Failed prevention of benzodiazepine withdrawal symptoms due to spontaneous expulsion of diazepam suppository administrated via stoma: A case report

Benzodiazepine receptor agonists (BZRAs) may cause withdrawal symptoms, including tremor, sweating, anxiety, and seizures, upon discontinuation.1, 2 When a patient with long-term BZRA use is unable to take drugs orally during the perioperative period, BZRAs may be administered by a non-oral route to prevent withdrawal. In addition to transvenous administration, enteral rectal administration is an option. We herein report a cautionary case of failed prevention of BZRA withdrawal symptoms by trans-stomal administration of diazepam suppositories. This case involved a woman who had developed ulcerative colitis at the age of 24 years. She developed insomnia at the age of approximately 30 years and was prescribed flunitrazepam. The dose of flunitrazepam was gradually increased, and 4 mg/day was prescribed for a long period of time. At the age of 47 years, laparoscopic subtotal colorectal resection was performed in our hospital for treatment of toxic megacolon caused by ulcerative colitis. The ascending to descending colon was resected, and an ileal stoma was constructed. The patient was referred to the department of psychiatry because of palpitations, sweating, and anxiety that appeared after postoperative discontinuation of the medication. She was diagnosed with BZRA withdrawal symptoms. A 10-mg diazepam suppository was administered via stoma instead of transvenous administration because of concerns regarding the risk of respiratory depression secondary to intravenous diazepam. The patient's symptoms improved shortly after starting diazepam. When she was able to resume oral medication, flunitrazepam was restarted and reduced to 1.5 mg/day, and she was discharged. After discharge, zolpidem was added at 5 mg/day by her primary care physician. Five months later, the patient was readmitted to our hospital for residual rectal resection and ileocecal anastomosis. She was referred again to our department because flunitrazepam 1.5 mg/day and zolpidem 5 mg/day required discontinuation in the perioperative period. In the perioperative period, because the withdrawal symptoms could be treated with trans-stomal administration of diazepam suppositories at the first admission, we replaced the oral BZRA with diazepam suppositories. On the day of surgery, a 6-mg diazepam suppository was administered via stoma before bedtime. However, the tablet was spontaneously expelled from the stoma. The day after surgery, the patient developed tremor with marked sweating. She complained of agitation and restlessness. On examination, her vital signs were as follows: blood pressure, 104/78 mmHg; heart rate, 109 beats/minute; respiratory rate, 20 breaths/minute; and body temperature, 36.9°C. Her SpO2 was 98% on room air. She had no cranial or pyramidal tract abnormalities and showed no evidence of paralysis. Her signs of acute agitation, generalized sweating, and tremor 39 h after discontinuing BZRA therapy were consistent with BZRA withdrawal syndrome. She received 5 mg intravenous diazepam, and the symptoms promptly disappeared. The same night, she received 10 mg of intravenous diazepam. The following day, she was able to take oral medication, and the flunitrazepam (1.5 mg/day) and zolpidem (5 mg/day) were resumed. No BZRA withdrawal symptoms were subsequently observed. Electroencephalography the following day showed no epileptic discharges. She was discharged after 10 days of hospitalization. The patient had a history of BZRA withdrawal symptoms, and BZRAs were administered via stoma to prevent BZRA withdrawal. However, the suppository was spontaneously expelled, resulting in failure to prevent withdrawal symptoms. Suppository administration via stoma may result in spontaneous expulsion due to the absence of sphincter control.3 Therefore, in patients with a high risk of withdrawal, as in this case, an administration route more reliable than the stoma should be chosen. If suppository administration via stoma is selected, the following measures are recommended to ensure that the inserted suppository dissolves: digitally examining the stoma to determine the presence of hard stool and holding the suppository by placing gauze or a hand over the stoma for approximately 20 min after administration.3 Suppository administration via the stoma itself is not recommended because of the risk of mucosal injury and the uncertain safety and efficacy.4 The pharmacokinetics of suppository administration from the stoma are not constant across drugs. The bioavailability of morphine suppositories has been shown to be increased by administration from the colonic stoma.5 By contrast, the bioavailability of diclofenac suppositories and carbamazepine suppositories has been shown to decrease.6, 7 With regard to the diazepam suppository used in the present case, there are no reports on the pharmacokinetics of trans-stomal administration. Suppository administration via stoma should be selected after a case-specific discussion of whether it is preferred over other routes of administration. In conclusion, administration of benzodiazepine suppositories via stoma should be avoided to ensure prevention of BZRA withdrawal symptoms in patients at high risk of BZRA withdrawal. Yuto Yamada and Misako Torigoe contributed to the patient's treatment. Yuto Yamada and Masaki Fujiwara wrote the first draft. All authors contributed to the discussion of the patient's symptoms and approved the final version of the manuscript. The authors thank Angela Morben, DVM, ELS, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. Yuto Yamada reports personal fees from Meiji, Sumitomo Pharma, and Lundbeck outside the submitted work. Masaki Fujiwara reports personal fees from Mochida outside the submitted work. Manabu Takaki reports personal fees from Daiichi Sankyo, Takeda, Tsumura, Otsuka, and Sumitomo Pharma outside the submitted work. Manabu Takaki is an Editorial Board member of Psychiatry and Clinical Neurosciences Reports and a co-author of this article. To minimize bias, he was excluded from all editorial decision-making. The remaining authors declare no conflicts of interest. Written informed consent was obtained from the patient to publish the case report. This is a case report which does not require ethics committee approval. Written informed consent was obtained from the patient to publish the case report. N/A. N/A.