Tag Archive: Morphine


Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events.

CYP = cytochrome P450; M1 = O-desmethyltramadol; M3G = morphine-3-glucuronide; M6G = morphine-6-glucuronide; UGT = uridine diphosphate glucuronosyltransferase

Opioids are a cornerstone of the management of cancer pain1 and postoperative pain2 and are used increasingly for the management of chronic noncancer pain.3,4 Understanding the metabolism of opioids is of great practical importance to primary care clinicians. Opioid metabolism is a vital safety consideration in older and medically complicated patients, who may be taking multiple medications and may have inflammation, impaired renal and hepatic function, and impaired immunity. Chronic pain, such as lower back pain, also occurs in younger persons and is the leading cause of disability in Americans younger than 45 years.5 In younger patients, physicians may be more concerned with opioid metabolism in reference to development of tolerance, impairment of skills and mental function, adverse events during pregnancy and lactation, and prevention of abuse by monitoring drug and metabolite levels.

Experienced clinicians are aware that the efficacy and tolerability of specific opioids may vary dramatically among patients and that trials of several opioids may be needed before finding one that provides an acceptable balance of analgesia and tolerability for an individual patient.69 Pharmacodynamic and pharmacokinetic differences underlie this variability of response. Pharmacodynamics refers to how a drug affects the body, whereas pharmacokinetics describes how the body alters the drug. Pharmacokinetics contributes to the variability in response to opioids by affecting the bioavailability of a drug, the production of active or inactive metabolites, and their elimination from the body. Pharmacodynamic factors contributing to variability of response to opioids include between-patient differences in specific opioid receptors and between-opioid differences in binding to receptor subtypes. The receptor binding of opioids is imperfectly understood; hence, matching individual patients with specific opioids to optimize efficacy and tolerability remains a trial-and-error procedure.69

This review primarily considers drug metabolism in the context of pharmacokinetics. It summarizes the basics of opioid metabolism; discusses the potential influences of patient-specific factors such as age, genetics, comorbid conditions, and concomitant medications; and explores the differences in metabolism between specific opioids. It aims to equip physicians with an understanding of opioid metabolism that will guide safe and appropriate prescribing, permit anticipation and avoidance of adverse drug-drug interactions, identify and accommodate patient-specific metabolic concerns, rationalize treatment failure, inform opioid switching and rotation strategies, and facilitate therapeutic monitoring. To that end, recommendations for tailoring opioid therapy to individual patients and specific populations will be included.

METHODS

Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed databases for literature published between January 1980 and June 2008. The opioid medication search terms used were as follows: codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, opioid, opioid analgesic, oxycodone, oxymorphone, and tramadol. Each medication search term was combined with the following general search terms: metabolism, active metabolites, pharmacokinetics, lipophilicity, physiochemical properties, pharmacology, genetics, receptor, receptor binding, receptor genetics or variation, transporter, formulations, AND adverse effects, safety, or toxicity. The reference lists of relevant papers were examined for additional articles of interest.

BASICS OF OPIOID METABOLISM

Metabolism refers to the process of biotransformation by which drugs are broken down so that they can be eliminated by the body. Some drugs perform their functions and then are excreted from the body intact, but many require metabolism to enable them to reach their target site in an appropriate amount of time, remain there an adequate time, and then be eliminated from the body. This review refers to opioid metabolism; however, the processes described occur with many medications.

Altered metabolism in a patient or population can result in an opioid or metabolite leaving the body too rapidly, not reaching its therapeutic target, or staying in the body too long and producing toxic effects. Opioid metabolism results in the production of both inactive and active metabolites. In fact, active metabolites may be more potent than the parent compound. Thus, although metabolism is ultimately a process of detoxification, it produces intermediate products that may have clinically useful activity, be associated with toxicity, or both.

Opioids differ with respect to the means by which they are metabolized, and patients differ in their ability to metabolize individual opioids. However, several general patterns of metabolism can be discerned. Most opioids undergo extensive first-pass metabolism in the liver before entering the systemic circulation. First-pass metabolism reduces the bioavailability of the opioid. Opioids are typically lipophilic, which allows them to cross cell membranes to reach target tissues. Drug metabolism is ultimately intended to make a drug hydrophilic to facilitate its excretion in the urine. Opioid metabolism takes place primarily in the liver, which produces enzymes for this purpose. These enzymes promote 2 forms of metabolism: phase 1 metabolism (modification reactions) and phase 2 metabolism (conjugation reactions).

Phase 1 metabolism typically subjects the drug to oxidation or hydrolysis. It involves the cytochrome P450 (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.

FACTORS INFLUENCING OPIOID METABOLISM

Metabolic Pathways

Opioids undergo phase 1 metabolism by the CYP pathway, phase 2 metabolism by conjugation, or both. Phase 1 metabolism of opioids mainly involves the CYP3A4 and CYP2D6 enzymes. The CYP3A4 enzyme metabolizes more than 50% of all drugs; consequently, opioids metabolized by this enzyme have a high risk of drug-drug interactions. 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 fentanyl10 and oxycodone,11 although normally a small portion of oxycodone undergoes CYP2D6 metabolism to oxymorphone (Table 11018). Tramadol undergoes both CYP3A4- and CYP2D6-mediated metabolism.16 Methadone is primarily metabolized by CYP3A4 and CYP2B6; CYP2C8, CYP2C19, CYP2D6, and CYP2C9 also contribute in varying degrees to its metabolism.1923 The complex interplay of methadone with the CYP system, involving as many as 6 different enzymes, is accompanied by considerable interaction potential.

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).24,25 Administration of CYP3A4 substrates or inhibitors can increase opioid concentrations, thereby prolonging and intensifying analgesic effects and adverse opioid effects, such as respiratory depression. Administration of CYP3A4 inducers can reduce analgesic efficacy.10,11,16 In addition to drugs that interact with CYP3A4, bergamottin (found in grapefruit juice) is a strong inhibitor of CYP3A4,26 and cafestol (found in unfiltered coffee) is an inducer of the enzyme.27

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.16 This risk is most pronounced when tramadol is administered concurrently with potent CYP3A4 inducers, such as carbamazepine, or with selective serotonin reuptake inhibitors, tricyclic antidepressants, or other medications with additive serotonergic effects.16

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TABLE 1. 

Metabolic Pathway/Enzyme Involvement

The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone,14 codeine,13 and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively), which in turn undergo phase 2 glucuronidation. These opioids (and to a lesser extent oxycodone, tramadol, and methadone) have interaction potential with selective serotonin reuptake inhibitors, tricyclic antidepressants, β-blockers, and antiarrhythmics; an array of other drugs are substrates, inducers, or inhibitors of the CYP2D6 enzyme (Table 328).

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. An estimated 5% to 10% of white people possess allelic variants of the CYP2D6 gene that are associated with reduced clearance of drugs metabolized by this isoenzyme,2931 and between 1% and 7% of white people carry CYP2D6 allelic variants associated with rapid metabolism.32,33 The prevalence of poor metabolizers is lower in Asian populations (≤1%)34 and highly variable in African populations (0%-34%).3539 The prevalence of rapid metabolizers of opioids has not been reported in Asian populations; estimates in African populations are high but variable (9%-30%).35,36

The clinical effects of CYP2D6 allelic variants can be seen with codeine administration. 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.40 Allelic variants altering CYP2D6-mediated metabolism can be associated with reduced efficacy of hydrocodone or increased toxicity of codeine, each of which relies entirely on the CYP2D6 enzyme for phase 1 metabolism.41,42 In patients treated with oxycodone, which relies on CYP3A4 and to a lesser extent on CYP2D6, inhibition of CYP2D6 activity by quinidine increases noroxycodone levels and reduces oxymorphone production. In one study, such alterations were not accompanied by increased adverse events.30 However, individual cases of reduced oxycodone efficacy42 or increased toxicity41 in CYP2D6 poor metabolizers have been reported.

Phase 2 Metabolism

Morphine, oxymorphone, and hydromorphone are each metabolized by phase 2 glucuronidation17,18,43 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.43 Of course, pharmacodynamic drug-drug interactions are possible with all opioids, such as additive interactions with benzodiazepines, antihistamines, or alcohol, and antagonistic interactions with naltrexone or naloxone.

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TABLE 2. 

Cytochrome P450 3A4 Substrates, Inhibitors, and Inducers

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)12,44 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.45 Moreover, preliminary data indicate that UGT2B7 metabolism of morphine may be potentiated by CYP3A4, although the clinical relevance of this finding is unknown.4648

The activity of UGT2B7 shows significant between-patient variability, and several authors have identified allelic variants of the gene encoding this enzyme.12,44 Although the functional importance of these allelic variants with respect to glucuronidation of opioids is unknown, at least 2 allelic variants (the UGT2B7-840G and -79 alleles) have been linked to substantial reduction of morphine glucuronidation, with resulting accumulation of morphine and reduction in metabolite formation.49,50 Moreover, research has shown that variation in the amount of messenger RNA for hepatic nuclear factor 1α, a transcription factor responsible for regulating expression of the UGT2B7 gene, is associated with interindividual variation in UGT2B7 enzyme activity.51

Clinical Implications of Metabolic Pathways

Most opioids are metabolized via CYP-mediated oxidation and have substantial drug interaction potential. 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.69 In some patients, the most effective and well-tolerated opioid will be one that undergoes CYP-mediated metabolism. For example, in a 2001 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. Adequate analgesia with acceptable tolerability was obtained in 40 (80%) of these patients.52

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TABLE 3. 

Cytochrome P450 2D6 Substrates, Inhibitors, and Inducers

In short, for some patients, selecting an opioid without considerable potential for drug interactions may not be possible. 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.

PRODUCTION OF ACTIVE METABOLITES

Some opioids produce multiple active metabolites after administration (Table 410,11,1618,28,43,5360). Altered metabolism due to medical comorbidities, genetic factors, or drug-drug interactions may disrupt the balance of metabolites, thereby altering the efficacy and/or tolerability of the drug. Moreover, opioids that produce metabolites chemically identical to other opioid medications may complicate the interpretation of urine toxicology screening.

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 metabolite42 and in rapid metabolizers who form too much morphine.61,62 In fact, a recent study found that adverse effects of codeine are present irrespective of morphine concentrations in both poor and rapid metabolizers,63 suggesting that a substantial proportion of patients with CYP2D6 allelic variants predisposing to poor or rapid codeine metabolism will experience the adverse effects of codeine without benefitting from any of its analgesic effects. Codeine is also metabolized by an unknown mechanism to produce hydrocodone in quantities reaching up to 11% of the codeine concentration found in urinalysis.58 The clinical effect of the hydrocodone metabolite of codeine is unknown.

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-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). 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.

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TABLE 4. 

Major Opioid Metabolites

Like morphine, M6G is a μ-opioid receptor agonist with potent analgesic activity. However, morphine has greater affinity than M6G for the μ2-opioid receptor thought to be responsible for many of the adverse effects of μ-receptor agonists,64,65 most notably respiratory depression, gastrointestinal effects, and sedation.65,66 Although the affinities of morphine and M6G for the μ1-opioid receptor are similar, a study of low-dose morphine, M6G, and M3G found that morphine had greater analgesic efficacy.67 The M3G metabolite of morphine lacks analgesic activity, but it exhibits neuroexcitatory effects in animals and has been proposed as a potential cause of such adverse effects as allodynia, myoclonus, and seizures in humans.6870 In a clinical trial, however, low-dose M3G exhibited no analgesic effects, did not potentiate the analgesic effects of morphine or M6G, and did not produce adverse effects.67

Clinical data regarding morphine and its glucuronide metabolites are unclear. Two studies found no correlation between plasma concentrations of morphine, M6G, or M3G in either clinical efficacy or tolerability.71,72 Moreover, in patients with impaired renal function, the pharmacokinetics of morphine appear to be less affected than that of its M6G and M3G metabolites, which were found to accumulate.7376 Although M6G appears to be better tolerated than morphine, increased toxicity in patients with reduced clearance was primarily related to the accumulation of the M6G metabolite.

Hydromorphone

The production of active metabolites is also an issue with hydromorphone. The primary metabolite of hydromorphone, hydromorphone-3-glucuronide, has neuroexcitatory potential similar to68,70 or greater than69 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.3,4

Tramadol

Like codeine, tramadol requires metabolism to an active metabolite, O-desmethyltramadol (M1), to be fully effective. The parent compound relies on both CYP3A4 and CYP2D6, with metabolism of M1 relying on CYP2D6.16 In a group of patients receiving multiple medications and treated with tramadol under steady-state conditions, the concentration of M1 after correcting for dose and the M1/ tramadol ratio were each approximately 14-fold higher in patients with a CYP2D6 allelic variant associated with extensive metabolism than in poor metabolizers.77 Both tramadol and its M1 metabolite exert analgesic effects through opioidergic mechanisms (μ-opioid receptor) and through 2 nonopioidergic mechanisms, serotonin reuptake inhibition and norepinephrine reuptake inhibition. Although M1 has more potent activity at the μ-opioid receptor,16,78 tramadol is the more potent inhibitor of serotonin and norepinephrine reuptake and the more potent promoter of serotonin and norepinephrine efflux.79,80 Although the precise function of M1 in humans remains unclear, tramadol-mediated analgesia appears to depend on the complementary contributions of an active metabolite with a route of metabolism that differs from that of the parent compound.

Oxycodone

Oxycodone is metabolized by CYP3A4 to noroxycodone and by CYP2D6 to oxymorphone.11 Noroxycodone is a weaker opioid agonist than the parent compound, but the presence of this active metabolite increases the potential for interactions with other drugs metabolized by the CYP3A4 pathway. The central opioid effects of oxycodone are governed primarily by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites.81 Oxymorphone is present only in small amounts after oxycodone administration, making the clinical relevance of this metabolite questionable. 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.41 The authors of this report suggested that failure to metabolize oxycodone to oxymorphone may have been associated with accumulation of oxycodone and noroxycodone, resulting in an inability to tolerate therapy.

OPIOIDS WITHOUT CLINICALLY RELEVANT ACTIVE METABOLITES

Fentanyl, oxymorphone, and methadone do not produce metabolites that are likely to complicate treatment. Fentanyl is predominantly converted by CYP3A4-mediated N-dealkylation to norfentanyl, a nontoxic and inactive metabolite; less than 1% is metabolized to despropionylfentanyl, hydroxyfentanyl, and hydroxynorfentanyl, which also lack clinically relevant activity.82 An active metabolite of oxymorphone, 6-hydroxy-oxymorphone, makes up less than 1% of the administered dose excreted in urine and is metabolized via the same pathway as the parent compound, making an imbalance among metabolites unlikely.18 Methadone does not produce active metabolites, exerting its activity—both analgesic and toxic—through the parent compound. However, methadone has affinity for the N-methyl-d-aspartate receptors83; 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.8486

ADHERENCE MONITORING: THE IMPORTANCE OF ACTIVE METABOLITES

Opioids that produce active metabolites structurally identical to other opioid medications can complicate efforts to monitor patients to prevent abuse and diversion. 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.87 However, in patients taking only codeine, the codeine-to-morphine ratio is less than 6, even in rapid metabolizers.87,88 Additionally, morphine alone may be detectable in the urine 30 hours after ingestion of a single dose of codeine.8992

The urine of patients treated with morphine may contain small amounts of hydromorphone (≤2.5% of the morphine concentration).53,54 Similarly, those treated with hydrocodone may test positive for both hydrocodone and hydromorphone, making it difficult to determine whether the parent opioid was taken as prescribed or a second opioid is being abused.

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-demethylation), 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, is unaffected by pH and is therefore preferable for assessing adherence to therapy.93,94

POPULATION PHARMACOKINETICS

Opioid metabolism differs with individual opioids in populations stratified according to age, sex, and ethnicity (Table 510,11,1318,43). Reduced clearance of morphine,43 codeine,13 fentanyl,10 and oxymorphone18 has been reported in older patients. Oxycodone concentrations are approximately 25% higher in women than in men after controlling for differences in body weight, making it important for physicians to consider the patient’s sex when prescribing this opioid.11 Chinese patients have higher clearance and lower concentrations of morphine.43 Similarly, codeine is a prodrug that exerts its analgesic effects after metabolism to morphine. Morphine concentrations were shown to be reduced in Chinese patients treated with codeine, providing confirmation of altered morphine metabolism in this large population.95 As already stated, altered opioid metabolism in ethnic populations is also a byproduct of allelic variants of the gene encoding CYP2D6,32,33,41 particularly in African populations.3539 Ethnic differences in the gene encoding UGT2B7 have also been identified, but these have not been associated with clinical differences in enzyme activity.44

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TABLE 5. 

Demographic/Medical Factors Influencing Opioid Metabolism

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 oxymorphone18 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.96,97

MEDICAL CONDITIONS

Hepatic Impairment

The liver is the major site of biotransformation for most opioids (Table 4). It is therefore not surprising that the prescribing information for most frequently prescribed opioids recommends caution in patients with hepatic impairment.10,11,13,14,17,18,43 For example, in patients with moderate to severe liver disease, peak plasma levels of oxycodone and its chief metabolite noroxycodone were increased 50% and 20%, respectively, whereas the area under the plasma concentration-time curve for these molecules increased 95% and 65%.11 Peak plasma concentrations of another active metabolite, oxymorphone, were decreased by 30% and 40%, respectively. 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.41 The differential effect of hepatic impairment on the metabolism of oxycodone relative to its active metabolite illustrates the complexities associated with opioids that have multiple active metabolites.

Hepatic impairment may also affect metabolism of opioids that undergo glucuronidation rather than CYP-mediated metabolism, such as morphine and oxymorphone. In a 1990 study, the elimination half-life and peak plasma concentrations of morphine were significantly increased in 7 patients with severe cirrhosis.98 The bioavailability of morphine in these patients was 101% compared with approximately 47% observed in healthy participants. 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. Hepatic extraction was 25% lower in patients with cirrhosis.99 This reduction was attributed to reduced enzyme capacity rather than to impairment in blood flow. 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 1.6-fold and 3.7-fold in patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment, respectively, compared with healthy controls. In 1 patient with severe hepatic impairment (Child-Pugh class C), the bioavailability was increased by 12.2-fold.18

The pharmacokinetics of fentanyl100 and methadone,101 2 of the frequently used opioids, are not significantly affected by hepatic impairment. 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 0.75 to 0.9 mL/min annually beginning at age 30 to 40 years.102,103 At this rate, a person aged 80 years will have approximately two-thirds of the renal function expected in a person aged 20 or 30 years.102104 Because most opioids are eliminated primarily in urine, dose adjustments are required in patients with renal impairment.10,11,13,1618,43

However, the effects of renal impairment on opioid clearance are neither uniform nor clear-cut. For example, morphine clearance decreases only modestly in patients with renal impairment, but clearance of its M6G and M3G metabolites decreases dramatically.105107 Accumulation of morphine glucuronides in patients with renal impairment has been associated with serious adverse effects, including respiratory depression, sedation, nausea, and vomiting.73,74,108 Similarly, patients with chronic renal failure who receive 24 mg/d of hydromorphone may have a 4-fold increase in the molar ratio of hydromorphone-3-glucuronide to hydromorphone.109 Conversely, in patients treated with oxycodone, renal impairment increases concentrations of oxycodone and noroxycodone by approximately 50% and 20%, respectively.11 Although renal impairment affects oxycodone more than morphine, there is no critical accumulation of an active metabolite that produces adverse events.11 Thus, selecting an opioid in patients with renal impairment requires an understanding not only of the anticipated changes in concentrations of the opioid and its metabolites but also of the differential effects of parent compounds and metabolites when they accumulate.

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 dialysis110; in anuric patients, methadone excretion in the feces may be enhanced with limited accumulation in plasma.111 However, for patients with stage 5 chronic kidney disease, the prudent approach remains to begin with very low doses, monitor carefully, and titrate upward slowly. 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.112 However, despite limited pharmacokinetic data, hepatic clearance and extraction of drugs with high hepatic extraction ratios (eg, fentanyl) could potentially be inhibited by uremia113; the theoretical potential for accumulation of fentanyl in patients with hepatic impairment makes caution advisable when prescribing opioids to these patients.

CLINICAL IMPLICATIONS OF MEDICAL CONDITIONS

The selection of an opioid analgesic may be affected by comorbidities and diminished organ reserve. Health care professionals need to be especially cautious when dealing with patients with diminished metabolic capacities due to organ dysfunction. In general, dose reduction and/or prolongation of dose intervals may be necessary depending on the severity of organ impairment. Moreover, clinicians should adopt a “start low and go slow” approach to opioid titration when hepatic or renal impairment is a factor.

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.18 Among opioids undergoing CYP-mediated metabolism, fentanyl100 and methadone101 appear to be less affected by liver disease. Nonetheless, data on these opioids are limited, making caution and conservative dosing advisable in this population.

In patients with substantial chronic kidney disease (stages 3-5), clinicians 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.73,74,108,114,115 Several authors have suggested that fentanyl and methadone are preferred in end-stage renal disease112,116; however, this advice needs to be tempered by the challenges inherent in dosing potent opioids in patients with poor renal function.

CONCLUSION

Patient characteristics and structural differences between opioids contribute to differences in opioid metabolism and thereby to the variability of the efficacy, safety, and tolerability of specific opioids in individual patients and diverse patient populations. 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.

Acknowledgments

Jeffrey Coleman, MA, of Complete Healthcare Communications (Chadds Ford, PA) provided research and editorial assistance for the development of the submitted manuscript, with support from Endo Pharmaceuticals (Chadds Ford, PA).

This article is freely available on publication.

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10.000 Drogenkranke werden in Österreich mit Ersatzdrogen therapiert. Ein Millionengeschäft für nur sehr wenige Anbieter von Substitutions-Mitteln, die sich nun ein Match um Marktanteile liefern.

Wien. 30.000 Österreicher sind süchtig nach Opiaten wie beispielsweise Heroin. 9828 davon befanden sich Ende 2008 in einer sogenannten Substitutionstherapie mit Ersatzdrogen. Statt den Stoff von der Straße (mit allen seinen Nebenwirkungen) konsumieren die Patienten vom Arzt verschriebene Medikamente. Weil nun durchsickerte, dass im Gesundheitsministerium einmal mehr darüber nachgedacht wird, ob bestimmte Medikamente anderen vorzuziehen und wieder andere gar zu verbieten wären, ist zwischen den Herstellern der Präparate ein Kampf um Marktanteile ausgebrochen.

Es geht ums Geld. Ein Millionen-Euro-Geschäft um eine sichere, weil süchtige Kundschaft, um das nur eine Handvoll Anbieter rittert. Vereinfacht dargestellt verläuft die Frontlinie zwischen den beiden Unternehmen Mundipharma (Jahresumsatz 2007: 25 Mio. Euro) und Aesca Pharma (59 Mio.). Das Mundipharma-Produkt Substitol hat in Österreich einen Marktanteil von 62 Prozent (Quelle: Agentur für Gesundheit und Ernährungssicherheit, Ages) und beschert dem Unternehmen ein Drittel des Umsatzes. Aesca kommt mit seinen Produkten Subutex und Suboxone zusammen auf 21 Prozent. Den Rest teilen sich Compensan von Lannacher (16 Prozent) und Kapanol von GlaxoSmithKline (ein Prozent). Weil Methadon direkt in Apotheken abgemischt wird, liegen der Ages dafür keine Zahlen zum Marktanteil vor. Insgesamt gaben die Sozialversicherungen 2007 20 Millionen Euro für Ersatzdrogen aus.Aesca stört nun, dass Österreichs Ärzte ihren Suchtpatienten nach wie vor häufig Substitol und Compensan, zwei sogenannte „retardierte Morphine“, verschreiben. Und das, obwohl ihre eigenen Produkte mit dem Wirkstoff Buprenorphin von der derzeit gültigen Verordnung des Gesundheitsministeriums als „Mittel erster Wahl“ bezeichnet werden.

Offenbar in der Hoffnung, mithilfe von medialem Druck in der geplanten Neufassung der Verordnung retardierte Morphine überhaupt zu verbieten, füttert Aesca über die Vermittlung einer PR-Agentur seit einiger Zeit Journalisten mit „Hintergrunddossiers“ über die Vorzüge der eigenen und die Nachteile der Konkurrenzprodukte von Mundipharma und Lannacher. Zum Teil mit Erfolg. In manchen Medien werden retardierte Morphine bereits als „Problemdrogen“ dargestellt. Im Zentrum der Kritik steht das relativ hohe Missbrauchspotenzial von retardierten Morphinen, die wegen möglicher Mehrfachverschreibungen von Ärzten und ihrer „kick“-ähnlichen Wirkung von Süchtigen gerne am Schwarzmarkt ver- und gekauft werden.

Dabei ist objektiv keines der genannten Medikamente besser oder schlechter, gefährlicher oder sicherer als das andere: Das sagt zumindest Marcus Müllner, Bereichsleiter für Arzneimittelsicherheit bei der Ages, die regelmäßig Ärzteberichte, Studien, Fachartikel und Pressemeldungen zum Thema analysiert. Interessant am Ages-Bericht ist auch, dass 2008 nur zwei ärztliche Meldungen über (geringfügige) Nebenwirkungen von Ersatzdrogen einlangten. Beide betrafen Suboxone von Aesca.

Ein der „Presse“ bekannter Arzt, der zahlreiche Suchtpatienten betreut, erinnert sich in diesem Zusammenhang an eine „seltsame Strategieänderung“ der Aesca-Vertreter, die ihn in den vergangenen Jahren regelmäßig aufsuchten, um die Vorzüge der eigenen Medikamente zu bewerben. Nachdem man jahrelang die angebliche Sicherheit von Subutex gegenüber den retardierten Morphinen in den Vordergrund gestellt hatte, legten die Vertreter dem Arzt bei ihrem letzten Besuch Studien vor, die plötzlich das hohe Missbrauchspotenzial von Subutex beschrieben und gleichzeitig die Vorzüge des direkten Nachfolgers Suboxone priesen.

Ärztekritik an Politvorschriften

Während die Politik die Entscheidung über bevorzugte Medikamente (und damit Marktanteile) hinausschiebt, wollen sich die Ärzte nicht mehr verunsichern lassen. Die Österreichische Gesellschaft für arzneimittelgestützte Behandlung von Suchtkrankheit (ÖGABS) hat daher ein (noch nicht veröffentlichtes) Grundsatzpapier erstellt, das auf Grundlage unabhängiger Studien feststellt, dass keines der am Markt befindlichen Medikamente generell besser oder schlechter ist als das andere.

Der Wiener Allgemeinmediziner Horst Schalk, der auch Drogenpatienten betreut, beschreibt das dann so: „Die Patienten sind verschieden und sprechen auf unterschiedliche Medikamente unterschiedlich an. Ein Arzt sollte seinen Patienten daher die Präparate verschreiben, auf die der Patient am besten anspricht

quelle:diepresse.com/home/panorama/oesterreich/477270/index.do

Rationalization and denial are key concepts in addiction treatment. To recover, addicts admit they have rationalized their habit („I use so much less than my friends.“) and denied they have a problem („I can handle it. It’s not affecting my job.“)
Here’s another barrier to recovery from addiction: „I’m too smart for this to become a problem.“

This week’s Journal of the American Medical Assn., contains a sad essay from a medical researcher who made headlines last year when his fiancee, also a medical researcher, died after the two injected themselves with what they thought was the narcotic buprenorphine for kicks.

The author of the essay, Clinton B. McCracken, a former pharmacologist at the University of Maryland, describes how he became a user of marijuana and intravenous opioids (morphine and oxycodone) over a decade while building his career as a successful neuroscientist who studied the effects of drugs on the brain.

He notes that people who work in medicine have addiction rates that are equal to, if not higher than, rates among the public. Drugs are easier to get, McCracken said. But he said an attitude of arrogance led him, as a medical professional, to believe that he could enjoy dangerous drugs and avoid serious consequences. For example, he was careful to schedule his opioid use to prove to himself that he did not need it to get through the day, made sure he was tending to his responsibilities at work and reviewed the criteria for drug dependence to assure himself that he was not an addict.

„By intellectually addressing the official criteria for abuse and dependence, I provided myself with the illusion of total control over the situation and was able to confidently tell myself that no problems existed,“ he wrote in the essay.

His world came crashing down last fall when his fiancee died while injecting Drugs with him. When the police arrived, they discovered McCracken’s Mariuhana plants. He was arrested and jailed, and he later agreed to a plea bargain to avoid more serious charges. Besides losing his girlfriend, he has since lost his career, his reputation and, as a citizen of Canada and convicted felon, he expects to be deported.

Addiction may look different in different people, but it seems that, in the end, everyone, no matter the level of intelligence, looks the same — ruined.

„The transition from my drug use having no apparent negative consequences, to both my personal and professional life being damaged possibly beyond repair, was so fast as to be instantaneous, highlighting the fact that when it comes to drug use, the perception of control is really nothing more than an illusion,“ he wrote.

— Shari Roan
May 20, 2010

Here is the „sad essay“ :

Health care professionals and physicians in particular have rates of substance abuse that are equal to and often exceed those observed in the general public.These estimates may even be low, as many studies rely on self-reported data. Health care professionals presumably use drugs for many of the same reasons as those of the general population.

Nonetheless, given the intelligence, years of education, and high levels of achievement found in this group, the relatively high incidence of substance abuse may be somewhat surprising. Ease of access to drugs is commonly cited, particularly with respect to the high rates of drug abuse among anesthesiologists; however, given the complex nature of addiction, the underlying causes are assuredly myriad.

One possible contributing factor that may receive insufficient attention is the ability of highly educated professionals to intellectualize their drug use, minimizing in their mind the potential disastrous consequences, both personal (eg, the possibility of death or serious harm due to factors such as overdose or toxicity, among others) and professional (ranging from a tarnished reputation to a ruined career). This intellectualization is particularly insidious because due to its very nature, it prevents the person from realizing the scope of the problem, or even admitting a problem exists. Thus, it is related to, yet distinct from, the phenomena of rationalization and denial. Rationalization and denial are universal components of substance abuse and unaffected by education or training.

By contrast, intellectualization actually relies on advanced education and training, particularly with respect to the effects of drugs and addiction, also incorporating confidence in one’s intelligence and abilities, and no small measure of arrogance, to provide the illusion of control or mastery. The end result of this intellectualization is the manifestation of hubris that produces blindness to the devastating consequences of drug abuse and addiction.

Here, I draw on my experience as a drug abuser who for years maintained a relatively successful career as a basic biomedical scientist studying the neuroscience of addiction and compulsion to present a cautionary tale regarding the extreme dangers of intellectualizing drug use. No matter how well versed one may be in pharmacology or the addictive process, the fact remains that severe problems due to drug abuse can arise almost instantly, and no matter how in control one may believe himself to be, these problems can lead to tragic and irreversibly life-altering consequences.

In my case, this intellectualization occurred on three main levels.

The first related to my drug use patterns. I was a daily user of cannabis for most of the past decade, and an intermittent user of opioids, primarily via the intravenous route, for approximately three years. This use occurred while I pursued a career in basic science research, with a heavy focus on addiction. Consequently, I was intimately familiar with the drug abuse literature and psychiatric diagnostic manuals such as the DSM-IV. I was able to finish my doctorate and conduct research at a high level at the same time I was a regular drug user.

Mindful of the DSM-IV criteria for substance abuse and dependence, I was able to rationalize my drug use in a number of different ways, all with the similar end result of deluding myself into thinking I did not have a problem. First among these was that I was able to maintain a high level of professional achievement while using drugs. In addition, I was able to form and maintain a number of fulfilling personal relationships over this time period. As such, I felt that I was not suffering dire consequences in my personal and professional lives. I was able to tell myself that those items on the DSM-IV clearly did not apply to my situation, and hence no problem existed. I used similar reasoning for other items on the DSM-IV checklists for substance abuse and dependence.

I identified my daily marijuana use as „stable“ for some time (ie, years), and I was able to cease use for weeks at a time without any serious difficulty. Thus, any worries of tolerance (ie, increased use over time) or dependence (ie, withdrawal symptoms upon cessation of use) were minimized. With respect to opioids, I was keenly aware of the potential for these drugs to produce tolerance and dependence and thus restricted my use to no more than two consecutive days spaced no closer than 2 or 3 months apart.

By intellectually addressing the official criteria for abuse and dependence, I provided myself with the illusion of total control over the situation and was able to confidently tell myself that no problems existed. This was in spite of the fact that my ongoing drug use was jeopardizing not only my health, but my career.

I was also able to intellectually justify using opioids via the intravenous route. My first experience with opioid medication came after they were prescribed for pain following an injury. I enjoyed the effects and began to seek other sources to attain these drugs. Although I was acutely aware that these drugs had strong potential to cause tolerance and dependence, I was secure in my ability to control the situation. So why inject? I initially began using these drugs via the IV route primarily to maximize bioavailability.

Many opioids, and morphine in particular, possess only a fraction of their IV bioavailability when taken orally. The euphoria due to rapid drug onset via the IV route (ie, the „rush“) was another attractive factor. While I was aware that IV use presented dangers when compared with oral administration, such as increased risk of overdose, infection, or embolism, I was confident that my technical experience (having performed injections into small-animal blood vessels) and access to sterile needles, sterile syringes, sterile saline as a diluent, and alcohol swabs would allow me to circumvent many of the typical problems associated with IV administration. In hindsight, in my overconfidence I minimized one of the key dangers of IV use—the fact that the extremely rapid onset can lead to irreversible effects if things should happen to go wrong.

The final method by which I was able to intellectualize my drug use dealt with the means by which I obtained drugs. I rationalized that small-scale marijuana cultivation was less risky than purchasing it and was associated with a relatively minimal risk of discovery and associated arrest. I obtained opioids (primarily morphine and oxycodone) from an overseas online pharmacy. In addition to less risk of arrest, I made the assumption that dosage would be more consistent and the chance of adulteration much lower than drugs purchased on the street, thus reducing the risk of possible overdose. Furthermore, in the initial stages of opioid use, I proceeded extremely cautiously to ensure the drugs I received from overseas were what they purported to be. After satisfying myself that this was indeed the case, at least at the beginning, I assumed that this form of quality control was no longer necessary.

There were no acute problems stemming from my drug use for approximately three years. My fiancée, a successful scientist in her own right, and with whom virtually all of my intravenous drug use occurred over the previous three years, lost her life after injecting a product that produced severe anaphylaxis, most likely due to some form of contamination. While waiting for the paramedics to arrive I tried unsuccessfully to resuscitate her. Despite heroic efforts, neither the paramedics nor the emergency department physicians were able to revive her.

As a consequence of her death, our house was searched by police, who then discovered the ongoing marijuana cultivation. I was immediately arrested, jailed, and charged with a number of felonies; then, in the space of a few days, my employment as a postdoctoral fellow was summarily terminated and I was evicted from my residence.

The impact of these events on my life has been enormous. First and foremost is the loss of the woman I loved, my best friend and partner, with whom I had planned to spend the rest of my life. Not only were we a team in the sense of personal life, but also professionally. We worked in the same field, attended the same meetings, and were well known as a couple in our part of the scientific community. Thus, my relationship with her came to define all aspects of both my work life and my home life.

Coming to terms with her loss has proven to be extremely challenging and will likely remain so for a long time. While paling completely compared to the loss of my fiancée, I face a number of other consequences. For one, my career as an academic research scientist has been undeniably derailed, if not destroyed. Reputation is critical in my field, and mine is likely to be damaged for the foreseeable future. I originally faced substantial time in prison; I was able to agree to a plea bargain whereby I avoided any additional incarceration. However, I have now been convicted of a felony, which will undoubtedly have a severely negative effect on any future job prospects and international travel. Finally, as a Canadian citizen, my ability to live in, work in, and even visit the United States, my home for the last ten years, is also compromised; I face imminent deportation with almost no hope of reentry in the future.

The transition from my drug use having no apparent negative consequences, to both my personal and professional life being damaged possibly beyond repair, was so fast as to be instantaneous, highlighting the fact that when it comes to drug use, the perception of control is really nothing more than illusion. Had these events not occurred as they did, it is possible, even probable, that my drug use would have escalated until it precluded a normal personal or professional life.

However, it is important to note here that problems associated with drug abuse can arise with devastating effects even in the apparent absence of many diagnostic criteria, such as overt tolerance and dependence.

Neither advanced education nor knowledge of pharmacology nor familiarity with the addictive process was able to prevent tragic consequences for me. It is my sincere hope that my experience may serve as a warning, help illuminate the dangers of intellectualizing drug use and abuse, and prevent similar tragedies in the lives of others.

Additional Contributions: I thank Lawrence R. Fishel, PhD, and Anthony A. Grace, PhD, for their comments and assistance with this article.

The drug subculture which developed as part of the rise in narcotic drug use in the
1960s has received much attention. Academic sociologists and the media found this, as
an area of deviant behaviour, a subject of considerable intellectual interest and also of
popular fascination. Drug taking as an alternative way of life, where, as Jock Young
puts it, „drug use is given a different meaning from that existing previously“, has
become part of the sociology of deviance. Issues such as the formation and role of the
altemative subculture, the social reaction against deviant drug use, and the particular
importance of the changing social class of drug takers as providing justification for a
moral response, have attracted attention. The transformation of the typical drug user
in the 1960s from a middle-class middle-aged female into a young working-class male
had, it is argued, much to do with the social reaction evoked, and the type of legal and
social controls put into effect.‘ In the 1980s, the link with unemployment has again
been stressed; and the reappearance of cocaine as a „smart“ drug has also provided
another source of sensationalism for the popular press. However, the widespread
assertion that drug taking has now become more „normal“ would seem to downgrade
the ’60s emphasis on drug use as a subcultural activity.2 Certainly, the „junkie“
stereotype is less prominent in media coverage.

Read more:medhist00064-0055

Morphine, as little as a single dose, blocks the brain’s ability to strengthen connections at inhibitory synapses, according to new Brown University research published in Nature

The findings, uncovered in the laboratory of Brown scientist Julie Kauer, may help explain the origins of addiction in the brain. The research also supports a provocative new theory of addiction as a disease of learning and memory.

„We’ve added a new piece to the puzzle of how addictive drugs affect the brain,“ Kauer said. „We’ve shown here that morphine makes lasting changes in the brain by blocking a mechanism that’s believed to be the key to memory making. So these findings reinforce the notion that addiction is a form of pathological learning.“

Kauer, a professor in the Department of Molecular Pharmacology, Physiology and Biotechnology at Brown, is interested in how the brain stores information. Long-term potentiation, or LTP, is critical to this process.

In LTP, connections between neurons – called synapses, the major site of information exchange in the brain – become stronger after repeated stimulation. This increased synaptic strength is believed to be the cellular basis for memory.

In her experiments, Kauer found that LTP is blocked in the brains of rats given as little as a single dose of morphine. The drug’s impact was powerful: LTP continued to be blocked 24 hours later – long after the drug was out of the animal’s system.

„The persistence of the effect was stunning,“ Kauer said. „This is your brain on drugs.“

Kauer recorded the phenomenon in the ventral tegmental area, or VTA, a small section of the midbrain that is involved in the reward system that reinforces survival-boosting behaviors such as eating and sex – a reward system linked to addiction. The affected synapses, Kauer found, were those between inhibitory neurons and dopamine neurons. In a healthy brain, inhibitory cells would limit the release of dopamine, the „pleasure chemical“ that gets released by naturally rewarding experiences. Drugs of abuse, from alcohol to cocaine, also increase dopamine release.

So the net effect of morphine and other opioids, Kauer found, is that they boost the brain’s reward response. „It’s as if a brake were removed and dopamine cells start firing,“ she explained. „That activity, combined with other brain changes caused by the drugs, could increase vulnerability to addiction. The brain may, in fact, be learning to crave drugs.“

Kauer and her team not only recorded cellular changes caused by morphine but also molecular ones. In fact, the researchers pinpointed the very molecule that morphine disables – guanylate cyclase. This enzyme, or inhibitory neurons themselves, would be effective targets for drugs that prevent or treat addiction.

Researchers at the University of Pennsylvania have demonstrated that morphine withdrawal complicates hepatitis C by suppressing IFN-alpha-mediated immunity and enhancing virus replication. The paper by Wang et al., �Morphine withdrawal enhances hepatitis C virus (HCV) replicon expression,� appears in the November issue of The American Journal of Pathology and is accompanied by a commentary.

Hepatitis C virus (HCV) is common among intravenous drug users, with 70 to 80% of abusers infected in the United States. This high association has peaked interest in determining the effects of drug abuse, specifically opiates, on progression of the disease. The discovery of such an association would impact treatment of both HCV infection and drug abuse.

Dr. Wen-Zhe Ho has been interested in such interplay for some time. His laboratory has previously shown using cell culture that morphine enhances virus replication and inhibits IFN-alpha (a natural anti-viral factor produced by immune, as well as host cells, and the only one approved in recombinant form for treating HCV infection). To further these results, his lab has used a cell model system to determine the consequences of morphine withdrawal, which is a common recurring event in opioid users.

Chuan-Qing Wang and colleagues examined the effects of morphine withdrawal (MW) on HCV-infected cultured liver cells by exposing cells to the drug for four days followed by its removal. They also assessed the effects of using naloxone, to block the opioid receptors, in conjunction with drug removal, i.e. precipitated morphine withdrawal (PW). To measure HCV replication, they used a virus-like �replicon� that mimics the events that occur in liver cells and expression of viral RNA and proteins that HCV uses. Although the replicon does not produce the infectious virus, the HCV replicon system represents the best available system for examining the impact of opiates on HCV at the time of their research study.

Similar to their previous results, the authors found that MW and PW increased levels of HCV replicon RNA and protein expression. In addition, both withdrawal scenarios inhibited IFN-alpha expression in liver cells in the presence or absence of HCV replicon. Since IFN-alpha is a critical self-defense mechanism utilized by liver cells to fight off viral infection, including HIV, this study suggests that morphine withdrawal weakens host cell immunity and provides a favorable environment for HCV growth in the liver.

The authors extended their study by examining the mechanism behind these observations. MW and PW inactivated the IFN-alpha promoter (the switch for making IFN-alpha) by directly inhibiting its activator, interferon regulatory factor-7 (IRF-7), and this effect was more pronounced in HCV replicon-containing cells. Finally, the ability of IFN-alpha treatment to block HCV replicon expression (85%) fell following MW (60%) and PW (50%). This finding, in conjunction with the earlier report by the same group, provides an explanation to the question of why so many HCV-infected patients fail to respond to IFN-alpha treatment.

Although the clinical relevance of this study remains to be determined, these data showing that withdrawal promotes HCV expression by suppressing anti-HCV factor (IFN-alpha) production by liver cells suggests that �opioid abuse may contribute to the chronicity of HCV infection and promote HCV disease progression.� The study also underscores the necessity of future clinical and epidemiological studies to define the role of opiate abuse in promoting HCV disease.

These results suggest that opioid abusers experiencing periods of drug abuse, followed by periods of withdrawal (due to lack of supplies) may lead to immunocompromised liver. These findings further support the need for methadone maintenance treatment as an additional benefit for opioid abusers.

Research was supported by National Institute on Drug Abuse, National Institutes of Health.

This work involved collaborators at Joseph Stokes, Jr. Research Institute at The Children’s Hospital of Philadelphia; The Center for Studies of Addiction, University of Pennsylvania School of Medicine; and The Children’s Hospital of Fudan University, Shanghai, China.

Wang C-Q, Li Y, Douglas SD, Wang X, Metzger DS, Zhang T, Ho W-Z: Morphine withdrawal enhances hepatitis C virus (HCV) replicon expression. Am J Pathol 2005, 167:1333-1340

The American Journal of Pathology, the official journal of the American Society for Investigative Pathology (ASIP), seeks to publish high-quality original papers on the cellular and molecular mechanisms of disease. The editors accept manuscripts which report important findings on disease pathogenesis or basic biological mechanisms that relate to disease, without preference for a specific method of analysis. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, biological, animal, chemical and immunological approaches in conjunction with morphology.

ntravenous (IV) drug users who abuse morphine, then withdraw from it later, may be unknowingly complicating the beneficial effects of their hepatitis C treatment or giving their hepatitis infection an unwanted boost. That’s the conclusion of a study by researchers at Children’s Hospital of Philadelphia, the University of Pennsylvania and in China.1 The findings are published in the November issue of the American Journal of Pathology.
Detrimental Effects of Morphine Withdrawal
Quitting morphine in this population of hepatitis C patients may suppress the benefits of interferon-alfa in the body and enhance the replication of the virus, the study investigators led by Wen-Zhe Ho, MD, a research associate professor in the division of Immunologic and Infectious Diseases at Children’s Hospital of Philadelphia, reported.
According to the study investigators, hepatitis C infection is common among IV drug users; up to 90 percent of such users are infected with HCV in the United States, and one-fifth to one-half have chronic infection.2 The high numbers of these patients with the disease has prompted medical researchers to study the effects of drug abuse, especially the use of opiates, on HCV progression.
„In the case of HCV infection, there is little information about whether drug abuse, such as heroin, enhances HCV replication and promotes HCV disease progression,“ wrote Ho and his team. „This lack of knowledge about the impact of opioid abuse on HCV disease is a major barrier to fundamental understanding of HCV-related morbidity and mortality among intravenous drug users and to the development of new therapeutic approaches for HCV infection.“
The scientists theorized that illicit drugs might be able to detrimentally alter the immune response against the viral infection in some way. Other studies, they pointed out, showed that these drugs have the ability to block the production of beneficial interferons in the body that normally fight the virus.

Morphine’s Effect on Hepatitis C Studied Previously
In a previous study, Ho and his colleagues found that morphine boosted the virus‘ growth and interfered with interferon alfa in a collection of liver cells.3 Interferon alfa is the basis for the pegylated interferon that people with hepatitis C take as medication for the disease today in combination with the antiviral oral drug, ribavirin.4 Also produced naturally in the body, interferon is an antiviral factor produced by certain cells.
The follow-up to that laboratory-based study was the latest research aimed at determining how withdrawing from morphine might affect the course of the disease. „Physical dependence on morphine is characterized by the occurrence of an abstinence or withdrawal syndrome on termination of the drug,“ wrote Ho and his fellow investigators. These abstinence syndromes also can occur during the use of an opioid antagonist such as naloxone (Narcan), a drug that reverses the effects of narcotics, the researchers explained. Thus, they also tested the effect of naloxone-induced morphine withdrawal for the study.
Ho and his team exposed a group of liver cells kept in culture to morphine for four days, then removed it. The scientists also used a model that mimicked the events that occur in liver cells when genetic material (HCV RNA) and proteins used by the hepatitis C virus to create infection are present. This allowed the researchers to mimic the replication patterns of the virus without actually using an infectious virus.
Effects of Morphine Withdrawal
Similar to what they found in their previous study,3 Ho and his colleagues learned that removing morphine boosted levels of HCV RNA (the genetic material used by the virus) and hepatitis C viral protein in the cells. This, in essence, indicates that the viral infection is spreading. However, 72 hours after morphine was removed, HCV RNA levels decreased, suggesting there was only a temporary surge.
Withdrawing the morphine also blocked interferon-alfa production in the liver cells compared to cells in which morphine was not withdrawn. Since interferon-alfa is a critical self-defense mechanism used by liver cells to fight off attacks by the hepatitis C virus or HIV, the findings suggest that drug abusers who quit using morphine can weaken their immune system’s ability to defend the body against an HCV infection, and provides a favorable environment for hepatitis C viral growth in the liver.
Underlying Causes Studied
Next, Ho’s group wanted to understand why removing morphine created such a beneficial environment for the hepatitis C virus. They learned that removing morphine from liver cells blocked the production of interferon-alfa by, in turn, suppressing its activator, interferon regulatory factor-7 (IRF-7). The team also found that the ability of interferon-alfa to block HCV replication (or the model of HCV in this case) fell by nearly two-thirds.
The same detrimental effect of morphine removal also occurred in relation to manmade interferon alfa. This manmade, or recombinant, form is similar to the interferon medication used for people with hepatitis C today. When synthetic interferon was added to the cell lines, they demonstrated a strong ability to fight off the hepatitis virus. However, when morphine was withdrawn from the cells, the anti-HCV ability of interferon-alfa „was significantly diminished,“ Ho and his colleagues wrote.
These results were observed when morphine was directly withdrawn or indirectly removed by using naloxone, they reported, and even to a greater extent in the latter case.
„Collectively, these new observations in conjunction with our earlier findings support the notion that opioid abuse is a co-factor that promotes HCV replication,“ wrote Ho and his colleagues.
The researchers point out that the clinical relevance of this study remains to be determined, but the findings suggest that „opioid abuse may contribute to the chronicity of HCV infection and promote HCV disease progression.“
They recommend both clinical and epidemiological studies be launched to better define the rule of drug abuse in the context of HCV infection. In the meantime, they say drug abusers who use such opioids as morphine, followed by periods of withdrawal due to lack of supplies, may be doing much more harm to their livers.
„Our findings provide a plausible interpretation of the high failure rate of interferon-alfa therapy in intravenous drug users,“ the investigators concluded. „The identification of mechanism(s) involved in morphine’s action on the anti-HCV effect of interferon-alfa has the potential to improve interferon-alfa-based treatment for HCV-infected IV drug users.“
Study Reaction
In an accompanying editorial,5 Kevin Moore, PhD, and Geoff Dusheiko, MD, both professors of Hepatology at Royal Free and University College Medical School in London, write that the findings suggest that IV drug abusers or those receiving opioid substitutes like methadone, and who are infected with HCV, may have more difficulty clearing the virus.
„Until recently, there were no data on the effects of opiates on HCV replication or the development of liver injury and fibrosis, one of the earliest features of progression to cirrhosis,“ wrote Moore and Dusheiko.
„The growing implication from these and other studies is that continued opiate abuse leads to enhanced viral replication, liver injury, and … fibrosis. Further studies are required to determine whether these effects occur in humans, as well,“ they wrote.

To their surprise, researchers at Georgetown University Medical Center (GUMC) have discovered that morphine (a derivate of the opium poppy that is similar to heroin) protects rat neurons against HIV toxicity – a finding they say might help in the design of new neuroprotective therapies for patients with the infection.

The discovery, being presented at the annual meeting of the Society of NeuroImmune Pharmacology, also helps explain why a subset of people who are heroin abusers and become infected with HIV through needle sharing don’t develop HIV brain dementia. This brain disorder includes cognitive and motor abnormalities, anxiety and depression.

„We believe that morphine may be neuroprotective in a subset of people infected with HIV,“ says the study’s lead investigator, Italo Mocchetti, PhD, Professor of neuroscience at GUMC. „That is not to say that people should use heroin to protect themselves – that makes no medical sense at all – but our findings gives us ideas about designing drugs that could be of benefit.


„Needless to say we were very surprised at the findings,“ he added. „We started with the opposite hypothesis – that heroin was going to destroy neurons in the brain and lead to HIV dementia.“

The researchers conducted the study because they knew that a number of HIV-positive people are also heroin abusers, and because of that, some are at high risk of developing neurological complications from the infection. Others, however, never develop these cognitive problems, Mocchetti says.

Because little is known about the molecular mechanisms linking opiates and HIV neurotoxicity, Mocchetti and his team conducted experiments in rats. They found that in the brain, morphine inhibited the toxic property of the HIV protein gp120 that mediates the infection of immune cells. With further investigation, they concluded that morphine induces production of the protein CCL5, which they discovered is released by astrocytes, a type of brain cell. CCL5 is known to activate factors that suppress HIV infection of human immune cells. „It is known to be important in blood, but we didn’t know it is secreted in the brain,“ says Mocchetti. „Our hypothesis is that it is in the brain to prevent neurons from dying.“

They say morphine blocked HIV from binding to CCR5 receptors it typically uses to enter and infect cells. The researchers believe CCL5 itself attached to those receptors, preventing the virus from using it. In this way, it prevented HIV-associated dementia. This effect, however, only worked in the M-trophic strain of HIV, the strain that most people are first infected with. It did not work with the second T-trophic strain that often infects patients later.

„Ideally we can use this information to develop a morphine-like compound that does not have the typical dependency and tolerance issues that morphine has,“ says Mocchetti.

April 17, 2010
Red Orbit
http://www.redorbit.com/news/health/…rain_from_hiv/

Background: Injections of mixtures prepared from crushed tablets contain insoluble particles
which can cause embolisms and other complications. Although many particles can be removed by
filtration, many injecting drug users do not filter due to availability, cost or performance of filters,
and also due to concerns that some of the dose will be lost.
Methods: Injection solutions were prepared from slow-release morphine tablets (MS Contin®)
replicating methods used by injecting drug users. Contaminating particles were counted by
microscopy and morphine content analysed by liquid chromatography before and after filtration.
Results: Unfiltered tablet extracts contained tens of millions of particles with a range in sizes from
< 5 μm to > 400 μm. Cigarette filters removed most of the larger particles (> 50 μm) but the
smaller particles remained.

Commercial syringe filters (0.45 and 0.22 μm) produced a dramatic
reduction in particles but tended to block unless used after a cigarette filter. Morphine was retained
by all filters but could be recovered by following the filtration with one or two 1 ml washes.

The combined use of a cigarette filter then 0.22 μm filter, with rinses, enabled recovery of 90% of the
extracted morphine in a solution which was essentially free of tablet-derived particles.
Conclusions: Apart from overdose and addiction itself, the harmful consequences of injecting
morphine tablets come from the insoluble particles from the tablets and microbial contamination.
These harmful components can be substantially reduced by passing the injection through a
sterilizing (0.22 μm) filter. To prevent the filter from blocking, a preliminary coarse filter (such as
a cigarette filter) should be used first. The filters retain some of the dose, but this can be recovered
by following filtration with one or two rinses with 1 ml water.

Although filtration can reduce the
non-pharmacological harmful consequences of injecting tablets, this remains an unsafe practice due
to skin and environmental contamination by particles and microorganisms, and the risks of bloodborne
infections from sharing injecting equipment.

Read the whole  story:Filtration_and_injection_2010

Context Substance use disorders among physicians are important and persistent
problems. Considerable debate exists over whether use of major opioids, especially
among anesthesiologists, is associated with a higher relapse rate compared with alcohol
and nonopioids. Moreover, the risk factors for relapse with current treatment and
monitoring strategies are unknown.
Objective To test the hypothesis that chemically dependent health care professionals
using a major opioid (eg, fentanyl, sufentanil, morphine, meperidine) as drug of
choice are at higher risk of relapse.
Design, Setting, and Participants Retrospective cohort study of 292 health care
professionals enrolled in the Washington Physicians Health Program, an independent
posttreatment monitoring program, followed up between January 1, 1991, and December
31, 2001.
Main Outcome Measure Factors associated with relapse, defined as the
resumption of substance use after initial diagnosis and completion of primary treatment
for chemical dependency.
Results Twenty-five percent (74 of 292 individuals) had at least 1 relapse. A family
history of a substance use disorder increased the risk of relapse (hazard ratio
[HR], 2.29; 95% confidence interval [CI], 1.44-3.64). The use of a major opioid
increased the risk of relapse significantly in the presence of a coexisting psychiatric
disorder (HR, 5.79; 95% CI, 2.89-11.42) but not in the absence of a coexisting
psychiatric disorder (HR, 0.85; 95% CI, 0.33-2.17). The presence of all 3 factors—
major opioid use, dual diagnosis, and family history—markedly increased the risk of
relapse (HR, 13.25; 95% CI, 5.22-33.59). The risk of subsequent relapses increased
after the first relapse (HR, 1.69; 95% CI, 1.13-2.53).
Conclusions The risk of relapse with substance use was increased in health care
professionals who used a major opioid or had a coexisting psychiatric illness or a family
history of a substance use disorder. The presence of more than 1 of these risk factors
and previous relapse further increased the likelihood of relapse. These observations
should be considered in monitoring the recovery of health care professionals.
JAMA. 2005;293:1453-1460

Read more: 1453 rueckfall beim aerzlichen personal

Background: Mu agonists have been an important component of pain
treatment for thousands of years. The usual pharmacokinetic parameters
(half-life, clearance, volume of distribution) of opioids have been known for
some time. However, the metabolism has, until recently, been poorly understood,
and there has been recent interest in the role of metabolites in modifying
the pharmacodynamic response in patients, in both analgesia and adverse
effects.

A number of opioids are available for clinical use, including
morphine, hydromorphone, levorphanol, oxycodone, and fentanyl. Advantages
and disadvantages of various opioids in the management of chronic
pain are discussed.
Objective: This review looks at the structure, chemistry, and metabolism of
opioids in an effort to better understand the side effects, drug interactions,
and the individual responses of patients receiving opioids for the treatment
of intractable pain.
Conclusion: Mu receptor agonists and agonist-antagonists have been used
throughout recent medical history for the control of pain and for the treatment
of opiate induced side effects and even opiate withdrawal syndromes.

Read more here: 2008;11;S133-S153

Abstract Relapse is a major clinical problem and
remains a major challenge in the treatment of addictions. A
goal of current research is to gain a greater understanding
of the neurochemistry underlying relapse to opiate use.
Factors which trigger relapse in humans such as stress,
exposure to opiates and/or drug-associated cues, can also
trigger opiate-seeking in animals. This review will overview
preclinical studies relating to the neurochemistry of
opiate-seeking with a focus on studies published from 2005
to present.

Read more:

Neurochemistry_underlying_relapse_to_opiate_seeking_behavior

HighdoseHeroinVsMorphine

Beschreibt in einer Doppel-Blind Studie den Effekt von Heroin versus Morphin.