Authors: Ioana Stanescu, Oana Vanta
Keywords: placebo treatment, neurorehabilitation, pain treatment, neurological disorders
What is the efficacy of placebos in managing pain for neurological disorders?
Many observations have proved that the effects of medical treatments could be influenced by suggestion, context, and relation with the therapist. Placebo is a treatment that does not contain an active substance or has no therapeutic properties. The placebo effect is the response of the patient to the intervention. It means the improvement of the patient’s symptoms in a context that induces hope and positive expectations about symptom relief [1–2].
The opposite of the placebo effect is the nocebo effect, which means the worsening of patient symptoms or the induction of adverse effects while using a sham or inactive treatment. Unmet expectations of the patient after the encounter with his physician or disclosure about the potential risks of therapy could induce this negative effect .
The mechanism of the placebo effect has long been under debate: it is not related to the nature of the inactive substance but to the psychological context in which the treatment is proposed and administered. The Italian Consensus Conference on Pain in Neurorehabilitation summarised the latest theories on the placebo effect and its application in pain treatment in patients during rehabilitation treatment. Thus, the placebo effect could be considered a “contextual healing” form. The relationship between the doctor and the patient during the consultation is essential.
Patient characteristics also contribute to the intensity of the placebo effect :
- Memories of other treatments
- Personality features
- The psychosocial context of the patient-doctor encounter
The placebo effect has a psychological basis related to the brain-body interface, which includes mental conditioning related to patient expectations from the treatment. A psychosocial mechanism is also involved in the context of patient-doctor interaction. The mechanisms of the placebo effect are based on the activation of neurobiological circuits: opioid, dopaminergic, and endocannabinoid pathways .
The psychological and biological background for the placebo effect is shown in Figure 1.
The complexity of involved mechanisms (psychological, neurobiological, psychosocial) makes the placebo effect extremely variable among individuals and diseases. The genetic background of the individual, the different activations of the brain’s reward systems, dopaminergic circuits involved in learning, and previous emotional experiences could influence a patient’s response to treatment. Also, people have different beliefs and expectancies regarding a treatment plan, which influence the final effect .
Anxious people may respond differently than optimistic people, so an individual’s psychological condition should be considered when assessing treatment efficacy. It has been suggested that hypnotisability and suggestibility influence the result .
The amplitude of the placebo effect varies during different neurologic disorders. Most studied placebo effects were in three neurological disorders: depression, Parkinson’s disease, and pain (Figure 2).
In depression, authors have noticed high rates of responsivity to placebo treatment during trials of antidepressant drugs, and an association with a prefrontal pattern of cortical activation was detected by quantitative EEG [6,7]. In Parkinson’s disease, the placebo effect is also prominent and related to the placebo-induced release of dopamine [6,8]. The variable effect of placebo treatment was mentioned in Tourette syndrome or immune-mediated disorders . Placebo treatment has adverse events similar to those observed during the treatment with active medication against which placebo is compared .
The placebo effect in the management of neurologic disorders with pain
The effects of placebo treatment have been extensively studied in pain management. The studies have important consequences in clinical practice, as placebo analgesia could be used as an adjuvant to pain treatment. Moreover, available analgetic treatments have adverse effects, usually dose-related, and the association of placebo could reinforce the drug’s effect without increasing the dose.
Also, the presence of pain symptoms could delay or limit the intensity and duration of rehabilitation treatment in patients with neurological disorders. Treating pain would increase the efficacity of neurorehabilitation.
A group of Italian authors  conducted a review study between 2014-2017 on PubMed articles to assess the magnitude of the placebo effect in the pain treatment of patients with neurological disorders during rehabilitation training. The quality of the selected studies was assessed using the Critical Appraisal Checklist for Systematic Reviews, and the results were synthesized in a narrative form. The effect of placebo treatment was evaluated separately in neuropathic and non-neuropathic pain disorders .
The effect of placebo in disorders associated with neuropathic pain
The study demonstrated that in neuropathic pain induced by central nervous system damage, the placebo effect is non-significant (for example, in pain associated with stroke, deafferentation pain, or phantom limb pain).
On the other hand, the amplitude of the placebo effect is moderate but significant in neuropathic pain induced by peripheral nervous system lesions. The highest response is observed in HIV-associated neuropathy, where almost 50% of patients were responders to placebo treatment. In painful diabetic neuropathy, there is an important placebo effect, with 20% of patients improving after treatment, but in postherpetic neuralgia, a milder placebo effect is observed, with only 11% responders. The lowest effect was detected in complex regional pain syndrome .
Other factors influence the intensity of the placebo effect in neuropathic pain. A longer duration of treatment is associated with better results, but the higher intensity and longer duration of the initial pain will decrease the placebo effect .
The placebo effect in disorders associated with non-neuropathic pain
The neurologic conditions in which placebo treatment has been used for pain treatment are:
- headache (especially migraine)
- joint-related nociceptive pain
- fibromyalgia (Figure 3).
In these disorders, placebo treatment alone or associated with other treatment modalities showed mild improvements in pain intensity.
In fibromyalgia, a 50% reduction in pain intensity after using a placebo was noticed in almost 20% of patients .
In migraine, placebo treatment is efficient in both acute and chronic treatment: 25% of patients report a decrease in pain intensity and 21% report improvements after using a placebo for migraine prophylaxis. The authors underline the high efficacy of a placebo, which is almost 50% of the efficacy of specific drug therapies for migraine [10, 11].
In pain related to inflammatory osteoarticular disorders, the average effect of a placebo is moderate. The reduction in pain intensity depends on the modality of treatment administration: topical and intra-articular therapies seem to be more effective than oral placebo .
Techniques for improving the placebo effect
Castelnuovo et al. stated the limitations of placebo treatment. The clinical studies that demonstrated its efficacy did not consider the spontaneous improvement of various neurologic conditions, overestimating the placebo effect. Furthermore, if a study uses subjective measures of outcome, the placebo effect is higher than in studies using objective measures. Moreover, individuals’ responses to placebo treatment are incredibly variable .
The placebo effect has mainly psychological mechanisms of action, which are developed in the context of a trustful patient-doctor relationship. The empathy of the medical personnel should reassure the patient and offer guidance on the pathway of self-management of pain symptoms. A patient’s confidence is a key element for an efficient treatment.
Various techniques are used to reinforce the effects obtained by placebo treatment, as shown in Figure 4.
Conclusion | Placebos in managing pain for neurological disorders
The placebo effect is based on a therapeutic relationship between a patient and his doctor. Its mechanism is related to the psychological context in which the treatment is proposed and administrated, considered “contextual healing“. Further studies are needed to clarify the genetic, neurobiological, psychological, and external factors involved in the variability of response to placebo treatment.
The placebo treatment has a mild to moderate effect in treating the pain associated with various neurological conditions. Neurological conditions which respond better to placebo analgesia are migraine, fibromyalgia, and peripheral neuropathies. Identification of a patient profile responder to a placebo is difficult. For this reason, using placebo treatment in selected cases is recommended when the traditional treatment modalities are unsuccessful.
In the neurorehabilitation of neurologic disorders associated with pain, the placebo treatment could be useful as adjuvant therapy in the attempts to reduce analgesic doses. Moreover, the placebo effect is useful for developing a more empathetic patient-doctor relationship and offering a tool to the patient to participate actively in his own therapeutic decisions .
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