gallstones: cholcystectomy often not relieve pain

A recent study of patients with abdominal pain and gallstones found that a more restrictive strategy for cholecystectomy was noninferior to usual care, that fewer cholecystectomies were done, but notably in both groups almost 40% had continued abdominal pain one year later (see cholecystectomy residual pain lancet2019 in dropbox, or doi.org/10.1016/S0140-6736(19)30941-9)

Details:

-- multicenter randomized noninferiority study in 24 academic and nonacademic hospitals in the Netherlands, between 2014-2017

-- 1067 patients aged 18 to 95 who had abdominal pain and ultrasound-proven gallstones or sludge

-- mean age 49, 73% female, BMI 28, ASA classification 2 (from American Society of Anesteriologists: mild systemic disease), history of abdominal surgery 38%, use of pain meds 48% (32% NSAIDs, 11% acetaminophen), current smoker 20%, current drinker 47%, baseline VAS (Visual Analog Scale) pain score 7.5/baseline Gastrointestinal Quality of Life Index score 108 (maximum 144, the higher the better)

-- randomized to usual care (as determined by the surgeon) vs a restrictive strategy where patients had to have the following 5 prespecified criteria to have a cholecystectomty

    -- severe pain attacks

    -- pain lasting 15 to 30 minutes or longer

    -- pain located in the epigastrium or right upper quadrant

    -- pain radiating to the back

   -- a positive pain response to simple analgesics

-- exclusion criteria included complicated cholelithiasis (e.g. biliary pancreatitis, cholangitis, common bile duct stones, cholecystitis); a history of current malignancy; American Society of Anesthesiologist physical status of 3 or 4; known liver cirrhosis; pregnancy

--endpoints:

    -- primary noninferiority, patient-reported endpoint: the proportion of patients who are pain-free at 12 months follow-up. A 5% noninferiority margin was chosen as being significant. Pain was assessed by the Izbicki Pain Score of 10 or less or a Visual Analog Scale pain score of <5

    -- secondary, superiority endpoints: number of cholecystectomies, time to being pain-free, complications due to gallstones, or cholecystectomy (including those who elected cholecystectomy independent of the study)

Results:

-- at 12 months follow-up:

    -- restrictive strategy group: 298 patients (56%) were pain-free, CI: 52-60.4%

    -- usual care group: 321 patients (60%) were pain-free, CI: 55.6-63.8%

    -- this difference of 3.6% suggested noninferiority by their criteria of >5%

-- about 30% of the patients in the restrictive group elected to have a cholecystectomy despite not fulfilling their complete criteria. But analysis on a per-protocol basis continued to show noninferiority (still 56% in the restrictive strategy vs 60% in usual care were pain-free at 12 months)

-- the restrictive strategy did result in fewer cholecystectomies: 68% vs 75%, p=0.01

-- patient satisfaction with treatment outcome at 12 months was similar between the groups, by the VAS and Izbicki Pain Score

-- of note, patients with preoperative biliary colic were more often pain-free at 12 months than those without classic biliary colic symptoms (61% vs 52%,p=0.005), per the Rome III criteria

-- gallstone related complications: 40 patients (8%) in usual care vs 38 patients (7%) in the restrictive strategy, p=0.77, and no difference in non-trial related serious adverse events

Commentary:

-- gallstones are remarkably common, found in approximately 20% of adults in the Western world, though only about one in 5 with gallstones develop symptoms

-- about 700,000 cholecystectomies are done in the US, at a cost of about $9.9 billion

-- the restrictive strategy group at baseline had more severe pain attacks and therefore were more likely to have a cholecystectomy than the usual care group, somewhat diluting the difference

-- though other studies have also found similar pain outcomes with conservative treatment vs cholecystectomy, about half the patients in the conservative group ultimately get a cholecystectomy.

-- other studies in the Netherlands have found that about 40% of patients continue to have abdominal pain after cholecystectomy, with data at 12 weeks, 24 weeks, 5 years, and 10 years after cholecystectomy

-- and, not so surprisingly, there are changes in the microbiome (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352247/pdf/jcm-08-00079.pdf ), with some decrease in microbiome diversity, and some increased prominence of Bacteroidetes post-cholecystectomy; and this species may be associated with increasing obesity, NAFLD, and hepatic fibrosis (eg, see https://gmodestmedblogs.blogspot.com/2016/08/non-alcoholic-fatty-liver-disease-2.html , or https://gmodestmedblogs.blogspot.com/2017/01/microbiome2-overview.html  ).  And, in patients with gallbladder disease or post-cholecystectomy, increases in Bacteroidetes are also found in colorectal carcinomas, especially proximal ones, though hard to know fully if the increase was related to the gallbladder disease itself or the surgery, see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376770/.

-- this study had a few significant findings:

    --a restrictive approach to cholecystectomy led to fewer cholestectomies done at 12 months, though other studies have found a persistent migration of patients who have gallstones and potentially related abdominal pain to cholecystectomy over years

    --there was no difference in post-cholecystectomy pain in this study, though it was notable that more patients with classic biliary colic (per Rome III criteria: acute severe abdominal pain located in the right upper quadrant or epigastrium lasting 15-30 minutes or longer), were somewhat more likely to be pain-free. BUT, this difference (61% vs 52%) is not clinically very impressive

          --which suggests that even the Rome III criteria are not terribly specific

    --it is certainly true that surgery does fundamentally change the "normal" pathway for bile acids, which could itself be related to downstream symptoms (as with potential microbiome changes noted), including potentially the pain itself ???

--one limitation of this study is that they do not have more specific information about the quality of the post-cholecystectomy pain.  was it a recurrence of the pre-surgery pain? was it pain related to the surgery itself (adhesions...)? was it just that people who have abdominal pain have a lower threshold for pain and just experience more pain, perhaps even in a totally different/unrelated area of the abdomen??  And abdominal pain itself is often related to stress/domestic violence/sexual trauma 

so, this whole issue is pretty murky:

-- it is pretty clear that we do not have a very specific methodology for determining whether abdominal pain is coming from the gallbladder/gallstones

-- the best we have is the Rome III criteria, which do not seem to be so great, assuming that the residual pain in 40+% of the patients is because the surgery did not correct the actual source of the pain.

-- and, my guess is that many people with chronic recurrent abdominal pain near the right upper quadrant, who also happen to have gallstones, might ultimately succumb to surgery at some point, given their and their clinicians exasperation with this recurrent and perhaps disabling symptom

-- so, it seems to me that our imperative in primary care is to not necessarily assume that the constellation of abdominal pain and gallstones should be "fixed" by cholecystectomy, and that the patients should understand that there is a high residual risk of continued abdominal pain

geoff

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