Sources of Gastrointestinal Pain

Educational Objectives

The goal of this program is to improve the management of noncardiac chest pain (NCCP), functional dyspepsia, and narcotic bowel syndrome (NBS). After hearing and assimilating this program, the clinician will be better able to:

1.   Utilize the most appropriate test to determine the cause of NCCP.

2.   Describe the pharmacologic and nonpharmacologic treatment of NCCP.

3.   Discuss the pathophysiology of functional dyspepsia.

4.   Recognize the typical clinical presentation of NBS.

5.   Discuss the importance of the physician-patient relationship in the narcotic withdrawal protocol.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Dross­man is a consultant for Takeda, Sucampo, and Prometheus and has received a research grant from Wyeth Pharmaceuticals. Drs. Dellon, Mertz, and the planning committee reported nothing to disclose. Drs. Dellon, Mertz, and Drossman present in­formation that is related to off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Dellon was recorded at Update in Gastroenterology and Hepatology: Applying Sound Principles in Daily Practice, held April 17-19, 2009, in Chapel Hill, NC, and sponsored by the University of North Carolina School of Medicine, Chapel Hill. Drs. Mertz and Drossman were recorded at Gastroenterology and Hepatology Update 2009, held September 11-12, 2009, in Nashville, TN, and sponsored by the Vanderbilt Digestive Disease Center.

Noncardiac Chest Pain

Evan S. Dellon, MD, MPH, Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill

Noncardiac chest pain (NCCP): definition  —  recurrent retrosternal pain or discomfort of noncardiac etiology; com­mon and nonspecific; multiple causes; typically, history and physical examination (PE) not helpful

Causes of NCCP: rule out cardiac causes; gastroesophageal reflux disease (GERD) most common gastrointestinal (GI) cause; erosive and nonerosive disease account for »50% of all cases of NCCP; esophageal dysmotility, 15%-25%; functional CP, 30% to 40%

Upper endoscopy: indicated if alarm symptoms present in history and PE; alarm symptoms include dysphagia, ody­nophagia, anemia, weight loss, GI bleeding, and new onset of symptoms in older patients; also indicated if struc­tural lesion that would chang management strongly suspected; findings limited to structural lesions; low yield in NCCP; study  —  retrospective look at endoscopies and their indications and findings; malignancy found in 0.2% of participants with NCCP; 44% had normal endoscopy; few differences seen when findings compared to those of GERD group; esophagogastroduodenoscopy (EGD) also low yield for GERD; yield slightly increased for esopha­geal inflammation and hiatal hernia, but low yield overall in NCCP

Trial of proton pump inhibitor (PPI): rationale that GERD most common cause of NCCP; most of EGD findings related to GERD; PPI used diagnostically and therapeutically; good noninvasive first-line option; cost-effective; meta-analyses showed reasonable pooled sensitivity and specificity for correct diagnosis of NCCP if response to PPI present (although not perfect); effective for treatment, compared to placebo; before prescribing PPI, exclude cardiac disease and ensure that no alarm symptoms present; typically, high-dose PPI recommended; immaterial which PPI used, but should use 2 to 4 wk and £2 mo before assessing response

pH impedance: typically used in NCCP to evaluate role and type of reflux (acid or nonacid); refluxate characterized by pH and impedance probes; indicated in patient on PPI with persistent CP; if test positive and shows reflux with acid, means reflux acid-mediated; if reflux seen but no acid, reflux nonacid; if pH impedance negative, symptoms not due to reflux disease

Esophageal manometry: detects underlying motility disorders; performed after excluding reflux disease and if clin­ical suspicion for esophageal dysmotility present; 2 studies  —looked at patients with NCCP and nonreflux CP with esophageal motility studies; found »25% had abnormal motility studies, indicating underlying motility disorder; specific conditions found included “nutcracker” esophagus, achalasia, and diffuse esophageal spasm; overall, mo­tility disorders account for 20% to 25% of NCCP; barium swallow  —  several simultaneous contractions in esopha­gus with corkscrew appearance indicative of diffuse esophageal spasms; differentiated from “nutcracker” esophagus (pressure >180 mm Hg)

Functional CP: second most common cause of NCCP; probably underdiagnosed formally; Rome III definition (re­quires all three characteristics)  —  1) midline CP or discomfort not of burning quality; 2) absence of evidence that gastroesophageal reflux cause of symptom; 3) absence of histopathology-based esophageal motility disorders; functional heartburn  —distinguished from functional CP by quality of discomfort; in functional CP, pain, pressure, or aching present; in functional heartburn, discomfort burning in quality; pathophysiology  —visceral hypersensitiv­ity; studies of esophagus demonstrate increased sensitivity of patient to balloon dilation and electrical stimulation of esophagus; altered central nervous system (CNS) processing of painful stimuli also present; comorbid psycho­logic disease possibly present

Management: depends on underlying problem (motility, spasm, or functional CP); reassurance and explanation of diagnosis crucial (first action); centrally acting medications quite effective in modulating pain in both conditions, even in spasm; anticholinergics and antispasmodics play role as possible first-line treatment, but data inadequate; muscle relaxants  —  nitrates; indicated for spasm; not much data, with inconsistent results in small open-label trials; sublingual nitroglycerin for on-demand use, and isosorbide dinitrate for longer use; tachyphylaxis possible; with nitrates, trading CP for severe splitting headache; calcium channel blockers  —  inconsistent results seen in small tri­als; nifedipine or diltiazem used in low doses in tid dosing or extended-release preparations; balance side effects with treatment effects; concern about hypotension, orthostasis, dizziness, and lightheadedness, as well as peripheral edema and bradycardia; botulinum toxin type A (Botox)  —  blocks release of acetylcholine at presynaptic terminals, leading to muscle paralysis; effective in achalasia (relaxes lower esophageal sphincter) and esophageal spasm; lim­ited data; not permanent (lasts 3-6 mo); patient followed long-term may require repeated therapy or other form of treatment; centrally acting agents  —  target pathophysiology of increased pain sensation at peripheral and central level; inadequate data; trial and error

General principles of treatment: start with low dose and titrate as tolerated or until desired effect achieved; may not see effects until several weeks after starting medication; important to educate patient and set expectations for them

Tricyclic antidepressants (TCAs): most data for treating esophageal conditions; thought to modulate pain via nor­epinephrine and serotonergic effects; several receptor effects seen (eg, calcium-channel receptors); clinical data suggest starting medications at dose of 10 to 25 mg, titrating to 75 to 100 mg as tolerated; doses typically below dose required for antidepressant effect; study showed 50% reduction in frequency of CP episodes with imipramine compared to placebo

Selective serotonin reuptake inhibitors (SSRIs): sertraline dose of 50 to 200 mg effective for severe pain, com­pared with placebo; citalopram in healthy volunteers found to decrease pain perception

Serotonin-norepinephrine reuptake inhibitors (SNRIs): no data on use for NCCP, but role possible based on use in functional abdominal pain and other neuropathic pain-mediated conditions

Others: trazodone  —  at dose of 100 to 150 mg, showed symptomatic improvement, compared to placebo; benzodiazepines  —little data for use, but effective in short term if anxiety component present or developed because of pain related to eating or excessive concern about symptoms; gabapentin  —  similar to SNRIs; no clinical data in NCCP; possible role based on pain modulatory effects in other conditions

Nonpharmacologic treatment: cognitive behavioral therapy (CBT)  —  effective; targeted at patient’s understanding of condition and learning different techniques to help manage symptoms in acute setting and over time (gaining im­provement of symptoms); randomized controlled trial (RCT) of CBT vs usual care found significantly improved pain severity and frequency in CBT arm, with »50% of CBT patients pain-free at 1 yr; hypnosis  —  RCT found global improvement in symptoms in 80% of patients in hypnosis arm, compared to 23% in placebo arm

Functional Dyspepsia

Howard Mertz, MD, Clinical Assistant Professor of Medicine, Vanderbilt University School of Medicine, Nashville, TN

Definition: Rome criteria  —  ³1 symptom for 3 to 6 mo, including postprandial fullness, early satiety, epigastric pain, or epigastric burning (heartburn excluded); structural disease (usually found on EGD) excluded

Pathophysiology: hypersensitivity to distention and nutrients (similar to irritable bowel syndrome [IBS]); motility disorder (delayed gastric emptying and abnormal meal accommodation); acid peptic disease, particularly reflux; 3 mechanisms overlap; gastric hypersensitivity  —  University of California Los Angeles study using balloon dilation of stomach found that only patients with functional dyspepsia (FD) had low pain, fullness, and discomfort thresh­olds, compared to controls; Belgian study showed duodenal hypersensitivity to acid infusion; in FD, stomach stiffer and unable to relax (accommodate) as much after meal; delayed gastric emptying  —  found in »25% of those with FD; study found that patients with delayed gastric emptying more likely to have postprandial fullness and vomiting; hypersensitivity to distention (seen in 40% of subjects) correlates with pain, belching, and weight loss; impaired accommodation  —correlates with early satiety and weight loss; postdysenteric FD  —  follow-up of Escherichia coli 0157:H7 outbreak found that longer duration of diarrhea, female sex, preexposure IBS, and preexposure psycho­logic stressors predicted occurrence of FD 8 yr later (similar to IBS)

Anxiety in FD: survey of >2500 community dwellers in Sweden found that anxiety particularly associated with FD (2.6% higher chance for anxious patient to have FD); postprandial distress, not epigastric pain, particularly associ­ated (odds ratio of 4.35); depression not associated with FD; nonsteroidal anti-inflammatory drugs (NSAIDs) also associated with FD; epigastric pain alone not associated with psychologic symptoms

Treatment: PPIs effective for acid peptic disorders; prokinetics probably effective, but availability limited; not much evidence for TCAs, but strong rationale seen; some evidence for efficacy of psychotherapy; no good evidence for Helicobacter pylori eradication; PPIs  —  empiric treatment indicated as part of test-and-treat strategy; still indicated even if EGD negative, due to prevalence of reflux; may treat duodenal hypersensitivity to acid; prokinetics  —  metoclopramide, cisapride (off market), domperidone (available only in Canada), and itopride effective, based on data; effective in subset of patients; worth trial in patient with poor response to other drugs; speaker starts with metoclopramide (antinausea effect); issue with black box warning and risk for tardive dyskinesia (nil if used only for 1-2 mo); antidepressants  —speaker uses low-dose TCAs (desipramine preferred because of lesser anticholiner­gic effects, unlike amitriptyline); small study by speaker found amitriptyline effective; desipramine effective in pa­tients with functional bowel disorders (mostly IBS); venlafaxine (Effexor) ineffective; SSRIs worth trial if symptoms severe; anxiolytic-antidepressant combination  —study found combination of mood stabilizer and anxio­lytic effective; due to role of anxiety as factor in FD; antispasmodics  —  found ineffective in clinical trials; effective in IBS; possibly useful in FD if given before meals in patients with significant postprandial symptoms; CBT  —ef­fective based on longitudinal data (similar data for IBS); more effective than education; hypnotherapy  —  effective; diet  —  no specific elimination diet proven effective; low-fat diet prudent and possibly helpful; avoidance of NSAIDs helpful; individualize management

Narcotic Bowel Syndrome

Douglas A. Drossman, MD, Professor of Medicine and Psychiatry, University of North Carolina School of Medicine, Cha­pel Hill

Adverse effects of opioid on bowel: opioid bowel dysfunction  —  slows bowel; includes constipation, nausea, vomit­ing, gastroparesis, bloating, ileus, and sometimes pain; narcotic bowel syndrome (NBS)  —  abdominal pain predom­inant symptom; progressive and paradoxical increase in pain, leading to escalating doses of narcotics to relieve pain; underrecognized

Typical clinical presentation: chronic or recurrent abdominal pain treated with narcotics; narcotics may relieve pain initially, but then tachyphylaxis occurs, requiring higher doses; pain worsens when narcotic effect wears off; shorter pain-free periods result in increasing narcotic doses; increasing doses further alter motility and aggravate pain; occurs in patients with functional GI disorders (eg, IBS), organic disease, and in healthy subjects

Prescription of narcotics in health care setting: prescribing shifted from acute severe pain or palliative care of ma­lignancies to prolonged use in chronic nonmalignant pain; pain treatment centers shifted to narcotic treatments (“quick fix”) over multidisciplinary pain treatment; no scientific evidence for long-term benefit of narcotics in non­malignant pain; greater sensitivity of bowel in functional disorders, leading to more side effects from narcotics; en­abled by third-party payers due to greater cost-benefit ratio

Physiology: high-dose opioids activate inhibitory receptors (inhibit pain, producing analgesia; mask excitatory recep­tors); as opioid given long-term and dose increased, tolerance develops in inhibitory receptors and excitatory recep­tors sensitized, paradoxically leading to hyperalgesia; glial cells  —inflam-matory cells; found in dorsal horn of central nervous system; amplify pathologic pain; cause release of inflammatory cytokines that enhance neuronal excitability; when used long-term, narcotics bind to glia via m receptors, causing release of cytokines; opioids  —  also activate dynorphin release, producing pain; long-term use activates glia via toll-like receptors (TLRs; “scaven­ger” receptors involved in inflammation and infection); low-dose antagonists (eg, naloxone) block receptors and enhance opioid analgesia

Diagnostic criteria: chronic or frequently recurring abdominal pain treated with acute high-dose or long-term nar­cotics; pain worsens or incompletely resolves with continued or escalating doses of narcotics; marked worsening of pain when narcotic dose wanes and improvement when narcotics reinstituted (“soar and crash”); progression of fre­quency, duration, and intensity of pain episodes; pain not explained by any other diagnosis

Narcotic withdrawal protocol: physician-patient relationship  —accept pain as real and give patient sense of hope; elicit pa­tient’s concerns and expectations and address them; discuss effects of narcotics on pain and GI function; advise patient that he or she will improve and not worsen when off narcotics and that other pain-control methods will be substi­tuted while narcotics tapered; use illustrations or graphics to present withdrawal program; involve responsible fam­ily member; assure that someone available to address patient’s issues; choice of clinical setting shifting to inpatient (faster, easier to handle complications, and appropriate if monitoring required); outpatient detoxification performed in 6 to 8 wk (few days for inpatient); gauge patient’s willingness to go through program; address challenging ques­tions; SSRIs  —  not as beneficial (more anxiolytic and antidepressant, rather than pain modulators); TCAs  —  watch for side effects; duloxetine  —  marketed with pain as separate indication; indicated in peripheral neuropathy and fi­bromyalgia; acts via central pain regulatory pathways; benzodiazepine, eg, lorazepam (Ativan) and clonidine used to cover during withdrawal period; tapering  —  should not taper frequency; maintain intervals but reduce dose; doses scheduled (not prn); clonidine  —  blocks withdrawal effects; a-2 adrenergic agonist; acts centrally to reduce anxiety and peripherally to reduce pain via bowel compliance; reduces diarrhea; prevents adrenergic effects of withdrawal; poor response seen in sociopathic patients with history of drug-seeking behavior, and not committed to program

Suggested Reading

Aro P et al: Anxiety is associated with uninvestigated and functional dyspepsia (Rome III criteria) in a Swedish population-based study. Gastroenterology 137:94, 2009; Fischler B et al: Heterogeneity of symptom pattern, psychosocial factors, and pathophysio­logical mechanisms in severe functional dyspepsia. Gastroenterology 124:903, 2003; Kusano M et al: Proton pump inhibitors im­prove acid-related dyspepsia in gastroesophageal reflux disease patients. Dig Dis Sci 52:1673, 2007; Longstreth GF: Functional dyspepsia – managing the conundrum. N Engl J Med 354:791, 2006; Margo KL: Psychological interventions for noncardiac chest pain. Am Fam Physician 72:1701, 2005; Miller CD et al: Is the initial diagnostic impression of "noncardiac chest pain" adequate to exclude cardiac disease? Ann Emerg Med 44:565, 2004; Erratum in: Ann Emerg Med. 45:87, 2005; Pearson RL: How effective are antidepressant medications in the treatment of irritable bowel syndrome and nonulcer dyspepsia? J Fam Pract 49:396, 2000; Sand­gren JE et al: Narcotic bowel syndrome treated with clonidine. Resolution of abdominal pain and intestinal pseudo-obstruction. Ann Intern Med 101:331, 1984; Talley NJ et al: Functional dyspepsia, delayed gastric emptying, and impaired quality of life. Gut 55:933, 2006; Wong WM et al: Attitudes and referral patterns of primary care physicians when evaluating subjects with noncardiac chest pain--a national survey. Dig Dis Sci 50:656, 2005.