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Placebo analgesia: A review

Time to rehash my fall term paper for the Behavioral Pharmacology course. -

Abstract: Our understanding of the neurophysiological and psychological mechanisms of placebo analgesic effects has expanded considerably over the last 20 years owing to the developments in brain mapping and imaging techniques. We have now identified a number of neural circuits in the brain involved in the modulation of pain perception based on emotional and cognitive factors. Numerous studies have shed light on the role of specific receptors and neurotransmitters involved in these circuits and how they regulate each other in different areas of the brain resulting in modulation of placebo analgesia. We also now understand the importance of environmental factors, learning, memory, emotional state, gender, personality traits, pre-notions and non-specific factors in pain interpretation. The identification of the clinical implications of placebo-nocebo effects will enable us to design better clinical studies and provide absolute data for new analgesic drugs. It is important to understand the ethical consequences of implementing psychosocial strategies based on placebo effects in conjunction with traditional treatments to improve pharmacotherapy.  Further studies in this field could provide new treatment strategies in disease conditions like chronic idiopathic pain, Parkinson’s disease and Alzheimer’s disease.

Introduction – What is Pain?
The origin and mechanism of pain has fascinated various philosophers and scientists over a number of centuries. Charles Darwin described pain as a ‘homeostatic emotion,’ which is essential for the survival of a species1. Over the years, our understanding of this phenomenon has improved remarkably. Today, the International Association for the Study of Pain (IASP) defines Pain as – “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”2. From the evolutionary and behavioral stand point, pain reflex is a part of the body’s defense mechanism that alerts the individual from harmful stimuli and prevents from reinjuring a wound.

The general mechanism of pain reflex has been well studied over the years. Noxious stimuli of various modalities are sensed by a specialized set of nerve fibers (unmyelinated C fibers and thinly myelinated A fibers). These nerve fibers with the help of Purinergic channels and receptors convert the physiochemical stimuli into electrical signals (Action potential). These sensory inputs are then integrated at the spinal dorsal horn and transmitted to specific areas of the brain through numerous neural pathways. The thalamus and limbic areas are believed to mediate the emotional and aversive components of pain. The cortex is identified to perceive the pain and accordingly relay back motor signals through the efferent nerve fibers to the spinal cord, which enables the withdrawal from the noxious stimuli. This general mechanism may not be true in case of chronic pain, which is usually idiopathic and serves no clear biological purpose.

Molecular physiology of Nociception:
The most important advances in pain and analgesia research have come through our understanding of basic molecular neurophysiology involving specific endogenous neurotransmitters and receptors. The peripheral sensory network mainly involves glutamate acting on ionotropic and metabotropic glutamate receptors, Substance P acting on TrkA tyrosine kinase receptors and Lectin analogues acting on P2X3 receptors1. The phosphorylation of Ionotropic glutamate receptors (NMDA and AMPA receptors) lead to biophysical changes and results in central sensitization, which is characterized by hyperalgesia, allodynia and chronic pain. This central sensitization can also be modulated by the metabotropic glutamate receptors and also through dis-inhibition of GABAergic signals3. Cannabinoid receptors have also been discovered to show anti-nociception action by inhibiting signals from periphery, through their interaction with opioid receptors and PAG, a neural analgesic substrate. Numerous other receptors and proteins are also currently being discovered that have implications in pain signal relay along the spinal chord to the brain.

The nociceptive processing in the supra-spinal sites is mainly carried out at the thalamic relay nuclei. They play a key role in pain modulation and further relay of signals to the cerebral cortex. It has been discovered that few descending inhibitory systems combine together at the brainstem rostral ventro-medial medulla (RVM) and modulate the spinal transmission1. These modulatory signals are controlled through the endogenous opioid system and are of evolutionary significance as they enable the organism to ignore pain in critical situations of stress and recovery. This relay system between the frontal cortex, limbic systems and thalamus enables cognitive and emotional control respectively over nociception and therefore plays a major part in placebo-based analgesia4,5.

Placebo and Nocebo effects:
Placebo effects are the psychobiological effects in the brain and/or body that occur following an inert treatment or procedure that has no direct pharmacological actions6. When these observed effects are harmful or undesirable they are termed as Nocebo effects. Numerous studies have confirmed that modulation of pain perception can be controlled by ‘expectation’ alone and that both placebo and nocebo effects can change when pre-conditioned6,7. Brain imaging and radiotracer studies have identified that all subtypes (μ, κ, and δ) of Opioid receptors are involved in placebo analgesic effects and that Cholecystokinin (CCK) system opposes this effect (therefore are usually involved in nocebo effects)7. These opioid-based effects were primarily discovered in specific brain regions - prefrontal cortex, Pre-aquaductal grey area and amygdala1.

Other systems have also been identified to be involved in placebo analgesia. Nucleus accumbens is a major area of the brain that is involved in placebo analgesia and features numerous dopamine neurons. It is considered that Dopaminergic responses to placebo interventions interact with downstream opioid signaling8. Another study has identified that central Serotonergic and Noradrenergic neurons also modulate the descending pain modulatory circuitry that mediates analgesia induced by opioids, which explains the analgesic effects of certain tricyclic antidepressants9.

Behavioral and Clinical Implications of placebo analgesia:
It has been confirmed that placebos have better effect than ‘no treatment’, in case of subjective continuous outcomes and for treatment of pain10.  We now understand that positive and negative expectations can be used to manipulate pain perception and thereby behavior11. It has been observed that under the expectation of high pain, the anxiety mechanisms are stimulated in the hippocampus and brain stem regions and thereby stimulating CCK systems resulting in nocebo effects12. Also both cognitive and emotional systems are involved in the modulation of pain perception through various mechanisms such as learning, memory, reward, beliefs, personality, psychological traits etc. The most well studied mechanisms involved in placebo analgesia are expectancy and conditioning. Pavlovnian conditioning which involves pairing an unconditioned stimulus (drug) with a conditioned stimulus (shape, color, flavor, taste, of the pill or route of administration of the drug) leads to a conditioned response (analgesia), even when only the conditioned stimulus is administered. The magnitude of the effect depends on the duration of the acquisition phase and the effect of the conditioning procedure13.

Reward expectation has also been shown to effect placebo analgesia perception through dopaminergic mechanisms14. This could have significant implications in clinical trial patient selection. The expectation created based on past experience and learned memory also influence perception of drug effect and is called cognitive reappraisal. This explains why red placebo pills are more likely to act as stimulants compared with blue placebo pills as red is associated with ‘danger’ or ‘hot’. Also more expensive placebo treatments produce higher analgesic effects than less expensive ones15. Personality traits also influence placebo analgesic effects through dopaminergic pathways and using this data, patients can be selected based on expected placebo analgesia16.

The influence of the study design, verbal suggestions and other environmental factors can indirectly affect the perception of pain due to placebo analgesia. It has been identified that the pharmacodynamics and efficacy of the drug can also be altered based on Expectation18. In a ‘hidden-open’ placebo-nocebo intervention study, patients perceived pain relief only after informing them that the drug infusion had began even though they had already begun the administered. Similarly, the patients stopped perceiving analgesia upon informing them that drug was stopped even though it wasn’t and the neuroimaging data confirmed this effect. The placebo/nocebo effect due to the Expectation was able to overcome the actual pharmacodynamics effect of the drug.18 

Placebo analgesia study models:
While designing studies for placebo-analgesia, the confounding factors such as natural history, personal biases and co-interventions should be taken into consideration and minimized so that the absolute pharmacological effect of the drug can be determined. Most analgesia studies use standardized pain intensity rating systems to obtained psychological details from patients directly. The common designs used are - Balanced placebo design, Double blind versus deceptive design, Open-hidden paradigm and Brain mapping using PET, fMRI and ECG17.

Balanced placebo design involves the comparison of the responses in patients to the informed amount of drug with the informed amount of placebo and between the actual doses of drug and actual doses of placebo. This design enables the study of the effects of verbal suggestions on placebo analgesia.

Double blind versus deceptive design compares the therapeutic outcome of a double-blind administration of an active drug with a deceptive one. The option of getting either a placebo or drug, during the double blind study, results in less placebo analgesia than when administering only the placebo, but disguised as a potent drug, during the ‘deception’ study.

Open-hidden paradigm is used to identify the placebo effect in context to specific instructions. The administration of active drug is hidden from patient initially and changes in the analgesia perception once informed are studies. Similarly, the cessation of the administration of the drug is hidden and informed later to observe changes in perception. This design has been used in studying placebo analgesia in case of anxiety, Alzheimer’s disease and Parkinson’s disease.

Brain mapping techniques enable the identification of the brain area and circuits involved in placebo analgesia under different physiological and pathological conditions. There are some drawbacks of using brain mapping techniques in that the brain patterns that predict placebo analgesia might differ among individuals as this does not take into account the affective information (Information on which aspects of pain that were actually judged by the patient). Data obtained from Pain intensity ratings includes this factor and therefore may differ from conclusions obtained from brain images.

Importance of placebo analgesia:
Most analgesic drugs show different efficacy and potency in different patients due to variability in the patients’ prior beliefs, personality traits, other environmental factors and study design factors19. Unexplained variability due to placebo analgesia makes it a challenge to control non-pharmacological responses in clinical trials and capitalize on them in clinical care. Clear understanding of placebo analgesia should provide new insight into development of efficient screening procedures for pain medication.

Placebo analgesia could also be harnessed either as a solitary treatment strategy or in conjunction with pharmacologically active drugs to improve the end-effects in patients. Better understanding of the effects of physician-patient interactions, clinical practices, verbal suggestions, patient expectations and classical conditioning techniques may pave way for new strategies for placebo-based analgesic therapy. Numerous brain-mapping studies have established that placebo effects of analgesia can be clinically implemented owing to its considerable magnitude and long duration of action. But, further large-scale clinical studies establishing these concepts are required for the wide-scale use of deception or non-deception-based strategies for placebo analgesia in the clinical environment.

Conclusion:
Although the primary molecular neurophysiology of placebo analgesia is complicated and involves a variety of receptor systems, it is irrefutable that it plays a major role in the efficacy of a number of drug classes such as Tricyclic antidepressants, opioid analgesics, etc. Comprehensive understanding of these mechanisms is crucial for the development of not just new drugs but also better treatment strategies. The use of placebo analgesic effects as a treatment using deception models are strictly prohibited due to obvious ethical reasons19. A recent study of the influence of placebo effects in IBS patients, at Harvard Medical School, highlights a new argument that placebo treatment can work even without deception20. Although further clinical studies are required to confirm this phenomenon and understand the underlying mechanism, it can potentially open new doors for the use of clinical placebo analgesia based therapies. For now, we can try to put into practice our knowledge of the positive effects of expectation and belief in the form of better clinical practices and patient care along with improving the patient-physician interactions.

References:
1.    Kuner, R. Central mechanisms of pathological pain. Nat Med 16, 1258-1266 (2010).
2.    Part III: Pain Terms, A Current List with Definitions and Notes on Usage (pp 209-214) Classification of Chronic Pain, Second Edition, IASP Task Force on Taxonomy, edited by H. Merskey and N. Bogduk, IASP Press, Seattle, ©1994.
3.    Fields, H.L. & Levine, J.D. Pain—Mechanisms and Management. West J Med 141, 347-357 (1984).
4.    Basbaum, A.I., Bautista, D.M., Scherrer, G & Julius, D. Cellular and Molecular Mechanisms of Pain. Cell 139, 267-284 (2009).
5.    Benedetti, F., Mayberg, H.S., Wager, T.D., Stohler, C.S. & Zubieta, J.-K. Neurobiological Mechanisms of the Placebo Effect. The Journal of Neuroscience 25, 10390 -10402 (2005).
6.    Benedetti, F. Mechanisms of placebo and placebo-related effects across diseases and treatments. Annu. Rev. Pharmacol. Toxicol. 48, 33-60 (2008).
7.    Bingel, U., Colloca, L. & Vase, L. Mechanisms and Clinical Implications of the Placebo Effect: Is There a Potential for the Elderly? A Mini-Review. Gerontology 57, 354-363 (2011).
8.    Scott, D.J. et al. Individual Differences in Reward Responding Explain Placebo-Induced Expectations and Effects. Neuron 55, 325-336 (2007).
9.    Porreca, F., Ossipov, M.H. & Gebhart, G.F. Chronic pain and medullary descending facilitation. Trends Neurosci. 25, 319-325 (2002).
10.    Review: placebo is better than no treatment for subjective continuous outcomes and for treatment of pain. Evidence Based Medicine 7, 11 (2002).
11.    Price, D.D. et al. An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain 83, 147-156 (1999).
12.    Benedetti, F. Cholecystokinin Type A and Type B Receptors and Their Modulation of Opioid Analgesia. Physiology 12, 263 -268 (1997).
13.    Siegel S. 2002. Explanatory mechanisms for placebo effects: Pavlovian conditioning. In The Science of the Placebo: Toward an Interdisciplinary Research Agenda, ed. HA Guess, A Kleinman, JW Kusek, LW Engel, pp. 133–57, London: BMJ Books
14.    de la Fuente-Fernández, R. The placebo-reward hypothesis: dopamine and the placebo effect. Parkinsonism Relat. Disord. 15 Suppl 3, S72-74 (2009).
15.    Blackwell, B., Bloomfield, S.S. & Buncher, C.R. Demonstration to medical students of placebo responses and non-drug factors. Lancet 1, 1279-1282 (1972).
16.    Schweinhardt, P., Seminowicz, D.A., Jaeger, E., Duncan, G.H. & Bushnell, M.C. The Anatomy of the Mesolimbic Reward System: A Link between Personality and the Placebo Analgesic Response. The Journal of Neuroscience 29, 4882 -4887 (2009).
17.    Colloca, L., Benedetti, F. & Porro, C.A. Experimental designs and brain mapping approaches for studying the placebo analgesic effect. Eur. J. Appl. Physiol. 102, 371-380 (2008).
18.    Finniss, D.G., Kaptchuk, T.J., Miller, F. & Benedetti, F. Biological, clinical, and ethical advances of placebo effects. The Lancet 375, 686-695 (2010).
19.    Price, D.D., Finniss, D.G. & Benedetti, F. A Comprehensive Review of the Placebo Effect: Recent Advances and Current Thought. Annual Review of Psychology 59, 565-590 (2008).
20.    Kaptchuk, T.J. et al. Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome. PLoS ONE 5, e15591 (2010).


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