Saturday, March 16, 2013

Placebos in Clinical Trials

The placebo effect has been an important consideration in medical treatment and clinical drug trials since its official identification in 1955.1 Placebos are typically regarded as inert agents or procedures designed to facilitate action against a given detrimental condition regardless of whether the action will have any positive effect on the condition. Some quibble with the use of the word ‘inert’ because the placebo effect encompasses an effect derived from the placebo. However, such a thought takes the word ‘inert’ to an unreasonable extreme. Clearly for the purposes of the definition, inert is assigned to the placebo element not having a direct biological effect against the targeted condition. Thus the placebo effect is regarded as any improvement of a detrimental condition without the aid of direct treatment under the presumption that such a treatment is being given.

One of the most troublesome areas of drug research complicated by the placebo effect is pain management or pain analgesia. For analgesia the biochemical methodology that governs the placebo effect is thought to occur through the release of endorphins stemming from signals derived from the prefrontal cortex with additional activity in the orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), rostral anterior cingulate cortex (rACC), and midbrain periaqueductal gray (PAG).2 This belief is further supported by information from Alzheimer’s patients in that neuronal degeneration of the DLPFC, OFC and rACC results in a loss of the placebo effect.3 The endorphin component of the placebo effect regarding analgesia was identified when such analgesia was neutralized by naloxone, an opioid antagonist.4 Follow up research confirmed this relationship between endorphins and placebo analgesia through the use of cholecystokinin (CCK), an anti-opioid peptide.5-7 Direct demonstration of opioid released occurred in 2005 through the PET observation of increased μ-opioid receptor neurotransmission in the ACC, OFC, the insula, and the nucleus accumbens.8

Despite a somewhat better understanding of the psychological and physiological mechanisms behind the placebo response there is still questions regarding its lack of universal application. For example in randomized controlled trials the drug-placebo difference has been reported at 40% for functional disorders,9 29% in depression, 31% in bipolar mania, 21% for treatment of migraines.10,11 Some conclude that the variable placebo rates involve differences in sample size, study time, patient recruitment and design characteristics. The best option seems to be design characteristics.12,13

Design characteristics are important because the placebo effect also has a conditioning expectation component, which exists in two separate parts beyond pure biological activation. The first component is the inherent anticipatory psychological reaction of a potential new stimuli and its influence. Basically if one is given an unknown drug by an individual of expertise and/or authority and is told that it will have a certain effect then one expects that effect to occur regardless of whether or not it actually will. Basically there is a value association with the treatment. The value impact is also applicable in that more expensive drugs are thought to have more positive influence.14

The second component is a conditioning physiological/psychological reaction derived from multiple exposures to a single given element. One of the chief examples of this placebo effect response is after numerous doses of morphine-like compound (buprenorphine), which had a side effect of reduced respiration, at a specific time in a specific manner, individuals were then given an inert compound in the same manner at the same time and the body responded by reducing respiration.15,16 Thus, there appears to be a Pavlovian biological response, which can induce a placebo effect beyond conscious psychological expectations. This response is somewhat mysterious in that it overcomes even an opioid inhibitory treatment, like naloxone, when using a non-opioid primer.16 Overall this behavior implies a ‘mimicry’ effect perhaps associated with long term potentiation (LTP).

One significant element that dictates the strength of these elements is the concentration and interaction rates of two separate neurotransmitters: dopamine and norepinephrine. In essence while dopamine is given chief credit as the ‘reward’ molecule its influence is augmented or dampened, depending on the situation, by norepinephrine. Basically dopamine determines what elements/actions are characterized as rewarding and norepinephrine grants the required focus, both consciously and seemingly unconsciously, to achieve and recognize the rewarding action. Therefore, if norephinephrine is not at a sufficient concentration the placebo effect ceases to operate. If this is the case then enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAO-A) are also important because they are responsible for the destruction of dopamine and norepinephrine respectively.17

Destruction of dopamine is important because the placebo effect has association with expectation. This expectation, either conscious or unconscious, will create an acute and significant increase in dopamine concentration; however, if dopamine concentrations are already high the additional increase provided by the placebo effect will not induce significant biochemical change because the percentage change will be small. For the placebo effect the percentage change is more important than the absolute change. Thus, in the context of treating pain and also depression the ‘ideal’ placebo effect candidate has high COMT activity (low dopamine concentration) and low MAO-A activity (high norepinephrine concentration).

Identifying potential placebo beneficial or detrimental genetic agents produces a useful secondary treatment strategy. For example individuals who are the ideal placebo candidates have an advantage in that they could be treated for pain through the placebo effect if other direct pain mitigation methods are unavailable due to bad reactions and/or excessive side effects. Also with this new information pertaining to the function of the placebo effect with regards to pain management one can design diets to augment this aspect of the placebo effect. Clearly there are ethical concerns with giving a known placebo to a patient in lieu of actual medication, but there are numerous situations where the side effects associated with the standard pain medication may reduce the quality of life of the patient to a level where taking the medication is not viewed as significantly beneficial. Therefore, individuals who have mid to high COMT activity and low to mid MAO-A activity could be candidates for an enhanced placebo effect either using direct placebos or even simple changes in diet which would augment dompaine and norepinephrine levels.

Another important consideration of the placebo effect beyond actual treatment is how it can influence results in clinical trials. Most pharmaceutical companies know that the clinical trial is the most frustrating part of creating a new drug because after spending hundreds of thousands to millions on research and development if clinical trial results are ambiguous or inconclusive the developed drug enters a state of limbo which can be even worse than if it simply fails to demonstrate improvement.

Part of the problem with identifying the placebo effects is the idea of responders and non-responders (those who exhibit a placebo effect and those who do not) is typically ignored. Instead in both clinical studies and placebo studies differences between group averages are analyzed over individual responses. Such practice creates situations where the identical mean change between a placebo group and non-treatment group can be demonstrated either by large number of individuals showing an average response or a small number of individuals showing a large response and others showing no response. This is one of numerous statistical situations where averages without standard deviations are dangerous.

When individual results are taken one of the big problems with confirming the placebo effect is the nature of pain progression relative to regression to the mean. Extremes in self-reported pain intensity, either high or low, eventually shifts towards average because they are extreme and more than likely short-lived. With regards to the placebo effect clearly the high extreme is more relevant than the low because individuals involved in these trials are in pain. However, the pain will abate over time from a self-reporting standpoint as the body adapts to the pain regardless whether or not the placebo effect activates. Therefore, in such a situation it is difficult to differentiate between the placebo effect reducing pain or regression to the mean adaptation to the pain.

There are a number of strategies designed to “neutralize” the placebo effect in clinical trails. The crossover design is where individuals serve as their own controls reducing inter-subject variability. Another focuses on eliminating expectations through concealing the psychological component by either initiating the medical treatment without the knowledge of the patient or by introducing uncertainty in its administration. Basically hiding the injection or infusion method from the patient eliminating knowledge of its administration or telling the patient that the treatment could make the patient feel better, but there are no guarantees.

However, as mentioned above despite strategies to reduce psychological triggering of the placebo effects the one thing that cannot be concealed is that patients do receive some form of treatment. Therefore, genetic elements like COMT and MAO-A will still play a significant role in driving the placebo effect. Identifying individuals who possess these genetic characteristics would allow for better post-experiment analysis regarding potential placebo effects pertaining to pain treatment and other treatments given the particular genetic agent. There are two immediate questions regarding the collection of this genetic information: first, the screenings would have to comprise of only the above agents, not a complete genetic analysis to ensure the privacy of the research subject. Second, the research must remain a double-blind study, thus the genetic information should only be used post-analysis and not revealed to anyone prior to or during the experiment.

Finally there has been some question to the legitimacy of the placebo effect.18 The problem with this critical analysis is it is too expansive coving too many different disease and treatment methodologies. Such analysis method makes it more difficult to see the statistical nuances in each separate study, which could muddle results and conclusions. For example it would be akin to judging the quality of an orange when eating it in a fruit salad. Therefore, it is difficult to view conclusions questioning the placebo effect without skepticism.

Overall the use of genetic mapping and better statistical analysis techniques should allow researchers to better separate real changes between drugs versus artificial changes like the placebo effect. Analysis accuracy is obviously important because if analysis remains suspect then society wastes time, money and resources on statistically insignificant drugs. The most important element to a more robust analysis methodology would be to standardize it through all laboratories. Such standardization would ensure effective analysis checking to maximize the probability of correct conclusions and effective drug action.

Citations –

1. Beecher, H. “The powerful placebo.” JAMA. 1955. 159(17):1602-1606.

2. Miller, E and Cohen, J. “An integrative theory of prefrontal cortex function.” Annu. Rev. Neurosci. 2001. 24:167-202.

3. Thompson, P, et Al. “Dynamics of gray matter loss in Alzheimer’s disease.” 2003. J. Neurosci. 23:994-1005.

4. Levine, J, Gordon, N, and Fields, H. “The mechanisms of placebo analgesia.” Lancet. 1978. 2:654-657.

5. Levine, J and Gordon, N. “Influence of the method of drug administration on analgesic response.” Nature. 1984. 312:755-756.

6. Benedetti, F. “The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia.” Pain. 1996. 64:535-543.

7. Benedetti, F and Amanzio M. “The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin.” Prog. Neurobiol. 1997. 52:109-125.

8. Zubieta, J and et Al. “Placebo effects mediated by endogenous opioid activity on u-opioid receptors.” J. Neurosci. 2005. 25:7754-7762.

9. Enck, P and Klosterhalfen, S. “The placebo response in functional bowel disorders: perspectives and putative mechanisms.” Neurogastroenterol Motil. 2005. 17:325-331.

10. Sysko R and Walsh, B. “A systematic review of placebo response in studies of bipolar mania.” J. Clin. Psychiatry. 2007. 68:1213-1270.

11. Macedo, A, Banos, J, and Farre, M. “Placebo response in the prophylaxis of migraine: A meta-analysis.” Eur. J. Pain. 2008. 12:68-75.

12. Walsh, B, et Al. “Placebo response in studies of major depression – variable, substantial and growing.” JAMA. 2002. 287:1840-1847.

13. Kobak, K, et Al. “Why do clinical trials fail? The problem of measurement error in clinical trials: time to test new paradigms?” J. Clin. Psychopharmacol. 2007. 27:1-5.

14. Waber, R, et Al. “Commercial features of placebo and therapeutic efficacy.” JAMA. 2008. 299(9):1016-1017.

15. Benedetti, F, et Al. “The specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression.” Pain. 1998. 75:313-319.

16. Benedtti, F, et Al. “Inducing placebo respiratory depressant responses in humans via opioid receptors.” Eur. J. Neurosci. 1999. 11:625-631

17. Leuchter, A, et Al. “Monoamine Oxidase A and Catechol-O-Methyltransferase Functional Polymorphisms and the Placebo Response in Major Depressive Disorder.” Journal of Clinical Psychopharmacology. 2009. 29(4):372-377.

18. Hrobjartsson, A and Gotzsche, P. “Placebo interventions for all clinical conditions.” Cochrane Database Syst. Rev. 2010. 106(1).

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