a self-test IM Board Review on a CME EDUCATIONAL OBJECTIVE: Readers will be aware of narcotic bowel syndrome as a consequence clinical CREDIT of prolonged narcotic use. case Markus Agito, MD Maged Rizk, MD Department of Internal Medicine, Quality Improvement Officer, Digestive Akron General Medical Center, Disease Institute, Cleveland Clinic; Assistant Akron, OH Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH Recurrent abdominal pain and

32-year-old man presents to the emer- Based on the information available, which A gency department with excruciating is the least likely cause of his symptoms? abdominal pain associated with multiple epi- 1 sodes of vomiting for the past 2 days. He re- □□ Acute ports no fevers, , , constipa- □□ Cyclic vomiting syndrome tion, , , musculoskeletal □□ Acute intermittent porphyria symptoms, or weight loss. His abdominal pain □□ is generalized and crampy. It does not radiate and has no precipitating factors. The pain is Acute pancreatitis is the least likely cause of relieved only with intravenous narcotics. his symptoms. It is commonly caused by gall- stones, alcohol, hypertriglyceridemia, and cer- See related editorial, page 441 tain drugs.1 The associated abdominal pain is usually epigastric, radiates to the back, and is He does not smoke, drink alcohol, or use accompanied by or vomiting, or both. illicit drugs. He has no known drug or food The onset of pain is sudden and rapidly increas- allergies. He says that his current condition es in severity within 30 minutes. CT shows en- causes him emotional that affects his largement of the pancreas with diffuse edema, A year ago, performance at work. heterogeneity of pancreatic parenchyma, peri- after a About a year ago, after a complicated sur- pancreatic stranding, and peripancreatic fluid gical procedure, he needed chronic high-dose collections.1 The diagnosis is based on two of complicated narcotics. A few months later, he developed the following three criteria: abdominal pain surgical multiple bouts of abdominal pain and vomit- characteristic of acute pancreatitis; a serum procedure, ing that required hospital visits. He now takes amylase or lipase concentration three or more oral oxycodone 10–15 mg every 4–6 hours. times the upper limit of normal; and character- he needed On admission, his vital signs are stable, but istic findings of acute pancreatitis on CT.1 chronic high he is in excruciating pain. He is alert and ori- ented to person, place, and time. His sclera are Cyclic vomiting syndrome doses anicteric, and the pupils are equal, round, and Cyclic vomiting syndrome is thought to be of narcotics reactive to light. Lung and heart examinations caused by episodic dysautonomia, mitochondri- are normal. The abdomen is soft and nondis- al DNA mutations, and hypothalamic emetic tended but tender in all four quadrants without response oversensitivity,2–4 but the exact patho- guarding; the liver and spleen are not palpable, genesis is unknown. The syndrome has been and no abdominal masses are detected. He has strongly linked to and to the chronic no skin rash, joint swelling or tenderness, or excessive use of cannabinoids.5–9 The Rome III peripheral edema. The neurologic examination diagnostic criteria10 are the following: the vom- is normal. Computed tomography (CT) of the iting episodes are stereotypical, ie, they are acute abdomen with contrast shows no signs of bowel and last for less than 1 week; the patient has had obstruction, pancreatic calcifications or edema, three or more episodes in the previous year; and , or hepatobiliary disease. Results the patient has no nausea or vomiting between of initial laboratory testing are shown in TABLE 1. episodes. The patient must meet all three crite- ria. A history of migraine or a family history of doi:10.3949/ccjm.80a.12148 migraine further supports the diagnosis.

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Acute intermittent porphyria TABLE 1 Acute intermittent porphyria is characterized by neurovisceral symptoms such as convul- Laboratory testing results at admission sions, paresis, autonomic dysfunction, con- Test Result Reference range stipation, and diarrhea that result from the overproduction of porphyrin precursors and Complete blood cell count deficiency of porphobilinogen deaminase.11 Most patients have poorly localized, se- Hemoglobin 13.4 g/dL 13.2–17.4 vere, steady abdominal pain that develops Leukocytes 12.3 x 109/L* 4.4–9.7 over hours to days and that may persist for days Platelets 283 x 109/L 150–370 to weeks.11 Since the pain is neuropathic, ab- dominal tenderness is usually minimal during Comprehensive metabolic panel an acute attack. Other clues include signs of Sodium 139 mEq/L 136–145 , such as , nausea, abdominal Potassium 3.2 mEq/L* 3.5–5.1 distention, or decreased bowel sounds; blad- der dysfunction, eg, urinary retention, incon- Chloride 104 mEq/L 98–107 tinence, or dysuria; reddish-brown urine; and Bicarbonate 28 mEq/L 21–32 sensory neuropathy of the chest, back, and ex- Blood urea nitrogen 4 mg/dL* 7.0–18 tremities.11 Blistering skin lesions are usually Creatinine 0.9 mg/dL 0.8–1.3 not seen. The presence of porphobilinogen in the urine confirms the diagnosis.11 Glucose 109 mg/dL* 74–106 Alanine aminotransferase 55 U/L 30–65 Gastroparesis Aspartate aminotransferase 19 U/L 15–37 Gastroparesis is a result of discoordination Alkaline phosphatase 110 U/L 50–136 between the sympathetic and parasympa- thetic nervous systems, neurons, and smooth Total protein 6.2 g/dL* 6.4–8.2 muscles within the stomach, causing a de- Total bilirubin 0.8 mg/dL 0–1.0 crease in gastric motility. Common causes Lipase 231 U/L 114–286 12 13 are diabetes, scleroderma, and neurologic Amylase 35 U/L 25–115 disorders.14 It can also be iatrogenic,15 re- sulting from visceral nerve injury and drug *Value outside the reference range treatment with narcotics, calcium channel blockers, muscarinic cholinergic antago- Esophagogastroduodenoscopy shows antral gas- nists, or certain antidepressants. Symptoms tritis, but the and appear are related to gastric stasis, ie, abdominal normal, and colonoscopy is normal as well. His- pain from gastric distention, bloating, vom- tologic study of biopsy specimens obtained dur- iting, and early satiety.15 Abdominal pain ing endoscopy is unrevealing. A gastric-empty- may worsen after eating, and vomitus usu- ing study shows delayed emptying. The patient’s ally consists of recently ingested food. These abdominal pain and vomiting persist with the patients may have abdominal distension or initial dose of intravenous narcotic but resolve tenderness and succussion splash. After ex- with escalating doses. When asked, the patient cluding possible mechanical obstruction, a denies an excessive need for hot baths. gastric-emptying study may be necessary to 15 make the diagnosis. Which is the most likely diagnosis at this point? ■■ Case Continued 2 □□ Narcotic bowel syndrome A serum and urine drug screen in our patient □□ Opioid withdrawal is positive only for opioids. Urine measures of □□ Crohn disease delta-aminolevulinic acid and porphobilinogen □□ are normal. CT angiography of the abdomen □□ Chronic mesenteric ischemia shows no signs of mesenteric vascular occlusion. □□ Cannabinoid hyperemesis

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Narcotic bowel syndrome hypersensitivity, these patients perceive more Narcotic bowel syndrome is the most likely severe abdominal pain than patients with gas- diagnosis. Grunkemeier et al16 described troparesis alone. it as chronic or frequently recurring ab- dominal pain that is treated with narcot- Opioid withdrawal ics, either chronically or acutely with high Symptoms of opioid withdrawal may appear doses, and that includes all the following as soon as 6 to 24 hours after cessation of the features16: opioid in patients known to be dependent on • The pain worsens or resolves incompletely opioids. These patients present with crampy with continued or increasing doses of nar- abdominal pain with nausea.18 Other symp- cotics toms include agitation, rhinorrhea, lacrima- • The pain markedly worsens when the tion, excessive yawning, arthralgias, papillary narcotic dose is decreased, and decreases dilation, and piloerection.18 when the drug is reinstituted (the “soar- Our patient did not have the typical signs and-crash” effect) of opioid withdrawal. • The frequency, duration, and intensity of the pain episodes gradually increase Crohn disease • The nature of the pain and its intensity are Crohn disease is a multisystem disorder with not explained by a current or previous gas- specific clinical and pathologic features. It trointestinal diagnosis.16 is characterized by focal, asymmetric, trans- This syndrome is common in patients mural, and occasionally granulomatous in- who receive high doses of narcotics for post- flammation primarily affecting the gastro- operative pain or for other, nonmalignant intestinal tract.19 Characteristic symptoms causes of pain. Patients eventually become include abdominal pain, chronic diarrhea dependent on the drugs but are not aware with or without rectal bleeding, and weight that chronic use activates and facilitates ar- loss. Extraintestinal signs may include ane- eas in the brain that enhance the perception mia and inflammatory changes in the eyes, Laboratory of pain.16 A study of a rat model of narcotic skin, and joints. The diagnosis is based on tests are bowel syndrome17 showed that morphine- endoscopic, radiographic, and pathologic induced hyperalgesia depends on central findings.19 usually normal; sensitization involving the activation of Our patient did not have diarrhea or signs imaging may spinal microglia. This eventually results in of Crohn disease on CT, endoscopy, or his- show only ileus concomitant peripheral sensitization in- tology. volving the colonic mucosal neuroimmune system, and also in central or peripheral ac- Chronic pancreatitis tivation of opioid kappa-receptors by dynor- Chronic pancreatitis involves progressive phin release.17 inflammatory changes resulting in perma- Patients tend to present with chronic or nent structural damage to the pancreas and intermittent colicky abdominal pain that re- subsequent exocrine and endocrine dysfunc- quires escalating doses of narcotics. Eventual- tion.20 Patients have epigastric abdominal ly, they develop tachyphylaxis and shortened pain that often radiates to the back20; it is pain-free periods and will require even higher associated with eating and is partly relieved doses of narcotics. This ultimately enhances with leaning forward. Symptoms of pancre- the perception of pain and worsens opioid atic insufficiency such as fat bowel symptoms, causing a vicious circle of (resulting in and fat-soluble pain and more narcotic use.16 vitamin deficiency) and diabetes are com- Laboratory tests are usually normal, and mon. Calcifications within the pancreas on imaging may show only ileus. Gastric empty- CT suggest chronic pancreatitis.20 Serum ing may be delayed in patients who have ei- lipase and amylase levels may be normal or ther narcotic bowel syndrome or gastroparesis, slightly elevated.20 but since abdominal pain from narcotic bowel Our patient’s abdominal pain was not typi- syndrome is a result of central and visceral cal of pancreatitis. He had no signs or symp-

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toms of pancreatic insufficiency and no calci- What is the cornerstone of treatment for fications within the pancreas. 3narcotic bowel syndrome? □□ Establishing a therapeutic relationship Chronic mesenteric ischemia □□ Detoxification Chronic mesenteric ischemia (“intestinal □□ Supportive management with intravenous angina”) is caused by a reduction in intesti- fluids, , and stool-softeners nal blood flow as a result of occlusion, vaso- □□ Medical management with a short-acting spasm, or hypoperfusion of the mesenteric narcotic, clonidine, , and vasculature.21 It is commonly seen in patients desipramine who smoke or who have atherosclerotic vas- cular disease. These patients have chronic ■■ ManagEMENT dull or crampy abdominal pain that usu- OF NARCOTIC BOWEL SYNDROME ally occurs within 1 hour after eating.21 To avoid pain, patients avoid eating, resulting An effective therapeutic relationship with the in weight loss.21 CT angiography with multi- patient is the cornerstone of treatment and detector CT is as effective as angiography should be established before starting detoxifi- (the gold standard) in depicting splanchnic cation.17 The physician must first learn to ac- arterial anatomy.22 cept that the patient’s condition is real and Our patient is young and has no known must show genuine empathy as well as provide risk factors for atherosclerosis such as smok- information about the pathophysiologic basis ing. His abdominal pain is more intermittent of the condition, the rationale for withhold- than chronic and is not associated with eat- ing narcotics, and the detrimental role nar- ing. cotics play in the vicious circle of pain. Detoxificationinvolves gradually with- Cannabinoid hyperemesis drawing the narcotic and substituting a Cannabinoid hyperemesis should be consid- nonnarcotic such as an antidepressant for ered in patients with long-term use pain control, as well as prescribing a drug presenting with cyclic vomiting, abdominal such as a or clonidine to Establishing pain, compulsive use of hot showers, and im- prevent withdrawal symptoms and a laxa- a therapeutic provement of symptoms with cannabis cessa- tive to prevent constipation.17,24 The physi- tion.23 Although cannabinoids have been rec- cian must reassure the patient that he or she relationship ognized for their effects, long-term will not be abandoned in pain and that all with the patient use may eventually cause autonomic instabili- medications will be continuously adjusted ty and disturbances in the hypothalamic-pitu- as needed to keep him or her comfortable promotes itary-adrenal axis, resulting in cyclic vomiting throughout the detoxification process.17,24 compliance 23 and thermoregulatory impairment. The physician must continuously gauge the and improves Although our patient presented with mul- patient’s willingness to continue with treat- tiple episodes of vomiting and abdominal ment and must also be readily available to outcomes pain, he denied using marijuana, he tested address the patient’s concerns in a timely negative for tetrahydrocannabinol, and he did manner.17,24 Involving family members and not associate any relief of his symptoms with friends may provide additional support to hot baths. the patient. Referral to a functional gastro- intestinal motility program, a pain special- ■■ Case Continued ist, and a psychologist may also be consid- ered.17,24 Follow-up care is essential, even Our patient receives intravenous hydration, after the withdrawal program has ended.17,24 antiemetics, and a narcotic in tapering in- travenous doses, and his symptoms gradu- ■■cBa k to the patient ally improve. He is discharged from the hospital. However, a few weeks later he is After successfully establishing a therapeu- readmitted with the same symptoms of ab- tic relationship and discussing the treat- dominal pain and nausea. ment plan with our patient, we started him

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on the same dosage of narcotic that he had ■■ Take-home message been receiving, calculated in intravenous morphine equivalents to achieve maximal In the United States, the number of patients tak- comfort, and then decreased the dosage by ing a narcotic for nonmalignant pain is increas- 10% to 33% daily until he was completely ing,25 and physicians should be more aware of off narcotics. An antidepressant and a ben- complications such as narcotic bowel syndrome. zodiazepine were given simultaneously with Narcotic bowel syndrome should be suspect- narcotic tapering. Oral clonidine (0.1–0.4 ed in any patient with prolonged narcotic use mg/day) was given after the narcotic dosage presenting with multiple recurrent episodes of was reduced to about half, and polyethyl- abdominal pain after other causes are ruled out. ene glycol was given as needed for consti- Establishing a good therapeutic relation- pation. The total duration of detoxification ship with the patient is the cornerstone of was 7 days. successful treatment. Patients who understand The patient was referred to a psychologist their condition and are willing to be treated for cognitive-behavioral and relaxation thera- tend to have better outcomes. py, as well as for encouragement and support. Supportive treatment, symptom relief, and At 6 months, he had had no recurrence of emotional support during detoxification in- symptoms. crease compliance. ■

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