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PMJ27810.1177/0269216312472383Palliative MedicineHawley
PALLIATIVE MEDICINE
Case Report
Case report of severe bradycardia due to transdermal fentanyl
Palliative Medicine 27(8) 793–795 © The Author(s) 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269216312472383 pmj.sagepub.com
Pippa Hawley Pain and Symptom Management/Palliative Care Program, BC Cancer Agency, Vancouver, BC, Canada
Abstract Background: This case report describes a patient who developed severe bradycardia due to transdermal fentanyl. There have been no prior case reports of this occurring in palliative care, but the frequency of association of fentanyl with bradycardia in the anesthesia setting suggests it may be more common than realized. Palliative care settings often have a policy of not routinely checking vital signs, and symptoms of bradycardia could be misinterpreted as the dying process. Case presentation: A patient with recurrent ovarian cancer was admitted with nausea and abdominal pain due to bowel obstruction and fever from a urinary tract infection. A switch from injectable hydromorphone to transdermal fentanyl resulted in symptomatic severe bradycardia within 36 h, without any other signs of opioid toxicity and with good analgesic effect. Case management: The fentanyl patch was removed. Atropine was not required. Case outcome: The patient made an uneventful recovery. Transdermal buprenorphine was subsequently used satisfactorily for longterm background pain control, with additional hydromorphone when needed. Conclusions: The delayed absorption of fentanyl via the transdermal route makes early identification of fentanyl-induced bradycardia key to prompt reversal. Patients with resting or relative bradycardia may be at higher than average risk.
Keywords Palliative care, side effects, bradycardia, fentanyl
Background
Case presentation
This case report describes a patient who developed severe bradycardia within 36 h of application of a fentanyl patch. Palliative care settings usually have a policy of not routinely checking vital signs, and symptoms of bradycardia could be misinterpreted as the dying process. Though there has been one case report of bradycardia due to methadone in which fentanyl was subsequently successfully used, there have been no case reports of bradycardia due to transdermal fentanyl in palliative care. The frequency of association of fentanyl with bradycardia in the anesthesia setting, however, suggests that it may be much more common than realized. This case report is presented to raise awareness of a potentially fatal side effect of a drug that is very commonly used in unmonitored settings. It raises the need for prospective study of transdermal fentanyl in order to understand the risk of bradycardia occurring in the palliative care setting and to be able to identify those patients at highest risk.
A 59-year-old woman was admitted to the Vancouver Cancer Centre’s inpatient acute oncology ward with a history of escalating abdominal pain, nausea, and urinary retention. Ten months earlier she had been diagnosed with a stage 2c grade 2 endometrioid carcinoma of the ovary. Her initial treatment had been total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed by total abdominal and pelvic radiotherapy and three cycles of taxol and carboplatin chemotherapy. A month prior to admission, she developed bowel obstruction and was found at laparotomy to have peritoneal carcinomatosis. She had a diverting colostomy and went on to receive carboplatin and liposomal doxorubicin (Caelyx) chemotherapy, last administered 8 days prior to admission. She had no other significant past medical history and did not smoke or drink alcohol. She had a family history of breast cancer (mother, at the age of 48 years) and type
Corresponding author: Pippa Hawley, Pain and Symptom Management/Palliative Care Program, BC Cancer Agency, Vancouver Centre, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada. Email:
[email protected]
794 2 diabetes (sibling). She had menopause at 52 years. She had no family history of cardiac disease or sudden death. The day after admission, she developed a fever of 38°C, and because of the associated urinary symptoms was assumed to have a urinary tract infection. She was started on ciprofloxacin. Her urine cultures subsequently grew Escherichia coli, and the fever resolved within 12 h of starting the ciprofloxacin. Prior to admission, the patient had been taking oral oxycodone and acetaminophen on an as-needed basis for pain. After admission, the oxycodone was switched to 2 mg subcutaneous hydromorphone every 2 h regularly, plus 2–4 mg i-v as needed. She also received dexamethasone (2 mg i-v twice a day), antiemetics including oral prochlorperazine followed by i-v and oral metoclopramide, then oral nabilone, and then ondansetron 8 mg i-v up to four times a day, because of ongoing nausea. At the time of admission, her pulse rate was 87/min and blood pressure was 105/65 mm. Over the next 4 days, her pulse ranged between 65 and 90/min, with systolic blood pressure reaching a minimum of 95 and a maximum of 110. An electrocardiogram (ECG) done preoperatively at the time of her cancer diagnosis had shown a heart rate of 69/minute. On the fourth day of admission, because of persistent nausea and poor pain control, she was started on a fentanyl patch at 75 µg/h. This was at the upper end of the range of the equianalgesic dose of hydromorphone she had been receiving. Approximately 36 h after application of the fentanyl patch, the patient’s pulse was noted on routine vital sign checking to have dropped to 55 from 72 the previous evening. Her temperature had also dropped overnight from 37.2°C to 36.0°C. After 2 h, her pulse dropped further to 42 beats/min. This was not associated with hypoxia or any symptoms. Over the next hour, her pulse, however, dropped to 34 beats/min and she experienced drowsiness, chest pain, and headache. An ECG showed sinus rhythm at 37 beats/min.
Case management The fentanyl patch was removed, and her opioid was switched back to subcutaneous hydromorphone.
Case outcome Within 10 h, her symptoms gradually resolved, and her pulse went up to 56/min. Her temperature returned to normal in parallel with the pulse rate. On further questioning, we found that her pulse when healthy had always been slow, usually in the 50s and even as low as the 40s at times. With hindsight, her admission pulse rate of 87 beats/min represented a relative tachycardia.
Palliative Medicine 27(8) She was discharged from hospital, and despite intermittent episodes of bowel obstruction, enterocutaneous fistula development, and bilateral nephrostomy placement, her pain was well managed with transdermal buprenorphine supplemented by oral or subcutaneous hydromorphone when needed. Bradycardia did not recur. She died comfortably at home 8 months later.
Discussion The potential for bradycardia from transdermal fentanyl has not been reported in the palliative care literature, despite being a relatively common side effect of intravenous fentanyl when used in anesthesia. A 2007 report of 92 gynecological surgical patients receiving fentanyl, halothane, and vecuronium for major abdominal surgery reported that 18% experienced bradycardia.1 A 2002 report from Thailand reported bradycardia in 10 of 60 patients (16.6%) having surgical repair of congenital cardiac defects.2 Though the product monograph for transdermal fentanyl lists dizziness as occurring in 3%–10% of patients, both tachycardia and bradycardia are listed as occurring in less than 1% of patients. An extensive 2009 review of fentanyl use in cancer pain3 did not even mention bradycardia as a possible side effect. Bradycardia has also been reported with other opioids in anesthesia.4,5 The mechanism for opioid-induced bradycardia is unclear, but based on animal experiments from the 1970s, it is believed that fentanyl causes bradycardia via µ-opioid receptors suppressing GABAergic neurotransmission to cardiac vagal efferent neurons from the nucleus ambiguus.6 In 2010, a myeloma patient on thalidomide was reported to have symptomatic bradycardia 3 days after starting methadone for pain.6 Interestingly, this patient tolerated high doses of fentanyl well. The mechanism for induction of bradycardia may therefore be different for different opioids. It is not known which opioids have the lowest risk, nor if there is a threshold for heart rate which should be considered a risk factor sufficient to require special attention from care providers. Cancer patients being treated outside hospital experience many side effects from treatment, very few of which are ever reported, and it is likely that the number of side effects formally documented is a small fraction of those actually experienced. There are no reported prospective studies of the incidence of bradycardia due to transdermal fentanyl. Other drugs may cause bradycardia, either alone or in combination with others. Liposomal doxorubicin has been reported to cause bradycardia in the immediate postadministration setting, but this patient had received the drug more than a week prior to the bradycardic episode. Similarly, carboplatin has only rarely been associated with bradycardia; this more usually being ascribed to the paclitaxel with
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Hawley which it is frequently combined, but which this patient had not received.7 Serotonin antagonists have been reported to cause mild bradycardia;8 however, ondansetron was continued with no change in dose throughout the patient’s recovery from the bradycardic episode. The temporal association between the onset of bradycardia with the known rate of rise of blood level following application of the fentanyl patch and subsequent recovery at a correspondingly appropriate rate following patch removal is most consistent with fentanyl being the culprit. Had this patient not been in a hospital setting with routine vital sign assessment, the bradycardia could have gone undiagnosed and may have caused premature death. The use of transdermal fentanyl in palliative care is very widespread, often in patients who are not having their vital signs routinely assessed. Chest pain may be misinterpreted as angina, leading to a vasodilator being administered, or as cancer pain, leading to additional doses of opioids, both of which could accelerate deterioration in peripheral perfusion. Prospective study is required to establish the true incidence of bradycardia in a large representative sample of patients. Particular attention should be paid to identifying patients who may be at higher than average risk, by documenting resting heart rate pretreatment and concurrent medications with potential to increase the risk of bradycardia such as ondansetron.
Conclusion Prescribers should be vigilant to the possibility of symptomatic bradycardia occurring within the first 2 days of transdermal fentanyl use. Patients who have a resting bradycardia, or a slower pulse than expected given their circumstances, should be watched particularly carefully. Future research on opioid rotation should include reporting on pre- and postswitch vital signs in order to assess the frequency with which potentially symptomatic bradycardia occurs and to identify any other risk factors for bradycardia.
Acknowledgements The patient and her next of kin gave permission for this report to be published. The author would like to thank BCCA pharmacist Victoria Kletas for her assistance in managing the patient.
Declaration of conflicting interests The author reports no conflict of interest.
Funding The author received the 2010 Gordon Dunn Pioneer Award from the Prostate Cancer Foundation of BC. This salary support award facilitated the preparation of this report.
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