|Year : 2014 | Volume
| Issue : 3 | Page : 125-128
Placebo analgesia: Does it have a role in pain management?
Department of Anesthesia, Christian Medical College Hospital, Vellore, Tamil Nadu, India
|Date of Web Publication||11-Aug-2014|
Department of Anesthesia, Christian Medical College Hospital, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Korula M. Placebo analgesia: Does it have a role in pain management?. Indian J Pain 2014;28:125-8
"Placebo effect is the ability of the mind to persuade your body that even a chalk, stick or water can make you feel better." ( Jerome Burne)
"Healing Power of Nothing" (Reader's Digest 2013 Jan)
Lately in pain medicine especially in chronic pain trials, immense interest in placebo responses has developed for two reasons. In clinical pain practice, there are suggestions of improvement in analgesia by placebo treatment when other treatments do not work. It has been advocated by researchers and experts all over the world. ,
Placebo derived from the Bible translation of the latin word "placeo" means "I will please". , Placebo effect (PE) is defined as a sham or simulated medical intervention that improves a given outcome like pain relief. Understanding these effects could lead to improvement in clinical conditions. , There is no formal definition for placebo as of now. In clinical trials, placebos are generally control treatments with similar appearance to study treatments, but without their essential components.
Typically clinical trials are designed to reveal high effects with the different drugs or doses compared to placebo groups. But in many clinical conditions and treatment, the placebo group has also achieved 50-80% of positive effect compared to the drug group especially in the area of pain management. , This proves there can be enormous potential for improvements using placebo strategies. Investigation biases can also be avoided. Relevant aspects of a pain disorder can be learned by analyzing data of placebo groups, this has been shown recently.
Placebo response (PR) is defined to be a reduction in a symptom as a result of factors related to a patient's perception of placebo intervention. The PR is determined by the placebo effect or psychological factors like expectation of benefits, classical conditioning, verbal suggestions, behaviors manifested by health care providers. 
Positive expectation is one of the basic mechanisms that underlie the development of placebo effects.  Studies show that social observer learning can have important implications for pain management. , Again positive results from placebo groups cannot be completely attributed to placebo reactions. Many questions still are unresolved. Is the placebo effect the same in the placebo group and drug group?
It is interesting that many patients experience serious side effects even though they are in the placebo groups. This is the "nocebo effect"- nocebo meaning "I will harm." Nocebo effects are shown to occur with verbal suggestions. Nocebo effects can also be produced by social observational learning.  Changes in anxiety levels can also affect placebo analgesia and hyperalgesia. So, it is true that reactions in the placebo groups are not independent of the expected side effects of the drug. New approaches are definitely required.
It has been assumed that psychological factors are responsible for the placebo effects. This may not actually be true as shown by Hauser et al. recently when they studied fibromyalgia and diabetic neuropathy along with placebo groups.  In their systematic review on placebo responses, placebo accounted for 45% response in the drug group in Fibromyalgia syndrome (FMS) and 62% in painful diabetic neuropathy (DNP). Placebo response was higher in painful DPN than in FMS. This was not associated with age, sex, race, but was associated with year of study initiation, pain baseline and effect size in the active drug groups in both disorders.
Placebo research has now entered the stage when placebo analgesia (PA), a subclass of placebo response, has come to be taken seriously and felt it can be exploited to treat pain. If a person experiences pain, feels a strong urge for pain relief, and expects to obtain relief from a treatment or medication, part or all of this relief may come from psychological factors. A number of mechanisms have been hypothesized. 
- Classical conditioning
- Changes in response expectancy
- Reduction in anxiety
- Release of endogenous opioids.
Now the emerging consensus is that multiple factors co-act to generate this placebo analgesia. Psychological factors are thought to mediate PA and expectancy is a real psychological mediator of PA. Many mechanisms have shown to be involved, like direct change in affective state, response expectancy, activation of descending control mechanisms, etc. , Earlier research has shown that the dose of expectation affects the magnitude of placebo response both in experimental and clinical settings. Studies investigated the differential effects of instruction on drug efficiency and showed that expectations that were "certain" was associated with larger responses than "uncertain" expectations. 
Nakamura et al. have attempted to find evidence for dose dependent effects of placebos in their study using a psychological approach and found this was statistically significant.  A recent study by Watson et al. showed the complexity and diversity of PA. Studies showed that dose of expectation does affect magnitude of placebo responses. In another recent study by Kaptchuk and colleagues also showed dose-dependent manipulation of placebo effects.  Pollo et al. documented that "certain" vs "uncertain" expectations led to different amounts of analgesics requested by three groups of trial patients in their study.
Recent neuroimaging studies have characterized the neural mechanisms and transmitters supporting PA effects. The cingulo-frontal regions of the brain interact with subcortical regions involved in endogenous antinociception to attenuate pain perception. Wager et al. measured brain activity associated with different stages of placebo analgesia - before, during, and after PA.  Lui et al. in their study documented dynamic charges in prefrontal areas and cortical nociceptive processing when using placebos. 
Conditioned placebo response was suppressed by naloxone, so endogenous opioids are most probably involved too. Placebo effects have been observed in immune responses, Parkinson disease, drug abuse as in analgesia. Despite all these studies and interest, neural mechanisms involving PA are still unclear.
Clinical trials have shown that the efficacy of placebos are determined or scaled against active drugs. Placebos compared with opioids in one trial may be more efficacious than placebos compared with ibuprofen.  Different drugs may activate different levels of expectations for pain relief and end up with different levels of efficacy. So, the construction of pain is not a passive reaction but an active anticipatory or intentional activity consisting of selection, organization, and transformation of knowledge and information. PA can be viewed as a consequence of altered construction of pain which can be due to expectation, physiological arousal, and somatic perception. Past success in decreasing pain from a modality or drug can increase expectation of future pain relief and vice versa. Evidences for genetic contribution also exist. Conditioning procedures whether unconscious (Pavlonian) or conscious (cognitively mediated) have been implicated too. 
Impact of placebo response in chronic pain trials have not been actually quantified. Whether placebo induces clinically relevant and stable improvement in pain syndromes have to be actively tested. Pharmaceutical companies naturally would try to resort to any technique that will enhance the benefits of their pharmacological treatments. Wager et al. also was able to show higher analgesic placebo effects if people expect the drug to be expensive and valuable. 
Observing others is thought to be one way in which pain related beliefs and attitudes are acquired in placebo analgesia i.e., social observational learning and this was seen to be associated with empathy. Men showed more responses to verbal suggestions alone while women to conditioning procedures. The exact impact of all these multiple factors as still unknown. In Vogtle et al.'s study, verbal suggestions did not induce nocebo effects like placebo effects. Observational learning can influence pain perception without doubt. Influence of quantity and quality of the patient-investigator relationship has been studied in IBS. Verbal suggestions and behaviors by health care providers and written information are likely to vary among the various studies and could influence outcome and variability in the placebo effect itself in the various research contexts. A recent study in IBS demonstrated placebo acupuncture effects could be augmented by patient-practitioner relationship such as warmth, attention, confidence. The impact of "helplessness on pain perception" has been implicated. In this study, the more helpless a patient felt, the more susceptible he/she was to a nocebo suggestion. Nocebo hyperalgesia can be induced by social observational learning. Catastrophisizng, helplessness, enchances nocebo responses too.  Induction of nocebo effects like itch & pain by verbal suggestions was shown by Van Laarhoven et al. Mulla MJ et al. in their article Will it hurt less if I believe I can control it? shows these various aspects.
It has been hypothesized that placebo effect requires intact descending pathways.  Probably in Post Zoster Neuropathy (PZN) and FMS, placebo effect is diminished as the descending pain pathways are deficient. But there are studies that demonstrate pain relief through expectation superseded pain pathway deficit. Charlotte et al. showed that anticipation of pain at a specific location of the body can induce tactile stimuli at that location. Attentional mechanisms and biases also play a vital role.  Our brain can prioritise tactile information at the threatened parts of the body. We really don't know!
Mechanisms underlying the different placebo response rates can only be speculated at the moment.  Placebo reactions are too potent to be neglected. They cannot be taken at face value but must be transformed and used as a clinically useful tool to benefit the patient ultimately. So placebo groups in clinical trials have strong potential to increase our understanding of what really happens to patients receiving different types of medications. 
Many consider this deceptive or "fake medicine!" Researchers should stop considering placebo reactions as a nuisance in clinical trials and try to understand the hidden information reported from placebo groups. As of now, placebos alone cannot be recommended for management of chronic pain. Situational factors are more important than individual factors for placebo responses. But positive expectations and suggestions could be used in clinical practice to increase the effects of active drug therapy. 
We must remember "a real-life pain stimulus is more threatening and ambiguous than a stimulus applied in experimental settings." But as Jerome says " if it makes people feel better, it is free and harmless, why not use it?"
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