtually identical to Pavlovian conditioning. Ivan Pavlov is
known for his experiment on dogs, in which dogs were given food that was
simultaneously accompanied by the ringing of bells. While the dogs were eating, they
salivated. The subsequent ringing of the bell without food resulted in the dogs salivating
in anticipation of receiving food. In this experiment, the conditioned stimulus (CS) was
food, and the unconditioned stimulus (US) was salivation. Effectively, Pavlov taught or
trained the dogs to salivate when a bell was ringing. Today, Pavlov’s CS and US are well
known and accepted, and scientists understand that it is possible to teach animals to
generate a US when a CS is administered. This has become known in science as
response conditioning, and several placebo effects can be elicited by this technique.
Note the sequence of teaching a US to be elicited. First there is a physically
observable stimulus (in this case food) that is given more than one time. The salivation
(US) observed was the result of the dog’s brain expecting food (CS). The cream
experiment is no different whereby the laser light was the CS, and the level of pain
protection (US), caused by the activation of pain-inhibitory pathways in the brain, was
proportional to the taught expectation of pain protection.
The placebo analgesia effect utilizes different regions in the brain; however, the
brain regions activated or inhibited varies between studies (Wager et al, 2015). Reduced
sensation of pain can be caused by specific groups of neurons in the brain not firing or
becoming inactivated. Pain conductivity in somatosensory systems is from unmyelinated
C-fibers (slower pain) and myelinated alpha-beta fibers for fast pain. Studies using
functional magnetic resonance imaging (fMRI), positron emission tomography (PET),
magnetoencephalography (MEG), and other modalities point to specific regions of the
brain involved in placebo-mediated pain relief. The medial thalamus (involved in pain
and sensory integration), anterior insula (has many functions, among which it is the key
hub in the salient network that puts valence to what’s in consciousness), dorsal anterior
cingulate cortex (avoidance of pain), and periaqueductal gray matter (pain regulation and
emotion) have been suggested to play a role in this process. These areas are involved in
the perception of pain, and have reduced activity after a placebo medication is
administered. Other areas of the brain increase their activity: the ventromedial
prefrontal cortex, dorsolateral PFC, lateral orbitofrontal cortex, the nucleus accumbens,
and the rostral ventral medulla. Most pain-relief behavior associated with placebos has
common areas of activation, including dorsal anterior cingulate cortex, and the anterior
insula. Significant pain relief, or analgesia, is said to be tied to reduced activity in those
regions.
Placebos might have efficacy in pain relief because of their connection to
endogenous (‘inbuilt’) pain relief circuitry. Some studies have shown that
placebo-induced analgesia can be blocked by naloxone. Naloxone is a common opiate
antagonist often used to reverse overdoses of opioids. This indicates that there are some
opioidergic pathways involved in placebo analgesia. These opioid signals reduce pain
activity and signals from the dorsal horn of the spinal cord.
In contrast, the protein receptor cholecystokinin (CCK) is also involved in the
placebo response because of CCK receptors of the endocannabinoid pathways. Thus,
there are at least two top-down brain inhibitory pathways for pain (opioids and CCKs).
CCK receptors are antagonists of the opioid pathway. In other words, if CCK receptors
are active, the opioid pathway is inhibited. Proglumide, a CCK antagonist, enhances the
placebo analgesic effect (due to CCK’s anti-opioid activity). Similarly, expectation of
pain (dubbed the ‘nocebo’ effect) is tied to increased CCK activity, as CCKs are
involved in pain perception as opposed to pain relief (Benedetti et al, 2014). The same
antagonist, proglumide, reduces the efficacy of CCK’s role in pain perception and causes
analgesia .
Patient outcomes are often influenced by the strength of their belief in their
medication, be it placebos or therapeutic drugs. A strong belief in the efficacy of a
placebo can lead to positive results such as pain relief or abating symptoms from other
medical problems in patients. Developing a proper understanding of placebos could be
of great therapeutic value for understanding both the neurophysiology of pain as well as
health in general.
References:
1. Brutcher RE, Kurihara C, Bicket MC, Moussavian-Yousefi P, Reece DE,
Solomon LM, Griffith SR, Jamison DE, Cohen SP. Compounded Topical Pain
Creams to Treat Localized Chronic Pain: A Randomized Controlled Trial. Ann
Intern Med. 2019 Mar 5;170(5):309-318. doi: 10.7326/M18-2736. Epub 2019 Feb
5. PMID: 30716769.
2. Bindra, S., and Pidgeon, C., 2021, Somatosensory Teacher’s Manual: for
Somatosensory Science Facts
3. Wager, T., Atlas, L. The neuroscience of placebo effects: connecting context,
learning and health. Nat Rev Neurosci 16, 403–418 (2015).
https://doi.org/10.1038/nrn3976
4. Benedetti F. Placebo effects: from the neurobiological paradigm to translational
implications. Neuron. 2014 Nov 5;84(3):623-37. doi:
10.1016/j.neuron.2014.10.023. Epub 2014 Nov 5. PMID: 25442940.
I would like to thank Xinyi Zhang for her helpful discussions and input. Dr. Charles Pidgeon
approved this blog post.
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