- Email: [email protected]
A Cautionary Tale of Oral Naloxone
Vol. 47 No. 2 February 2014
Journal of Pain and Symptom Management
e1
Letters
A Cautionary Tale of Oral Naloxone To the Editor: Constipation is the third most common symptom in palliative medicine, with prevalence ranging from 32% to 87%.1 Palliative care patients may have many risk factors for constipation, including the use of opioid analgesics. Opioids slow bowel transit time by acting on mu receptors in the gut. Newer treatments for opioid-induced constipation (OIC), such as prolonged-release oxycodone/naloxone (OXN) and methylnaltrexone, have focused on blocking this action on mu receptors to directly relieve OIC. OXN has been shown to improve bowel function without compromising analgesic efficacy.2 It is a fixed combination preparation, with prolonged-release oxycodone providing systemic analgesia, whereas naloxone improves gut motility by antagonizing mu receptors in the gut. Because of extensive first-pass metabolism, oral naloxone is reported to have less than 3% bioavailability, allowing antagonism of gastrointestinal, but not central, opioid receptors, thus allowing adequate analgesia to be maintained. The case presented here suggests that naloxone bioavailability in OXN may be increased in some patients.
was 10/15; she had pinpoint pupils and displayed myoclonic jerks. Respiratory rate was four per minute, and oxygen saturation was 77% on air. A diagnosis of opioid toxicity was made. She was treated with intramuscular naloxone and her GCS improved to 14. The history subsequently gathered from the patient and a relative revealed she had run out of OXN tablets and had used the equivalent opioid dose of OXY. The following day, she was discharged and given instructions to reduce OXN to 40/20 BD. Unfortunately, the hospital pharmacy was unable to dispense this drug and on return home, the patient took her OXY dose equivalent that evening and again the following morning. The day after discharge, she once again presented to hospital with evidence of severe opioid toxicity. Her GCS was 10/15, respiratory rate was six per minute, and pupils were pinpoint. She again improved after treatment with intramuscular naloxone. Her liver function tests were found to be significantly worse than they had been three weeks previously (Table 1). The patient was discharged home with OXN 40/20 twice a day and presented 12 hours later with poor pain control; she was subsequently transferred to the hospice for ongoing management. OXN was gradually reduced and replaced with OXY. On discharge from hospice three weeks later, she had been established on a greatly reduced dose of OXY at 20 mg twice a day.
Case A 65-year-old female with a diagnosis of breast cancer and liver metastases had been treated for cancer-related pain and OIC with OXN for 21 months and was on a stable dose of OXN 80/40 mg in the morning and OXN 40/20 mg plus 40 mg prolonged-release oxycodone (OXY) at night. The patient presented to her local hospital as an emergency with progressive drowsiness. On arrival, her Glasgow Coma Scale (GCS) score Ó 2014 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
Comment This patient appears to have had chronic systemic antagonism of opioid receptors by oral naloxone, resulting in profound opioid toxicity when equivalent doses of OXY were administered in the absence of naloxone. We concluded that the abnormal liver function found in this patient reduced enterohepatic first-pass metabolism of naloxone, increasing bioavailability. 0885-3924/$ - see front matter
e2
Letters
Table 1 Results of Patient’s Liver Function Tests
ALT ALP Bilirubin GGT Albumin
3 Weeks Before Admission
On Admission
One Week Later
20 193 8 197 47
117 442 6 820 42
206 659 30 1157 39
ALT ¼ alanine aminotransferase (normal range 5-55 U/L); ALP ¼ alkaline phosphatase (normal range 30-130 U/L); bilirubin normal range 0-21 umol/L; GGT ¼ gamma glutamyl transferase (normal range 0-55 U/L); albumin normal range 35-50 g/L.
We found no other reported cases of opioid toxicity related to switching from OXN to OXY. However, product literature does state that OXN is contraindicated in patients with moderate-to-severe hepatic disease and that increased plasma levels of oxycodone, but particularly naloxone, were found in liver impairment. Although clinical trials have shown OXN to be well tolerated in cancer patients compared with OXY,3 a case of poor pain control in a patient receiving OXN who improved after switching to an equivalent dose of OXY has been published in the literature. This patient had normal liver function.4 Furthermore, a case of acute opioid withdrawal in a patient who was switched from OXY to an equivalent dose of OXN, which then resolved after conversion back to OXY, has recently been published in this journal.5 This patient had known portal vein thrombosis, and so, like our patient, may have had reduced first-pass metabolism of oral naloxone. The case illustrated above suggests that caution should be exercised when using OXN in patients with liver dysfunction. This case, in addition to two others in the literature, shows that OXY and OXN should not be used interchangeably. Eilidh Burns, MBChB Kerry McWilliams, MBChB Catriona Ross, MBChB St. Andrew’s Hospice Airdrie, Lanarkshire United Kingdom E-mail: [email protected] http://dx.doi.org/10.1016/j.jpainsymman.2013.10.013
References 1. Larkin PJ, Sykes NP, Centeno C, et al. European Consensus Group on Constipation in Palliative Care. The management of constipation in palliative care:
Vol. 47 No. 2 February 2014
clinical practice recommendations. Palliat Med 2008;22:796e807. 2. Meissner W, Leyendecker P, Mueller-Lissner S, et al. A randomised controlled trial with prolongedrelease oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain 2009;13:56e64. 3. Ahmedzai SH, Nauck F, Bar-Sela G, et al. A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain. Palliat Med 2011; 26:50e60. 4. Mercadante S, Ferrera P, Adile C. High doses of oxycodone-naloxone combination may provide poor analgesia. Support Care Cancer 2011;19: 1471e1472. 5. Kang JH, Lee GW, Shin SH, Bruera E. Opioid withdrawal syndrome after treatment with low-dose extended-release oxycodone and naloxone in a gastric cancer patient with portal vein thrombosis. J Pain Symptom Manage 2013;46:15e16.
Hepatic Portal Venous Gas: A Rare Complication of Malignant Bowel Obstruction During the Administration of Octreotide To the Editor: Octreotide is a synthetic analogue of somatostatin and is frequently used in palliative settings for the management of malignant bowel obstruction (MBO) that is not cured by surgical procedures.1 In the pathophysiology of MBO, the accumulation of intestinal secretions and ineffective peristaltic movement become a vicious cycle that causes colicky abdominal pain, nausea, and vomiting. Octreotide decreases the symptom burden of patients with MBO through reducing intestinal secretion and motility. Hepatic portal venous gas is a rare radiographic finding that is associated with bowel necrosis or mesenteric ischemia. Since the first report of this condition by Wolfe and Evans in 1955,2 there have been increasing reports of cases recently because of the widespread use of sensitive modalities such as computed tomography (CT).3e5 However, no case of hepatic portal venous gas has been reported that occurred concurrently with MBO being treated with octreotide.
Journal of Pain and Symptom Management
e1
Letters
A Cautionary Tale of Oral Naloxone To the Editor: Constipation is the third most common symptom in palliative medicine, with prevalence ranging from 32% to 87%.1 Palliative care patients may have many risk factors for constipation, including the use of opioid analgesics. Opioids slow bowel transit time by acting on mu receptors in the gut. Newer treatments for opioid-induced constipation (OIC), such as prolonged-release oxycodone/naloxone (OXN) and methylnaltrexone, have focused on blocking this action on mu receptors to directly relieve OIC. OXN has been shown to improve bowel function without compromising analgesic efficacy.2 It is a fixed combination preparation, with prolonged-release oxycodone providing systemic analgesia, whereas naloxone improves gut motility by antagonizing mu receptors in the gut. Because of extensive first-pass metabolism, oral naloxone is reported to have less than 3% bioavailability, allowing antagonism of gastrointestinal, but not central, opioid receptors, thus allowing adequate analgesia to be maintained. The case presented here suggests that naloxone bioavailability in OXN may be increased in some patients.
was 10/15; she had pinpoint pupils and displayed myoclonic jerks. Respiratory rate was four per minute, and oxygen saturation was 77% on air. A diagnosis of opioid toxicity was made. She was treated with intramuscular naloxone and her GCS improved to 14. The history subsequently gathered from the patient and a relative revealed she had run out of OXN tablets and had used the equivalent opioid dose of OXY. The following day, she was discharged and given instructions to reduce OXN to 40/20 BD. Unfortunately, the hospital pharmacy was unable to dispense this drug and on return home, the patient took her OXY dose equivalent that evening and again the following morning. The day after discharge, she once again presented to hospital with evidence of severe opioid toxicity. Her GCS was 10/15, respiratory rate was six per minute, and pupils were pinpoint. She again improved after treatment with intramuscular naloxone. Her liver function tests were found to be significantly worse than they had been three weeks previously (Table 1). The patient was discharged home with OXN 40/20 twice a day and presented 12 hours later with poor pain control; she was subsequently transferred to the hospice for ongoing management. OXN was gradually reduced and replaced with OXY. On discharge from hospice three weeks later, she had been established on a greatly reduced dose of OXY at 20 mg twice a day.
Case A 65-year-old female with a diagnosis of breast cancer and liver metastases had been treated for cancer-related pain and OIC with OXN for 21 months and was on a stable dose of OXN 80/40 mg in the morning and OXN 40/20 mg plus 40 mg prolonged-release oxycodone (OXY) at night. The patient presented to her local hospital as an emergency with progressive drowsiness. On arrival, her Glasgow Coma Scale (GCS) score Ó 2014 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
Comment This patient appears to have had chronic systemic antagonism of opioid receptors by oral naloxone, resulting in profound opioid toxicity when equivalent doses of OXY were administered in the absence of naloxone. We concluded that the abnormal liver function found in this patient reduced enterohepatic first-pass metabolism of naloxone, increasing bioavailability. 0885-3924/$ - see front matter
e2
Letters
Table 1 Results of Patient’s Liver Function Tests
ALT ALP Bilirubin GGT Albumin
3 Weeks Before Admission
On Admission
One Week Later
20 193 8 197 47
117 442 6 820 42
206 659 30 1157 39
ALT ¼ alanine aminotransferase (normal range 5-55 U/L); ALP ¼ alkaline phosphatase (normal range 30-130 U/L); bilirubin normal range 0-21 umol/L; GGT ¼ gamma glutamyl transferase (normal range 0-55 U/L); albumin normal range 35-50 g/L.
We found no other reported cases of opioid toxicity related to switching from OXN to OXY. However, product literature does state that OXN is contraindicated in patients with moderate-to-severe hepatic disease and that increased plasma levels of oxycodone, but particularly naloxone, were found in liver impairment. Although clinical trials have shown OXN to be well tolerated in cancer patients compared with OXY,3 a case of poor pain control in a patient receiving OXN who improved after switching to an equivalent dose of OXY has been published in the literature. This patient had normal liver function.4 Furthermore, a case of acute opioid withdrawal in a patient who was switched from OXY to an equivalent dose of OXN, which then resolved after conversion back to OXY, has recently been published in this journal.5 This patient had known portal vein thrombosis, and so, like our patient, may have had reduced first-pass metabolism of oral naloxone. The case illustrated above suggests that caution should be exercised when using OXN in patients with liver dysfunction. This case, in addition to two others in the literature, shows that OXY and OXN should not be used interchangeably. Eilidh Burns, MBChB Kerry McWilliams, MBChB Catriona Ross, MBChB St. Andrew’s Hospice Airdrie, Lanarkshire United Kingdom E-mail: [email protected] http://dx.doi.org/10.1016/j.jpainsymman.2013.10.013
References 1. Larkin PJ, Sykes NP, Centeno C, et al. European Consensus Group on Constipation in Palliative Care. The management of constipation in palliative care:
Vol. 47 No. 2 February 2014
clinical practice recommendations. Palliat Med 2008;22:796e807. 2. Meissner W, Leyendecker P, Mueller-Lissner S, et al. A randomised controlled trial with prolongedrelease oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain 2009;13:56e64. 3. Ahmedzai SH, Nauck F, Bar-Sela G, et al. A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain. Palliat Med 2011; 26:50e60. 4. Mercadante S, Ferrera P, Adile C. High doses of oxycodone-naloxone combination may provide poor analgesia. Support Care Cancer 2011;19: 1471e1472. 5. Kang JH, Lee GW, Shin SH, Bruera E. Opioid withdrawal syndrome after treatment with low-dose extended-release oxycodone and naloxone in a gastric cancer patient with portal vein thrombosis. J Pain Symptom Manage 2013;46:15e16.
Hepatic Portal Venous Gas: A Rare Complication of Malignant Bowel Obstruction During the Administration of Octreotide To the Editor: Octreotide is a synthetic analogue of somatostatin and is frequently used in palliative settings for the management of malignant bowel obstruction (MBO) that is not cured by surgical procedures.1 In the pathophysiology of MBO, the accumulation of intestinal secretions and ineffective peristaltic movement become a vicious cycle that causes colicky abdominal pain, nausea, and vomiting. Octreotide decreases the symptom burden of patients with MBO through reducing intestinal secretion and motility. Hepatic portal venous gas is a rare radiographic finding that is associated with bowel necrosis or mesenteric ischemia. Since the first report of this condition by Wolfe and Evans in 1955,2 there have been increasing reports of cases recently because of the widespread use of sensitive modalities such as computed tomography (CT).3e5 However, no case of hepatic portal venous gas has been reported that occurred concurrently with MBO being treated with octreotide.