Gut-Brain Modulators for Functional GI Disorders: Irritable Bowel, Dyspepsia, Functional Heartburn, and Cyclic Vomiting Syndrome

A lengthy report (DA Drossman et al. Gastroenterol 2018; 154: 1140-71) thoroughly reviews the evidence for neuromodulators for functional GI disorders, including Irritable Bowel, Dyspepsia, Functional Heartburn, and Cyclic Vomiting Syndrome.

“Some general recommendations include: (1) low to modest dosages of tricyclic antidepressants provide the most convincing evidence of benefit for treating chronic gastrointestinal pain and painful FGIDs and serotonin noradrenergic reuptake inhibitors can also be recommended, though further studies are needed; (2) augmentation, that is, adding a second treatment (adding quetiapine, aripiprazole, buspirone α2δ ligand agents) is recommended when a single medication is unsuccessful or produces side effects at higher dosages; (3) treatment should be continued for 6-12 months to potentially prevent relapse; and (4) implementation of successful treatment requires effective communication skills to improve patient acceptance and adherence, and to optimize the patient-provider relationship.”

The report makes specific recommendations for several functional conditions (Table 4).

  • For dyspepsia, the authors recommend categorizing as either postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) as per Rome IV criteria.
  • They state that “Buspirone…may be used for PDS where early satiety, fullness and nausea predominate.”
  • “Mirtazapine is a good treatment option for PDS when there is chronic nausea and vomiting, or weight loss, and it may also help coexisting abdominal pain.”
  • For EPS, “studies mainly support the use of TCAs, either initially or after an unsuccessful response to a proton pump inhibitor.”

Figure 5 outlines general treatment advice:

  • SSRIs -“when anxiety, depression and phobic features are prominent with FGIDs”
  • TCAs -“first-line treatment when pain is dominant in FGIDs”
  • Tetracyclic antidepressant (mirtazapine, mianserin, trazodone) -“treatment of early satiety, nausea/vomiting, weight loss and disturbed sleep”
  • SNRIs (duloxetiine, venlafaxine, desvenlafaxin, milnacipran) -“treatment when pain is dominant in FGIDs or when side effects from TCAs preclude treatment”
  • Augmentation therapies are subsequently delineated including atyipical antipsychotics, pyschological treatments (like cognitive behavioral therapy) and hypnosis

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

 

Use of Antidepressant Medications to Treat Recurrent Abdominal Pain

A recent study (C AM Zar-Kessler et al. JPGN 2017; 65: 16-21) retrospectively reviewed a single center’s 8 year experience (2005-2013) using antidepressant medications to treat nonorganic abdominal pain. Of 531 cases, 192 initiated treatment with either a selective serotonin reuptake inhibitor (SSRI) or a tricyclic antidepressant (TCA).

Key findings:

  • 63 of 84 (75%) of SSRI-treated patients improved; 56 of 92 (61%) of TCA-treated patients improved.  The higher response rate to SSRIs persisted after control for psychiatric factors.
  • A much higher percentage of SSRI-treated patients, compared to TCA-treated patients, had anxiety (49% vs 22%); an additional 15% and 5%, respectively, had combined anxiety/depression.
  • The most common SSRI in this study was citalopram with median dose of 10 mg (range 5-60 mg).
  • The most common TCA in this study was nortriptyline with median dose of 20 mg (range 10-50).
  • Similar numbers of patients in each group had adverse effects, include 21 (25%) of SSRI-treated patients and 20 (22%) of TCA-treated patients.  14% of SRRI-treated patients discontinue medication due to adverse effects, compared with 17% of TCA-treated patients.
  • Mood disturbances were higher in this study among TCA-treated patients: 14% compared with 6% of SSRI-treated patients
  • TCAs were prescribed by gastroenterologists in 88% of cases; with SSRIs, only 39% of prescriptions were from gastroenterologists.

In the discussion, the authors note that “all patients who experienced GI adverse effect were prescribed medications that would worsen their underlying bowel complaint…these issues may have been mitigated if more attention was paid” to this.  “Specifically, TCAs should be used cautiously in those with constipation, whereas SSRIs should be avoided in those with diarrhea.”

My take: This study shows that both classes of antidepressants were associated with improvement.  The conclusions about effectiveness are limited as this is a retrospective study and could not control/evaluate many variables. That being said, particularly if there is coexisting anxiety, as was frequent in this study population, a SSRI may be more effective.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Tynn Church, Prague

 

Irritable Bowel Syndrome (part 2)

A terrific 12 page review of irritable bowel syndrome (IBS): AC Ford, BE Lacy, NJ Talley. NEJM 2017; 376: 2566-78. While yesterday’s post reviewed some of the updated diagnostic and pathophysiology information, today’s will focus on treatment.

The article’s Table 2 outlines the most frequent treatments, their efficacy, side effects, costs, and quality of evidence. I’ve tried to highlight the key points from table and discussion:

  1. Soluble fiber (eg. psyllium). Efficacy: effective -start at low doses. Quality of evidence: Moderate, Cost: $15-30 per month.
  2. Low-FODMAP diet. Efficacy: “May be effective, nutritionist guidance helpful.” While there have been studies showing this diet can be effective, two studies have shown that this diet is not significantly superior to conventional IBS diets (eg. “eating small, regular meals and avoiding insoluble fiber, fatty foods, and caffeine”).Quality of evidence: Very low.
  3. Gluten-free diet.  Efficacy: May be effective.  “No additive effect over that of a low-FODMAP diet in another small RCT.” Quality of evidence: Very low.
  4. Antispasmodic drugs (eg. dicyclomine).Efficacy: May be effective. Quality of evidence: Low, “No high-quality trials.” Cost: $50 per month.
  5. Peppermint oil. Efficacy: Effective, though few RCTs and no FDA-approved end points. Quality of evidence: Moderate. “No high-quality trials.”  Cost: $9-19 per month
  6. Lubiprostone. Efficacy: Effective, though “only a modest benefit over placebo, particularly for abdominal pain.” Quality of evidence: Moderate. Cost: ~$350 per month.
  7. Linaclotide.  Efficacy: Effective.. ” Quality of evidence: High. “No high-quality trials.”  Cost: ~$350 per month.
  8. Alosetron/5-HT3 receptor antagonists.  Efficacy: Effective. ” Quality of evidence: High. “No high-quality trials.”  Cost: ~$350-1100 per month. Alosetron may trigger ischemic colitis.
  9. Eluxadoline.  Efficacy: Effective, though “only a modest benefit over placebo for global symptoms and no benefit over placebo for abdominal pain.”  Quality of evidence: High. “No high-quality trials.”  Cost: ~$1100 per month. May trigger pancreatitis.
  10. Rifaximin. Efficacy: Effective. Quality of evidence: Moderate. “Modest benefit over placebo.”  “Relapse among patients who have a response is usual.” Cost: ~$1500 per month.
  11. Probiotics. Efficacy: May be effective.  Quality of evidence: Low. “Few high-quality trials and no FDA-approved end points.”  Cost: ~$20 per month.
  12. Tricyclic antidepressants. Efficacy: Effective. Quality of evidence: Moderate.  “Few high-quality trials and no FDA-approved end points.”   “A meta-analysis showed that tricyclic antidepressants were more effective than placebo in 11 randomized trials involving a total of 744 patients.” Cost: ~$5-10 per month.
  13. Psychological treatments. Efficacy: Effective. Quality of evidence: Low.  “Few high-quality trials and no FDA-approved end points.” “Their efficacy may be overestimated because of the lack of blinding.” There is also difficulty for many patients in finding an appropriate provider.  Cost: ??
  14. Placebo. In treatment trials, a placebo response is noted in 30-40%.
  15. Complementary/Alternative Therapies.  “Herbal therapies remain unclear.  STW5 (Iberogast) has been tested and “showed superiority over placebo.” Melatonin “has been reported to reduce abdominal pain in patients with IBS.”

The authors recommend judicious testing  “Any reassurance derived from colonoscopy to rule out organic disease in patients with IBS is short-lived.”

The authors outline their typical approach.  “Reassurance, explanation, and a positive diagnosis are essential steps in management. We recommend starting with dietary modification (slowly increasing soluble fiber if the patient has IBS with constipation or instituting a low-FODMAP diet temporarily  if the patient has IBS with diarrhea or the mixed subtype of IBS). We also recommend increased exercise and stress reduction.  A probiotic may be added, especially if bloating is prominent.  Pain may be ameliorated with an antispasmodic agent or a tricyclic antidepressant, diarrhea with loperamide or a bile acid sequestrant (eg. colestipol) and constipation with polyethylene glycol.” The other therapies may be used in those with persistent IBS symptoms.

My take: When a disease has this many treatments, usually this means that none of the treatments are all that great.

Related blog posts:

Chattahoochee River

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Don’t Skip this Article -Rome IV Summary

When I visited MIT, one of the slogans I heard was “Getting an Education from MIT is like taking a drink from a Fire Hose.” While this is a ridiculous notion, it is also true that the amount of information to consume, not just at MIT, but in so many areas is tremendous in quantity.  As such, one has to figure out what to read and what to toss.  For GI physicians, a recent summary (DA Drossman. Gastroenterol 2016; 1262-80) is worth a read due to the ubiquitous nature of the problems discussed.

Here were some key points:

  • “The possibility that passions or emotions could lead to the development of medical disease was first proposed by the Greek physician Claudius Galen.”
  • “Rome IV is a compendium of knowledge accumulated since Rome III” –10 years ago.

Some of the Changes:

  • New diagnoses:  Narcotic bowel syndrome, opioid-induced constipation, cannabinoid hyperemesis syndrome
  • Removal of functional terminology when possible…functional abdominal pain syndrome has been changed to centrally mediated abdominal pain syndrome
  • Threshold changes for diagnostic criteria
  • Addition of reflux hypersensitivity diagnosis.
  • Revision of Sphincter of Oddi  dysfunction disorder…  “driven by evidence that debunks the value of sphincterotomy for type III SOD.”
  • Emphasis that functional disorders exist on a spectrum with linked pathogenesis, particularly with regard to irritable bowel syndrome (IBS) subtypes.
  • Removal of the term discomfort for IBS criteria and using pain as the key criterion.

Approach to Patients with Functional GI Disorders:

  • The author discusses ways to engage patient to create partner-like interaction.
  • “Determine the immediate reason for the patient’s visit (eg. What led you to see me at this time?)”  Potential reasons: exacerbating factors, concern for serious disease, stressors, emotional comorbidity, impairment in daily functioning or hidden agenda (eg. disability, narcotics, litigation)
  • “Determine what the patient understands of the illness…What do you think is causing your symptoms?”
  • Provide a thorough explanation of the disorder.  “For example: ‘I understand you believe you have an infection that has been missed; as we understand it, the infection is gone but your nerves have even affected by the infection to make you feel like it is still there, similar to phantom limb.”
  • “Identify and respond realistically to the patient’s expectations for improvement (e.g. How do you feel I can be helpful to you?)”
  • Explain ways that stress can be associated.  “I understand you do not see stress as causing your pain, but you have mentioned how severe and disabling your  pain is.  How much do you think that is causing you emotional distress?”
  • “Set consistent limits..narcotic medication is not indicated because it can be harmful.”
  • “Involve patient in treatment plan (e.g. Let me suggest some treatments for you to consider).”
  • With regard to use of TCAs, the author explains that antidepressants can be used “to turn down the pain, and pain benefit occurs in doses lower than that used for depression.”  “Tricyclic antidepressants or the serotonin-norepinephrine reuptake inhibitors help control pain via central analgesia as well as provide relief of associated depressive symptoms.  The selective serotonin reuptake inhibitors are less effective for pain but can help reduce anxiety and associated depression.”
  • Establish an ongoing relationship.  “Whatever the result of this treatment, I am prepared to consider other options, and I will continue to work with you through this.”

My take: This summary provides a succinct update on a 6-year effort of 117 investigators/clinicians from 23 countries.  After reading this article, you will probably want to glance at the other articles in the same issue.

Vik Muniz Collage

Vik Muniz Collage

A closer look at the front wheel

A closer look at the front wheel

NEJM: Functional Dyspepsia

A recent NEJM had a concise review of functional dyspepsia (Talley NJ, Ford AC. NEJM 2015; 373: 1853-63).

With regard to functional dyspepsia in adults, the authors note that using the Rome III criteria, the global prevalence is between 5% and 11%.

While symptoms do not reliably distinguish organic and functional dyspepsia, they note that “with a relatively low rate of identification of organic disease, it is neither desirable nor realistic to perform this test [upper gastrointestinal endoscopy] in all patients with dyspepsia.”

Their review suggests several criteria to consider to help determine who needs endoscopy including age >55 yrs, GI bleeding, dysphagia, persistent vomiting, unintentional weight loss, family history of gastric or esophageal cancer, and iron-deficiency anemia.

With regard to workup, they suggest testing for H pylori non invasively with either breath testing or stool antigen testing.  The review covers treatment approaches including acid suppression (“effect is modest”), antidepressants (“tricyclic antidepressants…should be preferred over selective serotonin-reuptake inhibitors”), prokinetic agents, psychological treatments, and complementary approaches.  Figure 3 provides a helpful algorithm.

With regard to prognosis, “approximately 15 to 20% of people with functional dyspepsia have persistent symptoms and 50% have resolution of symptoms; in the remaining 30 to 35% of patients symptoms will fluctuate and meet the criteria for another functional gastrointestinal disorder.”

Briefly noted: “Acute Anxiety and Anxiety Disorders are Associated with Impaired Gastric Accommodation in Patients with Functional Dyspepsia” HG Ly et al. Clin Gastroenterol Hepatol 2015; 13: 1584-91.

Related blog posts:

Sunrise in Sandy Springs

Sunrise in Sandy Springs

AGA Guidelines on Medicines for Irritable Bowel

New guidelines on the use of medicines for irritable bowel syndrome from Atlanta Gastroenterology Association (AGA) have been published (Gastroenterol 2014; 1146-48, technical review: 1149-72).

Here’s the link: AGA IBS Guidelines.

In brief:

For IBS-C

  • Linaclotide: AGA recommends as better than no drug treatment in adult. This is the only “strong” recommendation with high-quality evidence.
  • Lubiprostone: AGA suggests over no drug treatment.
  • PEG Laxatives: AGA suggests over no drug treatment.

For IBS-D:

  • Rifaximin: AGA suggests over no drug treatment.
  • Alosetron: AGA suggests over no drug treatment.
  • Loperamide: AGA suggests over no drug treatment.

For IBS:

  • Tricyclic antidepressants: AGA suggests over no drug treatment.
  • Selective Serotonin Reuptake Inhibitors: AGA suggests against using for IBS.
  • Antispasmotics: AGA suggests over no drug treatment.

 

Also noted:

Am J Gastroenterol 2014; 109: 1547-61. (Thanks to Ben Gold for this reference.) Meta-analysis of prebiotics/probiotics for IBS.  43 RCTs were eligible for inclusion.  Key finding: IBS symptoms, including pain, bloating and flatulence were improved with RR of 0.79 compared with placebo.  “Probiotics are effective treatments for IBS, although which individual species and strains are the most beneficial remains unclear.”

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CCFA IBD Update -Conference Notes (part 1)

I wanted to share some notes from the Atlanta CCFA “Update in Inflammatory Bowel Disease” conference which was held March 23, 2013.

The first talk by Gil Melmed reviewed immunization issues in IBD.  One of the best quotes of the conference was on his first slide:  “The single most important thing a [rheumatologist] can do to optimize care for a [lupus] patient is to act as their internist, yet that is the last thing most [rheumatologists] wish to or feel qualified to do.” (Wallace DJ. Lupus 2008 (17) 91-2.

While trying to manage all aspects of the health care of our patients with chronic disease is an ideal, he also noted that 20-30% of adult IBD doctors do not understand the importance of avoiding live-virus vaccines (a list of these are noted in previous blog: Protecting the most vulnerable | gutsandgrowth).

One of the take-home points from this talk for me was to avoid use of rotavirus vaccine in newborn patients if their mother is receiving Infliximab or Adalimumab.  Another useful point would be to remind family members of immunosuppressed IBD patients to receive the influenza vaccine rather than the live-virus vaccine (flumist).

The second talk by Wallace Crandall focused on improving health care delivery.  The best quote of the day was from his first slide: “Every system is perfectly designed to achieve exactly the results it gets.”  (Donald Berwick).  One of his slides that I found intriguing showed 2007 data on immunomodulator use within the first 3 months of diagnosis from 10 different centers.  The rate varied from 30% to 98%.  He didn’t try to answer how frequent immunomodulator use in this time period should occur but there was no valid reason for this degree of variation.

In Columbus (Ohio), he stated that they are working to transform chronic care from 15-30 minute visits every 3-6 months to a more continuous process.  “Patients receive only 60% of recommended care.” With a better health care delivery system, this could be improved and potentially improve outcomes.

Another obstacle is the lack of evidence to guide decisions.  Recent “ECCO” guidelines for pediatric ulcerative colitis had 48% of recommendations based on level D evidence.

The third talk by Douglas Drossman was probably the most helpful.  He discussed pain management in IBD.  He reviewed a lot of recent data on irritable bowel syndrome (IBS) and discussed similarities between post-infectious IBS and many patients with treated IBD.

He also discussed central pain aspects and alluded to changes in the brain that happen with chronic treatment (Pain changes brain | gutsandgrowth).  He noted that antidepressants have the potential to reverse brain changes due to chronic pain but that regrowth of neurons can take a long time.  As such, he noted that agents like imipramine are needed for at least one year. Use of imipramine, he noted, has been shown to improve cognitive function in mice with traumatic brain injury (J Neurotrauma 2011; 28: 995).

With regard to IBD, Dr. Drossman noted a wide variability in pain response among patients.  Some who have very significant mucosal disease do not experience significant pain, likely due to downregulation of some central pathways.  He outlined his treatment model for pain in IBD.

  1. Effective communication improves clinical outcomes
  2. Just as there is a “treatment pyramid” for IBD, with IBS the treatment pyramid ncludes the following: motility agents, antispasmodics, antidepressants, psychological intervention, and central augmentation.
  3. With regard to antidepressants, he highlighted the differences between tricyclics, SSRIs, and SNRIs. He noted that SSRIs like citalopram, escitalopram, fluoxetine, paroxetine, and sertraline are not effective at reducing pain but can help anxiety/depression.
  4. Tricyclic antidepressants are effective at reducing pain and are inexpensive.  Side effects can include sedation, dry mouth, dizziness, and constipation.  Desipramine and nortriptyline have fewer side effects.
  5. SNRIs including duloxetine, venlafaxine, desvenlafaxine, and minacipran are effective at reducing pain and fewer side effects.  However, they are considerably more expensive.  Nausea, though, is not infrequent.
  6. Psychologic treatments: cognitive behavioral, psychotherapy, hypnosis, and relaxation training.  When to refer? moderate-severe symptoms, maladaptive coping (eg. “catastrophizing”), and motivated patient.
  7. What is central augmentation? If an antidepressant is not effective, augmentation is adding an agent that may target a different brain receptor.  Potential augmenters include pharmacologic and non-pharmacologic approaches.  Pharmacologics could include added gabapentin, added atypical antipsychotic (e.g.. quetiapine [Ability]), added clonidine, added buspirone, or added mirtazepine (e.g. remeron).  Most practitioners will need the help of a psychiatrist to manage these medications.