gastroparesis: high placebo/nocebo response rates

 

A recent systematic review and meta-analysis evaluated the placebo response and adverse event rates in treatments for gastroparesis (see placebo response rate in gastroparesis ClinGastroHep2023 in dropbox, or doi.org/10.1016/j.cgh.2022.09.033)

 

 

Details:

-- the medical literature was reviewed through August 2022 to identify RCTs comparing active drug with placebo in patients with gastroparesis

-- placebo response rates were assessed for at least one of nausea, vomiting, abdominal pain, bloating, or fullness (typical gastroparesis symptoms), as well as for adverse events.

-- 22 articles reported on the placebo response rates, with a total of 1011 patients

-- Primary outcome: magnitude of the placebo response as well as adverse events associated with placebo (i.e. the nocebo effect: adverse events associated with the belief that the placebo will cause harm)

 

Results:

-- overall pooled placebo response rate: 29.3% (23.7%-35.2%)

    -- significant heterogeneity within the studies for this outcome

    -- in patients with typical symptoms of gastroparesis: 34.7% (25.3%-45.2%)

 

-- placebo response rate by study design:

    -- idiopathic versus diabetic gastroparesis: 34.2% (5 studies with 139 patients) versus 28.1% (12 studies with 661 patients)

    -- trials not using validated symptom questionnaires: 31.2% (12 studies with 435 patients) versus 27.4% (11 studies with 576 patients)

    -- RCTs of shorter duration (<4 weeks vs >9 weeks): 32.6% (13 studies with 538 patients) versus 23.2% (6 studies with 424 patients)

    -- placebo event rates tended to be higher in patients taking the placebo more frequently: from 4 times a day at 35.3% (5 studies with 238 patients) to every other day dosing at 25.1% (5 studies with 226 patients) 

 

-- adverse events in patients on placebo (nocebo effect): 33.8% (26.4%-41.8%)

    -- significant heterogeneity with the studies for this outcome

    -- adverse events rates were higher in:

        -- people with diabetes: 43.4% (16 studies with 1050 patients) versus idiopathic 17.9% (4 studies with 74 patients [the latter had few patients, though the mixed etiology group had a rate of 21.7% with 7 studies and 242 patients)

        -- dosing schedule: every other day 52.5% (4 studies with 166 patients) vs 4 times a day 28.3% (8 studies with 395 patients)

        -- definition of gastroparesis: either typical symptoms or gastric emptying studies/breath testing 42.8% (5 studies with 269 patients) vs just gastric emptying studies/breath testing only 30.5% (21 studies with 1002 patients)

        -- longer trial duration: 40.7% (7 trials with 609 patients) vs  33.7% (17 trials with 717 patients)

 

Commentary:                                                                           

-- gastroparesis is a chronic GI sensorimotor disorder affecting 300 per 100,000 people, typically associated with nausea, vomiting, early satiety, bloating, and abdominal pain. However there is significant clinical overlap of symptoms with other gastrointestinal disorders, such as functional dyspepsia (FD), cannabinoid hyperemesis syndrome, and cyclic vomiting syndrome.

    -- Gastroparesis can be associated with significant functional impairment, including inability to work or perform normal daily activities

    -- the high overlap of symptoms does suggest a commonality of the mechanism. Perhaps this is related to the gut-brain axis:

        -- the gut/brain axis (see microbiome gut brain axis JClinInvest2015 in dropbox, or doi:10.1172/JCI76304) has been pretty well described showing that the gut microbiome can affect emotional behavior, stress- and pain-modulation, and brain neurotransmitters (the gut microbiota elaborates many neurotransmitters; animal studies have found major effects on the expression of brain signaling systems; some of these changes could affect appetite/diet/weight as well as the placebo effect (see https://www.frontiersin.org/articles/10.3389/fpsyt.2022.824468/full )

 

--nonmedical treatments include avoiding foods that do not slow gastric emptying (eg fats), foods that require more antral mobility (eg roughage, insoluble fiber), or others that decrease antral contractility (alcohol and smoking); hydration may help, especially in those with mild symptoms. the only drug approved by the FDA for gastroparesis is metoclopramide, though other medications are used elsewhere (including cisapride, another pro-kinetic agent, which was used in the United States until 2000 when it was voluntarily removed from the market given concerns of prolonged QT syndrome and potential severe arrhythmias). Those with diabetic gastroparesis may benefit from improved diabetic control (hyperglycemia can slow gastric emptying)

-- for a meta-analysis/systematic review of treatments for gastroparesis, see https://www.sciencedirect.com/science/article/pii/S0016508519303464?ref=pdf_download&fr=RR-2&rr=7dc6bd826fa03b6f

 

-- this current study confirms the very high levels of placebo and nocebo effects for gastroparesis (though these levels have also been found in many other studies as well). a few points:

    -- the level of placebo effect in this study is comparable to other GI studies including FD, irritable bowel syndrome, as well as ulcerative colitis and Crohn’s disease

        -- and, as mentioned, there is considerable overlap of symptoms with many of these GI diseases, especially between gastroparesis and functional dyspepsia. 35-40% of patients with symptoms highly suggestive of FD have abnormal emptying studies. I would imagine this is simply a manifestation of the huge overlap of symptoms, which suggests to me that people with gastroparesis symptoms might benefit from a trial of acid suppressant medications). also, perhaps by altering the gut microbiome by certain probiotics or fecal transplant????

    -- there were subgroup differences in the placebo/nocebo outcomes;

        -- for placebo ones, higher rates in: idiopathic vs diabetic gastroparesis, diagnosis not based on validated symptom questionnaires, shorter term studies, and those taking the placebo more frequently

        -- for nocebo ones, higher rates in: patients with diabetes, taking placebo less often, patients with typical symptoms, and in longer term studies

    -- interesting that the subgroups with higher incidence of placebo effects tended to have lower incidence of nocebo effects [one might have thought that someone more likely to have placebo effects might also be more likely to have nocebo effects…..]

 

-- there are so many studies confirming the profound placebo/nocebo effects throughout the medical literature:

    -- despite significant differences, this study found quite high placebo/nocebo effects, in patients in all of the subgroups assessed

    -- http://gmodestmedblogs.blogspot.com/2020/02/placebo-and-nocebo-effects.html  includes a pretty thorough description and analysis of placebo/nocebo effects, the associated proposed mechanisms/physiology, a description of the placebome (finding, for example, that there is a more intense placebo/nocebo effect in people with single nucleotide polymorphisms (SNPs) associated with increased opioid and dopamine receptor activation and systemic levels of these chemicals). It also includes one of my favorite studies: there was a set of studies on the effect of candesartan (an angiotensin receptor blocker) in different patient populations with heart failure (the CHARM studies), finding benefit in those with reduced ejection fraction. A subsequent analysis found that there was actually NO difference in response rate if one assessed those patients who actually had good adherence in taking the pills, independent of whether they were on the active medication or the placebo!! (see chf CHARM trial adherence lancet 2005 in dropbox, or DOI:10.1016/S0140-6736(05)67760-4). This suggests that those who really were engaged in treatment did better independent of the drug's specific effects. of course, those who adhered to the medicine may also be doing things that are more healthy overall, vs those not taking the meds...

 -- another study finding benefits of placebo in patients with chronic low back pain found a significant placebo effect even when the patients were aware that they were taking placebo!!! (see http://gmodestmedblogs.blogspot.com/2016/11/benefits-of-placebo-for-low-back-pain.html).  maybe there is utility in having a "placebo pill" where the patient understands that it is a placebo???

-- and, it is pretty clear that dopamine is produced in the microbiome, and that opioids affect the gut microbiome (see placebo gut brain axis Psychiatry2022 in dropbox, or https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908675/)

 

Limitations:

-- the high levels of study heterogeneity in this meta-analysis does challenge the strength of the conclusions

    -- other issues with meta-analyses in general: there is uncertaintly in combining outcome data from different studies with potentially different assessments of gastroparesis, different populations, different inclusion/exclusion criteria, different outcomes measured, different patients demographics, etc.

-- other therapies for treatment of gastroparesis were not assessed: eg the antiemetics diphenhydramine/ondestranone/phenothiazines (prochlorperazine); gastric decompression (endoscopic gastrostomy tube/jejunal tube feedings); tricyclic antidepressants and mirtazapine; acupuncture; gastric electrical stimulation; butolinum toxin; endoscopic myomectomy

 

So, I am bringing up this article because it brings up the broader areas of placebo and nocebo effects, which can be quite profound throughout the medical literature, and I have not brought up these issues of placebo for several years now (and I have many new readers). the extent of placebo/nocebo effects is pretty striking, as well as the increasing clarity on potential mechanisms, including the gut microbiome/brain axis.

 

geoff

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