Life-Threatening Dextromethorphan Intoxication Associated with Interaction with Amitriptyline in a Poor CYP2D6 Metabolizer: A Single Case Re-Exposure Study
Article Outline
Abstract
We report a case of life-threatening intoxication and a controlled re-exposure study to dextromethorphan. A 60-year-old man developed postsurgical neuropathic cervical pain treated by hydromorphone, gabapentin, clonazepam, and amitriptyline. He received a dextromethorphan preparation for a catarrhal syndrome. Two days later, he was admitted into an emergency department in a profound coma. Thirty-six hours later, after withdrawal of all drugs, the situation normalized. A genotyping for UDP-glucuronyltransferase 1A1 and CYP2D6 was followed by a re-exposure study. During the three days, vital parameters and side effects of drugs were prospectively recorded. The second day, dextromethorphan was introduced. No significant impairment in parameters nor influence on analgesic efficacy were noted. Dextromethorphan concentrations suggested an accumulation without reaching any steady state. Somnolence was noted for plasma concentrations around 100
ng/mL. The CYP2D6*4 variant leading to a poor metabolizer phenotype was found. Moreover, this phenotype was potentially aggravated by amitriptyline intake. This study allowed the identification and the confirmation of the cause of the coma. In conclusion, it is probably wise to recommend avoiding dextromethorphan in patients taking tricyclic antidepressants or another inhibitor of CYP2D6. Drug–drug interactions are probably underdiagnosed and underreported, and drugs considered as safe may induce serious complications.
Key Words: Dextromethorphan, amitriptyline, interaction, CYP2D6
Introduction
Polymorphisms of genes coding for drug-metabolizing enzymes and drug–drug interactions may expose patients either to lack of efficacy or to drug-induced toxicity and serious adverse effects, which can be life-threatening.1 The dramatic progress achieved recently in pharmacogenetics/pharmacokinetics allows better understanding of some of the difficulties observed in clinical practice.
Cytochrome P450 CYP2D6 is one of the best-studied polymorphic genes of pharmacologic interest.1 Frequency of polymorphism includes 1%–10% ultrarapid metabolizers. This condition has been recently reported to be associated with codeine intoxication.2 The poor metabolizer phenotype is mostly inherited as an autosomal recessive trait and has been reported to be 5%–13.5% in White populations, but as low as 0%–1% in Asians.1 The metabolism of numerous drugs is affected by the CYP2D6 polymorphism. These include antiarrythmics, tricyclic antidepressants, opioids, antipsychotics, β-adrenoreceptor antagonists, and dextromethorphan (DEX). Patients with a poor-metabolizer phenotype are at risk of increased plasma concentration and toxicity.
DEX is widely used for cough and less frequently for pain treatment. It is considered as safe for most patients. Its metabolism is extensively described, particularly in the pharmacogenetic context of poor and extensive metabolizers.3 CYP2D6 is responsible for O-demethylation of the majority of DEX to dextrorphan (DXO) and CYP3A4/5 is involved in N-demethylation of DEX to 3-methoxymorphinan. DXO and 3-methoxymorphinan concentrations provide a reliable index of CYP2D6 and CYP3A4/5 activity in phenotyping studies.3 DXO undergoes further glucuronidation, producing DXO-glucuronide.
Amitriptyline is a well-known tricyclic antidepressant prescribed for chronic pain syndromes. Its major metabolic pathway is mediated by CYP2C19 and CYP2D6. Amitriptyline is primarily demethylated to nortriptyline and then hydroxylated by CYP2D6 to 10-OH-nortriptyline.4 It has been recently shown that side effects can be related to genotype.5 Amitriptyline has been proven to inhibit CYP2D6 competitively in human liver microsomes,6 possibly impairing the dextromethorphan-O-demethylation.
No clinically relevant interaction has been described between amitriptyline and DEX. However, a few DEX intoxications were reported at therapeutic doses. These were attributed to innate (deficiency of CYP2D6) or acquired (fluoxetine-related CYP2D6 inhibition) poor metabolism.7, 8, 9
We report here a case of life-threatening DEX intoxication potentially due to an interaction with amitriptyline in a poor metabolizer-patient treated for acute cough and chronic pain. Because of several implications (diagnostic confirmation, optimization of analgesia, and clinical research), a well-controlled re-exposure protocol was proposed to the patient.
Case Report
The history of this 60-year-old man is marked by surgery 13 years ago for a malignant lingual tumor. Some months after surgery, he developed a neuropathic cervical pain, which was treated with an opioid—extended-release hydromorphone 48mg twice daily (Palladone®, Mundipharma, Mechelen, Belgium). Pain was not adequately controlled and other medications were added: gabapentin 600mg four times a day (Neurontin®, Pfizer, Brussels, Belgium), clonazepam 1mg (Rivotril®, Roche, Brussels, Belgium), and amitriptyline 50mg (Redomex®, Lundbeck, Brussels, Belgium) in the evening. The patient was also taking insulin for diabetes mellitus 25 IU subcutaneous (SC), in the morning and 11 IU SC in the evening (Mixtard 30/70®, Novo Nordisk, Brussels, Belgium). With this combined treatment, pain relief was quite good.
He developed a catarrhal syndrome, treated with paracetamol (Dafalgan®, Bristol-Myers Squibb, Brussels) 4 g per day and acetylsalicylic acid (Sedergine®, Bristol-Myers Squibb, Brussels). One day later, he received from his pharmacist a DEX preparation (dextromethorphan bromhydrate 15mg, guaifenesin 50mg per 5 mL, Acatar®, SMB, Brussels, Belgium) to take three times a day. After the fourth dose of DEX, he became very somnolent, and 12 hours later, he was admitted into an emergency department for profound coma. Punctiform pupils were noted.
Because of suspicion of drug-induced toxicity, all analgesic treatment was stopped. The situation normalized 36 hours later. His pain treatment was then reintroduced with lower doses of hydromorphone—24mg three times per day.
Analyses/Methods
After informed consent, the patient was hospitalized for a 72-hour period. Diagnostic assessment included genotyping (by polymerase chain reaction) for UDP-glucuronyltransferase 1A1 (UGT1A1) (for possible interaction with hydromorphone) and CYP2D6. Mutations searched in CYP2D6 genotyping were selected by frequencies in Caucasian population and clinical implications.10
During the three days, vital signs and side effects of drugs were prospectively recorded every three hours. Respiratory rate, heart rate, pupil diameter (miosis, mydriasis, intermediate), level of consciousness (normal or somnolent), and nausea/vomiting were prospectively noted. Pharmacological treatment was administered as reported before (hydromorphone 24mg at 0900, 1400, and 2000 hours, gabapentin 1200mg at 0900 and 600mg at 1700 hours, clonazepam 1mg and amytriptyline 50mg at 2200 hours, insulin at stable doses and bisacodyl 4mg plus sodium docusate 100mg (Softene®, Melisana, Brussels, Belgium) as laxative treatment at 0900 hours. The second day, DEX was introduced three times per day (dextromethorphan bromhydrate 30mg, guaifenesine 50mg) (0800, 1200, and 2000 hours). Venous blood samplings were taken four to five times per day from the first day.
Results
The genotyping study showed the homozygotic mutation 1846 G→A leading to a “splicing effect” for the CYP2D6 gene. This mutation corresponds to the CYP2D6*4 variant, leading to a poor metabolizer phenotype.9 No other mutations were observed, as described in Table 1, Table 2.
Table 1. Analysis of Mutations and/or Deletions in UDP-Glucuronyltransferase 1A1 in Blood by Polymerase Chain Reaction
| Mutations Searched | Results |
|---|---|
| In the promote-region: UGT1A1*28 | Wild type |
| In the codant-regions: 5 exons analyzed | Absence of mutation |
Table 2. Polymorphisms of CYP2D6 in Blood by Polymerase Chain Reaction
| Mutations Searched | Results |
|---|---|
| 2D6*3 | Wild type |
| 2D6*4 | Homozygote |
| 2D6*6 | Wild type |
| 2D6*9 | Wild type |
During the hospitalization, no significant impairment in hemodynamic and respiratory parameters was noted. Somnolence appeared on day three (30 hours after the first administration of DEX). No other side effect was noted nor was there any change in analgesic efficacy (Table 3).
Table 3. Vital Signs Recorded During the Hospitalization
| Hours | SpO2 | RR | BP | HR | Pupils | N/V | Vigil | |
|---|---|---|---|---|---|---|---|---|
| Day 1 | 08:00 | 93% | 16 | 12/6 | 61 | N | / | N |
| 11:00 | 94% | 18 | 12/7 | 74 | N | / | N | |
| 14:00 | 93% | 16 | 12/7 | 86 | N | / | N | |
| 17:00 | 94% | 16 | 11/7 | 76 | N | / | N | |
| 20:00 | 93% | 16 | 12/7 | 83 | N | / | N | |
| 23:00 | 93% | 14 | 11/6 | 85 | N | / | N | |
| Day 2 | 02:00 | 92% | 15 | 11/6 | 68 | N | / | N |
| 05:00 | 92% | 15 | 11/7 | 62 | N | / | N | |
| 08:00 | 92% | 20 | 12/6 | 69 | N | / | N | |
| 11:00 | 96% | 14 | 12/7 | 69 | N | / | N | |
| 14:00 | 91% | 20 | 11/8 | 80 | P | / | N | |
| 17:00 | 92% | 14 | 12/7 | 68 | P | / | N | |
| 20:00 | 97% | 14 | 14/8 | 68 | N | / | N | |
| 23:00 | 92% | 15 | 12/7 | 79 | N | / | N | |
| Day 3 | 02:00 | 92% | 13 | 11/6 | 60 | N | / | N |
| 05:00 | 91% | 14 | 10/6 | 64 | N | / | N | |
| 08:00 | 93% | 16 | 12/6 | 76 | P | / | N | |
| 11:00 | 95% | 16 | 11/7 | 72 | P | / | N | |
| 14:00 | 89% | 16 | 12/8 | 76 | P | / | S | |
| 17:00 | 93% | 11 | 13/7 | 60 | N | / | S | |
| 20:00 | 91% | 15 | 12/6 | 64 | N | / | S | |
Plasma drug concentration analysis showed relatively stable profiles (amitriptyline, nortriptyline, and hydromorphone). In contrast, DEX concentrations suggested an accumulation without reaching any steady state (Table 4 and Fig. 1). A 30mg first dose resulted in a four-hour plasma level of 13ng/mL, whereas in a volunteer study, a single 60mg dose resulted in an average concentration of 5.2ng/mL.11 DEX plasma concentrations kept increasing with following doses. Somnolence was noted for plasma concentrations around 100ng/mL of DEX.
Table 4. Plasma Concentrations of Different Drugs
| Time (hour) | Amitriptyline (ng/mL) | Nortriptyline (ng/mL) | Dextromethorphan (ng/mL) | Hydromorphone (ng/mL) | |
|---|---|---|---|---|---|
| Day 1 | Control | 24 | 14 | — | 1.5 |
| 12:00 | 29 | 14 | — | 8.3 | |
| 17:00 | 24 | 13 | — | 4.1 | |
| 21:00 | 19 | 12 | — | 3.7 | |
| Day 2 | 09:00 | 31 | 15 | 0 | 2.4 |
| 10:00 | 33 | 15 | 3 | 3.1 | |
| 12:00 | 32 | 15 | 13 | 8.5 | |
| 17:00 | 25 | 17 | 30 | 4.2 | |
| 21:00 | 24 | 15 | 44 | 5.2 | |
| Day 3 | 08:00 | 26 | 14 | 62 | 3.9 |
| 10:00 | 23 | 15 | 85 | 5.2 | |
| 12:00 | 23 | 13 | 90 | 5 | |
| 17:30 | 23 | 16 | 126 | 6.7 | |
Fig. 1
Plasma concentrations (ng/mL) of drugs. All concentrations remained stable except for dextromethorphan, which rapidly rose on Days 2 and 3.
Discussion
We report here a case of acute intoxication to DEX and a controlled re-exposure study in a poor metabolizer treated with amitriptyline. At the first exposure to DEX, a drug-related intoxication was suspected. The patient was admitted to another institution without any drug concentration analyses. The well-controlled re-exposure study allowed identification and confirmation of cause of the life-threatening, unresponsive coma that presented at home. Although a further objective of the re-exposure study was to evaluate if pain could be better controlled with low doses of DEX, the main benefit for the patient was indeed diagnostic. No optimization of analgesia was observed.
Polymorphism of genes coding for drug-metabolizing enzymes can affect an individual's risk of having an adverse drug reaction. Polymorphism determination is not an emergency procedure. But in recent years, genotyping has been proposed as part of therapeutic monitoring for dose adjustment, for avoiding side effects, and for clinical research.1, 12
Prospective genotyping of CYP2D6 is particularly exciting in chronic pain patients. Combinations of multiple drugs, particularly tricyclic antidepressants and analgesics metabolized by the same enzymes, may predispose to complex interactions. Inherited or acquired ultrarapid or poor metabolism has been reported to be associated with serious side effects.2, 7, 8 However, no clinically relevant interaction has been reported between amitriptyline and DEX.
Only one interaction has been reported at therapeutic doses between tricyclics and DEX.9 This is surprising for a well-known antidepressant and an often-prescribed antitussive. Moreover, it is well known that the incidence of poor metabolizers is not rare in most populations. One reason may be that pharmacovigilance, defined as reporting of side effects after commercialization of a drug, is not easy. Drug-related intoxications are difficult to establish and to confirm in polymedicated patients. This problem may eventually lead to underestimation of such complications.
Adding DEX to drug regimens has already been done with success in refractory epilepsy. DEX was added at doses between 160 and 200mg a day. It increased antiepileptic drug efficacy, with transient side effects. DEX was well tolerated even in patients (slow metabolizers) with high plasma levels of the drug (up to 150ng/mL).13
The addition of DEX to analgesic combinations has been discussed for several years but without clear evidence of benefit for chronic pain treatment.14 However, experimental data suggest better efficacy of this combination in poor CYP2D6 metabolizers.15 The reason for a better analgesic effect may be pharmacokinetic and/or pharmacodynamic. A direct spinal noncompetitive N-methyl-D-aspartate antagonism has been proposed. However, in our patient, no analgesic effect was observed.
The most important implication for our patient is avoidance of DEX. In light of this report, it is probably appropriate to recommend avoiding DEX in patients taking tricyclic antidepressants or another inhibitor of CYP2D6. Drug–drug interactions are probably underdiagnosed and underreported, and drugs considered safe for many years in most patients may induce serious complications. Pharmacokinetics, including pharmacogenetics, allows improved comprehension of the mechanisms of drug effects.
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PII: S0885-3924(08)00098-5
doi:10.1016/j.jpainsymman.2007.09.006
© 2008 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
