The Nocebo Effect

Author: Monica Basso
Date: 30/01/2013



May the perception of pain increase in a negative way because of suggestions? Are there any neurobiological bases of negative suggestions? Sometimes we hear about the placebo effect. Placebo is an inactive substance given to reinforce patient's expectation to get well. The term placebo derives from the latin word ‘placere’ that means “I shall please”. But there is also the opposite effect: the negative placebo effect or nocebo effect (derived from Latin with the meaning of “I shall harm”). In this case, a patient who does not believe in a treatment may worse his symptoms.


The nocebo effect is the presentation of certain somatic symptoms associated with the person's prior expectations of adverse effects from treatment as well as with the conditioning derived from prior experiences.
Negative expectations may result in pain amplification, unlike positive suggestions can reduce it.

The neurobiology of placebo analgesia:from endogenous opioids to cholecystokinin,1997

Several studies indicate that nocebo suggestions may result in pain amplification and in the alteration of somatosensory perception.
Negative verbal suggestions are capable of producing not only hyperalgesic responses but also allodynic ones.
The role of learning in nocebo and placebo effects,2008

Distraction or expectancy for either increased or decreased pain perception is associated with activation of brain regions proposed to contribute to descending pain modulatory circuits.
Some neuroimaging studies have been done in order to disentangle the effect of positive and negative cues of pain processing.
For instance, a study demonstrates that expecting a painful stimulus enhances both the subjective unpleasant experience of an innocuous stimulus and the objective responses in some brain regions. Brain regions involved are: the anterior cingulate cortex, the parietal operculum and posterior insula.
Expectation of pain enhances responses to nonpainful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study,2000

Likewise, other studies expose how the level of expected pain intensity magnifies the perceived intensity of pain through the activation of different brain regions (also during the anticipation of pain), like the ipsilateral caudal anterior cingulate cortex, the head of the caudate, the cerebellum, and the contralateral nucleus cuneiformis and the left hippocampus too (the last region may play an important role in nocebo hyperalgesia).
Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study,2006
A functional magnetic resonance imaging study on the neural mechanisms of hyperalgesic nocebo effect, 2008

By contrast, expectations of decreased pain reduce the activation of pain-related brain regions, such as the primary somatosensory cortex, the insular cortex and anterior cingulate cortex.

While placebo responses are associated with greater dopaminergic and endogenous opioid activity in the nucleus accumbens, during nocebo responses we have dopamine and opioid release deactivation.
Placebo and Nocebo Effects Are Defined by Opposite Opioid and Dopaminergic Responses, 2008

Stress and anxiety has been implicated in nocebo responses.
By studying ischemic arm pain in healty volunteers, Benedetti et al. found that the oral administration of an inert substance, along with verbal suggestions of hyperalgesia, induced hyperalgesia and hyperactivity of the hypothalamic-pituitary-adrenal axis, as assessed by means of adrenocorticotropic hormone (ACTH) and cortisol concentration.
Both hyperalgesia and hypothalamic-pituitary-adrenal hyperactivity were blocked by diazepam, one of the most used anti-anxiety benzodiazepines; this means that anxiety plays an important role in this phenomenon.
However, the administration of CCK type A/B receptor antagonist (proglumide) blocks nocebo-induced hyperalgesia completely, without any effect on hypothalamic-pituitary-adrenal hyperactivity.
It means that CCK (neuronal cholecystokinin) has a specific involvement of the nocebo effect.
The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect, 2006

In other words, this study suggests the important role of CCKergic system in modulation of anxiety and the link between anxiety and hyperalgesia. CCK-antagonist may prevent this effect.


Cholecystokinin (CCK) was originally discovered in the gut and showed to mediate pancreatic secretion and contraction of the gall bladder. In 1975 was first described in the mammalian central nervous system. The majority of neuronal CCK comprises the sulphated octopeptide.
It has been proposed that the brain contains at least three sub-populations of CCK neurons with different post-translational pathways.
Their transcription are largely unknown, but in neuronal cells, CCK mRNA is induced by growth factor, cAMP, dopamine, estrogen and injury situation.

Primary sequence of the most prominent mammalian forms of CCK, i.e., CCK-58, CCK-33, and CCK-8 are indicated, as are the tyrosine sulfate located at the seventh position from the α-amidated carboxy terminus.

CCK is synthesized de novo in the brain and it can be released from synaptosomes exposed to depolarizing stimuli in a calcium and sodium-dependent manner. CCK induces central neurons excitation.
An introduction to neuronal cholecystokinin, 2001

Two receptors have been identified: CCK A and CCK B.
They are organized in a similar manner: they measure 8kb in length, with homologous exon/intron splice sites, and they act in part through one or more G-coupled receptors which exhibit similar affinity for gastrin and CCK.
The human gastrin/cholecystokinin type B receptor gene: alternative splice donor site in exon 4 generates two variant mRNAs, 1993

CCK A (A means “appetite”) is located mainly in the periphery but also occurs in discrete brain areas, while CCK B (B for “brain”) receptors show a widespread distribution in the CNS, especially in dopamine-enriched regions.
Several studies indicate that the activation of either one of the two CCK receptors produces a variety of physiological and behavioral effects, including the regulation of feeding, anxiety, nociception, appetite control, depression, learning, memory, neuroprotection, drug dependence, and gastrointestinal dysmotility states.
Biological actions of cholecystokinin, 1994

The potential role of CCK in brain and behavior is focused on four main areas: CCK/dopamine interactions, CCK in anxiety and panic states, CCK in opioid nociception, and CCK in satiety. CCK's actions in modulating the activity of other neurotransmitters systems or in affecting behavior are actually object of study.
Neurobiology of cholecystokinin, 1994


The pro-nociceptive and anti-opioid action of CCK-neuropeptide has been documented. For instance, it has been shown that CCK is capable of reversing opioid analgesia by acting at the level of rostral ventromedial medulla (which plays a key role in pain modulation).
Circuitry underlying antiopioid actions of cholecystokinin within the rostral ventromedial medulla, 2001

The rostral ventromedial medulla is involved in pain descendant modulation, in union with several other structures as somatosensory cortex, hypothalamus, amygdala, peri-aqueductal gray area and raphe nucleus. These regions are able to reduce pain threshold, and release endorphins and enkephalins (endogenous opioids) on interneurons of ascending pathways of nociceptive transmission.
Theories of pain: from specificity to gate control, 2012

Many studies has been shown that CCK interacts with opioids in pain mechanisms.
Anatomical studies have shown that enkephalins and CCK8 have a strikingly similar distribution within many regions of the central nervous system.
For example intracerebroventricular administration of a mixed CCK A /CCK B agonist induced dose-dependent antinociceptive responses in mice (but also potentiated the antinociceptive effects of the mixed inhibitor of enkephalin degrading enzymes, that means this is an indirect involvement of μ-opioid receptors). In contrast, the administration of a selective CCK B agonist induces a hyperalgesic effect.
It seems that the activation of CCK B receptor could negatively modulate the opioid system directly and indirectly, while stimulation of CCK A receptors would enhance opioid release.

Modulation of opioid antinociception by CCK at the supraspinal level: evidence of regulatory mechanisms between CCK and enkephalin systems in the control of pain, 1993

Schematic representation of the proposed regulation loops between the CCK and the opioid systems. The CCK agonists, endogenuous and/or exogenous, stimulated the CCK B and/or the CCK A receptors which can modulate the epioidergic systems either directly or indirectly. In addition, activation of μ-opioid receptors, which leads to antinoceptive responses, could negatively modulate the release of endogenous CCK, while δ-opioid receptors may enhance it.

Hyperalgesia is an increased perception of pain caused by the local release of substances including bradykinin, prostaglandins, serotonin, hydrogen ions, histamine, NGF. These molecules are able to either directly activate or sensitize nociceptors and spinal dorsal horn neurons.
Leukotriene and prostaglandin sensitization of cutaneous high-threshold C- and A-delta mechanonociceptors in the hairy skin of rat hindlimbs,1987

Activation of descending facilitatory mechanism may promote hyperalgesia via ultimate release of PGE2 and serotonin in the spinal cord. It is known that PGE2 can activate the TRPV1 channels, which activate pathways involved in hyperalgesia genesis. With an opposite mechanism, the same pathways are inhibited by opioid and cannabinoid receptors. Anyway the correlations between CCK activation of descending facilitatory pathways and altered levels of PGE2 remain unknown yet.
Activation of descending pain facilitatory pathways from the rostral ventromedial medulla by cholecystokinin elicits release of PGE2 in the spinal cord. 2012

Several studies have suggested that a discrete part of RVLM neurons are serotoninergic, and significant portions of these are CCK- positive. It has been supposed the correlation between up-regulated endogenous-CCK and the descending pain facilitation.
Serotonin immunoreactivity is contained in one physiological cell class in the rat rostral ventrolateral medulla, 1994


Bradykinesia appears to be a symptom that is very sensitive to verbal suggestions.
Some studies analyzed the velocity of movements in Parkinson patients who had been implanted with electrodes in the subthalamic nuclei for deep brain stimulation, a highly effective anti-Parkinson treatment that is capable of relieving the motor parkinsonian symptoms.
In a study, these patients were tested in two opposite conditions. In the first condition, they expected a good motor performance whereas in the second they expected a bad motor performance. It was found that these two opposite expectations modulate the therapeutic effect of the subthalamic nucleus stimulation. In fact, by analyzing the effect of subthalamic stimulation on the velocity of movement of the right hand with a movement analyzer, it was found that the hand movement was faster when the patients expected a good motor performance than when they expected bad performance.
Expectation modulates the response to subthalamic nucleus stimulation in Parkinsonian patients, 2002


Placebo and nocebo effects are psychobiological phenomenons attributable to the overall therapeutic context. The psychosocial context surrounding the patient includes both patient and clinician individual factors and the interaction between patient, clinician and treatment environment. The latter represents many factors involved in a treatment context (such as the specific nature of the treatment and the way it is administered) and the doctor-patient relationship ( this is a term that encompasses a host of factors that constitute therapeutic interactions).
Neurobiological pathways connected both to psychical symptoms and biological responses suggest that the correlation between awesomeness and increase of negative sensations probably exist.
Due to intricate interactions between the complex mental activity (such as expectation or anticipation of benefit or pain) and different neuronal systems which are capable of modifying the course of a symptom, it is important to remember that the way the doctor interacts with the patient and the psychological condition of the patient himself may be a significant variable in the course of the patient treatment.

Chiara Massaglia, Monica Basso

AddThis Social Bookmark Button