Reconsidering the Placebo Response from a Broad Anthropological Perspective

This paper considers how the full range of human experience may catalyze a placebo response. The placebo effect has been characterized as something to control in clinical research, something to cultivate in clinical practice and something present in all healing encounters. We examine domains in which the term ‘placebo’ is used in discourse: clinical research, clinical practice, media representations of treatment efficacy and lay interpretations of placebo—an underresearched topic. We briefly review major theoretical frameworks proposed to explain the placebo effect: classical conditioning, expectancy, the therapeutic relationship and sociocultural ‘meaning.’ As a corrective to what we see as an overemphasis on conscious cognitive approaches to understanding placebo, we reorient the discussion to argue that direct embodied experience may take precedence over meaning-making in the healing encounter. As an example, we examine the neurobiology of rehearsing or visualizing wellness as a mode of directly (performatively) producing an outcome often dismissed as a ‘placebo response.’ Given body/mind/emotional resonance, we suggest that the placebo response is an evolutionarily adaptive trait and part of healing mechanisms operating across many levels—from genetic and cellular to social and cultural.

Reframing placebo in research and practice

The terms 'placebo' and 'placebo effects' cause confusion among patients, practitioners and scientists. This confusion results in both the adoption of practices that have no evidence of specificity yet considerable risk (such as surgery for low back pain) or the elimination of clinical practices proven to facilitate healing because they are not 'better than placebo' (such as acupuncture for low back pain). In this article, I discuss these issues and introduce the concept of optimal healing environment as a framework for disentangling what is useful from placebo research for adopting into clinical practice in a manner that is ethical and evidence-based.     

Pain and the placebo: what we have learned

Despite the recent blossoming of rigorous research into placebo mechanisms and the long-standing use of placebos in clinical trials, there remains widespread and profound misunderstanding of the placebo response among both practicing physicians and clinical researchers. This review identifies and clarifies areas of current confusion about the placebo response (including whether it exists at all), describes its phenomenology, and outlines recent advances in our knowledge of its underlying psychological and neural mechanisms. The focus of the review is the placebo analgesic response rather than placebo responses in general, because much of the best established clinical and experimental work to date has been done on this type of placebo response. In addition, this subfield of placebo research offers a specific neural circuit hypothesis capable of being integrated with equally rigorous experimental work on the psychological (including social psychological) and clinical levels. In this sense, placebo analgesia research bears all the marks of a genuine multilevel interdisciplinary research paradigm in the making, one that could serve as a model for research into other kinds of placebo responses, as well as into other kinds of mind-body responses.     

Placebo studies and ritual theory: a comparative analysis of Navajo, acupuncture and biomedical healing

Using a comparative analysis of Navajo healing ceremonials, acupuncture and biomedical treatment, this essay examines placebo studies and ritual theory as mutually interpenetrating disciplines. Healing rituals create a receptive person susceptible to the influences of authoritative culturally sanctioned 'powers'. The healer provides the sufferer with imaginative, emotional, sensory, moral and aesthetic input derived from the palpable symbols and procedures of the ritual process-in the process fusing the sufferer's idiosyncratic narrative unto a universal cultural mythos. Healing rituals involve a drama of evocation, enactment, embodiment and evaluation in a charged atmosphere of hope and uncertainty. Experimental research into placebo effects demonstrates that routine biomedical pharmacological and procedural interventions contain significant ritual dimensions. This research also suggests that ritual healing not only represents changes in affect, self-awareness and self-appraisal of behavioural capacities, but involves modulations of symptoms through neurobiological mechanisms. Recent scientific investigations into placebo acupuncture suggest several ways that observations from ritual studies can be verified experimentally. Placebo effects are often described as 'non-specific'; the analysis presented here suggests that placebo effects are the 'specific' effects of healing rituals.     

Oral nutritional supplementation accelerates skin wound healing: a randomized, placebo-controlled, double-arm, crossover study

Nutritional therapy is critical for wound healing in people with severe malnutrition or specific metabolic deficiencies. Medical claims from manufacturers of many oral supplements are marketed to surgical patients for decreasing edema, bruising, and discomfort. The effect of supplementing nutrients on soft-tissue wound healing in otherwise normal, healthy adults is an area of clinical importance, but little information is available. Proteolytic enzymes have been reported to moderate the inflammatory cycle and may up-regulate the healing process. The goal of this study was to perform a clinical trial in normal, healthy adults that examined the effects of an oral nutritional supplement (InflammEnz, Enzymes, Inc., Parkville, Mo.) on soft-tissue healing times. Twenty-six normal, healthy volunteers were recruited into a randomized, crossover, placebo-controlled, clinical trial consisting of two phases, each lasting 21 days. In phase I, subjects were subjected to a 3-mm forearm skin biopsy and randomly received a placebo or oral supplement (four capsules per day for 7 days). After a 2-week washout period, a second biopsy was performed to start phase II, with each subject receiving the respective placebo or supplement capsules. Digital photographs were taken during wound healing in both phases and analyzed for wound areas (in square millimeters) and perimeters (in millimeters). Twenty-two subjects completed the clinical trial. On the basis of wound surface areas, 17 subjects had improved wound healing and five subjects did not respond or responded only slightly to the supplement treatment. The mean +/- SD healing time of the subjects responding to supplement-treated wounds was 15 +/- 2.2 days, compared with 18 +/- 2.5 days for the placebo group. The 17 percent acceleration of wound-healing time was significant (p < 0.005). In subjects responding to oral supplements, less redness in the wounds was observed that may have been associated with less inflammation. The authors' results demonstrate that InflammEnz oral supplementation accelerated soft-tissue wound healing in 77 percent of normal, healthy subjects studied. The authors' study validates observations made that this supplement modulates the wound-healing process and suggests that many patients with minor soft-tissue wounds may benefit from treatment.     

Effectiveness and tolerance of selected Polish antacids in the therapy of duodenal ulcer disease. A placebo- and ranitidine-controlled study

In a randomized, open clinical trial we compared the efficiency of selected Polish antacids Alugastrin, Gastrin and Wikalina with ranitidine and placebo in the healing of duodenal ulcer, pain relief and drug toleration. One hundred and ten outpatients completed the study. The trial showed that antacids and ranitidine had similar rates of duodenal ulcer healing which were significantly better than placebo. After 4 weeks of treatment with Alugastrin, Gastrin, Wikalina and ranitidine the healing rates were 70%, 76%, 71% and 81%, respectively, compared to placebo 44%. Efficiency of antacids in pain relief was similar to placebo and slightly lower than ranitidine. Antacids were well tolerated, except for hypermagnezemia and urine alkalization caused by Gastrin and Wikalina. We conclude that studied antacids are as effective as ranitidine in promoting healing of duodenal ulcer, but because of side effects they are not recommended for maintenance therapy.     

William James, faith, and the placebo effect

Long considered a fact of medicine and of clinical investigation, the placebo effect has recently been challenged. The thought of the great American psychologist and philosopher William James, particularly his understanding of the practical value of faith, helps to illuminate the nature of the placebo effect and the implications of this puzzling phenomenon for understanding healing and the practice of medicine.     

Prediction of the intramembranous tissue formation during perisprosthetic healing with uncertainties. Part 2. Global clinical healing due to combination of random sources

This work proposes to examine the variability of the bone tissue healing process in the early period after the implantation surgery. The first part took into account the effect of variability of individual biochemical factors on the solid phase fraction, which is an indicator of the quality of the primary fixation and condition of its long-term behaviour. The next issue, addressed in this second part, is the effect of cumulative sources of uncertainties on the same problem of a canine implant. This paper is concerned with the ability to increase the number of random parameters to assess the coupled influence of those variabilities on the tissue healing. To avoid an excessive increase in the complexity of the numerical modelling and further, to maintain efficiency in computational cost, a collocation-based polynomial chaos expansion approach is implemented. A progressive set of simulations with an increasing number of sources of uncertainty is performed. This information is helpful for future implant design and decision process for the implantation surgical act.     

From structure to solutions: the role of basic research in developing anthrax countermeasures: Microbiology Graduate Program Seminar: Anthrax toxin

Dr. John Collier traced the discoveries that elucidated the structure and function of the anthrax toxin in his talk "Anthrax Toxin," which was part of the Microbiology Graduate Program Seminar Series at Yale School of Medicine on February 23, 2012. Dr. Collier, Professor of Microbiology and Immunobiology at Harvard University, began by noting the advantages to studying anthrax pathogenesis in a biosafety level-1 lab. This designation does not merely facilitate his research, but also reflects a larger trend of basic research being leveraged to develop translational applications. Basic research on toxin structure has led to the development of a vaccine by Dr. Collier's group. Next-generation prophylactics also may stem from recent discoveries uncovering a role for cellular cofactors that mediate toxin function. Finally, basic research into the toxin substructure has facilitated efforts to change the receptor tropism to target dysregulated cells for therapeutic purposes. The urgency around biodefense agents makes the choice of research priorities a salient issue. As such, this author submits that basic research occupies a unique and lucrative niche driving clinical applications.     

Harnessing the placebo effect: the need for translational research

Laboratory research recently has greatly enhanced the understanding of placebo and nocebo effects by identifying specific neuromodulators and brain areas associated with them. However, little progress has been made in translating this knowledge into improved patient care. Here, we discuss the limitations in our knowledge about placebo (and nocebo) effects and the need for translational research with the aim of guiding physicians in maximizing placebo effects and minimizing nocebo effects in their routine clinical practice. We suggest some strategies for how, when and why interventions to promote beneficial placebo responses might be administered in the clinical setting.     

The placebo response: an attachment strategy that counteracts the effects of stress-related dysfunction

The placebo response represents an enigmatic element of therapeutics. The potency of placebo effects is highlighted by the fact that the current gold standard for determining therapeutic efficacy, the randomized controlled clinical trial, is based on identifying treatment responses that are statistically superior to those elicited by a placebo. Although much has been written concerning the phenomenology of placebos, little is known concerning how they are elicited, although recent research has demonstrated that placebo effects are mediated via objective physiological pathways. I have previously argued that the placebo response is a developmental achievement, rooted in implicit procedural memories that are linked to background affects of well-being evoked by a relational dynamic with a caregiver. This article develops this idea further, suggesting that placebo response represents a nervous-system response aimed at countering the dysphoric effects attributable to chronic stress, and that it is dependent on developmental attachment dynamics. A range of behaviors by caregivers that mimic those achieved during secure attachment are suggested to promote placebo responses.     

New insights into the placebo and nocebo responses

In modern medicine, the placebo response or placebo effect has often been regarded as a nuisance in basic research and particularly in clinical research. The latest scientific evidence has demonstrated, however, that the placebo effect and the nocebo effect, the negative effects of placebo, stem from highly active processes in the brain that are mediated by psychological mechanisms such as expectation and conditioning. These processes have been described in some detail for many diseases and treatments, and we now know that they can represent both strength and vulnerability in the course of a disease as well as in the response to a therapy. However, recent research and current knowledge raise several issues that we shall address in this review. We will discuss current neurobiological models like expectation-induced activation of the brain reward circuitry, Pavlovian conditioning, and anxiety mechanisms of the nocebo response. We will further explore the nature of the placebo responses in clinical trials and address major questions for future research such as the relationship between expectations and conditioning in placebo effects, the existence of a consistent brain network for all placebo effects, the role of gender in placebo effects, and the impact of getting drug-like effects without drugs.     

The future of South East Asian rainforests in a changing landscape and climate

With a focus on the Danum Valley area of Sabah, Malaysian Borneo, this special issue has as its theme the future of tropical rainforests in a changing landscape and climate. The global environmental context to the issue is briefly given before the contents and rationale of the issue are summarized. Most of the papers are based on research carried out as part of the Royal Society South East Asia Rainforest Research Programme. The issue is divided into five sections: (i) the historical land-use and land management context; (ii) implications of land-use change for atmospheric chemistry and climate change; (iii) impacts of logging, forest fragmentation (particularly within an oil palm plantation landscape) and forest restoration on ecosystems and their functioning; (iv) the response and resilience of rainforest systems to climatic and land-use change; and (v) the scientific messages and policy implications arising from the research findings presented in the issue.     

A comparative multi-centre study of the efficacy of propolis, acyclovir and placebo in the treatment of genital herpes (HSV).

Ninety men and women with recurrent genital HSV type 2 participated in a randomized, single-blind, masked investigator, controlled multi-centre study comparing the efficacy of ointment of Canadian propolis containing natural flavonoids with ointments of acyclovir and placebo (vehicle) on healing ability and capacity to remedy symptoms. Thirty individuals were randomized to each group. Treatment was intended to start in the blister phase. All participants had HSV type 2 isolated, confirmed by serum immunoglobulin levels. The participants were examined on the 3rd, 7th and 10th days of treatment by gynaecologists, dermatovenerologists or urologists at seven different medical centres. Apart from clinical symptoms the number and size of the herpetic lesions were noted. At each examination the lesions were classified into four stages: vesicular, ulcerated, crusted and healed. The study ointments were applied to affected areas four times daily. In women with vaginal or cervical lesions a tampon with the appropriate ointment was inserted four times daily for 10 days. Endpoint variables were healing time and time until loss of symptoms. RESULTS: On Day 10, 24 out of 30 individuals in the propolis group had healed. In the acyclovir group 14 out of 30 and in the placebo group 12 out of 30 had healed. (p = 0.0015). The healing process appeared to be faster in the propolis group. In the propolis group 15 individuals had crusted lesions on Day 3 compared to 8 individuals in the acyclovir group and none in the placebo group (p = 0.0006). On Day 7, 10 participants in the propolis group, 4 in the acyclovir group and 3 in the placebo group had healed. At the initial examination all patients had local symptoms and 28% general symptoms. At Day 3, 3 patients in the propolis group had local symptoms compared to 8 and 9 in the acyclovir and placebo groups respectively. Of the women, 66% had vaginal superinfections of microbial pathogens at the initial examination. In the acyclovir and placebo groups no change in the vaginal flora was found following treatment whereas in the propolis group the incidence of superinfection was reduced by 55%. (p = 0.10 n.s.). CONCLUSION: An ointment containing flavonoids appeared to be more effective than both acyclovir and placebo ointments in healing genital herpetic lesions, and in reducing local symptoms.     

Extracellular matrix considerations for scar-free repair and regeneration: Insights from regenerative diversity among vertebrates

The extracellular matrix (ECM) is an essential feature of development, tissue homeostasis and recovery from injury. How the ECM responds dynamically to cellular and soluble components to support the faithful repair of damaged tissues in some animals but leads to the formation of acellular fibrotic scar tissue in others has important clinical implications. Studies in highly regenerative organisms such as the zebrafish and the salamander have revealed a specialist formulation of ECM components that support repair and regeneration, while avoiding scar tissue formation. By comparing a range of different contexts that feature scar-less healing and full regeneration vs. scarring through fibrotic repair, regenerative therapies that incorporate ECM components could be significantly enhanced to improve both regenerative potential and functional outcomes. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation.     

Oxpentifylline treatment of venous ulcers of the leg.

OBJECTIVE--To determine the effect of oxpentifylline on the healing of venous ulcers of the leg. DESIGN--Double blind, randomised, prospective, placebo controlled, parallel group study. SETTING--Four outpatient clinics treating leg ulcers in England and the Republic of Ireland. PATIENTS--80 Consecutive patients with clinical evidence of venous ulceration of the leg in whom appreciable arterial disease was excluded by the ratio of ankle to brachial systolic pressure being greater than 0.8. INTERVENTIONS--All patients received either oxpentifylline 400 mg three times a day by mouth or a matching placebo for six months (or until their reference ulcer healed if this occurred sooner) in addition to a locally standardised method of compression bandaging. MAIN OUTCOME MEASURES--The primary end point was complete healing of the reference ulcer within six months. The secondary end point was the change in the area of the ulcer over the six month observation period. RESULTS--Complete healing of the reference ulcer occurred in 23 of the 38 patients treated with oxpentifylline and in 12 of the 42 patients treated with a placebo. Life table analysis showed that the proportion of ulcers healed at six months was 64% in the group treated with oxpentifylline compared with 34% in the group treated with a placebo (log rank test chi 2 = 4.78, p = 0.03), which was significant (odds ratio = 1.81, 95% confidence interval 1.20 to 2.71). CONCLUSION--Oxpentifylline used in conjunction with compression bandaging improves the healing of venous ulcers of the leg.     

Failure of acyclovir cream in treatment of recurrent herpes labialis.

A double blind, randomised, crossover placebo controlled trial of 5% acyclovir cream, applied topically five times a day for five days, was carried out in 45 patients with recurrent herpes labialis. These patients had a total of 72 episodes, 34 of which were treated with the 5% acyclovir cream and 38 with placebo cream. Treatment was begun by the patients as soon as possible after the onset of prodromal symptoms. There was no significant clinical benefit from treatment with acyclovir cream compared with placebo cream. The median healing times were nine days with acyclovir cream, 10 days with placebo cream, and 13 days when no treatment was given. The possibility that the 40% propylene glycol cream base alone has a therapeutic effect must therefore be considered.     

Parallel and divergent landscapes: cultural encounters in the ethnographic space of Tuareg medicine

This essay explores the dialogue between the local quest for healing and the anthropological quest for healing knowledge, and local assessments of knowledge-power relationships in these processes. The context is medical discourse among the Tuareg of Niger Republic, West Africa, and my research experiences among these people. I examine local medical specialists and their traditional and changing practice in terms of how they perceive and respond to wider knowledge and power systems that impinge on local health care. Paramount in these systems are central state policies and medical anthropological research on healing, as these intersect in a postcolonial and post-separatist/rebellion setting. The essay analyzes parallels between the exchange of medicine and the exchange of knowledge and reflects upon how anthropological knowledge of African healing systems is constructed in an environment highly charged with power and danger--of political violence and economic crisis. The broader issue addressed here is how to give greater empowerment to local residents' voices in their "indigenous critique" of the medical anthropological project.