Tag Archive: oxycodone

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.


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.


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.


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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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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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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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.


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 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.


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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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.


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


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 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.


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


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


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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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


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.


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.


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.


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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Treatment for OIC

Treatment options for OIC

Although opioids are very effective for treating and managing pain, their use frequently results in opioid-induced constipation (OIC). Treatment options for OIC may be as simple as changing diet or as complicated as requiring several medicines and laxatives.

How can changing lifestyle factors treat OIC?

Changing lifestyle factors is usually the first recommendation that physicians make for the prevention or treatment of constipation. This includes:

  • Increasing dietary fiber
  • Increasing fluid intake
  • Increasing exercise or physical activity
  • Increasing time and privacy for toileting

Changes in lifestyle, however, may not be possible for many patients. In addition, these changes may be ineffective in treating OIC. If there is a concurrent underlying disease or medicine that is causing constipation, the disease may need to be treated separately or another treatment regimen may have to be considered.

What drugs or medicines treat OIC?


OIC treatment usually requires additional medicines to be prescribed along with the opioid painkillers that are causing the constipation. Withholding the opioid treatment is ill-advised because it results in a decrease in the patient’s quality of life. Often, laxatives and/or cathartics are prescribed at the same time as the opioid painkillers so that treatment for the constipation beings immediately. A cathartic accelerates defecation, while a laxative eases defecation, usually by softening the stool; some medicines are considered to be both laxatives and cathartics.

For the treatment of OIC, doctors may prescribe:

  • Osmotic laxatives – increase the amount of water in the gut, increasing bulk and softening stools.
  • Emollient or lubricant cathartics – soften and lubricate stools.
  • Bulk cathartics – increase bulk and soften stools.
  • Stimulant cathartics – directly counteract the effect of the opioid medications by increasing intestinal motility, helping the gut to push the stools along.
  • Prostaglandins or prokinetic drugs – change the way the intestines absorb water and electrolytes, and they increase the weight and frequency of stools while reducing transit time.
  • Other medicines block the effects of opioids on the bowel to reverse opioid-induced constipation.

Although the treatments listed above are usually successful in treating OIC, sometimes a physician will recommend rectal intervention. As discussed, prophylaxis with laxatives are/or cathartics is considered usual – as some clinicians assume [constipation] to be virtually universal in patients who are prescribed opioid analgesics1.

Rectal interventions are indicated if the appropriate oral measures have been ineffective2. Rectal intervention means the following treatments:

  • Suppositories
  • Enemas (micro and larger volume)
  • Rectal irrigation (sometimes known as colonic irrigation)
  • Manual evacuation

The first choice rectal intervention for uncomplicated constipation is glycerine suppositories2. If these are ineffective, then a stimulant enema might be administered. Oral and rectal stimulant laxatives should be avoided if there is possible or proven bowel obstruction. Gentle rectal measures can sometimes be effective in emptying the rectum and lower colon. Oral softening agents are useful if the obstruction is incomplete. It should be remembered that constipation can cause bowel obstruction.

If none of the rectal laxatives above prove adequate to remove impacted faeces, rectal irrigation with normal saline can be performed3. Manual evacuation should be used as a last resort when all other methods of bowel management have been shown to be ineffective.

Combination therapy

Constipation is a known side effect of opioid analgesics and should be addressed before opioid therapy begins. As opioid-induced constipation can be severe and adversely impact quality of life and compliance with therapy, prophylaxis with laxatives is considered to be the best approach. A British Pain Society survey conducted in March 2009 showed that nearly half of GPs (44%) surveyed believe that the negative impact of such side effects is the key factor in patient non-compliance with prescribed opioid treatments.

Concurrent management on initiation of opioids frequently includes recommending certain lifestyle or dietary adjustments (as listed above) and initiating a scheduled regimen of laxatives. Laxative and cathartic therapy may be needed throughout opioid therapy and beyond. Effective management requires a composite of strategies, including behavioral and lifestyle changes (diet, activity, and fluid intake, as appropriate).

However medications used to manage opioid-induced constipation, such as laxatives, do not address the underlying opioid receptor-mediated cause of constipation and are often ineffective4.

Newer targeted treatments for opioid induced constipation

Methylnaltrexone (available as Relistor(R)) helps restore bowel function in patients who have advanced illness and receive opioids for pain relief. Methylnaltrexone is delivered via subcutaneous injection and specifically targets opioid-induced constipation. When given alongside opioid therapy, it is designed to displace the opioid from binding to peripheral receptors in the gut, decreasing the opioid’s constipating effects and inducing laxation.

Methylnaltrexone is a peripherally acting mu-opioid receptor antagonist that decreases the constipating effects of opioid pain medications in the gastrointestinal tract without diminishing their ability to relieve pain.

Methylnaltrexone blocks peripheral opioid receptors in the gut and unlike other opioid antagonists has restricted ability to cross the blood-brain barrier. As a result, it antagonizes only the peripherally located opioid receptors in the GI tract, so it’s action reverses opioid-induced constipation without precipitating withdrawal symptoms or affecting or reversing the central analgesic effects of opioids5.

Another new medication for severe pain (long-term pain that can be experienced as a result of conditions such as back pain, arthritis and osteoarthritis)6, are tablets combining prolonged release oxycodone, an opioid which treats pain, and prolonged release naloxone, a compound which counteracts the potential negative effects of the opioid on the GI function (available as TarginactTM). This novel combination has been proven to provide equivalent pain relief to oxycodone alone, whilst significantly improving bowel function7. Naloxone is an opioid receptor antagonist that, when taken orally, has negligible systemic bioavailability8 providing a full inhibitory effect on local opioid receptors in the gut – counteracting opioid-induced constipation – without impacting on the centrally acting analgesic efficacy of oxycodone.

diagram of opioids with mu-opioid receptors

* Image borrowed from Wyeth library

1. Hanks G, Cherny N, Fallon M. Symptom Management. The management of pain: Opioid Analgesic Therapy. In Oxford textbook of Palliative Medicine, 3rd Ed. Oxford University Press, 2003.
2. Cancer – a cpomprehensive clinical guide, By David L. Morris, John Henry Kearsley, Christopher John Hacon Williams
3. Oxford textbook of palliative medicine, By Derek Doyle, Geoffrey Hanks, Nathan I. Cherny, Kenneth Calman
4. Reimer K, Hopp M, Zenz M, Maier C, Holzer P, Mikus G, Bosse B, Smith K, Buschmann-Kramm C, Leyendecker P: Meeting the Challenges of Opioid-Induced Constipation in Chronic Pain Management – A Novel Approach.
Pharmacology 2009;83:10-17 (DOI: 10.1159/000165778)
5. Ho et al. 2003; Kurz and Sessler 2003; Schmidt 2001; Foss 2001
6. Severe pain, which can be adequately managed only with opioid analgesics
7. Vondrackova D, Leyendecker P, Meissner W. et al. Analgesic efficacy and safety of oxycodone in combination with naloxone as prolonged release tablets in patients with moderate to severe chronic pain.J Pain. 2008; 9(12): 1144-1154.
Meissner W, Leyendecker P, Müller-Lissner S, et al. A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain. 2008; doi:10.1016/j.ejpain.2008.06.012.
Simpson K, Leyendecker P, Hopp M, et al. Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe non-cancer pain. Curr Med Res Opin. 2008; 24(12): 3503-3512.
8. Nadstawek J, Leyendecker P, Hopp M, et al. Patient assessment of a novel therapeutic approach for the treatment of severe, chronic pain. Int J Clin Pract. 2008; 62: 1159-116.

source: http://www.medicalnewstoday.com/info/oic/treatment-for-opioid-induced-constipation.php


Oral Naloxone Reverses Opioid-Associated Constipation

Meissner W, Schmidt U, Hartmann M, et al
Pain. 2000; 84(1):105-9

Opioid-related constipation is one of the most frequent side effects of chronic pain treatment. Enteral administration of naloxone blocks opioid action at the intestinal receptor level but has low systemic bioavailability due to marked hepatic first-pass metabolism. The aim of this study was to examine the effects of oral naloxone on opioid-associated constipation in an intraindividually controlled manner. Twenty-two chronic pain patients with oral opioid treatment and constipation were enrolled in this study. Constipation was defined as lack of laxation and/or necessity of laxative therapy in at least 3 out of 6 days. Laxation and laxative use were monitored for the first 6 days without intervention (‚control period‘). Then, oral naloxone was started and titrated individually between 3×3 to 3×12 mg/day depending on laxation and withdrawal symptoms. After the 4-day titration period, patients were observed for further 6 days (’naloxone period‘). The Wilcoxon signed rank test was used to compare number of days with laxation and laxative therapy in the two study periods. Of the 22 patients studied, five patients did not reach the ’naloxone period‘ due to death, operation, systemic opioid withdrawal symptoms, or therapy-resistant vomiting. In the 6 day ’naloxone‘ compared to the ‚control period‘, the mean number of days with laxation increased from 2.1 to 3.5 (P<0.01) and the number of days with laxative medication decreased from 6 to 3.8 (P<0.01). The mean naloxone dose in the ’naloxone period‘ was 17.5 mg/day. The mean pain intensity did not differ between these two periods. Moderate side effects of short duration were observed in four patients following naloxone single dose administrations between 6 and 20 mg, resulting in yawning, sweating, and shivering. Most of the patients reported mild or moderate abdominal propulsions and/or abdominal cramps shortly after naloxone administration. All side effects terminated after 0.5-6 h. This controlled study demonstrates that orally administered naloxone improves symptoms of opioid associated constipation and reduces laxative use. To prevent systemic withdrawal signs, therapy should be started with low doses and patients carefully monitored during titration.


source is: http://www.medscape.com/viewarticle/435954

WASHINGTON — The FDA has approved a new sublingual film formulation of the opioid dependence treatment combination buprenorphrine/naloxone (Suboxone).

The new formulation will be released in the same 2 mg buprenorphrine/0.5 mg naloxone and 8 mg buprenorphrine/2 mg naloxone doses as the drug’s sublingual tablet form.

„During clinical tests, Suboxone sublingual film was shown to be faster dissolving than Suboxone sublingual tablets,“ Shaun Thaxter, president of manufacturer Reckitt Benckiser Pharmaceuticals, said in a prepared statement.

Drug approval included a risk evaluation and mitigation strategy program, which requires the company to monitor patients to determine whether potential treatment benefits outweigh potential risks, especially with accidental overdose, misuse, and abuse of the film, the brief said.

The drug can be abused in ways similar to other opioids. Healthcare professionals should monitor patients for proper use, the company said in the statement.

Buprenorphrine reduces patient opioid cravings and withdrawal symptoms, and also blocks the effects of other opioids. Naloxone triggers withdrawal symptoms in patients who crush and inject the drug, but has limited bioavailability when taken sublingually, and should cause no adverse events.

Chronic use of the drug may result in physical dependence and a sudden or rapid decrease in dose may result in withdrawal symptoms, though the symptoms are milder and more delayed than those occurring with full opioid agonists, the brief said.

Patients taking the film, particularly if injected or through other improper means and with central nervous system depressants, may experience life-threatening respiratory depression or death. Healthcare professionals should consider a reduced dose of the central nervous system depressant, the combination, or both when prescribing buprenophrine/naloxone, the statement said.

Pediatric patients taking the drug may have severe, potentially fatal respiratory depression.

Those taking the film should have liver function monitored before and during drug treatment.

Patients who take the drug prior to use or abuse of other full agonists, such as heroin or oxycodone, may experience withdrawal symptoms due to interactions with the drug’s naloxone.

Healthcare professionals should only prescribe pregnant or nursing patients the drug combination if potential gain outweighs potential risk, due to possible neonatal withdrawal symptoms associated with the drug, according to the manufacturer.

The drug is contraindicated in patients hypersensitive to buprenophrine or naloxone.

Adverse events associated with the film include numb mouth, sore tongue, mouth redness, headache, nausea, vomiting, sweating, constipation, insomnia, pain, swelling of limbs, attention disturbance, palpitations, blurred vision, cytolytic hepatitis, jaundice, and anaphylactic shock.

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.

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

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

Pain Therapeutics, Inc. (Nasdaq: PTIE) today announced the initiation of a Phase III study with Oxytrex, an investigational drug. Oxytrex is a unique oral painkiller for patients who suffer from persistent severe chronic pain. The Company believes Oxytrex offers less physical dependence/withdrawal than oxycodone, an 80-year-old prescription painkiller still widely used today to treat persistent severe chronic pain.

„We remain encouraged by the strong science around Oxytrex published in several top journals, including a recent article in Journal of Neurobiology that further elucidates the unique attributes of ultra-low-dose opioid antagonists,“ said Remi Barbier, president and chief executive officer.

This study is being referred to as the „Extreme Study“ in deference to patients who depend on extremely high daily doses of oxycodone (greater than or equal to 120 mg per day) to treat severe chronic pain. The Company believes this sub-population of patients is prone to physical dependence/withdrawal.

In the second half of 2007, Pain Therapeutics plans to initiate a large study with Oxytrex in a broad patient population.

„Extreme Study“ Design

This clinical study is randomized, double-blinded, multi-center and placebo-controlled. The study will enroll approximately 120 patients who have each been taking greater than or equal to 120 mg of oxycodone per patient per day for over a year. Patients who meet this and all other eligibility requirements are randomized to receive twice-daily doses of 100 nanograms (i.e., 0.0001 mg) ultra-low-dose naltrexone or matching placebo for two weeks. At the conclusion of the treatment period, patients check into a clinic and receive an injection of a high-dose opioid antagonist to precipitate withdrawal. During the withdrawal phase of the study, patients are closely monitored and measured for signs and symptoms of physical dependence/withdrawal using the Subjective Opiate Withdrawal Scale. The study’s primary endpoint is prospectively defined as physical dependence/withdrawal scores in the treated arm compared to placebo. For ethical and other reasons, the study protocol allows an interim analysis.

About Oxytrex

Pain Therapeutics owns commercial rights to Oxytrex, a unique oral painkiller that preferentially inhibits an excitatory effect of opioid receptors. This excitatory effect is believed to counteract analgesia (pain relief) and cause tolerance. Its inhibition enhances pain relief and minimizes opioid tolerance. The FDA has not yet evaluated the merits, safety or efficacy of Oxytrex.


Oxytrex (Pain Therapeutics, Inc.) is an oral opioid that combines a therapeutic amount of oxycodone with an ultra-low dose of the antagonist naltrexone. Animal data indicate that this combination minimizes the development of physical dependence and analgesic tolerance while prolonging analgesia. Oxytrex is in late-stage clinical development by Pain Therapeutics for the treatment of moderate-to-severe chronic pain. To evaluate the safety and efficacy of the oxycodone/naltrexone combination, three clinical studies have been conducted, one in healthy volunteers and the other two in patients with chronic pain. The putative mechanism of ultra-low-dose naltrexone is to prevent an alteration in G-protein coupling by opioid receptors that is associated with opioid tolerance and dependence. Opioid agonists are initially inhibitory but become excitatory through constant opioid receptor activity. The agonist/antagonist combination of Oxytrex may reduce the conversion from an inhibitory to an excitatory receptor, thereby decreasing the development of tolerance and physical dependence.

PMID: 17685875 [PubMed – indexed for MEDLINE]

Achieving effective, durable, and safe pain relief, especially
in patients with chronic and/or severe pain conditions,
can be a clinical challenge. For many types of pain, prescription
opioids are among the most effective analgesics [Fine
and Portenoy 2004]. However, there could be concerns about the
development of opioid tolerance or adverse effects, and in some
cases opioids seem to worsen pain (eg, hyperalgesia) [Compton
2008; DuPen et al. 2007; Stein et al. 2003]. For certain difficult
conditions, such as fibromyalgia or neuropathies, opioids alone are
sometimes considered of limited effectiveness [Chou et al. 2009].
Healthcare providers interested in pain management must be
alert to new or novel approaches that help to overcome deficiencies
of opioids, such as treatment-limiting side effects, and as aids
in relieving difficult-to-treat pain conditions. In this regard, there is
a growing body of evidence suggesting potential benefits of opioid
Opioid antagonists — in particular, naloxone and naltrexone —
have been available and studied for decades as agents that displace
opioid molecules from their neuroreceptors, and block
opioids from attaching to and activating those receptors. Such
qualities can be of important benefit, as short-acting antagonists
like naloxone are used effectively to quickly reverse toxic effects of
opioid overmedication or overdose.
Laboratory research and clinical trials have demonstrated the
unexpected, paradoxical effects of opioid antagonists as adjuvants
for enhancing rather than attenuating analgesic effects of opioids
like morphine, oxycodone, and others. Further benefits of opioid
antagonists, as monotherapy, for better managing certain chronic
pain conditions also have been discovered.