This blog is an extract from Hengeveld E & Bucher Dollenz G. Chapter 8: Pain and Pain Management.

In: Hengeveld E & Bucher Dollenz (2025) The Maitland Concept of NMSK Physiotherapy. Assessment and Management of NMSK Movement Functions. Vol. 1: Principles of the Maitland Concept. Elsevier. Submitted for publication).

The placebo effect has long been a topic of debate, often provoking discomfort due to its association with quackery or deception. As Wall (1994, p. 1294) points out, the placebo effect is full of "surprise, power, and paradox," and it should not be dismissed as mere trickery. The concept of placebo has led to costly placebo-controlled trials in pharmacological and cross-over trials in RCTs in non-pharmacological research. Placebo effects may also be disconcerting, as one may doubt his own senses if a placebo shows pain-reduction and even improves symptoms such as swelling. Above all, the topic may lead to cruel attitudes of doubting a patient’s mental capacity when placebos appear to be effective. Instead of considering placebo being equivalent to “no therapy”, the placebo effect should be seen as a legitimate therapeutic tool, capable of influencing pain perception and other symptoms. No therapeutic approach seems to be free of placebo effects, including surgery (Wall, 1994), (Harris, 2016) and pharmacological treatment (Schönbächler, 2007). 

In an essay on pain perspectives, Schönbächler (2007) argues that pain exists at the intersection of body and mind, involving the whole person despite being experienced at a specific location. He warns that if pain were described solely from a neurophysiological standpoint, the phenomenological aspects would be overlooked, reducing pain to a biologically defined phenomenon consisting of anatomical structures, molecules, and receptors. The challenge lies in describing the connection between body and mind, as dualistic paradigms struggle to explain how "mental processes would work in the physical space defined by causality" (p. 247), as seen in placebo effects. While Descartes, a proponent of dualism, located pain within the physical body, he appeared aware of the modulatory effects of mood and emotions on pain, as illustrated by his remark: ..ainsi que souvent une même action, qui nous est agréable lors que nous sommes en bonne humeur nous peut déplaire lors que nous sommes tristes ou chagrins..[..as often the same action, can be pleasing when one is in a good mood but displeasing when one is sad or upset..] (as cited in Schönbächler, p. 250).

Moreover, pain is not only a body-mind phenomenon but also a cultural one, influenced by societal beliefs about its meaning and treatment. Placebo effects, particularly in pharmacotherapy, are shaped by cultural perspectives on medicine, with factors such as prior experiences with medication, personal narratives, and advertising affecting outcomes. Schönbächler (2007) concludes that the therapeutic effect of a drug is not only due to its molecular composition but also the cultural context of drug administration, where the act of care and attention contributes to positive outcomes.

Price (1999) expands on the placebo effect in pain treatment, highlighting the complex interaction between psychological and neurobiological mechanisms. Psychologically, he emphasizes the role of expectations, beliefs in pain relief, and conditioning, where the association of a specific stimulus (e.g., a medication) with pain relief can lead to an automatic analgesic response in the brain, activating endogenous pain-relief systems such as endorphin release. Price notes that placebo responses vary across individuals, influenced by factors such as personality traits, prior pain experiences, and the individual's trust in the treatment.

Benedetti (2014) supports the recognition of placebo effects as a legitimate component of medical treatment, emphasizing their potential to enhance therapeutic outcomes. He explores the placebo phenomenon from biological, psychological, and ethical perspectives, suggesting multiple placebo responses, each driven by different mechanisms. Conscious physiological functions like pain perception are influenced by expectation and anticipation of clinical benefits, while unconscious functions, such as hormone secretion, are shaped by classical conditioning.

Placebo analgesia, the most studied form of the placebo effect, demonstrates how pain, as a subjective experience, is modulated by psychological and social factors, which can be manipulated in experimental settings involving pain induction in both healthy and pain-affected individuals. From a neurobiological perspective, placebo effects are linked to specific brain processes, including the release of endogenous opioids, the activation of the endocannabinoid system, and the involvement of the dopaminergic reward system. Regions such as the dorsolateral prefrontal cortex and areas related to reward mechanisms play a key role in placebo analgesia, providing the biological substrate for placebo effects on pain (Benedetti, 2014). (Fig.1).

1.      Characteristics of strong placebo responses

In line with Price’s (2000) observation, Benedetti (2014) outlines several scientific findings that likely contribute to robust placebo responses:

o  Verbal suggestion and expectations: In experimentally induced pain, the strength of the placebo response appears to be closely related to verbal suggestions that generate expectations of analgesia. For instance, statements such as, “This agent is known to significantly reduce pain in some patients,” are associated with stronger placebo responses. In contrast, when verbal information conveys uncertainty, the placebo effect diminishes. Some studies indicate that overt suggestions of pain relief can enhance placebo analgesia to levels comparable to those of active agents (Benedetti, 2014, p. 115). 

o  Previous experiences with analgesic treatment:
The placebo effect can last 4-7 days following positive prior experiences with analgesic treatments, suggesting that placebo responses are influenced by learning processes.

o  Influence of medical rituals:
Placebo responses also seem to depend on behaviors embedded within medical rituals, which may shape different expectations in patients.

o  Interaction between desire and expectation:
Desire and expectation appear to interact and influence common emotional responses, such as sadness, anxiety, and relief. In the context of analgesic studies, it is reasonable to assume that participants harbor a desire to avoid or alleviate pain, which may enhance the placebo effect.

o  Neurobiological basis: . Placebo analgesia is linked to the reward dopaminergic system, specifically the release of dopamine in the nucleus accumbens, a region associated with reward mechanisms, including the positive anticipation of pain relief. Large placebo responses are correlated with significant dopamine and opioid activity in the nucleus accumbens, whereas nocebo responses are marked by decreased opioid and dopamine release (Benedetti (2014), p.133).

o  Role of the prefrontal cortex:
In patients with impaired prefrontal cortex function, such as those with dementia, placebo responses do not occur. The prefrontal cortex is critical for executive functions such as planning, working memory, attention, and stimuli discrimination. The cortical-subcortical loops also involve the limbic system, and when these regions are compromised, individuals may exhibit uninhibited or impulsive behavior, further inhibiting placebo responses (Benedetti (2014), p. 137). (Fig. 1).

2.    Nocebo Effects

Nocebo responses, the flip side of placebo effects, occur when negative expectations lead to symptom increase. This underscores the importance of managing patients' perceptions in medical care. Negative diagnoses and prognoses may lead to an amplification of pain intensity. Also, negative communication processes may have an impact on patients’ emotions, such as anxiety, feeling misunderstood or insignificant. Furthermore, nocebo effects may occur when a patient distrusts medical personnel and treatment approaches. Verbal suggestions, health reports or negative information about the diagnosis of a condition without therapeutic options and possible outcomes, may lead to negative expectations with strong nocebo effects as a result.

 Cholecystokinin secretion and dopamine inhibition have been shown to play a role in the nocebo hyperalgesia response and activation of the hypothalamic-pituitary-adrenal (HPA)-responses with increased plasma adrenocorticotropic hormone and cortisol (Rossettini, Carlina, & Testa, 2018).

Also, the fear-avoidance model of pain can be seen as a type of nocebo-effect, whereby the fear of pain may lead to an increase in pain. Functional neuroimaging has shown involvement of areas of the brain involved with anticipatory anxiety, for which the clinical correlate may be fear avoidance, and in the commonly observed scenario when the patient flinches or withdraws before touch or palpation in the expectation of pain (Perfitt, Plunkett, & Jones, 2020).

See also Figure 1.

3.    Therapeutic relationship.

The psychosocial context of treatment can influence the patient’s central nervous system (“brain”) through conscious and unconscious mechanisms. Conscious processes involve complex cognitive functions such as expectations, anticipation of benefits, belief in the treatment, trust, and hope. Unconscious mechanisms are associated with learning and classical conditioning; for example, the color and shape of a pill may trigger a conditioned response to a placebo resembling the same characteristics.

From a biological standpoint, higher brain functions play a crucial role in the therapeutic relationship, encompassing expectations, beliefs, hope, trust, empathy, and compassion. Placebo responses are closely intertwined with the dynamics of the therapeutic relationship.

From a neuroscientific point of view, there are four steps in the therapeutic relationship (“social grooming”) (Benedetti, 2014, p. 74):

o   Feeling sick: the starting point of the subsequent behavior. It involves sensory systems and brain regions that lead to conscious awareness. Pain perception, for example, is the result of a bottom-up process and top-down modulation.

o   Seeking relief: behavior aimed at suppressing discomfort. These behaviors are in the same class as behaviors related to suppressing hunger or thirst, in which the brain reward systems play a central role

o   Meet the therapist moment: a special and unique social interaction in which the clinician represents the means to suppress discomfort. Hence, the clinician becomes a powerful reward. Trust and hope, on the one hand, and empathy and compassion, on the other, are intricate mechanisms at play.

o   Receiving the treatment: the final act and the most important part of the clinician-patient interaction(s). The rituals of the therapeutic act may evoke strong placebo responses. 

Fig. 1 Psycho-neurobiological mechanisms of contextual factors influencing brain networks, neurochemistry and therapeutic outcomes. The contextual factors may trigger placebo and nocebo effects in musculoskeletal pain.. (From (Perfitt, Plunkett, & Jones, 2020). DLPFC, dorsolateral prefrontal cortex; HT, hypothalamus; PAG, periaqueductal grey; rACC, rostral anterior cingulate cortex; RVM, rostral ventromedial medulla

4.  The power of words

In a comparative study, where therapists were asked to express themselves differently in their communication with patients, it was found that the therapeutic relationship was the most robust factor for change. The therapists who appeared warm and empathetic and expressed possible therapy results positively instead of being neutral and "businesslike" without being directly negative showed that patients showed significant improvement in pain intensity and quality of life after 3 and 6 weeks compared to the neutral group.  In particular, the authors cited the following factors of the therapeutic relationship (Kaptchuk, Kelley, Conboy, & al, 2008):

• ·     A client-centered attitude that radiates warmth and empathy
• ·     The integration of contributing psychosocial factors in the survey
• ·     Taking into account patients' thoughts and feelings about the illness or disability
• ·     Capture the patient's personal experience and  ideas about the possible causes and best possible treatments
• ·     Active listening
• ·     A positively emphasized communication about the possible therapy results.

In an experimental study where participants were requested to perform a squat exercise, pressure-pain thresholds (PPT) were measured in the mm. quadriceps and descending trapezius. Those participants who were given negative information about post-exercise pain tended to have a lower PPT, with increased pain. On the other hand, those who received positive or neutral information showed a higher PPT. The authors conclude that clinicians should consider the “power of the words” with which they frame instructions and expectations to the effects of exercises  (Vaegter, Thingaard, Madsen, & Hasenbring, 2020)

5.    Meaning response

Moerman and Jonas (2002) propose replacing the term "placebo effects or responses" with "meaning responses," emphasizing that it is not the "fake" treatment itself that matters, but rather the meaning conveyed by the treatment context, ritual, and therapeutic relationship, which elicits psychological responses. Moerman (2013) further argues that the findings of placebo studies are better understood by examining how meaningful interactions occur, rather than attempting to assess the efficacy of "nothing." As he states, "there is never nothing going on here" (p. 125).

Moerman (2013, p. 130) also contends that a placebo, being inert, does not directly cause any effects. However, notable changes can occur following placebo administration, and these effects are not attributable to the placebo itself. Instead, as various studies demonstrate, the meanings attributed to drugs or treatments by patients, clinicians, families, friends, and the wider community play a critical role. Moerman critiques the continued use of the term "placebo effect," asserting that people do not respond to placebos per se, but to the meanings embedded in placebos, treatments, clinicians, and others involved in the care process. Even in studies without placebos, individuals respond to the person administering the treatment.

He concludes. 

People respond to what we know, think, and feel. . . 
People respond to what we are told, believe and know. . .
People respond to their various cultural backgrounds. . .
They respond to language, to caring, to culture, to community, to history. In a word, they respond to meaningful phenomena.

References

Benedetti, F. (2014). Placebo effects. 2nd ed. Oxford: Oxford University Press.

Harris, I. (2016). Surgery, the ultimate placebo. A surgeon cuts through the evidence. Sydney, Australia: New South Publishing.

Kaptchuk, T., Kelley, J., Conboy, L., & al, e. (2008). Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ, 336: 999-1003. doi: 10.1136/ bmj.39524.439618.25.

Moerman, D. (2013). Against the “placebo effect”: a personal point of view. . Complementary therapies in medicine, 21(2), 125-130. doi.org/10.1016/j.ctim.2013.01.005.

Moerman, D., & Jonas, W. (2002). Deconstructing the placebo effect and finding the meaning response. Ann Intern Med, 136: 471-476. doi.org/10.7326/0003-4819-136-6-200203190-00011.

Perfitt, J. S., Plunkett, N., & Jones, S. (2020). Placebo effect in the management of chronic pain. . BJA education, 20(11), 382-387., 20(11), 382-387. doi: 10.1016/j.bjae.2020.07.002.

Rölli, D. (2004). Nozeboeffekt-unerwünschter Therapiebegleiter. [Nocebo effect - unwanted therapy concomitant]. Manuelle Therapie, 8(02), 47-54. DOI: 10.1055/s-2004-813080.

Rossettini, G., Carlina, E., & Testa, M. (2018). Clinical relevance of contextual factors as triggers of placebo and nocebo effects in musculoskeletal pain. BMC Musculoskeletal Disorders, 19-27. DOI 10.1186/s12891-018-1943-8.

Schönbächler, G. (2007). Schmerzperspektiven [Perspectives on pain]. In G. (. Schönbächler, SchMerz - Perspektiven auf eine menschliche Grunderfahrung [Pain, perspectives on a human basic experience] (pp. 247-254). Zürich, Switzerland: Chronis Verlag & Collegium Helveticum.

Vaegter, H., Thingaard, P., Madsen, C., & Hasenbring, M. (2020). Power of Words: Influence of Preexercise Information on Hypoalgesia after Exercise—Randomized Controlled Trial. Medicine & Science in Sports & Exercise, 2373-2379. DOI: 10.1249/MSS.0000000000002396.

Wall, P. (1994). Placebo and the placebo response. In R. Melzack, & P. Wall, Textbook of Pain, 3rd ed (p. Chapter 71). Edinburgh: Chruchill Livingstone.

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