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Doi:10.1016/j.pnpbp.2006.03.018

Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1356 – 1358 Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer Margaret T. Susce, Elaina Murray-Carmichael, Jose de Leon ⁎ University of Kentucky, Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA Available online 24 April 2006 Codeine is metabolized by the cytochrome P450 2D6 (CYP2D6) to morphine. Codeine is a much weaker agonist at μ opioid receptors than morphine. Therefore, codeine analgesia is highly dependent on CYP2D6 activity. Large prospective studies in the clinical environment do notexist, but it appears reasonable to avoid codeine use in CYP2D6 poor metabolizers (PMs). CYP2D6 metabolizes other opioid analgesics,including tramadol, dihydrocodeine, oxycodone and hydrocodone, although they have been less systematically studied. It is unclear whether theseother pro-drugs may be as completely dependent on CYP2D6 for their analgesia as codeine. We describe a patient identified as a CYP2D6 PMwith a history of problems with opioid analgesics.
The patient was an 85-year-old female Caucasian who had hip surgery. The patient had a long-standing intolerance to codeine. In her first admission, she couldn't tolerate the regimen of oxycodone combined with tramadol prns (as needed). She was genotyped as a CYP2D6 PM andafter the information was provided to the treating physician in her second admission, she seemed to have a better response to hydrocodone. Largecase-control naturalistic studies followed by randomized trials in patients taking opioid analgesics may be needed to definitively establish thatCYP2D6 genotyping has clinical relevance in the use of several opioid analgesics.
2006 Elsevier Inc. All rights reserved.
Keywords: Analgesia; Codeine; Cytochrome P450 2D6; Genotyping; Hydrocodone; Oxycodone; Pain ). Five of those studies reported Codeine is metabolized by the cytochrome P450 2D6 lack of analgesic effects for codeine treatment, and one reported (CYP2D6) to morphine. Codeine is a much weaker agonist at μ decreased analgesia in postoperative pain opioid receptors than morphine. Therefore, codeine analgesia is Large prospective studies in the clinical environment do not exist, highly dependent on CYP2D6 activity. CYP2D6 poor meta- but it appears reasonable to avoid codeine use in CYP2D6 PMs or bolizers (PMs), who lack CYP2D6, account for 7% of Caucasians in those taking these powerful CYP2D6 inhibitors.
and 1–3% of other races. Powerful CYP2D6 inhibitors (such as CYP2D6 metabolizes other opioid analgesics, including tra- quinidine, paroxetine, fluoxetine and bupropion) can change the madol, dihydrocodeine, oxycodone and hydrocodone, although phenotype of normal subjects (called extensive metabolizers, they have been less systematically studied (It EMs) to the PM phenotype as long as they are taking these is unclear whether these other pro-drugs may be as completely medications. The review of found six studies dependent as codeine on CYP2D6 for their analgesia.
focused on codeine analgesic response, including 45 CYP2D6 We describe a patient identified as a CYP2D6 PM with a PMs identified by pheno or/and genotyping ( history of problems with opioid analgesics.
Abbreviations: CYP, cytochrome P450; CYP2D6, cytochrome P450 2D6; CYP3A, cytochrome P450 3A; EM, extensive metabolizer; PM, poormetabolizer; PRN, as needed; UM, ultrarapid metabolizer.
The patient was an 85-year-old female Caucasian who had ⁎ Corresponding author. Mental Health Research Center at Eastern State hip surgery. She had a long history of codeine intolerance Hospital, 627 West Fourth St., Lexington, KY 40508, USA. Tel.: +1 859 246 resulting in nausea and vomiting. Codeine was even noted as an 7487; fax: +1 859 246 7019.
E-mail address: (J. de Leon).
allergy on her chart. After the problems she had during her first 0278-5846/$ - see front matter 2006 Elsevier Inc. All rights reserved.
M.T. Susce et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1356–1358 admission, she agreed to sign a consent form for one of our studies and be genotyped for CYP2D6. Her genotype in ourlaboratory () was CYP2D6 PM (⁎4/⁎6).
The patient had a long-standing intolerance to codeine, which was noted as an allergy on her chart. Codeine appears clearly dependent on CYP2D6 for its analgesic effects. However, co-deine appears to be able to directly cause some of its side effects.
3.1. First admission In a randomized double-blind placebo-controlled study usingmorphine and codeine in 9 CYP2D6 PMs and 9 CYP2D6 EMs, The patient fractured her right hip, and was transferred to a demonstrated that CYP2D6 PMs can rehabilitation hospital after stabilization pins were placed. The show codeine side effects but lack analgesic response.
rehabilitation process was complicated by multiple episodes of The patient couldn't tolerate the regimen of oxycodone nausea and vomiting during oxycodone treatment. She was combined with tramadol prns during her first admission, having threatened with discharge due to noncompliance at one point; significant side effects. She obtained no pain relief and was the family had to intervene. The experience was very negative considered a difficult patient for not collaborating with her treat- to the patient, who lost 20 lb during her 17-day admission to the ment. We are aware of no studies on oxycodone's analgesic rehabilitation hospital. Her medications included nifedipine effects on CYP2D6 PMs, but described loss of sustained release (240 mg/day), doxazosin (4 mg/day), enteric- oxycodone analgesic effects after adding CYP2D6 inhibitors.
coated aspirin (81 mg/day), hydrochlorothiazide (25 mg/day) Conversely, adding quinidine did not appear to change oxy- and loratadine (10 mg/day). Loratadine is metabolized by the codone psychomotor or subjective effects cytochrome P450 3A (CYP3A) and has a minor CYP2D6 but quinidine may not be an ideal drug to block CYP2D6 in the component. None of the other drugs appeared to have sub- brain. This case report appears to suggest that, like codeine, stantial CYP2D6 involvement in their metabolism. Combined oxycodone may need CYP2D6 to provide analgesic effects. The oxycodone and acetaminophen was used as an analgesic. Initially patient was taking some other medications, which arguably could prescribed at 5 mg of oxycodone and 500 mg of acetaminophen have contributed to the lack of response to oxycodone. However, (5/500) every 12 h, it was increased to 10/1000 every 12 h and none of her medications (nifedipine, doxazosin, enteric coated then 7.5/750 every 6 h. Finally the dose was slowly reduced until aspirin, hydrochlorothiazide and loratadine) appear likely to she was discharged on 5/500 every 12 h. Analgesia was not inhibit CYP2D6 in a significant way.
achieved; she received several doses of tramadol 100 mg prn Hydrocodone is metabolized by CYP2D6 to hydromorphone every 6 h during the admission. She also received several treat- We are aware of no studies on hy- ments for nausea/vomiting including prns of aluminum hydrox- drocodone's analgesic effects on CYP2D6 PMs, but hydrocodone ide and magnesium hydroxide, promethazine, and three days of by itself appears to have some agonist effects on μ opioid unsuccessful treatment with ranitidine. Finally, she was dis- receptors ). Some animal studies supported this, charged on famotidine 80 mg/day to try to control her nausea suggesting that inhibiting the CYP analog to CYP2D6 does not associated with oxycodone treatment.
decrease hydrocodone analgesia ). Also, human studies propose that CYP2D6 inhibition 3.2. Second admission (genotype was known) does not affect hydrocodone abuse liability ).
Per the literature and our case, the very limited data suggest A year later, the patient had a second surgery to replace her that hydrocodone may be a better option for CYP2D6 PMs than right hip secondary to avascular necrosis from the previous hip codeine, and perhaps oxycodone. More importantly, a study pinning. After four days, she was sent to the same rehabilitation needs to explore whether patients with unusual responses to hospital for 16 days. This time a family member informed about hydrocodone, oxycodone, tramadol and dihydrocodeine over- CYP2D6 genotyping explained the possible pharmacological represent subjects with unusual CYP2D6 genetic variations, reason for her previous lack of appropriate response to opioid such as CYP2D6 PMs or even CYP2D6 ultrarapid metabolizers analgesics to the anesthesiologist. He prescribed tegaserod, a (UMs) ). Next, a large serotonin 5-HT4 receptor agonist, ahead of time and hydro- case-control study in patents taking these analgesics may be codone/acetaminophen 5/500 was used for analgesia 4–5 times a needed, controlling for confounders ( day. She tolerated this regimen better and received promethazine associated with lack of response. It may be even better to conduct only once during the second stay. The difference was remarkable; a double-blind randomized study using CYP2D6 genotyping; she was able to fully participate in her rehabilitation. Other unfortunately there is limited experience in the practical aspects medications were aspirin (81 mg/d), hydrochlorothiazide (25 mg/ of combining well-controlled designs in the real world with d), olmesartan (40 mg/d), cetirizine (10 mg/day) and docusate CYP2D6 genotyping.
(200 mg/day). Cefuroxime, an antibiotic, was prescribed for10 days of the 16-day admission. This case suggests that the patient was considered uncooperative because she was unable totolerate rehabilitation due to pain and opioid analgesics side This CYP2D6 PM had problems with several opioid effects, but received better care after her physician considered a analgesics and knowing her CYP2D6 genotype helped to treat possible genetic reason for unusual drug response.
her. The patient had a long-standing intolerance to codeine. She M.T. Susce et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 30 (2006) 1356–1358 couldn't tolerate the regimen of oxycodone combined with Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, et al. Codeine tramadol prns during her first admission, having significant side intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med2004;351:2827–31.
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