It is well established that codeine must be O-demethylated to morphine to produce . Statistical significance was determined by ANOVA followed by the Student's t test. . Structure-Activity Relationships for Codeine and Morphine Congeners. morphine and codeine were monitored following the ingestion Samples that were tested above l~g/mL were proceeded to . Correlation coeff: Both morphine and codeine are naturally occurring alkaloids derived from the seed amounts, poppy seeds may produce urines which test positive for opiates .
In patients prescribed complicated treatment regimens, physicians may consider initiating treatment with an opioid that is not metabolized by the CYP system.
However, interactions between opioids that undergo CYP-mediated metabolism and other drugs involved with this pathway often can be addressed by careful dose adjustments, vigilant therapeutic drug monitoring, and prompt medication changes in the event of serious toxicity. Response to individual opioids varies substantially, and factors contributing to this variability are not clearly understood.
Because an individual patient's response to a given opioid cannot be predicted, it may be necessary to administer a series of opioid trials before finding an agent that provides effective analgesia with acceptable tolerability. For example, in a clinical trial, 50 patients with cancer who did not respond to morphine or were unable to tolerate it were switched to methadone, which undergoes complex metabolism involving up to 6 CYP enzymes.
Under such conditions, an understanding of opioid metabolism can guide dose adjustments or the selection of a different opioid when analgesia is insufficient or adverse events are intolerable.
Moreover, opioids that produce metabolites chemically identical to other opioid medications may complicate the interpretation of urine toxicology screening. Open in a separate window Codeine Codeine is a prodrug that exerts its analgesic effects after metabolism to morphine. Patients who are CYP2D6 poor or rapid metabolizers do not respond well to codeine. Codeine toxicity has been reported in CYP2D6 poor metabolizers who are unable to form the morphine metabolite 42 and in rapid metabolizers who form too much morphine.
Morphine In addition to its pharmacologically active parent compound, morphine is glucuronidated to 2 metabolites with potentially important differences in efficacy, clearance, and toxicity: Morphine may also undergo minor routes of metabolism, including N-demethylation to normorphine or normorphine 6-glucuronide, diglucuronidation to morphine-3, 6-diglucuronide, and formation of morphine ethereal sulfate.
A recent study found that a small proportion of morphine is also metabolized to hydromorphone, 55 although there are no data suggesting a meaningful clinical effect. Two studies found no correlation between plasma concentrations of morphine, M6G, or M3G in either clinical efficacy or tolerability. Hydromorphone The production of active metabolites is also an issue with hydromorphone.
The primary metabolite of hydromorphone, hydromorphoneglucuronide, has neuroexcitatory potential similar to 6870 or greater than 69 the M3G metabolite of morphine.
Clinical data on the neuroexcitatory potential of hydromorphone during long-term therapy are unavailable. However, hydromorphone is available only in short-acting formulations and extended-release formulations are recommended in patients with chronic pain requiring long-term therapy.
The central opioid effects of oxycodone are governed primarily by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites. Although the CYP2D6 pathway is thought to play a relatively minor role in oxycodone metabolism, at least 1 study has reported oxycodone toxicity in a patient with impaired CYP2D6 metabolism. However, methadone has affinity for the N-methyl-d-aspartate receptors 83 ; this affinity is thought to account not only for a portion of its analgesic efficacy but also for neurotoxic effects that have been observed with this opioid.
Current urine toxicology tests do not provide easily interpretable information about the source or dose of detected compounds. Thus, in a patient prescribed oxycodone, both oxycodone and oxymorphone will appear in toxicology results, but the urine test results will not establish whether the patient took the prescribed oxycodone alone or also self-medicated with oxymorphone.
Patients treated with codeine will have both codeine and morphine in urine samples. If too much morphine is present, the patient may be taking heroin or ingesting morphine in addition to codeine. CYP2D6 rapid metabolizers may have an unusually high morphine-to-codeine ratio, making interpretation of the morphine-to-codeine ratio challenging.
Clinicians may find it easier to monitor patients for adherence and abuse if the opioid prescribed does not produce active metabolites similar to other opioid medications. If abuse is suspected, choosing opioids such as fentanyl, hydromorphone, methadone, or oxymorphone may simplify monitoring. Sometimes an inactive metabolite provides a more reliable test of adherence than does the parent opioid. Urinary concentrations of methadone depend not only on dose and metabolism but also on urine pH.
In contrast, the concentration of an inactive metabolite of methadone via N-demethylation2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, is unaffected by pH and is therefore preferable for assessing adherence to therapy.
Reduced clearance of morphine, 43 codeine, 13 fentanyl, 10 and oxymorphone 18 has been reported in older patients. Morphine concentrations were shown to be reduced in Chinese patients treated with codeine, providing confirmation of altered morphine metabolism in this large population.
Open in a separate window In most cases, altered opioid metabolism in older patients, women, or specific ethnic groups can be addressed by careful dose adjustment. For example, morphine, 43 codeine, 13 fentanyl, 15 and oxymorphone 18 should be initiated at lower doses in older patients, and physicians prescribing oxycodone to women may consider starting at a lower dose relative to men.
Morphine or codeine dose reductions may also be necessary in Asian populations. Given the genetic variability of metabolism in specific ethnic populations, it may make sense for patients with an unexplained history of poor response or an inability to tolerate a particular opioid to be switched to an opioid that relies on a different metabolic pathway.
It is therefore not surprising that the prescribing information for most frequently prescribed opioids recommends caution in patients with hepatic impairment. Although oxymorphone itself does not undergo CYP-mediated metabolism, a portion of the oxycodone dose is metabolized to oxymorphone by CYP2D6.
Failure to biotransform oxycodone to oxymorphone may result in accumulation of oxycodone and noroxycodone, with an associated increase in adverse events. Hepatic impairment may also affect metabolism of opioids that undergo glucuronidation rather than CYP-mediated metabolism, such as morphine and oxymorphone.
In a study, the elimination half-life and peak plasma concentrations of morphine were significantly increased in 7 patients with severe cirrhosis. The ratio of morphine to its inactive metabolite M3G was significantly higher in cirrhotic patients than in controls.
In another study, morphine hepatic extraction was compared in 8 healthy participants and 8 patients with cirrhosis. The authors of that study suggested that cirrhosis affected the metabolism of morphine less than other high-clearance oxidized drugs, perhaps indicating that cirrhosis has less of an effect on glucuronidation relative to CYP-mediated metabolism.
Currently, no comparable data exist on metabolism of oxymorphone in patients with cirrhosis. However, hepatic disease may certainly have significant effects on oxymorphone pharmacokinetics. Specifically, the bioavailability of oxymorphone increased by 1. In 1 patient with severe hepatic impairment Child-Pugh class Cthe bioavailability was increased by Although dose adjustments for these opioids may not be required in certain patients with hepatic impairment, clinicians should nonetheless be extremely cautious when prescribing any opioid for a patient with severe hepatic dysfunction.
Renal Impairment The incidence of renal impairment increases significantly with age, such that the glomerular filtration rate decreases by an average of 0.
For example, morphine clearance decreases only modestly in patients with renal impairment, but clearance of its M6G and M3G metabolites decreases dramatically. As in liver disease, methadone and fentanyl may be less affected by renal impairment than other opioids.
Codeine Therapy and CYP2D6 Genotype - Medical Genetics Summaries - NCBI Bookshelf
Methadone does not seem to be removed by dialysis ; in anuric patients, methadone excretion in the feces may be enhanced with limited accumulation in plasma. Fentanyl is metabolized and eliminated almost exclusively by the liver; thus, it has been assumed that its pharmacokinetics would be minimally altered by kidney failure.
Health care professionals need to be especially cautious when dealing with patients with diminished metabolic capacities due to organ dysfunction. Although metabolism of drugs undergoing glucuronidation rather than oxidation may be less affected by hepatic impairment, this does not appear to be a major advantage with respect to opioids. Morphine clearance and accumulation of its M3G metabolite are increased in cirrhosis, making dose adjustments advisable.
Oxymorphone, which also undergoes glucuronidation, is contraindicated in patients with moderate or severe hepatic dysfunction. Nonetheless, data on these opioids are limited, making caution and conservative dosing advisable in this population. In patients with substantial chronic kidney disease stagesclinicians should carefully consider their options before choosing morphine.
Nausea, vomiting, profound analgesia, sedation, and respiratory depression have been reported in patients who have kidney failure and are taking morphine.
To optimize treatment for individual patients, clinicians must understand the variability in the ways different opioids are metabolized and be able to recognize the patient characteristics likely to influence opioid metabolism. With a Guide to Opioid Availability 2nd ed. WHO Office of Publication; Practice guidelines for acute pain management in the perioperative setting: J Am Geriatr Soc. SS [ PubMed ] 4. American Pain Society; Epidemiological features of chronic low-back pain.
Opioid rotation in the treatment of joint pain: Joint Bone Spine ;69 5: Opioid rotation for cancer pain: Mercadante S, Bruera E. Opioid substitution to improve the effectiveness of chronic noncancer pain control: Duragesic fentanyl transdermal system [package insert] Titusville, NJ: Janssen Pharmaceuticals, Inc; Purdue Pharma LP; Codeine Contin codeine controlled-release tablets [product monograph] Pickering, Ontario, Canada: Hydrocodone [package insert] Corona, CA: Methadone hydrochloride tablets [package insert] Hazelwood, MO: Endo Pharmaceuticals Inc; Methadone N-demethylation in human liver microsomes: Br J Clin Pharmacol.
Enantiomeric metabolic interactions and stereoselective human methadone metabolism. J Pharmacol Exp Ther. The Medical Review Officer examined donors for evidence of drug abuse by taking a clinical history and performing a physical examination, and often requested a test for 6-AM to confirm heroin use. In the guidelines, no cutoff was mandated for 6-AM confirmation. Generally, the limit of detection LOD of a procedure was used to confirm the presence of 6-AM in urine.
Because the LOD varied considerably between laboratories, the 6-AM results were misleading in some forensic investigations. Later in a separate memorandum, the DHHS postponed the implementation date until December 1,because additional time was needed to validate immunoassay test kits and 6-AM confirmatory procedures.
Because 6-AM is a unique metabolite of heroin, its presence in urine would be used to confirm heroin use. The objective of the new cutoff concentrations was to eliminate a considerable number of specimens that may be positive from poppy seed use. The objective of this study was to determine appropriate cutoff concentrations for free codeine, free morphine, and 6-AM that could be substituted for the cutoff concentrations for total morphine, total codeine, and 6-AM, using retrospective published data 7 8 9and to develop a confirmatory assay that would allow simultaneous measurement of free morphine, free codeine, and 6-AM.
The combined objective was to propose a method for identifying codeine, morphine, and heroin use with one urine immunoassay and one confirmation test.
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Materials and Methods chemicals, reagents, and supplies Codeine and morphine were purchased from Sigma Chemical Co. Propionic anhydride and pentafluoropropionic anhydride were purchased from Aldrich Chemical Co.
The MSD was operated under electron impact mode. The ion window and dwell time were 0.
The electron multiplier was set at the autotune voltage for codeine and morphine, and V above autotune for 6-AM. The flow rate of helium through a DB-5MS capillary column [5: In brief, the samples for morphine analysis were hydrolyzed with acid. After an acid-base separation, the morphine was extracted by solvent and then detected by GC-MS as acetyl derivative. Acid hydrolysis was avoided for 6-AM analysis. The compound was extracted using a procedure similar to morphine and was detected as the propionyl derivative.
All positive samples were quantified, allowing a retrospective application of different cutoffs for study purposes. For extraction, a mixture of internal standards, d6-codeine, d3-morphine, and d6-AM 15, 15, and 0. A negative control was used to verify contamination during analysis. Calibrators and controls were used in each batch analysis. Phosphate buffer 2 mL of 0. The pH values of the solutions were 6. At this pH range, the opiates were in cationic forms. The solutions were poured into solid-phase extraction columns prewashed with methanol 3 mLdeionized water 3 mLand phosphate buffer 1 mL of 0.
The solutions were allowed to pass through the columns by gravity flow. The columns were washed with deionized water 2 mLHCl 2 mL of 0. Methanol removed most of the nonionic compounds.
The columns were dried for 2 min using suction. The opiates were extracted from the sorbent with 3 mL of a mixture of methylene chloride—isopropanol—