{"id":703,"date":"2015-05-07T11:00:25","date_gmt":"2015-05-07T11:00:25","guid":{"rendered":"http:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/?p=703"},"modified":"2017-08-21T11:47:35","modified_gmt":"2017-08-21T11:47:35","slug":"primary-care-corner-with-geoffrey-modest-md-placebo-genetics-and-the-placebome","status":"publish","type":"post","link":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2015\/05\/07\/primary-care-corner-with-geoffrey-modest-md-placebo-genetics-and-the-placebome\/","title":{"rendered":"Primary Care Corner with Geoffrey Modest MD: Placebo genetics and the “placebome”"},"content":{"rendered":"

By: Dr. Geoffrey Modest<\/strong><\/p>\n

-A new article just came out of the Program in Placebo Studies in Boston that link the “placebo effect” to specific genes in the newly-defined “placebome<\/span>”\u00a0(see\u00a0<\/span><\/strong>here<\/a>), also noted in a more popular forum<\/a>.\u00a0<\/span><\/p>\n

Background, promoting the concept that placebo effects are legitimate biological responses to environmental cues:<\/span><\/p>\n

–studies on placebos have dated back decades. Old studies have found red placebos and those in capsule form to be more effective. Another found that blue placebos are more effective for sleep,\u00a0across cultures (though, per NPR, not so only\u00a0for males but\u00a0not females in Italy, where blue perhaps\u00a0evokes images of their national soccer league and may\u00a0increase\u00a0arousal).<\/span><\/p>\n

–other old studies have found that in some patients\u00a0pain could be suppressed by placebo, equivalent to up to 8mg<\/span> of morphine, and blocked by the opioid receptor antagonist naloxone<\/span><\/p>\n

In this setting, this article explores what is known about the genetic component of the placebo response, noting that behavioral\/personality assessments have had limited success in\u00a0predicting placebo response.<\/span><\/p>\n

–A very large limitation in assessing the placebo response is the lack\u00a0of NTC<\/span> (no-treatment control) trials. Just as we compare active drugs with placebo to assess the added effect of the active drug, we need to compare placebo to NTC<\/span> to see if placebo has additional effects over doing nothing\u00a0(thereby accounting for “regression-to-the-mean” as well as other\u00a0changes in the natural history). As a real-world example I use in my lipid talk, there was a study of hyperlipidemic<\/span> patients with elevated ALT levels put on a statin, compared to hyperlipidemic<\/span> patients with normal ALT put on a statin, but they also had a 3rd group with elevated ALT given no statin: results were that there was an increase in ALT in the first group\u00a0on statin, as\u00a0compared to\u00a0those in the 2nd group\u00a0with baseline normal ALT, which suggested that statins in the\u00a0setting of an elevated ALT are\u00a0associated with higher ALT levels<\/span>. But in fact there was no difference between the 1st and 3rd groups, suggesting that there is enough variability in ALT values in those with\u00a0an elevated ALT that the statin actually had no additional\u00a0effect on ALT levels…).<\/span><\/p>\n

–There are several studies suggesting that there is a “placebome<\/span>“, areas of the genome which may predispose individual patients to a placebo response:<\/span><\/p>\n

–much of the research has assessed areas of the genome that affect the opioid (pain suppression) and dopamine (reward) systems.<\/span><\/p>\n

–pain studies have found that those patients with more profound placebo response have higher opioid and\u00a0dopamine receptor activation; patients with higher pain sensation with placebo\u00a0had decreased signaling in both systems<\/span><\/p>\n

–several studies have looked at genetic polymorphisms of the catechol-O-methyltranserase<\/span> gene (COMT<\/span> is responsible for dopamine metabolism), finding in different studies that homozygotes for a less-active allele\u00a0(a common polymorphism in the population, varies with ethnicity\/race but is in 20-25% in the Causasian<\/span> population)<\/span>\u00a0have higher levels of dopamine in the prefrontal cortex;\u00a0patients with this polymorphism and\u00a0irritable bowel syndrome had the greatest placebo response; a pain study found increasing\u00a0placebo-induced pain suppression in those with increasing numbers of this allele; and, conversely, in those with high levels of the “normal” allele, there were more nocebo<\/span> effects (adverse effects from the\u00a0placebo). Similar results were found with variants of the monoamine oxidase A polymorphisms (MAO-A metabolizes monoamines, including dopamine and serotonin), where people with a particular\u00a0polymorphism had decreased MAO-A activity and\u00a0higher basal dopamine levels;\u00a0and, in patients with clinical depression who had this polymorphism and were given placebo vs\u00a0one of 3 selective\u00a0serotonin reuptake inhibitors (SSRIs<\/span>),\u00a0they had a higher placebo response. A\u00a0study of genetic variations of dopamine beta-hydroxylase (converts dopamine to norepinephrine) has found that patients with alcohol dependence who had this polymorphism did better with placebo and worse on\u00a0naltrexone<\/span><\/strong>. Other studies have looked at variations in the mu opioid receptor, finding variability in\u00a0placebo-induced pain perception. There are also some data on placebo response variability with\u00a0endocannabinoid and seratonergic<\/span> signaling genetic variants.<\/span><\/p>\n

I don’t mean to overplay this, but I do think this article raises a few interesting points:<\/span><\/p>\n

–there is utility in having a no-treatment control in studies, to help control for clinical variability in symptoms over time, and making it easier to tease out a placebo effect.<\/span><\/p>\n

–identifying those with genetic variants associated with less placebo response could, at some point in the future, lead to needing smaller studies to determine medication efficacy<\/span><\/p>\n

–identifying those with more profound placebo response could lead to more effective\u00a0non-medical (or placebo) interventions<\/span><\/p>\n

–it is important to be aware that\u00a0in those instances with known high placebo-response (eg<\/span> depression, irritable bowel), it is much harder to assess drug efficacy, with results biased to null even if the medication were really effective in those\u00a0patients genetically predisposed to minimal placebo response (more likely to be an issue in smaller trials). Awareness of placebo-sensitive genotypes might be particularly\u00a0useful in these cases.<\/span><\/p>\n

–there may be important gene-drug-placebo effects. \u00a0There is the potential that in\u00a0some patients with specific genetic pro-placebo\u00a0polymorphisms and given an active drug,\u00a0they may then get both the drug effect\u00a0as well as the placebo effect, and these 2 effects could interact with each other in different ways: eg, these placebo\u00a0effects could\u00a0significantly augment or compete with the drug effect (especially if the drug and placebo focus on the same target in the body). The point here is that even the active drug’s effects may be very different in those predisposed to a placebo effect than those not, and that the placebo and drug effects are not necessarily simply\u00a0additive.\u200b The above example of alcohol dependence\/naltrexone may indicate an adverse placebo-drug interaction.<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

By: Dr. Geoffrey Modest -A new article just came out of the Program in Placebo Studies in Boston that link the “placebo effect” to specific genes in the newly-defined “placebome”\u00a0(see\u00a0here), also noted in a more popular forum.\u00a0 Background, promoting the concept that placebo effects are legitimate biological responses to environmental cues: –studies on placebos have […]<\/p>\n

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