Prolonged central apnoea after intravenous morphine administration in a 12‐year‐old male with a UGT1A1 loss‐of‐function polymorphism

Abstract

Adverse event

Repeated and prolonged episodes of central apnoea and hypoxia after receiving intravenous morphine for analgesia and ketamine for sedation.

Drug implicated

Intravenous morphine sulfate.

The patient

Previously healthy 12‐year‐old male with no history of sleep apnoea who presented with distal tibia and fibula fracture.

Evidence that links drug to event

Pharmacogenomic testing revealed that the patient was homozygous for the T allele at the rs887829 SNP in UGT1A1, an enzyme involved in the metabolism of morphine. This polymorphism is a loss‐of‐function variant, leading to impaired metabolism of morphine.

Mechanism

Morphine is metabolized by UDP‐glucuronosyltransferase (UGT)‐2B7 and UGT1A1 to form its major metabolites morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G). Our patient was a poor metabolizer through UGT1A1, likely leading to increased respiratory depression as morphine has greater respiratory depressant effects compared to its metabolites.

Implications

When appropriate, physicians should enquire about prior receipt of opioids, in both the patient and family, to be better prepared for potential adverse reactions. In the patient with excessive sedation or respiratory depression to standard doses of morphine, genetic testing may be warranted, especially if there is a family or past history that supports a metabolic defect in morphine metabolism and/or excretion.

Introduction

We present the case of a healthy 12‐year‐old male who developed prolonged and repeated intervals of central apnoea after receiving analgesia with morphine at a referring institution and subsequent procedural sedation with ketamine at our facility for fracture reduction. Pharmacogenomic testing revealed a defect in UDP‐glucuronosyltransferase (UGT)‐1A1, an enzyme involved in morphine metabolism. Prior studies describing morphine‐associated apnoea in patients with UGT1A1 mutations are lacking, and this report highlights the potential clinical effects of impaired morphine metabolism. Per our institution, the review of records for three or less patients to report as a case study or case series is not considered human subject research under the jurisdiction of the Institutional Review Board (IRB) and may proceed without IRB review. Written informed consent was obtained from the patient's family prior to publication. All drug/molecular target nomenclature conforms to the IUPHAR/BPS Guide to Pharmacology nomenclature classification 1, 2, 3, 4.

Case Report

A previously healthy 12‐year‐old Caucasian male weighing 45 kg with no known drug allergies presented to an emergency department after a traumatic injury to his right lower extremity. Imaging revealed a distal tibia and fibula fracture. He received 650 mg of enteral acetaminophen, 4 mg of intravenous ondansetron and 2 mg of intravenous morphine sulfate and was transferred to our institution. No additional medications were administered during transport.

He presented with normal vital signs: temperature 37.6°C, heart rate 88 beats per minute, blood pressure 129/55 mmHg, respiratory rate 20 breaths per minute, 100% SpO2 on room air. His physical exam was unremarkable except for the affected extremity which was tender to palpation, swollen and ecchymotic. Pupils were 3 mm and reactive. He was able to answer questions appropriately. He was evaluated by orthopaedics, and the fracture was subsequently reduced and casted. For the reduction, he received 60 mg (1.33 mg kg⁻¹) IV ketamine hydrochloride as a single bolus (+160 min from morphine administration) over 30 s. Vital signs, including continuous pulse oximetry and capnography, were monitored throughout the sedation. Patient was placed on 2 l of oxygen via nasal cannula prior to administration of ketamine and remained on oxygen throughout the sedation. During the sedation, the patient's oxygenation and ventilation remained normal (SpO2 100%, end tidal CO₂ 37–47 mmHg, respiratory rate 10–23 breaths per minute). At the completion of the procedure, the patient was answering questions appropriately with a normal mental status.

Approximately 10 min after the completion of the procedure (+202 min from administration of morphine, +42 min from administration of ketamine), the patient had a period of central apnoea that lasted 20–30 s with desaturation to SpO2 89% that resolved with tactile stimulation. Leading up to this event, the patient had become somnolent and then became progressively hypopneic and eventually apnoeic. After stimulation, the patient was able to answer questions appropriately but fell asleep quickly. Thirty‐one minutes after the initial apnoeic event (+233 min from morphine administration, +73 min from administration of ketamine), the patient had a 45‐s period of central apnoea (no chest wall movement, flatline CO₂ waveform) during which he desaturated to 61%, again resolving with tactile stimulation. He continued to have repeated episodes of central apnoea with desaturations and was admitted to the ICU for further monitoring. Because the events resolved with stimulation and patient's mental status was appropriate when awake, naloxone administration was deferred.

On HD #1, patient continued to have repeated periods of apnoea with desaturations that required tactile stimulation. The frequency of the events began to wane on HD #2, and he was transferred to the pulmonary service on HD #4. On HD #5/6, the patient had an overnight sleep study to rule out underlying primary central sleep disorder, which was normal. He was discharged home on HD #6.

The family stated that the patient had no prior history of sleep apnoea and had not previously received opioids. The mother reported that she received morphine after her caesarean section and, due to prolonged sedation, required naloxone >24 h after morphine administration. The pharmacogenomics service was consulted to determine whether the patient had a defect in morphine metabolism and/or excretion. A Drug‐Metabolizing Enzymes and Transporters (DMET™) Plus microarray assay was performed to identify the presence of variants in 230 genes involved in drug metabolism and response including two genes involved in the metabolism of morphine, UGT1A1 and UGT2B7 (Supporting Information Data S1). Genotypes were defined as the pair of inherited nucleotides present at a specific single nucleotide polymorphisms (SNPs) within the genes. SNPs are identified by unique “rs” ID numbers. Our patient's genotype for UGT1A1 at rs887829 was TT, and for UGT2B7, the genotype at rs7439366 was CC 5, 6. A urine drug immunoassay screen was positive for morphine (cut‐off 300 ng ml⁻¹) with a confirmatory level of 309 ng ml⁻¹ via quantitative liquid chromatography–tandem mass spectrometry, as well as amphetamine (patient was prescribed amphetamine/dextroamphetamine for ADHD). This sample was collected almost 9 h (525 min) after administration of morphine and analysed immediately after collection.

Discussion

We present a case of a 12‐year‐old male who developed prolonged central apnoea, lasting more than 24 h, after receiving a single dose of intravenous morphine for analgesia and a single dose of intravenous ketamine for procedural sedation. His course was notable for recurrent periods of central apnoea and desaturations requiring tactile stimulation. These episodes waned with time, making a drug effect more probable. Given the maternal history of prolonged effects from morphine, a genetic defect in morphine metabolism was suspected and subsequently confirmed by pharmacogenomics testing.

Morphine is primarily metabolized in the liver by UDP‐glucuronosyltransferase (UGT)‐2B7 to form its major metabolites morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) 7. This process of glucuronidation serves to facilitate the renal excretion of morphine and its metabolites by increasing the water solubility of the molecules. Morphine‐6‐glucuronide has potent analgesic effects and has been extensively studied as a substitute for morphine 8. Compared with M6G, morphine causes significantly more respiratory depression 8, 9, 10.

Certain variants in genes involved in drug metabolism are associated with variable response to medications. Our patient's genotype for UGT2B7 of CC is associated with significantly lower dose requirements of morphine compared with those with the TT genotype 11. In addition to UGT2B7, UGT1A1 has been shown to participate in glucuronidation and formation of M3G and M6G 12. Polymorphisms in the UGT1A1 gene affect morphine metabolic ratios 13. Our patient was homozygous for the T allele at the rs887829 SNP in UGT1A1. The T allele is a loss‐of‐function variant, which means that the patient was considered a poor metabolizer through UGT1A1. This could have led to an increase in the morphine to M6G ratio and greater than expected respiratory depression. Our findings coincide with the fact that other loss‐of‐function genetic variants of UGT1A1 that are in significant linkage disequilibrium with the rs887829 SNP, such as the *28 allele, are associated with significantly reduced glucuronidation of other medications, such as the chemotherapy agent irinotecan, which can lead to an increased risk of severe neutropenia, diarrhoea and other adverse drug reactions 14. UGT1A1 is also critical to the glucuronidation of bilirubin, and homozygotes for UGT1A1 loss‐of‐function variants develop high serum concentrations of unconjugated bilirubin in Gilbert's syndrome and Criglar–Najjar disease 15.

There are no prior reports of morphine‐induced apnoea in the setting of UGT1A1 mutations. Nishimura et al. described a case of prolonged sedation in a patient with Gilbert's syndrome who receive IV morphine while undergoing cardiac surgery. The patient was obtunded, bradypneic and miotic and required IV naloxone to facilitate extubation 16.

Hepatic metabolism and renal clearance of morphine are also dependent on the transport of morphine and its metabolites in and out of physiologically relevant compartments, including important transporters such as SLC22A1 (OCT1), ABCB1, ABCC2, ABCC3 and SLCO1B1 17, 18. Our patient's inferred diplotype for ABCB1, ABCC2 and ABCC3 could not be determined, and his haplotype for SLCO1B1 was *1a/*1a, which corresponds to normal function. Of note, the patient's SLC22A1 haplotype was determined to be *1/*2, with the *2 haplotype defined by the deletion of the GAT codon from cDNA position 1260–1262 and the methionine from position 420 in the amino acid sequence. This frameshift variant is associated with a decrease in function of the transport protein 19. As morphine would have been transported out of the bloodstream into the hepatocytes before UGT‐mediated glucuronidation could occur, we can speculate that impaired transport, in conjunction with impaired metabolism, might have contributed to overall increased systemic exposure to the parent drug morphing.

Additionally, our patient had a urine free morphine (unconjugated) level of 309 ng ml⁻¹ almost 9 h after administration of a single 2‐mg IV dose of morphine, with the half‐life of intravenous morphine being approximately 2 h 20. This value seems high given that a previous study of morphine pharmacokinetics in human urine samples following a 2‐mg oral dose of morphine showed urine concentrations of less than 300 ng ml⁻¹ in more than half of the assayed samples after just 7–8 h following the dose 21. This is striking when accounting for the faster absorption kinetics of parenterally versus enterally administered morphine. It appears that impaired glucuronidation of morphine, which normally increases water solubility of morphine and facilitates renal clearance, has led to the increased concentration of unconjugated morphine in the urine and its prolonged presence of several half‐lives.

Given that respiratory depression and apnoea did not occur until >3 h after administration of intravenous morphine, it is possible that fracture pain provided sufficient stimulation to counteract the sedating effects of morphine. However, postsedation, the patient had evidence of opioid intoxication, with miotic pupils, depressed mental status and respiratory depression.

It is unlikely that ketamine was responsible for the prolonged and repeated episodes of apnoea. Serious adverse events and significant interventions in procedural sedation with ketamine alone are rare, occurring in less than 1% of patients 22. Additionally, ketamine rarely (<1%) causes apnoea 23. The combination of ketamine and morphine does increase the risk of respiratory depression and desaturation 22, 24, and ketamine's short (2–4 h) half‐life makes prolonged events unlikely 25. Finally, ketamine is metabolized by cytochrome P450 2B6, 2C9 and 3A4 into partially active metabolites 25. Our patient had no identified deleterious alleles in any of these pathways.

Physicians should be cognizant of morphine's complex metabolism and recognize that defects in metabolism and excretion do exist and can have clinically relevant consequences. When appropriate, patients should be queried about family history and past experience receiving opioids. In the patient with excessive sedation or prolonged respiratory depression to standard doses of morphine, genetic testing may be warranted.

Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 26, and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 1, 2.

Competing Interests

There are no competing interests to declare.

Contributors

M.S.T. drafted the initial manuscript, provided toxicology expertise, critically reviewed the manuscript and made edits and approved the final version as submitted; H.K. provided pharmacology/pharmacogenomics expertise, critically reviewed the manuscript and made edits and approved the final version as submitted; S.C. provided emergency medicine expertise, critically reviewed the manuscript and made edits and approved the final version as submitted; B.S.K. provided emergency medicine and sedation expertise, critically reviewed the manuscript and made edits and approved the final version as submitted.

Supporting information

Data S1 Drug Metabolizing Enzymes and Transporters (DMET™) Plus microarray assay marker list

Toce, M. S. , Kim, H. , Chung, S. , and Krauss, B. S. (2019) Prolonged central apnoea after intravenous morphine administration in a 12‐year‐old male with a UGT1A1 loss‐of‐function polymorphism. Br J Clin Pharmacol, 85: 258–262. 10.1111/bcp.13779.