Morphine and codeine relationship problems

Codeine Therapy and CYP2D6 Genotype - Medical Genetics Summaries - NCBI Bookshelf

morphine and codeine relationship problems

Codeine is a prescription pain medication used to treat mild to a gateway drug to other opiates, including morphine and even heroin. CYP2D6 converts codeine in to its active metabolite, morphine, which provides its analgesic effect. However, pain relief may be inadequate in. Codeine is an opiate used to treat pain, as a cough medicine, and for diarrhea. It is typically Codeine works following being broken down by the liver into morphine. .. Drugs bearing resemblance to codeine in effects due to close structural relationship are variations on the methyl groups at the 3 position including.

These enzymes promote 2 forms of metabolism: Phase 1 metabolism typically subjects the drug to oxidation or hydrolysis. It involves the cytochrome P CYP enzymes, which facilitate reactions that include N- O- and S-dealkylation; aromatic, aliphatic, or N-hydroxylation; N-oxidation; sulfoxidation; deamination; and dehalogenation. Phase 2 metabolism conjugates the drug to hydrophilic substances, such as glucuronic acid, sulfate, glycine, or glutathione. The most important phase 2 reaction is glucuronidation, catalyzed by the enzyme uridine diphosphate glucuronosyltransferase UGT.

Glucuronidation produces molecules that are highly hydrophilic and therefore easily excreted. Opioids undergo varying degrees of phase 1 and 2 metabolism.

Phase 1 metabolism usually precedes phase 2 metabolism, but this is not always the case. Both phase 1 and 2 metabolites can be active or inactive. The process of metabolism ends when the molecules are sufficiently hydrophilic to be excreted from the body.

The CYP2D6 enzyme metabolizes fewer drugs and therefore is associated with an intermediate risk of drug-drug interactions. Drugs that undergo phase 2 conjugation, and therefore have little or no involvement with the CYP system, have minimal interaction potential.

Phase 1 Metabolism The CYP3A4 enzyme is the primary metabolizer of fentanyl 10 and oxycodone, 11 although normally a small portion of oxycodone undergoes CYP2D6 metabolism to oxymorphone Table 1 10 - Open in a separate window Each of these opioids has substantial interaction potential with other commonly used drugs that are substrates, inducers, or inhibitors of the CYP3A4 enzyme Table 2.

Administration of CYP3A4 inducers can reduce analgesic efficacy. Open in a separate window Induction of CYP3A4 may pose an added risk in patients treated with tramadol, which has been associated with seizures when administered within its accepted dosage range.

Open in a separate window Although CYP2D6-metabolized drugs have lower interaction potential than those metabolized by CYP3A4, genetic factors influencing the activity of this enzyme can introduce substantial variability into the metabolism of hydrocodone, codeine, and to a lesser extent oxycodone.

Patients who are poor opioid metabolizers experience reduced efficacy with codeine because they have a limited ability to metabolize codeine into the active molecule, morphine. In contrast, patients who are rapid opioid metabolizers may experience increased opioid effects with a usual dose of codeine because their rapid metabolism generates a higher concentration of morphine. In one study, such alterations were not accompanied by increased adverse events.

morphine and codeine relationship problems

Phase 2 Metabolism Morphine, oxymorphone, and hydromorphone are each metabolized by phase 2 glucuronidation 171843 and therefore have little potential for metabolically based drug interactions. Oxymorphone, for example, has no known pharmacokinetic drug-drug interactions, 18 and morphine has few.

However, the enzymes responsible for glucuronidation reactions may also be subject to a variety of factors that may alter opioid metabolism. The most important UGT enzyme involved in the metabolism of opioids that undergo glucuronidation eg, morphine, hydromorphone, oxymorphone 1244 is UGT2B7. Research suggests that UGT2B7-mediated opioid metabolism may be altered by interactions with other drugs that are either substrates or inhibitors of this enzyme. The exceptions are morphine, hydromorphone, and oxymorphone, which undergo glucuronidation.

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.

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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.

Opioid Metabolism

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. 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.

This Is What Happens to Your Brain on Opioids - Short Film Showcase

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. Patients maintained on oral morphine without respiratory depression who then receive successful nerve blocks must have their morphine dose reduced otherwise respiratory depression may occur in the absence of pain. Cardiovascular - the administration of morphine to supine patients has little effect on blood pressure, but there is considerable peripheral vasodilatation.

If the patient is standing, morphine may produce orthostatic hypotension due to inhibition of sympathetic outflow, diminishing any compensatory tachycardia for the vasodilatation.

Morphine releases histamine and this may explain in part the arteriolar and venous relaxation. In addition, morphine may reduce heart rate both by increased vagal tone and by direct suppression of the activity of the sinoatrial node. The slowed gastrointestinal transit means that water absorption in the colon is increased.

Constipation is a common side effect of morphine administration.

In the biliary tract as in the bladder and uretermorphine increases tone and constricts the sphincter of Oddi, which may worsen biliary spasm. Miosis - morphine produces pupillary constriction by stimulation of the Edinger-Westphal nucleus. Pinpoint pupils are characteristic features of morphine overdosage but are not always present. Cutaneous - morphine dilates cutaneous blood vessels and the skin of the face neck and upper chest may become flushed. This may be due to histamine release, which may also account for urticaria at the injection site.

Morphine may also produce pruritus, especially when given spinally and can be reversed by small doses of naloxone. We know the side effects of morphine but we are also aware that morphine is extremely useful to manage severe postoperative pain.

Given this knowledge, it is surprising therefore, that more preventative management is not undertaken in anticipation of the side effects. For instance, better postoperative fluid management for hypotension, stool softener and laxative for constipation, regular and appropriate antiemetics for PONV etc. Diamorphine Heroin Diamorphine is diacetylmorphine and the parent structure has no opioid activity. Tissue and plasma esterases metabolise diamorphine to monoacetylmorphine; both are more lipid soluble than morphine and cross the blood-brain barrier more easily.

In the central nervous system diamorphine and monoacetylmorphine are converted to the active morphine molecule. Diamorphine may be a more euphoriant drug than morphine and may produce less nausea. In many countries diamorphine is unavailable as it is considered to be a dangerous drug of abuse. However, used appropriately, it should not cause addiction. As diamorphine is more soluble than morphine it can be injected in smaller volumes; this is an advantage in cachectic patients and for subcutaneous use.

Codeine Codeine is methylmorphine and the methyl group at the C3 position increases the oral bioavailability of the compound, but as it is less effective than morphine it is used for mild to moderate pain.

Interestingly, however, when 60mg codeine is combined with mg paracetamol the NNT drops to 2. Codeine has a low abuse potential and is often used in oral preparations in combination with non-opioid narcotics. The side-effect profile of codeine, a weak opioid, is the same as with a strong opioid.

Dihydrocodeine Dihydrocodeine, is a synthetic opioid analgesic which was developed in the early s. Its structure and pharmacokinetics are similar to codeine and it is used for the treatment of postoperative pain and as an antitussive. Innearly one tenth of all analgesic preparations issued in England were for dihydrocodeine [4]. A single 30mg oral dose of dihydrocodeine does not provide effective analgesia and a 60mg dose is significantly less effective than ibuprofen mg.

Therefore, patients should be offered a more effective analgesic in the treatment of postoperative pain [4]. Doses in excess of the recommended mg every 4 hours may be associated with nausea and vomiting. Pethidine The phenylpiperidine compound pethidine is an effective analgesic but some of its clinical effects are quite different from morphine. It is shorter acting than morphine and produces less sedation and pupillary constriction than morphine; the latter is related to an atropine-like effect, which also results in the patient having a dry mouth.

Based on small numbers of patients, pethidine 50mgs does not appear to offer effective pain relief. In the cardiovascular system blood pressure may fall with pethidine and a tachycardia may be observed.

Pethidine is metabolised in the liver and one metabolite, norpethidine, may accumulate with prolonged or high dosage or with impaired renal clearance, producing tremor, twitching, agitation and convulsions [6].

Pethidine should not be used in patients who have recently taken monoamine oxidase inhibitors as a serious interaction can develop with convulsions and coma, unstable blood pressure and high temperatures.

Due to its high first pass metabolism, oral pethidine is similar in potency to codeine. Therefore, given that pethidine is not associated with any specific advantage over morphine, it is a poor choice if multiple doses are needed [7]. Fentanyl Fentanyl is a synthetic opioid agonist that is related to the phenylpiperidines.

It is a highly potent and lipid-soluble opioid, which is mainly used by intravenous injection as a component of general anaesthesia. As an analgesic it is some times more potent than morphine.

A single intravenous dose of fentanyl has a more rapid action 5 - 6 minutes than morphine, reflecting the greater lipid solubility, which also accounts for a rapid redistribution around the body and a short duration of effect.

With multiple doses or continuous infusions of fentanyl, saturation of the body tissues may occur and the duration of effect and side effects such as ventilatory depression may be prolonged. Fentanyl does not affect arterial blood pressure; even with high doses histamine is not released, but cardiac output can fall due to bradycardia.

Secondary peaks in plasma fentanyl concentration can occur, with respiratory depression, due to gastric sequestration or release from muscle or the lungs after anaesthesia.

Fentanyl can be used safely by epidural administration for postoperative pain relief as localisation in the fatty tissues and rapid absorption into the blood stream of the spinal cord prevents rostral spread, i. It has also been shown to be beneficial when combined with bupivacaine for wound infiltration [8]. Tramadol Tramadol is aphenyl-substituted aminometyl-cyclohexanol derivative. It is classed as a weak opioid and as such is often used as a step-down analgesic from morphine.

It appears to be a useful analgesic with minimal sedative effects or abuse potential, but it is weaker than morphine [9]. A dose of mg has an NNT of 4.

Codeine - Wikipedia

The mechanism of action of tramadol is not understood fully, but it is an agonist at opioid receptors and also has a spinal action on noradrenergic pathways. Tramadol inhibits neural uptake of noradrenaline and serotonin. Tramadol is available in oral and parenteral forms.

morphine and codeine relationship problems

In general they are weaker analgesics than the pure agonists and so have not found widespread use in clinical practice.

In contrast to the linear dose-response relationship of the pure agonists, this group tends to have a ceiling to their analgesic effect and an increase in dose may only result in more side-effects. Pentazocine Pentazocine is a benzomorphan derivative and has a quarter of the analgesic potency of morphine.

It is most often used for the relief of mild to moderate pain and can be given in similar doses orally or by injection.