Turk J Gastroenterol 2010; 21 (1): 42-44

Pure naratriptan-induced ischemic colitis: A case report Naratriptan’a ba¤l› iskemik kolit: Olgu sunumu

Hans M. WESTGEEST1, Halil AKOL2, Tim C.M.A. SCHREUDER2 Departments of 1Internal Medicine and 2Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands

A 60-year-old female with sudden onset of abdominal pain and Migren tedavisi için düzenli olarak naratriptan kullanan 60 hematochezia was diagnosed with histology-proven ischemic co- yafl›nda kad›n hastaya ani bafllayan kar›n a¤r›s› ve hematokez- litis. She used naratriptan on a regular basis for migraine. By ya nedeni ile yap›lan tetkikleri ve biyopsi sonucunda iskemik exclusion of other causes for colonic ischemia and the absence of kolit tan›s› konulmufltur. Kolonik iskemiye neden olabilecek di- cardiovascular risk factors, naratriptan was considered the ¤er faktörlerin ekarte edilmesi ve kardiyovasküler risk faktörle- causal agent. Discontinuation resulted in a complete clinical re- rinin de olmamas› dikkate al›narak hastadaki iskemik kolitin covery. With the increasing use of triptans, health care provi- naratriptan’a ba¤l› olabilece¤i düflünülmüfltür. ‹lac›n kesilme- ders should be aware of the possible serious ischemic events as- si ile hastan›n tam olarak iyileflti¤i görülmüfltür. Sa¤l›k çal›- sociated with these drugs. flanlar›n›n, triptanlar›n kullan›m›ndaki art›fl› da dikkate ala- rak, bu ilaçlar›n olas› ciddi iskemik yan etkileri hakk›nda bil- gi sahibi olmalar› gerekmektedir. Key words: Naratriptan, ischemia, colitis Anahtar kelimeler: Naratriptan, iskemi, kolit

INTRODUCTION Triptans are selective 5-hydroxytryptophan (5HT) with a sudden onset of abdominal pain and hema-

1B/1D-receptor agonists, a class of drugs widely used tochezia one day before admission. She reported for the treatment of acute symptoms of migraine. with severe lower abdominal cramping pain with Their therapeutic effect is based on predominant frequent episodes of bloody diarrhea accompanied vasoconstriction of the cerebral circulation. When by nausea without vomiting. She denied any fever prescribed to patients with low risk of cardiovascu- or chills, and no signs of exposure to infectious lar events, triptans have proven to be safe without agents (e.g. shellfish, undercooked food, or travel) evidence of increased occurrence of ischemic condi- were noted. Vigorous physical exercise, the use of tions (e.g. stroke or ischemic heart disease) (1). Ho- illicit drugs and smoking were denied. Her past wever, triptans are contraindicated in all patients medical history was unremarkable except for pri- with a past history of coronary heart or cerebro- or appendectomy and hemorrhoids. In particular, vascular disease (2). Although rare, the use of su- there was no history of hypertension, diabetes matriptan and naratriptan has been associated mellitus or coronary artery disease. with several cases of ischemic colitis (3-7). We pre- Naratriptan was prescribed, which was used fre- sent a case of a female patient suffering from isc- quently on demand. Additional analysis of data hemic colitis due to the prolonged use of naratrip- retrieved from her pharmacist revealed the use of tan in the absence of cardiovascular risk factors. 12 tablets of naratriptan 2.5 mg every six weeks, with a maximum of 5.0 mg a day during the last CASE REPORT eight years. Recently, three days before and eight A 60-year-old Caucasian female with a past his- hours after the onset of her symptoms, 5.0 mg of tory of migraine-associated headache presented naratriptan had been used.

Address for correspondence: Hans M. WESTGEEST Manuscript received: 18.09.2008 Accepted: 08.07.2009 P.O. Box 7057 1007 MB Amsterdam, The Netherlands doi: 10.4318/tjg.2010.0047 Phone: + 31 20 444 44 44 E-mail: [email protected] Naratriptan induced ischemic colitis 43

Physical examination revealed a patient in mild (repeat) lower endoscopy was performed without distress due to abdominal discomfort. Her tempe- signs of ischemia. A new CT-scan was unremar- rature was 37.6°C and she remained hemodyna- kable and two months later her complaints had mically stable. Abdominal examination showed fully resolved. normal peristaltic sounds without murmurs and left lower quadrant tenderness without signs of lo- DISCUSSION cal peritonitis. The presence of rectal blood loss This case report demonstrates the occurrence of was found on digital rectal examination. histology-proven ischemic colitis in the absence of Laboratory findings including full blood count, major vascular obstruction, atrial fibrillation, blo- prothrombin time, electrolytes, creatinine, and li- od dyscrasia, or intermittent low flow state of the ver enzymes were normal. Stool and blood cultu- systemic circulation. Often, a specific etiology can res remained negative. On day one of admission, a not be identified. However, drug-induced alterati- colonoscopy was performed, revealing severe sub- ons of the mesenteric circulation resulting in isc- mucosal edema and mucosal ulceration of the des- hemic mucosal damage is an under-recognized cending colon extending to a sharp delineated seg- cause (8). ment of at least 15 cm in the sigmoid, consistent Naratriptan is known to be a selective 5-HT with the blood supply of the inferior mesenteric ar- 1B/1D agonist with minimal affinity to other 5-HT recep- tery. Due to an increased risk of perforation, the tors. It has a relative short elimination half-life procedure was prematurely terminated. Multiple (T1/ = 6 hours) and excellent renal clearance (9). random colonic biopsies demonstrated ulcerating 2 Serotonin-induced mesenteric vasoconstriction is mucosa with extravasation of erythrocytes, crypt mainly mediated through 5-HT receptors (10). atrophy and dilated vessels in the lamina propria 2A However, vasoconstriction is also mediated, albeit (Figure 1), compatible with ischemic colitis. in a less and variable extent, by 5-HT1B/1D recep- Combined abdominal computed tomography (CT- tors. This 5-HT1B/1D mediated response varies gre- scan) and angiography demonstrated circumferen- atly among patients (11). Sumatriptan, a triptan tial thickening of the descending colon without with similarity to naratriptan, exerts even more creeping fat or lymphadenopathy (Figure 2). The effect when mesenteric vasoconstriction is amplifi- arterial and venous blood supply was normal. ed by precontraction with various contractile subs- After discontinuation of naratriptan and intrave- tances (e.g. phenylephrine, histamine or potassi- nous rehydration, she recovered quickly and could um chloride) or by endogenous factors (12). The be discharged four days after admission. Due to Naranjo Adverse Drug Reactions Probability Sca- persistent abdominal complaints, an upper and le (NADRPS) is a tool used to determine the like-

Figure 1. Ulcerative epithelium and vasodilatation with extra- Figure 2. Left-sided colonic wall thickening (arrow) consistent vasation of erythrocytes and inflammation. with colitis. 44 WESTGEEST et al.

lihood that an adverse drug reaction is caused by tion and normal renal function in the absence of the implicated medication (13). Ten questions are any other risk factor. Despite the latency of eight answered and assigned a weighted score of +2 to - years, we suggest a direct causal relation by exclu- 2. Where there is insufficient data available, the sion of other causes, the disappearance of symp- particular question receives a 0. Based on this sco- toms and resolution of mucosal lesions after dis- re (<1 - >9), an assessment of the likelihood of cau- continuation of naratriptan, and a NADRPS of 8. sing an adverse drug reaction can be made. When Rechallenge with this drug was not performed du- applied in this case, a score of 8 indicates a pro- e to its severe adverse reaction. bable likelihood of naratriptan as the cause for isc- A proposed pathophysiological mechanism is the hemic colitis. agonistic effect of triptans on the mesenteric 5-

The frequency of ischemic colitis associated with HT1B/1D receptors leading to vasoconstriction, amp- naratriptan, according to the Netherlands Phar- lified by unknown endogenous conditions. macovigilance Centre, is rare (<1:1000). Although In conclusion, although ischemic colitis may occur rare, there have been reports of sumatriptan-asso- without an obvious precipitating event, the use of ciated ischemic colitis (14-16) and naratriptan-as- triptans can act as an etiological factor for ische- sociated ischemic colitis with oral contraceptive mic complications including ischemic colitis. With use (17) or other co-medication including quetiapi- the increasing use of triptans prescribed by diffe- ne and topiramate (18). No reports of ischemic co- rent healthcare providers, awareness of this po- litis associated with the other triptans (zolmitrip- tential severe adverse event is needed. tan, rizatriptan, almotriptan, frovatriptan and Acknowledgement: We would like to thank Dr. eletriptan) are available. G.D. Zielinski (Department of Clinical Pathology, As far as we know, this is the first report of narat- VU Medical Center, Amsterdam) for providing riptan-induced ischemic colitis without co-medica- histopathologic pictures.

REFERENCES 1. Hall GC, Brown MM, Mo J, MacRae KD. Triptans in mig- 11. Gul H, Yildiz O, Simsek A, et al. Pharmacologic characteri- raine: the risks of stroke, cardiovascular disease, and death zation of contractile serotonergic receptors in human isola- in practice. Neurology 2004; 62: 563-8. ted mesenteric artery. J Cardiovasc Pharmacol 2003; 41: 2. Jamieson DG. The safety of triptans in the treatment of pa- 307-15. tients with migraine. Am J Med 2002; 112: 135-40. 12. Gul H, Yildiz O. Amplification of sumatriptan-induced con- 3. Charles JA, Pullicino PM, Stoopack PM, Shroff Y. Ischemic tractions with phenylephrine, histamine and KCl in the colitis associated with naratriptan and oral contraceptive isolated human mesenteric artery: in-vitro evidence for su- use. Headache 2005; 45: 386-9. matriptan-induced mesenteric ischaemia. Naunyn Schmi- edebergs Arch Pharmacol 2002; 366: 254-61. 4. Knudsen JF, Friedman B, Chen M, Goldwasser JE. Ische- mic colitis and sumatriptan use. Arch Intern Med 1998; 13. Naranjo CA, Busto U, Sellers EM, et al. A method for esti- 158: 1946-8. mating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239-45. 5. Liu JJ, Ardolf JC. Sumatriptan-associated mesenteric isc- hemia. Ann Intern Med 2000; 132: 597. 14. Knudsen JF, Friedman B, Chen M, Goldwasser JE. Ische- mic colitis and sumatriptan use. Arch Intern Med 1998; 6. Schwartz DC, Smith DJ. Colonic ischemia associated with 158: 1946-8. naratriptan use. J Clin Gastroenterol 2004; 38: 790-2. 15. Liu JJ, Ardolf JC. Sumatriptan-associated mesenteric isc- 7. Naik M, Potluri R, Almasri E, Arnold GL. Sumatriptan-as- hemia. Ann Intern Med 2000; 132: 597. sociated ischemic colitis. Dig Dis Sci 2002; 47: 2015-6. 16. Naik M, Potluri R, Almasri E, Arnold GL. Sumatriptan-as- 8. Hass DJ, Kozuch P, Brandt LJ. Pharmacologically media- sociated ischemic colitis. Dig Dis Sci 2002; 47: 2015-6. ted colon ischemia. Am J Gastroenterol 2007; 102: 1765-80. 17. Charles JA, Pullicino PM, Stoopack PM, Shroff Y. Ischemic 9. Jamieson DG. The safety of triptans in the treatment of pa- colitis associated with naratriptan and oral contraceptive tients with migraine. Am J Med 2002; 112: 135-40. use. Headache 2005; 45: 386-9. 10. Wallerstedt SM, Tornebrandt K, Bodelsson M. Characte- 18. Schwartz DC, Smith DJ. Colonic ischemia associated with ristics of contractile 5-HT receptors in isolated human naratriptan use. J Clin Gastroenterol 2004; 38: 790-2. omental arteries: presence of 5-HT1 and 5-HT2 receptors. Pharmacol Toxicol 1996; 78: 50-4.