Animals and humans can be readily conditioned to associate ...



TITLEBehavioral Conditioning, the Placebo Effect, and Emergency Department Pain Management(in press, The Journal of Emergency Medicine, accepted April, 2020)byKenneth Frumkin PhD, MD, FACEP (VOL)Emergency Medicine DepartmentNaval Medical Center, Portsmouth, VirginiaMobile: 757-482-9384Kenneth.Frumkin@ABSTRACTAnimals and humans can be readily conditioned to associate a novel stimulus (often a unique taste) by pairing it with the effects of a drug or other agent. When later presented with the stimulus alone, their body’s systems respond as if the drug or agent were given. The earliest clinical applications demonstrated both conditioned suppression and enhancement of immune processes. Unique benign stimuli, paired with chemotherapy, come to elicit T-cell suppression when administered alone. The beneficial immune responses to an antigen can be conditioned in the same manner. Further study of what came to be called psychoneuroimmunology led to the understanding that the familiar placebo effect, previously attributed to suggestion and expectation, is at least equally dependent on the same sorts of behavioral conditioning. The demonstrated ability to manipulate the immune system by a conditioned taste stimulus is, by definition, a placebo: a therapeutic effect caused by an inactive agent. The purpose of this analysis is to stimulate research in and the application of placebo response conditioning to emergency medicine. Clinical and experimental studies confirm the usefulness of conditioned placebos in analgesia and in placebo-controlled dose reduction. Such conditioning paradigms demonstrate “one-trial learning,” making them potentially useful in pain and addiction management within a single ED encounter. KEYWORDSConditioning, Placebo, Pain Management, PsychoneuroimmunologyREQUIRED DISCLAIMERSThe views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense or the United States Government.Copyright constraints: The author is a volunteer with the U.S. Government. This work was prepared as part of his official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.INTRODUCTIONThere is no question that the daily volume of emergency department (ED) patients with acute and chronic pain, combined with efforts to reduce our contribution to the opioid crisis(1), are appropriately inspiring our specialty’s research, policies, and practices. In our role as front door to the healthcare system and as providers to nearly 150 million patients yearly, emergency medicine is working diligently to meet this challenge, as we have with trauma, stroke, coronary disease, domestic violence, infectious diseases, and so many other public health threats.(2) With our other successes we have drawn from and cooperated with multiple medical disciplines. The objective of this analysis is to expand our search for solutions beyond our specialty and its traditional “house of medicine” allies to a substantial volume of untapped data from the behavioral sciences, immunology, and neurobiology. That body of literature, which began with studies of animal survival mechanisms, has the potential to drive the next phase of non-opioid management of acute and chronic pain. One discipline, largely unfamiliar to physicians, began in the 1970s. Christened psychoneuroimmunology (PNI)(3), PNI explains and integrates the foundations of the placebo response: the non-pharmacologic enhancement of neurologic, endocrine, immunologic, and pharmacologic mechanisms.(4) It is hoped that increased familiarity with the principles underlying this body of work will stimulate clinical and experimental investigations of powerful (and benign) placebo phenomena for emergency patients. It is the potential created by recent advances in understanding the behavioral and neuropharmacological mechanisms underlying the placebo response in managing pain and opioid use in the ED that prompted this publication.BACKGROUNDOrigins of PsychoneuroimmunologyThe Beginning: Conditioned Taste Aversion (CTA) The behavioral phenomenon underlying all research in PNI began in the 1950s with animal studies in psychology, physiology, pharmacology, and behavior.(5) When ingestion of a substance with a novel taste is followed by poisoning, rats decrease consumption of that substance on a subsequent exposure. CTA is an example of classical (Pavlovian) conditioning. Learned associations are made by pairing a novel “conditioned stimulus” and an active agent, the “unconditioned stimulus,” a drug, chemical, or physical agent that produces a negative effect (cellular injury, pain, or digestive malaise). After pairing, the neutral unconditioned stimulus alone comes to elicit a response characteristic of the active (unconditioned) agent. The CTA paradigm is an extremely powerful form of learning with obvious substantial evolutionary advantages. It can occur within just one trial. Poisons used to induce CTA included illness-producing negative reinforcers like intraperitoneal lithium chloride or apomorphine and cytotoxic agents like ionizing radiation and chemotherapeutic agents.(6, 7) Conditioning the Immune Response The immune system can be suppressed or enhanced through behavioral conditioning(8, 9): Learned Immunosuppression is the Pavlovian conditioning of the immune response to chemotherapy agents. Initial work with immunosuppressive drugs utilized their capacity to negatively reinforce ingestive behavior by establishing condition taste aversions. Then Ader, in 1974, noticed increased mortality in rats conditioned to avoid saccharin by a single pairing with cyclophosphamide when they were subsequently exposed repeatedly to the saccharine alone.(10) The mortality rate varied with the strength of the conditioned aversion. This observation led to the hypothesis that, in addition to conditioning a behavioral response (aversion), pairing cyclosporine with saccharine also allowed cyclosporine’s immunosuppression to be elicited by re-exposure to the taste stimulus. This conditioned immunosuppression was believed to have increased the susceptibility of the aversion-conditioned animals to pathogens in the laboratory environment.(11) Beginning in the 1970s with that observation, the paradigm originally developed to study poison avoidance by rats was employed to condition the immune system in animals, and then humans. The basic protocol was the same. The cytotoxic chemotherapeutic agents used as the “poison” in many taste aversion studies were paired with a distinctive taste stimulus. After pairing, the taste stimulus alone resulted in measurable and reproducible decreases in antibody production to an allergic challenge(12) as well as conditioned suppression of natural killer cell cytotoxicity(13). “Clinically,” the morbidity and mortality of animals with autoimmune disease were improved via conditioning, substituting the benign conditioned taste stimulus for cytotoxic agents.(14-16) Learned immunosuppression was similarly demonstrated in humans. Examples included demonstrations of conditioned suppression of the T-cell response, general leukopenia, and other measures of immune function.(17-19) The significant potential benefits of these findings include fewer side effects, longer safe courses of treatment, and lower cost.Learned immunoenhancement of the response to an antigen occurs when a neutral stimulus previously paired with the antigen is subsequently administered alone. Like a “booster” the conditioned stimulus enhances antibody production.(20-24) Generalized “conditioned immunostimulation” was similarly demonstrated by pairing recombinant human interferon-gamma with oral propylene glycol generating increased markers of immune activation with propylene glycol exposure alone.(25)Conditioning of the Neuroendocrine System: A developing body of literature describes the expansion of the same paradigm to the classical conditioning of endocrine responses.(26) Conditioning of dopamine transporter binding(27), and of the effects of exogenous insulin on humans(28-30) has been demonstrated. Psychoneuroimmunology, Conditioning, and the Placebo EffectThe placebo effect, the therapeutic use of substances and interventions with no intrinsic beneficial action, is in fact “ancient history”.(31, 32) Although physicians are very familiar with the placebo effect, we are less aware of its behavioral underpinnings. PNI is the interdisciplinary field studying the interaction of behavioral, neural, endocrine, and immune systems and their bidirectional connections with the brain.(33) PNI-based interventions are well suited to mitigating disease progression and/or side effects of pharmacological treatment via conditioning and its role in the placebo effect.(34) Conditioning as a Basis for the Placebo Effect: The shift of PNI from the study of aversions and immunomodulation to placebo research came with the recognition that behavioral conditioning is one of the two pillars of the placebo response: conditioning and expectation.(11) Manipulation of the immune system by a conditioned taste stimulus, is, by definition, a placebo, a therapeutic effect caused by an inactive agent. The benefits of the placebo effect are attributed to two fundamental psychological mechanisms: classical conditioning, established by pairing neutral stimuli with active treatments, and expectations created by suggestions, verbal instructions, social learning, and the rituals, symbols, and interactions that make up the therapeutic encounter.(24, 32, 35-39) The relative contributions of conditioning and expectation vary with the therapeutic context and conditioning paradigm(40-43), as well as with individual differences in brain structure and neurobiological system function(36, 44). While manipulation of expectation has been the primary placebo mechanism exploited clinically(16), the placebo effect can occur with conditioning alone, independent from explicit expectation(45-47).A major demonstration of the clinical value of PNI is the phenomenon of Placebo-Controlled Dose Reduction (PCDR), the pairing of a placebo with a drug to achieve satisfactory treatment outcomes with a lower medication dose. Some doses are replaced by the conditioned inert placebo while treatment efficacy is maintained.(48) In cancer treatment, substituting the conditioned taste stimulus for the chemotherapy agent can significantly reduce side effects and complications by allowing smaller cumulative doses of the active agent. In children treated for ADHD, a visually distinct placebo pill was first paired with usual doses of amphetamine salts, and later taken along with a reduced dose. The (open label) placebo allowed effective treatment with a 50% reduction in subjects’ previous optimal stimulant dose.(49)Mechanisms of the Placebo Effect The principal mechanisms of the placebo effect are still being clarified, but certainly include the likelihood that placebos stimulate the same biochemical pathways and neural circuits that are activated by drugs.(50) The complex neurobiological mechanisms under study include neurotransmitters, such as endorphins, cannabinoids, serotonin, and dopamine. Functional neuroimaging links neurotransmitters with specific and quantifiable activation of relevant areas of the brain by placebos. Many common medications act through these same pathways. Genetic and functional neuroanatomic signatures identify individual patients who are more likely to respond to placebos.(36-38, 51-55) “Placebo Effect” “Placebo Response” and “Nocebo”: Scientific studies establishing the existence of the classic “placebo effect” have always had to differentiate that result from the alternative, the “placebo response.” Beneficial “placebo effects” result from Pavlovian conditioning and/or the creation of expectation. “Placebo responses” reflect other uncontrolled mechanisms such as spontaneous improvement (regression to the mean), patient bias, or the many other unknowable factors that influence the natural course of disease.(56) In standard drug studies “placebo responses” are seen in both experimental and control (placebo) groups.(35) “Just as responses following drug treatment do not necessarily indicate true drug effects, so responses to placebo do not necessarily constitute placebo effects.”(42)Nocebo effects are considered to be the undesirable opposite of a placebo. Nocebos are patient-perceived side effects of treatments and medications that are “actually caused by anticipation of negative effects or heightened attentiveness to normal background discomforts of daily life in the context of a new therapeutic regimen.”(37, 51). Nocebo effects are most commonly recorded and quantified in standard drug trials as the nature and number of side effects experienced by the group not receiving the active drug. The mechanism behind the nocebo effect is believed similar to those placebo effects that are based on expectation.(32) Patient knowledge of potential adverse effects influences the reported incidence of these symptoms. Thus, the frequency and profile of adverse effects manifested by patients randomized to receive placebo in controlled, double-blind clinical trials are similar to those they have been told may occur with the active comparator drug. Increased symptoms can also follow when patients are provided test results of dubious clinical significance.(57) Potential ApplicationsPlacebo responses have long been recognized as common, with an average prevalence of 35% .(58) Placebos can be more effective than active agents, with fewer side effects.(59) In the past, investigators directed their efforts toward eradicating placebo effects. More recently, researchers have turned to the benefits of incorporating placebos into clinical therapeutic strategies.(60) The recognition of the placebo effect as a learned response opens every drug or treatment to the possibility of creating safe conditioned stimuli to substitute for active agents. Multiple illustrations exist(61), with placebo-controlled dose reduction as one very successful example(48, 62). Ethical concerns about the deception inherent in placebo substitution are resolved by recent successes with “open- label” placebos. Even when patients are informed they are receiving inactive agents, beneficial placebo effects persist.(49, 63-65) The success of open label placebos counters the assumption that the deceptions involved in suggestion and expectation are critical for placebo effects.(66)Pain Management and Placebo Analgesia (PA): Of all possible clinical applications of the placebo effect, the greatest potential benefit to emergency patients is the addition of placebo-based analgesia or dose reduction to the outpatient management of acute and chronic pain.(48, 60, 67) ED pharmacologic pain management practices and their negative consequences (opioid dependence, diversion, and misuse) have been dramatically chronicled and critiqued over the last several years.(68, 69). Attempts at opioid use reduction have created concerns for the unintended consequence of inadequate pain management.(70) Placebo analgesia may help balance those concerns.Conditioned placebo analgesia was demonstrated in human subjects as early as the 1980s(71, 72), and is finding uses in the management of chronic pain.(63) Psychological factors may be less important than Pavlovian conditioning, since conditioning alone, independent from expectation, can produce PA.(47) The effectiveness of open label placebos appears to confirm the relative value of conditioning over suggestion while minimizing deception and related ethical concerns.(63, 64) Individual variation in the magnitude of beneficial effects in “placebo responders” can be predicted by detectable differences in each subject’s psychological traits, and in their brain structure and function as identified by neuroimaging.(44) Multiple challenges exist: The ability to successfully condition PA in animals is variable.(73) The inherent 35% placebo response rates require large samples and careful statistical analysis. Addiction: In addition to conditioning analgesia, it is equally possible to create conditioned placebos for agents used in treating opioid use disorder and other dependencies like alcohol or nicotine (e.g., substituting for methadone, buprenorphine, naloxone and its congeners, and disulfiram). For instance, naloxone-precipitated morphine withdrawal can be conditioned to taste cues in the rat.(74, 75) A recently proposed clinical trial of open-label methadone dose-extending placebos for opioid use disorder is enrolling patients.(67) The capacity for developing learned associations in just one trial, analogous to the conditioned avoidance of poisons, is powerful and potentially adaptable to ED initiation (similar to current efforts with ED initiation of buprenorphine therapy(76)). Knowledge of the role of neurobiological pathways in pain, addiction, and placebo analgesia is evolving.(55) Dopamine neurons have been considered central to addiction and pleasure(77, 78) and can be conditioned to sensory cues. Those cues can subsequently both evoke dopamine neuronal activity and elicit cue-associated conditioned behavior.(27, 54)Placebo-controlled dose reduction (PCDR): Substituting a placebo for the active drug some of the time can maintain the therapeutic efficacy of drug treatment while decreasing the cumulative dose of the active agent.(48, 62) PCDR has been demonstrated in anti-rejection therapy after renal transplantation(79), autoimmune diseases(11, 80), cancer chemotherapy(81), and ADHD treatment(49). This well-supported early application of psychoneuroimmunology has the potential to expand options in multiple areas of pharmacotherapeutics. Varying the ratio between active drug and placebo is a means to optimize the balance among dosage, efficacy, treatment duration, side effects, tapering, easing withdrawal, total dose, and cost.(3) PCDR can be “open label,” without deception.(64)Interventional pharmacoeconomics: The discipline of pharmacoeconomics originated in the UK National Health Service (NHS) as a means to evaluate the value and affordability of pharmacologic interventions. Economic analyses of data from disparate sources inform clinical choices in the setting of financial constraints.(82) Interventional pharmacoeconomics (IVPE) uses research-based active means to “to disruptively decrease prescribing costs through the development of new dosing regimens while maintaining equivalent efficacy.”(83) Like PNI three decades ago, successful IVPE research to date primarily addresses chemotherapeutic agents. Strategies yielding lower costs include lower doses, less frequent dosing, shorter treatment duration, and therapeutic substitution. An added benefit can be a reduction in adverse reactions.(83) The potential benefits from adding behavioral means like PCDR to the IVPE approach are clear.DISCUSSION AND IMPLICATIONS FOR FUTURE RESEARCH Pain will likely remain the number one reason patients come to the ED. Placebo-based sedation, analgesia, and dose reduction are credible, important, and previously neglected areas of emergency department research. They directly relate to emergency medicine’s daily mission and would benefit millions of our patients. Research funding will be a challenge. On the positive side, when compared with studying new drugs or indications, research on placebo dose reduction with approved drugs is likely to have fewer regulatory hurdles. Traditional pharmaceutical research compares the active drug under study with an inactive substance. The placebo group has been the competition, a nuisance, the “one to beat”. Evidence supporting the effectiveness of placebos has emerged largely from outside the pharmaceutical industry, often by simply including a third untreated control arm in randomized trials.(35) However, pharmaceutical manufacturers would appear to have little motivation for supporting or initiating studies of PCDR or conditioned substitution for their active drugs. The absence of financial incentives may explain why most of this work has been done outside the US, and why many studies are small.(34) As an example, two-thirds of this paper’s 44 references describing placebo pharmacotherapy (those with “placebo” in the title) were published outside the United States.The opioid epidemic has become a strong motivator for research. Perhaps opioid manufacturers can be encouraged to fund studies of alternative pain relief as a way to mitigate criticism of and liability for their past behaviors. If not drug manufacturers, other stakeholders should have an interest in funding studies leading to safe and less expensive pharmacotherapy. Payers (like governments, closed health care systems, and self-insured corporations) should all be motivated to decrease health care costs while maintaining treatment efficacy. Public health funding sources, wellness advocates and philanthropic institutions may come to recognize the social value of these methods in issues of dependence, affordabilty, and health disparity. The resulting savings to the health care system from lower and less frequent doses, shorter treatment duration, and therapeutic substitution are estimated to be in the tens of billions of dollars annually.(83)New research tools. While the paradigms underlying behavioral pain management have been around since the 1950s(84), exciting new means and models are being developed and explored. There is room at all levels (from the biochemical, neurological, and genetic to the social, economic, and behavioral) to study and apply the mechanisms underlying the placebo effect. The use of functional nueoroimaging as a pharmacodynamic biomarker enables the objective measurement of analgesic efficacy while clarifying the neural pathways and mechanisms involved.(53) The neurologic pain signature (NPS),is an example of an objective measure of neurophysiological patterns associated with specific aspects of pain.(85) An EEG-based measure of nociceptive brain activity is evoked by noxious stimuli and is sensitive to analgesic modulation.(86) “Conditioned pain modulation” in which one noxious (conditioning) stimulus modulates another (“pain inhibits pain”, “counterirritation”), has been validated successfully, but not studied in the acute setting.(87) ED Implementation does not have to wait. In the management of acute and chronic pain, there is room for increased use of all non-pharmacologic techniques(88), as well as for both parts of the placebo paradigm (expectations and classical conditioning). One can add conditioning and suggestion to multimodal, non-opioid pain therapy and procedural sedation for adults and children (in whom we already use behavioral techniques)(89-91). Some aspects of the placebo effect are already consciously or unconsciously employed. Examples include white coats, “verbal anesthesia,” relaxation techniques, distraction, hypnosis, and simple reassurance and suggestion (“You’ll just feel a little pressure,” or “This drug is ‘the good stuff’”). The fact that conditioned placebo responses, like conditioned taste aversions, can occur in one trial opens the possibility for PCDR and other behavioral techniques in the ED. The evolution of this single-trial learning represents a primal mechanism for the preservation of the species. In the age of spiraling addiction and drug-related deaths why not harness that power for the treatment and very survival of our patients? As an example: one could administer a placebo taste stimulus with the first dose of pain medication, then pair it with a reduced subsequent dose. This can even be done “open label,” without deception.(64) Better crafted provider-patient communication can decrease patient pain and stress. How physicians deliver information, when instituting a new medication, obtaining informed consent, presenting ambiguous laboratory results, and preparing patients for painful procedures, can both positively and negatively impact responses to therapy and interventions. This “viscerosomatic amplification” of placebo or nocebo effects merits study and ED provider education.(57) One would hope for increased application of these principles to pharmacotherapeutics in general. A recent consensus of placebo researchers concluded that “maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects.”(92) Psychoneuroimmunology began with studies facilitating immunotherapy and cancer chemotherapy. Along with the neuroendocrine system(61) the mechanisms behind these are susceptible to conditioning and contribute to most biological processes of health and disease.(23, 26) We draw on other scientific disciplines every day in both research and practice. Why not explore the behavioral science behind psychoneuroimmunology for the benefit of our millions of patients?SUMMARYDemonstrations of the psychoneurobiological bases for the placebo effect offer techniques from the behavioral sciences that can be applied in the ED, and more broadly to pharmacotherapy and immunotherapy in general. Recognizing that the placebo effect is an example of behavioral conditioning can greatly expand the role of that phenomenon in treatment. Broader application of conditioning principles has the potential to mitigate drug side effects and cost, while enriching diverse areas of investigation. The opioid crisis has spurred advancements in the management of pain and withdrawal across the breadth of medicine. As the broadest specialty, emergency medicine continually integrates and improves upon innovations in other disciplines for the benefit of emergency patients (e.g., RSI, ultrasound, procedural sedation, regional anesthesia and more). To enhance our approach to pain management and addiction, emergency medicine can benefit from applying the 60-plus years of behavioral techniques described and the evolving understanding of their neurobiological basis. Placebos work. We should use them.REFERENCES[1] Weiner SG, Baker O, Poon SJ, et al. 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