Psychological Dimensions in Clinical Adverse Events - Research Paper Example

? “I Will Harm” An exploration of psychological dimensions in clinical adverse events Anyone having studied health care, or the details of pharmaceutical research will be familiar with that complication of clinical research, the placebo effect. The confounding influence of what might be termed 'psycho-medical' factors; obscuring whether a drug or treatment truly yields the desired result. The placebo effect of course, is both a weakness, yet also an ally in clinical tests. This inevitable consequence of medical research is routinely targeted; many modern drug studies measure themselves against the placebo effect; requiring a statistically-significant deviation as proof that their concoction is more than just sugar-water. Yet thinking one’s self well – or sick can be more important than earlier clinicians realized. (Enck et al. 2008) Placebo effects have received considerable publicity in recent decades, and the technological march that permits advances in brain imaging, and the tools thereof, have dramatically increased our comprehension of the associated neurobiology. But researchers have now begun the investigation of the phenomenon that is the opposite of the beneficial placebo. These, are the nocebo effects – adverse effects, including worsening of medical status or increased negative severity of symptoms due simply to the expectation or suggestion involving some inert treatment – is a somewhat more obscure area of study in the field of neuroscience. Among these effects are findings of anticipatory anxiety that can heighten pain, through Cholecystokinin activation, among the activity of other neurotransmitters. (Colloca et al. 2007) A growing body of research has demonstrated that while the mind has the power to convince the body to heal, a dark cousin of the same phenomenon swings the other way, as well. Taken from a Latin word 'I will harm', rather than placebo's 'To appease'. Medication-caused adverse effects are seen as a common reason for low compliance in medical practice and during clinical studies. These events can be disturbingly common in patients receiving only placebo. Headache/migraine studies appear prone to this mistaken pathology, (Mitsikostas et al. 2011) with trial participants dropping out over effects of a drug that is not a drug. The emergence of adverse effects in placebo-only groups can simplify anomalies in the assessment of clinical monitors that must report, and define adverse events. A study by Rief et el. found that 4% to 26% of patients in the control groups of large, pharmaceutical trials of statin drugs discontinued placebo use because of the perception of adverse effects that seemed real to the patient. (Rief et al. 2006) Several studies suggest that the effects of the nocebo, which can be termed “negative placebo effects,” form a significant contribution to a wide range of medical symptoms and adverse effects. Clinical trials and medical care are both influenced by these effects; in which an adverse event can be seemingly derived from an agent with no pharmacological activity. These nocebo effects can be invoked through the generation of negative expectancy to a phony treatment, subjective pain rankings increased by a significant factor on nocebo sites of the arm in comparison with control sites. fMRI investigations confirmed a variety of brain regions involved in an hyperalgesic nocebo effect. Functional Magnetic Resonance Imaging can be used to measure, and map out these brain regions specifically, and these fMRI studies have demonstrated brain activity corresponding to an increased pain reaction. Signaling increases can be found in the bilateral dorsal ACC, insula, superior temporal gyrus; left frontal and parietal operculum, medial frontal gyrus, orbital prefrontal cortex, superior parietal lobule and hippocampus; right claustrum / putamen, lateral prefrontal gyrus and middle temporal gyrus. In addition, changes in the basal ganglia have been observed. (Jian et al. 2008) (Benedetti, 2011) Which raises questions concerning the nature of pain expression within the brain. Studies suggest seem to localize a central pain matrix comprised of roughly two parallel subsystems, the lateral (sensory-discriminatory) and medial (affective-cognitive evaluation) system(s). This lateral system extends through the lateral thalamic nuclei into the cortex. It also includes both the primary and secondary somatosensory cortices. Next, the medial system extends through the medial thalamic nuclei into the cortex, also comprising the anterior cingulate cortex (ACC), insula and prefrontal cortices. (Jian et al. 2008) (Apkarian et al. 2005) Once a nocebo effect has been established, this activity can also heighten sensitivity to non-painful stimuli as well, increasing the intensity and range by which activation occurs in the anterior cingulate cortex. (Sawamoto et al. 2000) And all this occurs after subjects are given an inert treatment. Humans can be conditioned to anticipate pain, and when expecting it, suffer heat pain even without the presence of any 'genuine' stimuli. An affective cognitive pain pathway connected to the left hippocampus may be a crucial factor in the phenomenon. (Jian et al. 2008) Health care professionals have noted outbreaks of what could be termed, 'mass psychogenic illness', and of course, 'negative placebo during hospitalization, and clinical trials. (Barsky et al. 2002) The symptom rate in groups receiving only placebo varied considerably across different trials (up to a ratio of 13:1 for presumed drug-related symptoms, eg, headache, 0.2%-2.7%, or abdominal pain, 0.9%-3.9%) and were often considerably less than those found in the general population. Fatigue, for example occurred 1.9%-3.4% in statin drug trials of as opposed to 17.7% in the general population. Clinical monitors and health care professionals must be aware of the effect, and how these rates compare with that of the rest of the population. In addition, improvement in the identification of these adverse effects would benefit researchers, and the standards of clinical investigations. The phenomenon is widespread through many forms of clinical research, but can also be confused with bias on the part of investigators, such as during vaccine development. It is known that vaccines can indeed cause adverse reactions (AR), usually due to rare, immunological sensitivities in a tiny subset of the population, ideally below one percent. Usually, these events occur following immunization (AEFIs) due to the vaccine itself, such as localized skin reactions or febrile symptoms. It is also known that live, attenuated vaccines which live and replicate in recipients, (But which have been adapted through multiple generations towards an affinity with a non-human host) Can be culprits in disease-specific AR, such as measles-like rashes following measles vaccination. An alternative approach is the killed vaccine method; while not always as effective as attenuation, killed vaccines are safer than live virus, because they do not replicate in the patient, and thus there should be nothing able to inflict disease-specific AR. A French study has reported gynecological symptoms with the quadrivalent human papillomavirus (qHPV) vaccine; trismus and tetanus vaccines; hepatobiliary disorders and hepatitis B vaccines. It concludes an unforeseen adverse reaction category; “disease-specific adverse events following nonlive vaccines", a theoretical impossibility. The study raises the risk factor that clinicians and health-care personnel are subject to reporting bias corresponding with the diseases which are under investigation. This creates a likelihood for slanted data matching the disease; which will no doubt complicate a more thorough comprehension and identification when nocebo effects do occur. (Okais et al. 2011) The Nocebo phenomenon is nonetheless, a true issue that must be understood, acknowledged and counteracted. When one is engaged in the testing of a hostile agency; the argument must be weighed for ethical considerations. It would not be truly ethical to attempt to test or induce this effect for medically-relevant phenomenon. Health care professionals must regard their Hypocratic oaths as more than just suggestions. But harmful agencies must still be defined before they can be cured. To this end, a two-phase study can be proposed to minimize the ethical dilemmas inherent with such research, while at the same time advancing medical knowledge. The aforementioned headache studies are an excellent starting point. The onset of a headache falling short of a migraine while unpleasant, would not cause lasting harm to interfere with a person’s quality of life. Future pharmaceutical trials involving these products should use a modified protocol for the placebo group. A deceptive informed consent agreement could be presented implying that for a limited subset of patients, headache symptoms will temporarily worsen With participants under this expectation, the test should provide statistical gold for psycho-somatic research on both dimensions of thought-controlled medical outcomes. Again, the ethical constraints still come into play, because it would involve a knowing violation of the principle of informed consent. While it has been demonstrated that the expectation of pain can intensify that pain, or other sensations, a test similar to the heat-pain studies may prove insufficient. A true comprehension of the phenomenon would require a study of negative health outcomes over a prolonged period. But the ethics would not be a factor under the second phase of this proposal. If permission can be secured from researchers having finished nocebo-plagued headache studies, the participants that dropped out of the study should be interviewed for an exact documentation of their symptoms, and thought-process, if not readily available via the organized study. Whether the patients consciously told themselves they were going to suffer, and whether their apparent symptoms had any correlation to the disease-state under investigation should be recorded, and compared. In this way, useful data would be accumulated without causing any new harm that has not already occurred. With this understanding, it will then be possible to better distinguish between true psycho-somatic incidents and the threat of biased, experimental error. The awareness of this effect must be cultivated amongst clinicians and researchers to adopt a higher level of integrity in their investigations. How do investigators identify when patients are being adversely affected by their own expectations, and when research bias assumes pathologies that should not exist; such as with the vaccine study? An additional layer of separation is needed to ensure integrity. An excellent strategy would be an expansion on the practice of double-blind studies and methodology. Even if researchers possess an unconscious bias in favor of a particular condition; the study should be formulated in ways that separate the investigators from the identities of the agents being studied. Codes can be used, in case of emergency only, to identify which patient belongs to which group. In cases of the vaccine studies; an idea might be to set up one phase of the approval process with multiple vaccines, circumventing any potential researcher bias. References Apkarian AV, Bushnell MC, Treede RD, Zubieta 2005 Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain. 2005;9:463–484. [PubMed] (Description of two parallel cognitive neural systems forming a pain-matrix; a lateral sensory-discriminatory, and a medial affective cognitive evaluation system) Barsky AJ, Saintfort R, Rogers MP, Borus JF. 2002 Nonspecific medication side effects and the nocebo phenomenon. Jama. 2002;287:622–627.[PubMed] (Summary of adverse clinical events with a variety of clinical effects due to a ‘negative placebo effect, and a comparison of these effects with more expected health benefits.) Benedetti, F. Amanzio, M. 2011 The placebo response: How words and rituals change the patient's brain. Patient Educ Couns. 2011 May 26. [Epub ahead of print] Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. PMID:21621366[PubMed - as supplied by publisher (Contrast study of the factors involving placebo and nocebo effects from a psycho-social context; the factors and beliefs that influence patient outcomes in a positive, or negative way.) Colloca, L. Benedetti, F. 2007. Nocebo hyperalgesia: how anxiety is turned into pain. Curr Opin Anaesthesiol. 2007 Oct;20(5):435-9. PMID:17873596[PubMed - indexed for MEDLINE] (A study of anticipatory anxiety, and an exploration of other factors causing the release of cholecystokinin which facilitates pain transmission, as well as a characterization of pain-important neurotransmitters.) Enck, P. Benedetti, F. Schedlowski, M. (2008) New insights into the placebo and nocebo responses. Neuron. 2008 Jul 31;59(2):195-206. Department of Internal Medicine VI: Psychosomatic Medicine and Psychotherapy, University Hospital, 72076 Tubingen, Germany. paul.enck@uni-tuebingen.de PMID:18667148[PubMed - indexed for MEDLINE] (Study of expectation-induced, and anticipatory reward circuitry in the brain as it pertains to the placebo-nocebo health-effect dichotomy) Kong, Jian. Gollub, Randy. Polich, Ginger. Kirsch, Inving. LaViolette, Peter. Vangel, Mark. Rosen, Bruce. Kaptchuk, Ted 2008. An fMRI study on the neural mechanisms of hyperalgesic nocebo effect. J Neurosci. Author manuscript; available in PMC 2009 June 3. Published in final edited form as: J Neurosci. 2008 December 3; 28(49): 13354–13362. doi: 10.1523/JNEUROSCI.2944-08.2008 (Pain intensity studies using a quantification scale. Investigation of the changing sensitivities of pain perception.) Mitsikostas, DD. Mantonakis, LI. Chalarakis, NG. 2011 Nocebo is the enemy, not placebo. A meta-analysis of reported side effects after placebo treatment in headaches. Cephalalgia. 2011 Apr;31(5):550-61. Epub 2011 Jan 7. PMID:21216874[PubMed - in process] (Investigation of headache patients reporting adverse events upon receiving placebo treatments during drug trials.) Okais, C. Gay, C. Seon, F. Buchaille, L. Chary, E. Soubeyrand, B. 2011. Disease-specific adverse events following nonlive vaccines: A paradoxical placebo effect or a nocebo phenomenon? Vaccine. 2011 May 31. [Epub ahead of print] Sanofi Pasteur MSD, Lyon, France. Copyright © 2011 Elsevier Ltd. All rights reserved. (The investigation of apparent adverse effects including disease-like symptoms matching those of the infections being vaccinated against; apparently due to researcher bias.) Rief, Winfried PhD; Avorn, Jerry MD; Barsky, Arthur J. MD. 2006 Medication-Attributed Adverse Effects in Placebo Groups. Implications for Assessment of Adverse Effects. Arch Intern Med. 2006;166:155-160. (Adverse effects of patients taking placebos during statin drug studies, and the investigation of the symptoms and causes thereof.) Sawamoto, N. Honda, M. Okada, T. Hanakawa, T. Kanda, M. Fukuyama, H. Konishi, J. Shibasaki, H. Expectation of pain enhances responses to nonpainful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study. J Neurosci. 2000;20:7438–7445. [PubMed] (Studies showing anticipation and uncertainty concerning physical sensations can enhance pain stimuli, and trigger a pain response to non-painful stimuli) Read More